Title of Invention	IL-23 P40 SPECIFIC IMMUNOGLOBULIN DERIVED PROTEINS, COMPOSITION AND METHOD
Abstract	Novel anti-IL-23p40 specific human Ig derived proteins, including, without limitation, antibodies, fusion proteins, and mimetibodies, isolated nucleic acids that encode the anti- IL-2340 Ig derived proteins, vectors, host cells, transgenic animals or plants, and methods of making and using thereof, are useful for therapeutic compositions, methods and devices. Preferably, the anti-IL-23p40 specific human Ig derived proteins do not bind the p40 subunit of IL-12 and, thus, do not neutralize IL-12 related activity.

Title of Invention

IL-23 P40 SPECIFIC IMMUNOGLOBULIN DERIVED PROTEINS, COMPOSITION AND METHOD

Abstract

Novel anti-IL-23p40 specific human Ig derived proteins, including, without limitation, antibodies, fusion proteins, and mimetibodies, isolated nucleic acids that encode the anti- IL-2340 Ig derived proteins, vectors, host cells, transgenic animals or plants, and methods of making and using thereof, are useful for therapeutic compositions, methods and devices. Preferably, the anti-IL-23p40 specific human Ig derived proteins do not bind the p40 subunit of IL-12 and, thus, do not neutralize IL-12 related activity.

Full Text	FIELD OF THE INVENTION The present invention relates to at least one IL-23p40 specific human Ig derived protein or fragment thereof, encoding and complementary nucleic acids, host cells, and methods of making and using thereof, including therapeutic formulations, administration and devices. BACKGROUND OF THE INVENTION Interleukin-23 (IL-23) is the name given to a factor that is composed of the p40 subunit of IL- 12 (IL-12beta, IL-12-p40) and another protein of 19 kDa, designated pl9. pl9 is structurally related to DL6, G-CSF, and the p35 subunit of IL-12. Like IL-12 p35, IL-23 pl9 cannot be secreted as a monomer and has not demonstrated biological function. Rather, each subunit must partner with p40 to be expressed by antigen presenting cells (APC) and mediate biologic effects. The active complex is secreted by dendritic cells after cell activation. Mouse memory T-cells (CD4 (+)CD45 Rb(low)) proliferate in response to IL-23 but not in response to IL-12. Human IL23 has been shown to stimulate the production of IFN-gamma by PHA blast T-cells and memory T-cells. It also induces proliferation of both cell types. Human monocyte-derived macrophages produce IL23 in response to virus infection (Sendai virus but not Influenza A virus). IL-23 binds to the beta-1 subunit but not to the beta-2 subunit of the IL-12 receptor, activating one of the STAT proteins, STAT-4, in PHA blast T-cells. The EL-23 receptor consists of a receptor chain, tenned IL-23R, and the beta-1 subunit of the DL-12 receptor. The human IL-23R gene is on human chromosome 1 within 150 kb of the gene encoding EL-12Rbeta2. EL-23 activates the same signaling molecules as EL-12: JAK2, Tyk2, and STAT-1, STAT-3, STAT-4, and STAT-5. STAT-4 activation is substantially weaker and different DNA-binding STAT complexes form in response to IL-23 compared with IL-12. IL-23R associates constirutively with JAK2 and in a ligand-dependent manner with STAT-3. Expression of pl9 in transgenic mice leads to ranting, systemic inflammation, infertility, and death before 3 months of age. The animals show high serum concentrations of the pro-inflammatory cytokines TNF-alpha and IL1 The number of circulating neutrophils is increased. Acute phase proteins are expressed constitutively. Animals expressing pl9 specifically in the liver do not show these abnormalities. Expression of p19 is most likely due to hematopoietic cells as bone marrow transplantation of cells expressing pl9 causes the same phenotype as that observed in the transgenic animals. Biologically active DL-12 exists as a heterodimer comprised of 2 covalently linked subunits of 35 (p35) and 40 (p40) kD. IL-12 acts by binding to both the IL-12beta 1 and beta 2 receptor proteins and thereby induces signaling in a cell presenting both of these receptors. Several lines of evidence have demonstrated that IL-12 can induce robust Thl immune responses that are characterized by production of IFNy and IL-2 from CD4+T cells. IL-12 is produced by APCs in response to a variety of pathogens. One example is the protozoan parasite Leishnaiiia major, which has been used as an in vivo model for defining factors involved in T cell development. Resistant strains of mice developed Thl responses characterized by robust IFNy production. In contrast, susceptible mice demonstrate a Th2 cytokine profile most often described by IL-4, IL-5, and IL-10 production. It was shown that EL-12 could restore immune function in susceptible mice and administration of a neutralizing anti-p40 antibody resulted in disease onset in otherwise resistant strains. This change in disease susceptibility was associated with a reversal of T cell cytokine profiles. Therefore, IL-12 has been identified as a critical parameter in defining Thl differentiation. Inappropriate Thl responses, and thus IL-12 expression, are believed to correlate with many immune-mediated inflammatory diseases and disorders, such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, insulin-dependent diabetes mellitus, and uveitis. In animal models, IL-12 neutralization through its p40 subunit was shown to ameliorate immune-mediated inflammatory diseases. For example, administration of recombinant IL-12 exacerbated EAE, and reatment with neutralizing anti-p40 antibodies inhibited EAE onset or relapses. In addition, IL-12 p40+mice are completely resistant to EAE even though mice deficient in other pro-inflammatory cytokines, such as IFN, TNFα, or LTα, remain susceptible. IL-12 p35+mice are fully susceptible to HAE, which suggests that alternative p40 cytokines, such as IL-23, are responsible for such diseases. The role of IL-23 in EAE and collagen-induced arthritis (CIA) has been recendy confirmed in studies using p19+ mice. These animals demonstrated complete resistance to disease induction, similar to p40+mice. Non-human, chimeric, polyclonal (e.g., anti-sera) and/or monoclonal antibodies (Mabs) and fragments (e.g., proteolytic digestion products thereof) are potential therapeutic agents that are being developed in some cases to attempt to treat certain diseases. However, such antibodies ihat comprise non-human portions elicit an immune response when administered to humans. Such an immune response can result in an immune complex- mediated clearance of the antibodies from the circulation, and make repeated administration unsuitable for therapy, thereby reducing the therapeutic benefit to the patient and limiting the readmininistration of the Ig derived protein. For example, repeated adrninistration of antibodies comprising non-human portions can lead to serum sickness and/or anaphalaxis. In order to avoid these and other such problems, a number of approaches have been taken to reduce the iminunogenicity of such antibodies and portions thereof, including chimerization and "humanization," as well known in the art These approaches have produced antibodies having reduced immunogenicity, but with other less disirable properties. Accordingly, there is a need to provide anti-IL-23p40 antibodies or specified portions or variants, nucleic acids, host cells, compositions, and methods of making and using thereof, that overcome one more of these problems. SUMMARY OF THE INVENTION The present invention provides immunoglobulin (Ig) derived proteins that are specific for the p40 subunit of IL-23 and which preferably do not bind to the p40 subunit of IL-12 ("anti-IL-23p40 Ig derived protein" or uIL-23p40 Ig derived protein"). Such Ig derived proteins including antibody and antagonist or receptor fusion proteins that block the binding of IL-23 to at least one of its receptors (e.g., but not limited to, IL-23 receptor and/or IL-12 beta 1 receptor) by binding to the p40 subunit of IL-23. Preferably, such anti-lL-23p40 Ig derived proteins do not bind and/or inhibit binding of IL-12 to one or more of its receptors, e.g., but not limited to IL-12 beta 1 receptor and/or IL-12 beta 2 receptor. The present invention further provides compositions, formulations, methods, devices and uses of such anti-IL-23p40 Ig derived proteins, including for therapeutic and diagnostic uses. In a further embodiment, the present invention provides Ig derived proteins that selectively inhibit IL-23 related activities, and optionally further do not inhibit IL-12 specific activities that are mediated by ±e binding of IL-12 to one or more of its receptors (e.g., but not limited to, IL-12 beta 1 receptor, or D.-12 beta 2 receptor). In another embodiment, the present invention provides Ig derived proteins that inhibit IL-23 activity in antigen presenting cells (APCs), such as but not limited to, macrophages, microglia, mcsangial phagocytes, synovial A cells, stem cell precursors, Langerhans cells, Kuppfer cells, dendritic cells, B cells, and the like. Such APC's can be present in different tissues, e.g., but not limited to, skin, epidermis, liver, spleen, brain, spinal cord, thymus, bone marrow, joint synovial fluid, idneys, blood, and the like. Such APC's can also be limited to outside or inside the blood brain barrier. In a further embodiment, the present invention provides Ig derived proteins that are suitable for treating at least one IL-23 related condition by blocking IL-23 binding to one or more of its receptors, and optionally where the Ig derived proteins do not block IL-12 binding to one or more of its receptors. The present invention thus provides isolated anti-IL-23p40 human Ig derived proteins (Ig derived proteins), including immunoglobulins, receptor fusion proteins, cleavage products and other specified portion;: and variants thereof, as well as anti-IL-23p40 Ig derived protein compositions, enc oding or complementary nucleic acids, vectors, host cells, compositions, formulations, devices, transgenic animal 5, transgenic plants, and methods of making and using thereof, as described and enabled herein, in combination with what is known in the art Such anti-IL-23p40 Ig derived proteins act as antagonists to IL-23p40 proteins and thus are useful for treating IL-23p40 pathologies. IL- 23p40 proteins include, but are not limited to, IL-23 and IL-12, particularly, the p40 subunit of IL-23 and IL-12, as well as the p35 subunit of IL-12 or pl9 subunit of IL-23. The present invention also provides at least one isolated IL-23p40 Ig derived protein or specified portion or variant as described herein and/or as known in die art. The present invention provides, in one aspect, isolated nucleic acid molecules comprising, complementary, or hybridizing to, a polynucleotide encoding specific IL-23p40 Ig derived proteins or specified portions or variants thereof, comprising at least one specified sequence, domain, portion or variant thereof. The present invention further provides recombinant vectors comprising said isolated EL-23p40 Ig derived protein nucleic acid molecules, host cells containing such nucleic acids and/or recombinant vectors, as well as methods of making and/or using such Ig derived protein nucleic acids, vectors and/or host cells. At least one Ig derived protein or specified portion or variant of the invention binds at least one specified epitope specific to at least one IL-23p40 protein, subunit, fragment, portion or any combination thereof. The at least one epitope can comprise at least one Ig derived protein binding region that comprises at least one portion of said protein, which epitope is preferably comprised of at least one extracellular, soluble, hydrophillic, external or cytoplasmic portion of said protein. Non- limiting examples include 1,2,3,4,5,6,7,8,9,10,11,12,13 or 14 amino acids of at least one of, 1- 10,10-20,20-30,30-40,40-50,50-60,60-70,70-80,80-90,90-100,100-110,110-120,120-130,130- 140,140-150,150-160,160-170,170-180,180-190,190-200,200-210,210-220,220-230.230-240, 240-250,250-260,260-270, 280-290, 290-300, 300-306,1-7,14-21, 29-52,56-73, 83-93, 96-105, 156-175,194-204,208-246,254-273, 279-281, or 289-300 of SBQ ED NO:l, the human p40 subunit (306 amino acids). The at least one Ig derived protein or specified portion or variant can optionally comprise at least one specified portion of at least one CDR (e.g., CDR1, CDR2 or CDR3 of the heavy or light chain variable region) and/or at least one framework region. The at least one Ig derived protein or specified portion or variant amino acid sequence can further optionally comprise at least one specified substitution, insertion or deletion. The present invention also provides at least one composition comprising (a) an isolated IL- 23p40 Ig derived protein or specified portion or variant encoding nucleic acid and/or Ig derived protein as described herein; and (b) a suitable carrier or diluent. The carrier or diluent can optionally be pharmaceutically acceptable, according to known methods. The composition can optionally further comprise at least one further compound, protein or composition. The present invention also provides at least one method for expressing at least one IL-23p40 Ig derived protein or specified portion or variant in a host cell, comprising culturing a host cell as described herein and/or as known in the art under conditions wherein at least one IL-23p40 Ig derived protein or specified portion or variant is expressed in detectable and/or recoverable amounts. The present invention further provides at least one IL-23p40 Ig derived protein, specified portion or variant in a method or composition, when administered in a therapeutically effective amount, for modulation, for treating or reducing the symptoms of immune, neurological, and related disorders, such as, but not limited to, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondilitis, gastric ulcer, seronegative arthropathies, osteoarthritis, inflammatory bowel disease, ulcerative colitis, systemic lupus erythematosis, antiphospholipid syndrome, iridocyclitis/uveitis/optic neuritis, idiopathic pulmonary fibrosis, systemic vasculitis/Wegener's granulomatosis, sarcoidosis, orchitis/vasectomy reversal procedures, allergic/atopic diseases, asthma, allergic rhinitis, eczema, allergic contact dermatitis, allergic conjunctivitis, hypersensitivity pneumonitis, transplants, organ transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis syndrome, gram positive sepsis, gram negative sepsis, culture negative sepsis, fungal sepsis, neutropenic fever, urosepsis, meningococcemia, trauma/hemorrhage, burns, ionizing radiation exposure, ac ute pancreatitis, adult respiratory distress syndrome, rheumatoid arthritis, alcohol-induced hepatitis, chronic inflammatory pathologies, sarcoidosis, Crohn's pathology, sickle cell anemia, diabetes, nephrosis, atopic diseases, hypersensitity reactions, allergic rhinitis, hay fever, perennial rhinitis, conjunctivitis, endometriosis, asthma, urticaria, systemic anaphalaxis, dermatitis, pernicious anemia, hemolytic disesease, thrombocytopenia, graft rejection of any organ or tissue, kidney translplant rejection, heart transplant rejection, liver transplant rejection, pancreas transplant rejection, lung transplant rejection, bone marrow transplant (BMT) rejection, skin allograft rejection, cartilage transplant rejection, bone graft rejection, small bowel transplant rejection, fetal thymus implant rejection, parathyroid transplant rejection, xenograft rejection of any organ or tissue, allograft rejection, anti receptor hypersensitivity reactions. Graves disease, Raynoud's disease, type B insulin- resistant diabetes, asthma, myasthenia gravis, antibody-meditated cytotoxicity, type III tiypersensitivily reactions, systemic lupus erythematosus, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes syndrome, iintiphospholipid syndrome, pemphigus, scleroderma, mixed connective tissue disease, idiopathic Addison's disease, diabetes mellitus, chronic active hepatitis, primary Miliary cirrhosis, vitiligo, vasculitis, post-MI cardiotomy syndrome, type IV hypersensitivity, contact dermatitis, hypersensitivity pneumonitis, allograft rejection, granulomas due to intracellular organisms, drug sensitivity, metabolic/idiopathic, Wilson's disease, hemachromatosis, alpha-1-antitrypsin deficiency, diabetic retinopathy, hashimoto's thyroiditis, osteoporosis, hypothalamic-pituitary-adrenal axis evaluation, primary biliary cirrhosis, thyroiditis, encephalomyelitis, cachexia, cystic fibrosis, neonatal clironic lung disease, chronic obstructive pulmonary disease (COPD), familial hematophagocytic Iymphohistiocytosis, dermatologic conditions, psoriasis, alopecia, nephrotic syndrome, nephritis, glomerular nephritis, acute renal failure, hemodialysis, uremia, toxicity, preeclampsia, okt3 therapy, anti-cd3 therapy, cytokine therapy, chemotherapy, radiation therapy (e.g., including but not limited to, asthenia, anemia, cachexia, and the like), chronic salicylate intoxication, acute or chronic bacterial infection, acute and chronic parasitic or infectious processes, including bacterial, viral and fungal infections, HIV infection/HIV neuropathy, meningitis, hepatitis (e.g., A, B or C, or the like), septic arthritis, peritonitis, pneumonia, epiglottitis, e. Coli 0157:h7, hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura, malaria, dengue hemorrhagic fever, leishmaniasis, leprosy, toxic shock syndrome, streptococcal myositis, gas gangrene, mycobacterium tuberculosis, mycobacterium avium intracellulare, Pneumocystis carinii pneumonia, pelvic inflammatory disease, orchitis/epidydimitis, legionella, lyme disease, influenza a, epstein-barr virus, vital-associated hemaphagoeytic syndrome, vital encephalitis/aseptic meningitis, neurodegenerative diseases, multiple sclerosis, migraine headache, AIDS dementia complex, demyelinatmg diseases, such as multiple sclerosis and acute transverse myelitis; extrapyramidal and cerebellar disorders, such as lesions of the corticospinal system; disorders of die basal ganglia; hyperkinetic movement disorders, such as Huntington's Chorea and senile chorea; drug-induced movement disorders, such as those induced by drugs which block CNS dopamine receptors; hypokinetic movement disorders, such as Parkinson's disease; Progressive supranucleo Palsy; structural lesions of the cerebellum; spinocerebellar degenerations, such as spinal ataxia, Friedreich's ataxia, cerebellar cortical degenerations, multiple systems degenerations (Mencel, Dejerine-Thomas, Shi-Drager, and Machado-Joseph); systemic disorders (Refsum's disease, abetalipoprotemia, ataxia, telangiectasia, and mitochondrial multisystem disorder); demyelinating core disorders, such as multiple sclerosis, acute transverse myelitis; and disorders of the motor unit, such as neurogenic muscular atrophies (anterior horn cell degeneration, such as amyotrophic lateral sclerosis, infantile spinal muscular atrophy and juvenile spinal muscular atrophy); Alzheimer's disease; Down's Syndrome in middle age; Diffuse Lewy body disease; Senile Dementia of Lewy body type; Wernicke-Korsakoff syndrome; chronic alcoholism; Creutzfeldt-Jakob disease; Subacute sclerosing panencephalitis, Hallerrorden-Spatz disease; and Dementia pugilistica, neurotraumalic injury (e.g., but not limited to, spinal cord injury, brain injury, concussion, and repetitive concussion), pain, inflammatory pain, autism, depression, stroke, cognitive disorders, epilepsy, and the like, as needed in many different conditions, such as but not limited to, prior to, subsequent to, or during a related disease or treatment condition, as known in the art. The present invention further provides at least one IL-23p40 Ig derived protein, specified portion or variant in a method or composition, when administered in a therapeutically effective amount, for modulation, for treating or reducing the symptoms of at least one IL-23p40 disease in a cell, tissue, organ, animal or patient and/or, as needed in many different conditions, such as but not limited to, prior to, subsequent to, or during a related disease or treatment condition, as known in me art and/or as described herein. The present invention also provides at least one composition, device and/or method of delivery of a therapeutically or propfaylactically effective amount of at least one IL-23p40 Ig derived protein or specified portion or variant, according to the present invention. The present invention also provides at least one isolated IL-23p40 Ig derived protein, comprising at least one immnuoglobulin complementarity determining region (GDR) or at least one ligand binding region (LBR) that specifically binds at least one IL-23p40 protein, wherein (a) said IL- 23p40 Ig derived protein specifically binds at least one epitope comprising at least 1-3, to the entire amino acid sequence, selected from the group consisting of the p40 subunit of a human interleukin-23 (1-306 of SEQ ID NO:l), such as but not limited to, 1,2,3,4,5,6,7,8,9,10,11,12,13 or 14amino acids of at least one of, 1-10,10-20,20-30,30-40,40-50,50-60,60-70,70-80,80-90,90-100,100- 110,110-120,120-130,130-140,140-150,150-160,160-170,170-180,180-190,190-200,200-210, 210-220,220-230,230-240,240-250,250-260,260-270,280-290,290-300,300-306,1-7,14-21,29- 52,56-73,83-93,96-105,156-175,194-204,208-246,254-273,279-281, or 289-300 of SEQ ID NO:l. In a preferred embodiment, the anti-human IL-23p40 Ig derived protein binds IL-23p40 with an affinity of at least 10"9 M, at least 10"10 M, at least 10'" M, or at least 10"12 M. In another preferred embodiment, the human Ig derived protein substantially neutralizes at least one activity of at least one ID-23p40 protein or receptor. The invention also provides at least one isolated IL-23p40 human Ig derived protein encoding nucleic acid, comprising a nucleic acid that hybridizes under stringent conditions, or has at least 95% identity, to a nucleic acid encoding a IL-23p40 Ig derived protein. The invention further provides an isolated EL-22 p40 human Ig derived protein, comprising an isolated human Ig derived protein encoded by such a nucleic acid. The invention further provides a IL-23p40 human Ig derived protein encoding nucleic acid composition, comprising such an isolated nucleic acid and a carrier or diluent. The invention further provides an Ig derived protein vector, comprising such a nucleic acid, wherein t he vector optionally further comprises at least one promoter selected from the group consisting of a late or early SV40 promoter, a CMV promoter, an HSV tk promoter, a pgk (phosphoglycerate kinase) promoter, a human immunoglobulin promoter, or an EF-1 alpha promoter. Such a vector can optionally f urther comprise at least one selection gene or portion thereof selected from at least one of methotrexate (MTX), dihydrofolate reductase (DHFR), green fluorescent protein (GFP), neomycin (G418), or glutamine synthetase (GS). The invention further comprises a mammalian host cell comprising such an isolated nucleic acid, optionally, wherein said host cell is at least one selected from COS-1, COS-7, HEK293, BHK21, CHO, BSC-1, Hep G2,653, SP2/0,293, HeLa, myeloma, or lymphoma cells, or any derivative, immortalized or transformed cell thereof. The invention also provides at least one method for producing at least one EL-23p40 human Ig derived protein, comprising translating such a nucleic acid or an endogenous nucleic acid that hybridizes therei.o under stringent conditions, under conditions in vitro, in vivo or in situ, such that the IL-23p40 humar Ig derived protein is expressed in detectable or recoverable amounts. The invention also provides at least one EL-23p40 human Ig derived protein composition, comprising at least one isolated IL-23p40 human Ig derived protein and a carrier or diluent, optionally further wherein said carrier or diluent is pharmaceutically acceptable, and/or further comprising at least one compound or protein selected from at least one of a TNF antagonist, an antirheumatic, a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteriod, an anabolic steroid, an IL-23p40 agent, a mineral, a nutritional, a thyroid agent, a vitamin, a calcium related hormone, an anndiarrheal, an antitussive, an antiemetic, an antiulcer, a laxative, an anticoagulant, an erythropoietin, a filgrastim, a sargramostim, an immunization, an immunoglobulin, an immunosuppressive, a growth hormone, a hormone replacement drug, an estrogen receptor modulator, a mydriatic, a cyclopkgic, an alkylating agent, an antimetabolite, a mitotic inhibitor, a radiopharmaceutical, an antidepressant, an antimanic agent, an antipsychotic, an anxiolytic, a hypnotic, a sympamomimetic, a stimulant, donepeztl, tacrine, an asthma medication, a beta agonist, an inhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn, an epinephrine or analog, dornase alpha, a cytokine, and a cytokine antagonist The present invention also provides at least one method for treating a IL-23p40 condition in a cell, tissue, organ or animal, comprising contacting or administering an immune related- or infectious related-condition modulating effective amount of at least one EL-23p40 human Ig derived protein with, or 1:0, said cell, tissue, organ or animal, optionally wherein said animal is a primate, optionally, a monkey or a human. The method can further optionally include wherein said effective amount is 0.001-100 mg/kilogram of said cells, tissue, organ or animal. Such a method can further include wherein said contacting or said administrating is by at least one mode selected from intravenous, intramuscular, bolus, intraperitoneal, subcutaneous, respiratory, inhalation, nasal, vaginal, rectal, buccal, sublingual, intranasal, subdermal, and transdermal. Such a method can further comprise administering, prior, concurrently or after said (a) contacting or administering, at least one composition comprising a therapeutically effective amount of at least one compound or protein selected from at least one of a TNF antagonist, an antirheumatic, a muscle relaxant, a narcotic, a non- steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anethetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteriod, an anabolic steroid, an EL- 23p40 agent, a mineral, a nutritional, a thyroid agent, a vitamin, a calcium related hormone, an anndiarrheal, an antitussive, an antiemetic, an antiulcer, a laxative, an anticoagulant, an erythropoietin, a filgrastim, a sargramostim, an immunization, an immunoglobulin, an immunosuppressive, a growth hormone, a hormone replacement drug, an estrogen receptor modulator, a mydriatic, a cycloplegic, an alkylating agent, an antimetabolite, a mitotic inhibitor, a radiopharmaceutical, an antidepressant, antimanic agent, an antipsychotic, an anxiolytic, a hypnotic, a sympathomimetic, a stimulant, donepezil, tacrine, an asthma medication, a beta agonist, an inhaled steroid, a. leukotriene inhibitor, a memylxanthine, a cromolyn, an epinephrine or analog, domase alpha, a cytokine, and a cytokine antagonist. The present invention also provides at least one medical device, comprising at least one IL- 23p40 human Ig derived protein, wherein said device is suitable to contacting or adrninisterting said at least one IL-23p40 human Ig derived protein by at least one mode selected from intravenous, intramuscular, bolus, intraperitoneal, subcutaneous, respiratory, inhalation, nasal, vaginal, rectal, buccal, sublingual, intranasal, subdermal, or transdermal. The present invention also provides at least one human immunoglobulin light chain IL-23p40 protein, comprising at least one portion of a variable region comprising at least one human Ig derived protein fragment of the invention. The: present invention also provides at least one human immunoglobulin heavy chain or portion thereof, comprising at least one portion of a variable region comprising at least one IL-23p40 human Ig derived protein fragment The invention also includes at least one human Ig derived protein, wherein said human Ig derived protein binds the same epitope or antigenic region as an IL-23p40 human Ig derived protein. The invention also includes at least one formulation comprising at least one IL-23p40 human Ig derived protein, and at least one selected from sterile water, sterile buffered water, or at least one preservative selected from me group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkylparaben, benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, or mixtures thereof in an aqueous diluent, optionally, wherein die concentration of EL- 23p40 human Ig derived protein is about 0.1 mg/ml to about 100 mg/ml, further comprising at least one isotonicity agent or at least one physiologically acceptable buffer. The invention also includes at least one formulation comprising at least one IL-23p40 human lg derived protein in lyophilized form in a first container, and an optional second container comprising at least one of sterile water, sterile buffered water, or at least one preservative selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkylparaben, benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, o; • mixtures thereof in an aqueous diluent, optionally further wherein me concentration of IL-23p40 human Ig derived protein is reconsitituted to a concentration of about 0.1 mg/ml to about 500 mg/ml, further comprising an isotonicity agent, or further comprising a physiologically acceptable buffer. The invention further provides at least one method of treating at least one IL-23p40 mediated condition, comprising administering to a patient in need thereof a formulation of the invention. The invention also provides at least one article of manufacture for human pharmaceutical use, comprising packaging material and a container comprising a solution or a lyophilized form of at least one IL-23p40 human Ig derived protein of the invention, optionally further wherein said container is a glass or plastic container having a stopper for multi-use administration, optionally further wherein said container is a blister pack, capable of being punctured and used in intravenous, intramuscular, bolus, intraperitoneal, subcutaneous, respiratory, inhalation, nasal, vaginal, rectal, buccal, sublingual, intranasal, subdermal, or transdermal administration; said container is a component of a intravenous, intramuscular, bolus, intraperitoneal, subcutaneous, respiratory, inhalation, nasal, vaginal, rectal, buccal, sublingual, intranasal, subdermal, or transdermal delivery device or system; said container is a component of an injector or pen-injector device or system for intravenous, intramuscular, bolus, intraperitoneal, subcutaneous, respiratory, inhalation, nasal, vaginal, rectal, buccal, sublingual, intranasal, subdermal, or transdermal. The invention further provides at least one method for preparing a formulation of at least one IL-23p40 human Ig derived protein of the invention, comprising admixing at least one IL-23p40 human Ig derived protein in at least one buffer containing saline or a salt. The invention also provides at least one method for producing at least one IL-23p40 human Ig derived protein of the invention, comprising providing a host cell, transgenic animal, transgenic plant or plant cell capable of expressing in recoverable amounts said human Ig derived protein, optionally further wheiein said host cell is a mammalian cell, a plant cell or a yeast cell; said transgenic animal is a mammal; said transgenic mammal is selected from a goat, a cow, a sheep, a horse, and a non-human primate. The invention further provides at least one transgenic animal or plant expressing at least one human Ig derived protein of the invention. The invention further provides at least one IL-23p40 human Ig derived protein produced by a method of the invention. The invention further provides at least one method for treating at least one IL-23p40 mediated disorder, comprising at least one of (a) administering an effective amount of a composition or pharmaceutical composition comprising at least one IL-23p40 human Ig derived protein to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy; and further administering, before concurrently, and/or after said administering in (a) above, at least one selected from at least one of an immune related therapeutic, a TNF antagonist, an antirheumatic, a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, 2 local anesthetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteriod, an anabolic steroid, a neurological agent, a mineral, a nutritional, a thyroid agent, a vitamin, a calcium related hormone, an antidiarrheal, an antitussive, an antiemetic, an antiulcer, a laxative, an anticoagulant, an erythropoietin, a filgrastim, a sargramostim, an immunizing agent, an immunoglobulin, an immunosuppressive, a growth hormone, a hormone replacement drug, an estrogen receptor modulator, a mydriatic, a cycloplegic, an alkylating agent, an antimetabolite, a mitotic inhibitor, a radiopharmaceutical, an antidepressant, antimanic agent, an antipsychotic, an anxiolytic, a hypnotic, a sympathomimetic, a stimulant, adonepezil, a tacrine, an asthma medication, a beta agonist, an inhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn, an epinephrine or analog, a domase alpha, or a cytokine and a cytokine antagonist. The present invention further provides any invention described herein and is not limited to any particular description, embodiment or example provided herein. BRIEF DESCRIPTION FIGURES Figure 1A is a graph showing the specificity of the anti-IL-23 antibody for IL-23. Figure IB is a graph showing die specificity of me anti-IL-23 antibody for the IL-23 p40 subunit Figure 1C is a graph showing the effect of antibodies on IL-17 levels. Figure ID is a graph showing the effect of antibodies on JFNv levels. Figure IE is a graph showing the clinical suppression of EAE by the antibodies. Figure 2A is a graph showing the correlation of brain and spinal cord pathology with the clinical score severity. Figure 2B is a graph showing the histopatbology rankings of the antibodies. Figure 3A is a graph showing T cell response to myelin basic protein in the presence of antibodies. Figure 3B is a graph showing IFNy levels in the presence of antibodies. Figure 3C is a graph showing EL-17 levels in the presence of antibodies. Figure 3D is a graph showing IL-5 levels in the presence of antibodies. Figure 3E is a graph showing IL-10 levels in the presence of antibodies. DESCRIPTION OF THE INVENTION The present invention provides immunoglobulin (Ig) derived proteins that are specific for the p40 subunit of IL-23 and which preferably do not bind to the p40 subunit of IL-12. Such Ig derived proteins including antibody and receptor fusion proteins that block the binding of EL-23 to at least one of its receptors (e.g., but not limited to, IL-23 receptor and/or IL-12 bete 1 receptor) by binding to the p40 subunit of IL-23. Preferably, such anti-IL-23p40 Ig derived proteins do not bind and/or inhibit binding of IL-12 to one or more of its receptors, e.g., but not limited to IL-12 beta 1 receptor and/or IL-12 beta 2 receptor. The present invention further provides compositions, formulations, methods, devices and uses of such anti-IL-23p40 Ig derived proteins, including for therapeutic and diagnostic USiS. The present invention also provides Ig derived proteins mat selectively inhibit IL-23 related activities, and optionally further does not inhibit IL-12 specific activities that are mediated by the binding of IL-12 to one or more of its receptors (e.g., but not limited to, IL-12 beta 1 receptor, or IL- 12 beta 2 receptor). The present invention further provides Ig derived proteins that ate suitable for treating at least one IL-23 related condition by blocking IL-23 binding to one or more of its receptors, and optionally where me Ig derived proteins do not block IL-12 binding to one or more of its receptors. The present invention also provides Ig derived proteins that inhibit IL-23 activity in antigen presenting cells (APCs), such as but not limited to, macrophages, microglia, mesangutl phagocytes, synovial A cells, stem cell precursors, Langerhans cells, Kuppfer cells, dendritic cells, B cells, and the like. Such APC's can be present in different tissues, e.g., but not limited to. skin, epidermis, liver, spleen, brain, spinal cord, thymus, bone marrow, joint synovial fluid, kidneys, blood, and the like. Such AI'C's can also be limited to outside or inside the blood brain barrier. The present invention provides isolated, recombinant and/or synthetic IL-23p40 Ig derived proteins or specified portions or variants, as well as compositions and encoding nucleic acid molecules; comprising at least one polynucleotide encoding at least one IL-23p40 Ig derived protein. Such Ig derived proteins or specified portions or variants of the present invention comprise specific full length Ig derived protein sequences, domains, fragments and specified variants thereof, and methods of making and using said nucleic acids and Ig derived proteins or specified portions or variants, including therapeutic compositions, methods and devices. As used herein, a "anti-IL-23p40 Ig derived protein," "anti-IL-23p40 Ig derived protein portion," "anti-IL-23p40 Ig derived protein fragment," "anti-IL-23p40 Ig derived protein variant" "IL- 23p40 Ig derived protein," "IL-23p40 Ig derived protein portion," or "IL-23p40 Ig derived protein fragment" and/or "IL-23p40 Ig derived protein variant" and the like decreases, blocks, inhibits, abrogates or interferes with IL-23p40 protein activity, binding or IL-23p40 protein receptor activity or binding in vitro, in situ and/or preferably in vivo. As used herein, "IL-12p40" refers to the p40 subunit of IL-23, as well as active portions, fragments, isoforms, splice variants, and the like, as known in the art For example, a suitable IL-23p40 Ig derived protein, specified portion or variant of the present invention can bind at least one IL-23p40 protein or receptor and includes anti-IL-23p40 Ig derived proteins, antigen-binding fragments thereof, and specified portions, variants or domains thereof that bind specifically to IL-23p4G. A suitable IL-23p40 Ig derived protein, specified portion, or variant can also decrease block, abrogate, interfere, prevent and/or inhibit IL-23p40 protein RNA, DMA or protein synthesis, IL-23p40 protein release, IL-23p40 protein or receptor signaling, membrane IL-23p40 protein cleavage, IL-23 related activity, IL-23p40 protein production and/or synthesis, e.g., as described herein or as known in the art. Anti-IL-23p40 Ig derived proteins (also termed anti~IL-23p4G Ig derived proteins) useful in the methods and compositions of me present invention are characterized by high affinity binding to IL-23p40 proteins, and optionally and preferably having low toxicity. In particular, an Ig derived protein, specified fragment or variant of the invention, where the individual components, such as the variable region, constant region and framework, individually and/or collectively, optionally and preferably possess low immunogenicity, is useful in the present invention. The Ig derived proteins that can be used in the invention are optionally characterized by their ability to treat patients for extended periods w.th good to excellent alleviation of symptoms and low toxicity. Low immunogenicity and/or high affinity, as well as other suitable properties, may contribute to the therapeutic results achieved "Low immunogenicity" is defined herein as raising significant HAHA, HACA or HAMA responses in less than about 75%, or preferably less than about 50% of the patients treated and/or raising low titres in the patient treated Qess than about 300, preferably less than about 100 measured with a double antigen enzyme immunoassay) (Elliott et al.. Lancet 344:1125-1127 (1994), each of the above references entirely incorporated herein by reference. Utility The isolated nucleic acids of the present invention can be used for production of at least one IL- 23p40 Ig derived protein, fragment or specified variant thereof, which can be used to effect in an cell, tissue, organ or animal (including mammals and humans), to modulate, treat, alleviate, help prevent the incidence of, or reduce the symptoms of, at least one IL-23p40 condition. Such a method can comprise administering an effective amount of a composition or a pharmaceutical composition comprising at least one anti-IL-23p40 Ig derived protein or specified portion or variant to a cell, tissue, organ, animal or patient in need of such modulation, treatment, alleviation, prevention, or reduction in symptoms, effects or mechanisms. The effective amount can comprise an amount of about 0.001 to 500 mg/kg per single or multiple administration, or to achieve a serum concentration of 0.01-5000 ug/ml serum concentration per single or multiple adminstration, or any effective range or value therein, as done and determined using known methods, as described herein or known in the relevant arts. Citations All publications or patents cited herein are entirely incorporated herein by reference, whether or not specifically designated accordingly, as they show the state of the art at the time of die present invention and/or to provide description and enablement of the present invention. Publications refer to any sci entific or patent publications, or any other information available in any media format, including all recorded, electronic or printed formats. The following references are entirely incorporated herein by reference: Ausubel, et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., NY, NY (1987-2003); Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor, NY (1989); Harlow and Lane, Ig derived proteins, a Laboratory Manual, Cold Spring Harbor, NY (1989); Colligan, et al., eds., Current Protocols in Immunology, John Wiley & Sons, Inc., NY (1994-2003); Colligan et al., Current Protocols in Protein Science, John Wiley & Sons, NY, NY, (1997-2003). Ig derived proteins of the Present Invention The term "Ig derived protein" is intended to encompass Ig derived proteins, digestion fragments, specified portions and variants thereof, including Ig derived protein mimetics or comprising portions of Ig derived proteins that mimic the structure and/or function of an antibody or specified fragment or portion thereof, including single chain Ig derived proteins and fragments thereof, and is also intended to encompass proteins mat contain miitaetics to therapeutic proteins, antibodies, arid digestioi fragments, specified portions and variants thereof, wherein the protein comprises at least one functional EL-23p40 protein ligand binding region (LBR) that optionally replaces at least one complementarity determing region (CDR) of the antibody from which the Ig- derived protein, portion or variant is derived. Such IL-23p40 IgG derived proteins, specified portions or variants include those that mimic the structure and/or function of at least one IL-23p40 protein antagonist, such as an IL-23p40 protein antibody or receptor or ligahd protein, or fragment or analog. Functional fragments include antigen-binding fragments that bind to human IL-23p40 proteins or fragments thereof. For example, Ig derived protein fragments capable of binding to human IL-23p40 proteins or fragments thereof, including, but not limited to, Fab (e.g., by papain digestion), Fab' (e.g., by pepsin digestion and partial reduction) and F(ab')2 (e.g., by pepsin digestion), facb (e.g., by plasmin digestion), pFc' (e.g., by pepsin or plasmin digestion), Fd (e.g., by pepsin digestion, partial reduction and reaggregation), Fv or scFv (e.g., by molecular biology techniques) fragments, are encompassed by the invention (see, e.g., Colligan, Immunology, supra). Such fragments can be produced by enzymatic cleavage, synthetic or recombinant techniques, as known in the art and/or as described herein. Ig derived proteins can also be produced in a variety of truncated forms using Ig derived protein genes in which one or more stop codons have been introduced upstream of the natural stop site. For example, a chimeric gene encoding a F(abr)2 heavy chain portion c an be designed to include DNA sequences encoding the CH1 domain and/or hinge region of the heavy chain. The various portions of Ig derived proteins can be joined together chemically by conventional techniques, or can be prepared as a contiguous protein using genetic engineering techniques. For example, a nucleic acid encoding the variable and constant regions of a human Ig derived protein chain can be expressed to produce a contiguous protein. See, e.g., Colligan, Immunology, supra, sections 2.8 and 2.10, for fragmentation and Ladner etal, U.S. Patent No. 4,946,778 and Bird, R.E. et al, Science, 242:423-426 (1988), regarding single chain Ig derived proteins, each of which publications are entirely incorporated herein by reference. As used herein, the term "human Ig derived protein" refers to an Ig derived protein in which i ubstantially every part of the protein (e.g., CDR, LBR, framework, CL, CHdomains (e.g., CH1, CH2, CH3), hinge, (VL, VH)) is substantially non-immunogenic, with only minor sequence changes or variations. Such changes or variations optionally and preferably retain or reduce the immunogenicity in humans relative to non-modified human Ig derived proteins. Thus, a human Ig derived protein is distinct from a chimeric or humanized Ig. It is pointed out that a hurflan Ig derived protein can be produced by a non-human animal or prokaryotic or eukaryotic cell that is capable of expressing functionally rea rranged human immunoglobulin (e.g., heavy chain anoVor light chain) genes. Further, v/hen a human ig derived protein is a single chain Ig derived protein, it can comprise a linker peptide that is not found in native human Ig derived proteins. For example, an Fv can comprise a linker peptide, such as two to about eight glycine or other amino acid residues, which connects the variable region of the heavy chain and the variable region of the light chain. Such linker peptides are considered to be of human origin. IL-23p40 Ig derived proteins mat comprise at least one IL-23p40 protein ligand or receptor thereof can be designed against an appropriate ligand, such as isolated and/or IL-23p40 protein, or a portion thereof (including synthetic molecules, such as synthetic peptides). Preparation of such IL-23p40 Ig derived proteins are performed using known techniques to identify and characterize ligand binding regions or sequences of at least one IL-23p40 protein or portion thereof. Human Ig derived proteins that are specific for the p40 subunit can be raised against an appropriate immunogenic antigen, such as isolated IL-23 protein or a portion thereof (including synthetic molecules, such as synthetic peptides). Preparation of immunogenic antigens, and monoclonal Ig derived protein production can be performed using any suitable technique. A variety of methods have been described (see e.g., Kohler etaL, Nature, 256:495-497 (197S) and Eur. J. Immunol 6:511-519 (1976); Milstein et al. Nature 266:550-552 (1977); Koprowski et al, U.S. Patent No. 4,172,124; Harlow, E. and D. Lane, 1988, Ig derived proteins: A Laboratory Manual, (Cold Spring Harbor Laboratory: Cold Spring Harbor, NY); Current Protocols In Molecular Biology, Vol. 2 (e.g., Supplement 27, Summer "94), Ausubel, F.M. et al., Eds., (John Wiley & Sons: New York, NY), Chapter 11, (1991-2003)), each of which is entirely incorporated herein by reference. Generally, a hybridoma is produced by fusing a suitable immortal cell line (e.g., a myeloma cell line such as, but not limited to, Sp2/0, Sp2/0-AG14, NSO, NS1, NS2, AE-1, L.5, >243, P3X63Ag8.653, Sp2 SA3, Sp2 MAI, Sp2 SSI, Sp2 SA5, U937, MLA 144, ACT IV, MOLT4, DA-1, JURKAT, WEffl, K-562, COS, RAJL NIH 3T3, HL-60, MLA 144, NAMAIWA, NEURO 2A, or the like, or heteromylomas, fusion products thereof, or any cell or fusion cell derived therefrom, or any other suitable cell line as known in the art, see, e.g., www.atcc.org. www.lifetech.com., and the like, each of which is entirely incorporated herein by reference) with Ig derived protein, producing cells, such as, but not limited to, isolated or cloned spleen cells, or any other cells expressing heavy or light chain constant or variable or framework or CDR sequences, either as endogenous or heterologous nucleic acid, as recombinant or endogenous, viral, bacterial, algal, prokaryotic, amphibian, insect, reptilian, fish, mammalian, rodent, equine, ovine, goat, sheep, primate, eukaryotic, genomic DNA, cDNA, rDNA, mitochondrial DNA orRNA, chloroplast DNA orRNA, hnRNA, mRNA, tRNA, single, double or triple stranded, hybridized, and the like or any combination thereof. See, e.g., Ausubel, supra, and Colligan, Immunology, supra, chapter 2, each entirely incorporated herein by reference. Ig derived protein producing cells can be obtained from the peripheral blood or, preferably the spleen or lymph nodes, of humans or other suitable animals that have been immunized with the antigen of interest. Any other suitable host cell can also be used for expressing heterologous or endogenous nucleic acid encoding an Ig derived protein, specified fragment or variant thereof, of the present invention. The fused cells (hybridomas) or recombinant cells can be isolated using selective culture conditions or other suitable known methods, and cloned by limiting dilution or cell sorting, or other known methods. Cells which produce Ig derived proteins with the desired specificity can be selected by a suitable assay (e.g., ELISA). Other suitable methods of producing or isolating antibodies of the requisite specificity can be used, including, but not limited to, methods that select recombinant antibody from a peptide or protein library (e.g., but not limited to, a bacteriophage, ribosome, oligonucleotide, RNA, cDNA, or the like, display library; e.g., as available from Cambridge antibody Technologies, Cambridgeshire, UK; MorphoSys, Martinsreid/Planegg, DE; Biovation, Aberdeen, Scotland, UK; Biolnvent, Lund, Sweden; Dyax Corp., Enzon, Affymax/Biosite; Xoma, Berkeley, CA; Ixsys. See, e.g., EP 368,684, PCT/GB91/01134; PCT/GB92/01755; PCT/GB92/002240; PCT/GB92/0O883; PCT/GB93/00605; US 08/350260(5/12/94); PCT/GB94A)1422; PCT/GB94/02662; PCT/GB97/01835; (CAT/MRC); WO90/14443; WO90/14424; WO90/14430; PCT/US94/1234; W092/18619; WO96/07754; (Scripps); W096713583, WO97/08320 (MorphoSys); WO95/16027 (Biolnvent); WO88/06630; WO90/3809 (Dyax); US 4,704,692 (Enzon); PCT/US91/02989 (Affymax); WO89/06283; EP 371 998; EP 550 400; (Xoma); EP 229 046; PCT/US91/07149 (Ixsys); or stochastically generated peptides or proteins - US 5723323,5763192,5814476,5817483,5824514,5976862, WO 86/05803, EP 590 689 (Ixsys, now Applied Molecular Evolution (AME), each entirely incorporated herein by reference) or that rely upon immunization of transgenic animals (e.g., SCID mice, Nguyen et al., Microbiol. Immunol. 41:901-907 (1997); Sandhu et al., Crit Rev. Biotechnol. 16:95-118 (1996); Eren et al., Immunol. 93:154-161 (1998), each entirely incorporated by reference as well as related patents and applications) that are capable of producing a repertoire of human antibodies, as known in the art and/or as described herein. Such techniques, include, but are.not limited to, ribosome display (Hanes et al., Proc. Nad. Acad. Sci. USA, 94:4937-4942 (May 1997); Hanes et al., Proc. Nad. Acad. Sci. USA, 95:14130- 14135 (Nov. 1998)); single cell antibody producing technologies (e.g., selected lymphocyte antibody method ("SLAM") (US pat. No. 5,627,052, Wen et al., J. Immunol. 17:887-892 (1987); Babcook et al., Proc. Natl. Acad. Sci. USA 93:7843-7848 (1996)); gel microdroplet and flow cytometry (Powell et al., Biotechnol. 8:333-337 (1990); One Cell Systems, Cambridge, MA; Gray et al., J. Imm. Meth. 182:155-163 (1995); Kenny et al., Bio/Technol. 13:787-790 (1995)); B-cell selection (Steenbakkers et al., Molec. Biol. Reports 19:125-134 (1994); Jonak et al., Progress Biotech, Vol. 5, In Vitro Immunization in Hybridoma Technology, Borrebaeck, ed., Elsevier Science Publishers B.V., Amsterdam, Netherlands (1988)). each of which is entirely incorporated herein by reference. Methods for humanizing non-human Ig derived proteins can also be used and are well known in the art. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as "import" residues, which are typically taken from an "import" variable domain. Humanization can be essentially performed following the method of Winter and co-workers (Jones et al., Nature 321:522 (1986); Riechmann et al., Nature 332:323 (1988); Verhoeyen et al., Science 239:1534 (1988), each of which is entirely incorporated herein by reference), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such "humanized" Ig derived proteir s are chimeric Ig derived proteins (Cabilly et al., supra), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized Ig derived proteins are typically human Ig derived proteins in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent Ig derived proteins. The choice of human variable domains, bom light and heavy, to be used in making the humanized Ig derived proteins can be used to reduce antigenicity. According to the so-called "best- fit" method, the sequence of the variable domain of a rodent antibody is screened against the entire library of known human variable-domain sequences. The human sequence which is closest to that of the rodent is then accepted as the human framework (FR) for the humanized antibody (Sims et al., J. Immunol. 151:2296 (1993); Chothia and Lesk, J. Mol. Biol. 196:901 (1987), each of which is entirely incorporated herein by reference). Another method uses a particular framework derived from the consensus sequence of all human Ig derived proteins of a particular subgroup of light or heavy chains. The same framework can be used for several different humanized Ig derived proteins (Carter et al., Proc. Natl. Acad. Sci. U.SA. 89:4285 (1992); Presta et al., J. Immunol. 151:2623 (1993), each of which is entirely incorporated herein by reference). Ig derived proteins can also optionally be humanized with retention of high affinity for the antigen and other favorable biological properties. To achieve this goal, according to a preferred method, humanized Ig derived proteins are prepared by a process of analysis of the parental sequences and various conceptual humanized products using three-dimensional models of die parental and humanized sequences. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art Computer programs are available which illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. Inspection of these displays permits analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, i.e., the analysis of residues that influence the ability of the candidate immunoglobulin to bind its antigen. In this way, FR residues can be selected and combined from the consensus and import sequences so that the desired antibody characteristic, such as increased affinity for the target antigen(s), is achieved. In general, the CDR residues are directly and most substantially involved in influencing antigen binding. Human monoclonal Ig derived proteins can be made by the hybridoma method. Human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal Ig derived proteins have been described, for example, by Kozbor, J. Immunol. 133:3001 (1984); Brodeur st al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boemer et al., J. Immunol. 147:86 (1991% each of which is entirely incorporated herein by reference. Alternatively, phage display technology and, as presented above, can be used to produce human Ig derived proteins and antibody fragments in vitro, from immunoglobulin variable (V) domain gene repertoires from unimmunized donors. According to one none limiting example of this technique, antibody V domain genes are cloned in-frame into either a major or minor coat protein gene of a filamentous bacteriophage, such as M13 or fd, and displayed as functional antibody fragments on the surface of the phage particle. Because the filamentous particle contains a single- stranded DNA copy of the phage genome, selections based on die functional properties of the antibody also result in selection of the gene encoding die antibody exhibiting those properties. Thus, the phage mimics some of the properties of the B-cell. Phage display can be performed in a variety of formats; for their review see, e.g., Johnson et al., Current Opinion in Structural Biology 3:564 (1993), each of which is entirely incorporated herein by reference. Several sources of V-gene segments can be used for phage display. Clackson et al., Nature 352:624 (1991) isolated a diverse array of anti- oxazolone Ig derived proteins from a small random combinatorial library of V genes derived from the spleens of immunized mice. A repertoire of V genes from unimmunized human donors can be constructed and Ig derived proteins to a diverse array of antigens (including self-antigens) can be isolated essentially following the techniques described by Marks et al., J. Mol. Biol. 222:581 (1991), or Griffith et al., EMBO J. 12:725 (1993), each of which is entirely incorporated herein by reference. In a natural immune response, antibody genes accumulate mutations at a high rate (somatic hypermutation). Some of the changes introduced will confer higher affinity, and B cells displaying high-affinity surface immunoglobulin are preferentially replicated and differentiated during subsequent antigen challenge. This natural process can be mimicked by employing the technique known as "chain shuffling" (Marks et al., Bio/Technol. 10:779 (1992)). In this method, the affinity of "primary" human Ig derived proteins obtained by phage display can be improved by sequentially replacing the heavy and light chain V region genes with repertoires of naturally occurring variants (repertoires) of V domain genes obtained from unimmunized donors. This technique allows die production of Ig derived proteins and antibody fragments with affinities in the nM range. A strategy for making very large phage antibody repertoires has been described by Waterhouse et al., Nucl. Acids Res. 21:2265 (1993). Gene shuffling can also be used to derive human Ig derived proteins from rodent Ig derived proteins, where the human antibody has similar affinities and specificities to the starting rodent antibody. According to this method, which is also referred to as "epitope imprinting," the heavy or light chain V domain gene of rodent Ig derived proteins obtained by phage display technique is replaced with a repertoire of human V domain genes, creating rodent-human chimeras. Selection with antigen results in isolation of human variable capable of restoring a functional antigen- binding site, i.e., the epitope governs (imprints) the choice of partner. When the process is repeated in order to replace the remaining rodent V domain, a human antibody is obtained (see PCT WO 93/06213, published 1 April 1993). Unlike traditional humanization of rodent Ig derived proteins by CDR grafting, this technique provides completely human Ig derived proteins, which have no framework or CDR residues of rodent origin. Bispecific Ig derived proteins can also be used that are monoclonal, preferably human or humanized. Ig derived proteins mat have binding specificities for at least two different antigens. In die present case, one of the binding specificities is for at least one IL-23p40 protein, the other one is for any other antigen. For example, bispecific Ig derived proteins specifically binding a IL-23p40 protein and. at least one neurotrophic factor, or two different types of IL-23p40 polypeptides are within the scope of the present invention. Methods for making bispecific Ig derived proteins are known in the art Traditionally, the recombinant production of bispecific Ig derived proteins is based on the co-expression of two immunoglobulin heavy chain-light chain pairs, where me two heavy chains have different specificities (Milstein and Cuello, Nature 305:537 (1983)). Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of 10 different antibody molecules, of which only one has the correct bispecific structure. The purification of the correct molecule, which is usually done by affinity chromatography steps, is rather cumbersome, and the product yields are low. Similar procedures are disclosed in WO 93/D8829 published 13 May 1993, and in Traunecker et al., EMBO J. 10:3655 (1991), entirely incorporated herein by referece. According to a different and more preferred approach, antibody-variable domains with the desired binding specificities (antibody-antigen combining sites) are fused to immunoglobulin constant-domain sequences. The fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, the second heavy chain constant region (C.sub.H 2), and the third heavy chain constant region (C.sub.H 3). It is preferred to have the first heavy-chain constant region (C.sub.H 1), containing the site necessary for light-chain binding, present in at least one of the fusions. DNAs encoding the immunoglobulin heavy chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host organism. This provides for great flexibility in adjusting the mutual proportions of the three polypeptide fragments in embodiments when unequal ratios of the three polypeptide chains used in the construction provide the optimum yields. It is, however, possible to insert the coding sequences for two or all three polypeptide chains in one expression vector when the production of at least two polypeptide chains in equal ratios results in high yields or when the ratios are of no particular significance. In a preferred embodiment of this approach, the bispecific Ig derived proteins are composed of a hybrid immunoglobulin heavy chain with a first binding specificity in one arm, and a hybrid immunoglobulin heavy chain-light chain pair (providing a second binding specificity) in the other aim. This asymmetric structure facilitates the separation of the desired bispecific compound from unwanted immunoglobulin chain combinations, as the presence of an immunoglobulin light chain in only one half of the bispecific molecule provides for a facile way of separation. For further details of generating bispecific Ig derived proteins, see, for example, Suresh et al., Methods in Enzymology 121:210 (1986). Heteroconjugate Ig derived proteins are also within the scope of the present invention. Heteroconjugate Ig derived proteins are composed of two covalently joined Ig derived proteins. Such Ig derived proteins have, for example, been proposed to target immune system cells to unwanted cells (U.S. Pat No. 4,676,980), and for treatment of HIV infection (WO 91/00360; WO 92/00373; and EP 03089). Heteroconjugate Ig derived proteins can be made using any convenient cross-linking methods. Suitable cross-linking agents are well known in the art, and are disclosed in U.S. Pat No. 4,676,980, along with a number of cross-linking techniques. In a preferred embodiment, at least one anti-IL-23p40 Ig derived protein or specified portion or variant of the present invention is produced by a cell line, a mixed cell line, an immortalized cell or clonal population of immortalized cells. Immortalized IL-23p40 producing cells can be produced using suitable methods, for example, fusion of a human Ig derived protein-producing cell and a heteromyeloma or immortalization of an activated human B cell via infection with Epstein Barr virus (Niedbala et al, Hybridoma, 77(3):299-304 (1998); Zanella et aL, J Immunol Methods, /Jd(2):205- 215 (1992); Gustafsson et aL, Hum Ig derived proteins Hybridomas, 2(1)26-32 (1991)). Preferably, the human anti-human IL-23p40 proteins or fragments or specified portions or variants is generated by immunization of a transgenic animal (e.g., mouse, rat, hamster, non-human primate, and the like) capable of producing a repertoire of human Ig derived proteins, as described herein and/or as known in the art. Cells that produce a human anti-IL-23p40 Ig derived protein can be isolated from such animals and immortalized using suitable methods, such as the methods described herein. Transgenic mice that can produce a repertoire of human Ig derived proteins that bind to human antigens can be produced by known methods (e.g., but not limited to, U.S. Pat Nos: 5,770,428,5,569,825,5,545,806,5,625,126,5,625,825,5,633,425,5,661,016 and 5,789,650 issued to Lonberg et al.; Jakobovits et al WO 98/50433, Jakobovits et al WO 98/24893, Lonberg et al WO !>8/24884, Lonberg et al WO 97/13852, Lonberg et al WO 94/25S85, Kncherlapate et al WO y6/34096, Kucheriapate et al EP 0463 151 Bl, Kucherlapate et al. EP 0710 719 Al, Surani et al US. Pat. No. 5,545,807, Bruggemann et al. WO 90/04036, Bruggemann et al EP 0438 474 Bl, Lonberg et ci EP 0814 259 A2, Lonberg ef aL GB 2 272 440 A, Lonberg et al. Nature 368:856-859 (1994), Taylor et aL. Int. Immunol 6(4)579-591 (1994), Green et aL Nature Genetics 7:13-21 (1994), Mendez et al, Nature Gemtics 15:146-156 (1997), Taylor et al, Nucleic Acids Research 20(23):6287-6295 (J 992), Tuaillo:i et al. Proc Natl Acad Sci USA 90(8)3720-3724 (1993), Lonberg et al. hit Rev Ivmuuwl 13(l):65-93 (1995) and Hshwald etal, Nat Biotechnol 14(7):845-851 (1996), which are each entirely incorporated herein by reference). Generally, these mice comprise at least one transgene comprising DNA from at least one human immunoglobulin locus that is functionally rearranged, or which can undergo functional rearrangement. The endogenous immunoglobulin loci in such mice can be disrupted or deleted to eliminate the capacity of the animal to produce Ig derived proteins encoded b> endogenous genes. The term "functionally rearranged," as used herein refers to a segment of DNA from an immunoglobulin locus that has undergone V(D)J recombination, thereby producing an immunoglobulin gene that encodes an immunoglobulin chain (e.g., heavy chain, light chain), or any portion thereof. A functionally rearranged immunoglobulin gene can be directly or indirectly identified using suitable methods, such as, for example, nucleotide sequencing, hybridization (e.g., Southern blotting. Northern blotting) using probes that can anneal to coding joints between gene segments or enzymatic amplification of immunoglobulin genes (e.g., polymerase chain reaction) with primers that can anneal to coding joints between gene segments. Whether a cell produces an Ig derived protein comprising a particular variable region or a variable region comprising a particular sequence (e.g., at least one CDR sequence) can also be determined using suitable methods. In one example, mRNA can be isolated from an Ig derived protein-producing cell (e.g., a hybridoma or recombinant cell or other suitable source) and used to produce cDNA encoding the Ig derived protein or specified portion or variant thereof. The cDNA can be cloned and sequenced or can be amplified (e.g., by polymerase chain reaction or other known and suitable methods) using a first primer that anneals specifically to a portion of the variable region of interest (e.g., CDR, coding joint) and a second primer that anneals specifically to non-variable region sequences (e.g., CH1, VH). Screening Ig derived protein or specified portion or variants for specific binding to similar proteins or fragments can be conveniently achieved using peptide display libraries. This method involves (he screening of large collections of peptides for individual members having the desired function or structure. Ig derived protein screening of peptide display libraries is well known in the art The displayed peptide sequences can be from 3 to 5000 or more amino acids in length, frequently from 5-100 amino acids long, and often from about 8 to 25 amino acids long. In addition to direct chemical synthetic methods for generating peptide libraries, several recombinant DNA methods have been described. One type involves the display of a peptide sequence on the surface of a bacteriophage or cell. Each bacteriophage or cell contains the nucleotide sequence encoding the particular displayed peptide sequence. Such methods are described in PCT Patent Publication Nos. 91/17271,91/18980,91/19818, and 93/08278. Other systems for generating libraries of peptides have aspects of both in vitro chemical synthesis and recombinant methods. See, PCT Patent Publication Nos. 92/05258,92/14843, and 96/19256. Sea also, U.S. Patent Nos. 5,658,754; and 5,643,768. Peptide display libraries, vector, and screening kits are commercially available from such suppliers as Invitrogen (Carlsbad, CA), and Cambridge Ig derived protein Technologies (Cambridgeshire, UK). See, e.g., U.S. Pat. Nos. 4704692, 4939666,494(5778,5260203,5455030,5518889,5534621,5656730,5763733,5767260,5856456, assigned to Enzon; 5223409,5403484,5571698,5837500, assigned to Dyax, 5427908,5580717, assigned to Af fymax; 5885793, assigned to Cambridge Ig derived protein Technologies; 5750373, assigned to Genentech, 5618920,5595898,5576195,5698435,5693493,5698417, assigned to Xoma, Colligan, supra; Ausubel, supra; or Sambrook, supra, each of the above patents and publications entirely incorporated herein by reference. Ig derived proteins, specified portions and variants of the present invention can also be prepared using at least one EL-23p40 Ig derived protein or specified portion or variant encoding nucleic acid to provide transgenic animals or mammals, such as goats, cows, horses, sheep, and the like, that produce such Ig derived proteins or specified portions or variants in their milk. Such animals can be provided using known methods. See, e.g., but not limited to, US patent nos. 5,827,690; 5,849,992; 4,873,316; 5,849,992; 5,994,616; 5,565,362; 5,304,489, and the like, each of which is entirely incorporated herein by reference. Ig derived proteins, specified portions and variants of the present invention can additionally be prepared using at least one IL-23p40 Ig derived protein or specified portion or variant encoding nucleic acid to provide transgenic plants and cultured plant cells (e.g., but not limited to, tobacco and maize) that produce such Ig derived proteins, specified portions or variants in the plant parts or in cells cultured therefrom. As a non-limiting example, transgenic tobacco leaves expressing recombinant proteins have been successfully used to provide large amounts of recombinant proteins, e.g., using art inducible promoter. See, e.g., Cramer et al., Curr. Top. Microbol. Immunol. 240:95-118 (1999) and references cited therein. Also, transgenic maize have been used to express mammalian proteins at commercial production levels, with biological activities equivalent to those produced in other recombinant systems or purified from natural sources. See, e.g., Hood et al., Adv. Exp. Med. Biol. 464:127-147 (1999) and references cited therein. Ig derived proteins have also been produced in large amount;; from transgenic plant seeds including Ig derived protein fragments, such as single chain Ig derived proteins (scFv's), including tobacco seeds and potato tubers. See, e.g., Conrad et al., Plant Mol. Biol. 38:101-109 (1998) and reference cited therein. Thus, Ig derived proteins, specified portions and variants of the present invention can also be produced using transgenic plants, according to known methods. See also, e.g., Fischer et al., Biotechnol. Appl. Biochem. 30:99-108 (Oct., 1999), Ma et al., Trends Biotechnol. 13:522-7 (1995); Ma et al., Plant Physiol. 109:341-6 (1995); Wbitelam :t al., Biochem. Soc. Trans. 22:940-944 (1994); and references cited therein. Each of the above references is entirely incorporated herein by reference. The Ig derived proteins of the invention can bind human IL-23p40 proteins or fragments with a. wide range of affinities (KD)- In a preferred embodiment, at least one human mAb of the present invention can optionally bind human IL-23p40 proteins or fragments with high affinity. For example, a human mAb can bind human EL-23p40 proteins or fragments with a KD equal to or less than about 10 ' M or, more preferably, with a KD equal to or less than about 0.1-9.9 (or any range or value therein) X 10"lc M, 10"", 10'12,10"13or any range or value therein. The affinity or avidity of an Ig derived protein for an antigen can be determined experimentally using any suitable method. (See, for example, Berzofsky, et al., "Ig derived protein- Antigen Interactions," In Fundamental Immunology, Paul, W. E., Ed., Raven Press: New York, NY (1984); Kuby, Janis Immunology, W. H. Freeman and Company: New York, NY (1992); and methods described herein). The measured affinity of a particular Ig derived protein-antigen interaction can vary if measured under different conditions (e.g., salt concentration, pH). Thus, measurements of affinity and other antigen-binding parameters (e.g., KD, Ka, Kd) are preferably made with standardized solutions of ]g derived protein and antigen, and a standardized buffer, such as the buffer described herein. Nucleic Acid Molecules Using the information provided herein, a nucleic acid molecule of the present invention encoding at least one IL-23p40 Ig derived protein or specified portion or variant can be obtained using methods described herein or as known in die art Nucleic acid molecules of the present invention can be in me form of RNA, such as mRNA, hnRNA, tRNA or any other form, or in the form of DNA, including, but not limited to, cDNA and genomic DNA obtained by cloning or produced synthetically, or any combinations thereof. The DNA can be triple-si randed, double-stranded or single-stranded, or any combination thereof. Any portion of at least one strand of the DNA or RNA can be the coding strand, also known as the sense strand, or ; t can be the non-coding strand, also referred to as the anti-sense strand. Isolated nucleic acid molecules of die present invention can include nucleic acid molecules c omprising an open reading frame (ORF), optionally with one or more introns, e.g., but not limited to, jit least one specified portion of at least one CDR, as CDR1, CDR2 and/or CDR3 of at least one heavy chain or light chain, respectively; nucleic acid molecules comprising the coding sequence for a IL- 23p40 Ig derived protein or specified portion or variant; and nucleic acid molecules which comprise a nucleotide sequence substantially different from those described above but which, due to the degeneracy of die genetic code, still encode at least one IL-23p40 Ig derived protein as described h'irein and/or as known in the art. Of course, the genetic code is well known in the art. Thus, it would be routine for one skilled in the art to generate such degenerate nucleic acid variants that code for specific EL-23p40 Ig derived protein or specified portion or variants of the present invention. See, e.g., Ausubel, et al., supra, and such nucleic acid variants are included in the present invention. As indicated herein, nucleic acid molecules of the present invention which comprise a nucleic acid encoding a IL-23p40 Ig derived protein or specified portion or variant can include, but are not limited to, those encoding the amino acid sequence of an Ig derived protein fragment, by itself; the coding sequence for the entire Ig derived protein or a portion thereof; the coding sequence for an Ig derived protein, fragment or portion, as well as additional sequences, such as the coding sequence of at east one signal leader or fusion peptide, with or without the aforementioned additional coding secfuonces, such as at least one intron, together with additional, non-coding sequences, including but noi limited to, non-coding 5' and 3' sequences, such as the transcribed, non-translated sequences that play a role in transcription, mRNA processing, including splicing and polyadenylation signals (for example - ribosome binding and stability of mRNA); an additional coding sequence that codes for additional amino acids, such as those that provide additional functionalities. Thus, the sequence encoding an Ig derived protein or specified portion or variant can be fused to a marker sequence, such as a sequence encoding a peptide that facilitates purification of the fused Ig derived protein or specified portion or variant comprising an Ig derived protein fragment or portion. Polynucleotides Which Selectively Hybridize to a Polynucleotide as Described Herein The present invention provides isolated nucleic acids that hybridize under selective hybridization conditions to a polynucleotide encoding a IL-23p40 Ig derived protein of the present invention. Thus, the polynucleotides of this embodiment can be used for isolating, detecting, and/or quantifying nucleic acids comprising such polynucleotides. For example, polynucleotides of the present invention can be used to identify, isolate, or amplify partial or full-length clones in a deposited library. In some embodiments, the polynucleotides are genomic or cDNA sequences isolated, or otherwise complementary to, a cDNA from a human or mammalian nucleic acid library. Preferably, the cDNA library comprises at least 80% full-length sequences, preferably, at least J'i5% or 90% fud-lengm sequences, and, more preferably, at least 95% full-length sequences. The cDNA libraries can be normalized to increase the representation of rare sequences. Low or moderate stringency hybridization conditions are typically, but not exclusively, employed with sequences having a reduced sequence identity relative to complementary sequences. Moderate and high stringency conditions can optionally be employed for sequences of greater identity. Low stringency conditions allow selective h ybridization of sequences having about 70% sequence identity and can be employed to identify orthologous or paralogous sequences. Optionally, polynucleotides of this invention will encode at least a portion of an Ig derived protein or specified portion or variant encoded by the polynucleotides described herein. The polynucleotides of this invention embrace nucleic acid sequences that can be employed for selective hybridization to a polynucleotide encoding an Ig derived protein or specified portion or variant of the present invention. See, e.g., Ausubel, supra; Colligan, supra, each entirely incorporated herein by reference. Construction of Nucleic Adds The isolated nucleic acids of the present invention can be made using (a) recombinant methods, (b) synthetic techniques, (c) purification techniques, or combinations thereof, as well-known in the art The nucleic acids can conveniently comprise sequences in addition to a polynucleotide of the present invention. For example, a multi-cloning site comprising one or more endonuclease restriction sites can be inserted into the nucleic acid to aid in isolation of the polynucleotide. Also, translatable sequences can be inserted to aid in the isolation of the translated polynucleotide of the present invention. For example, a hexa-histidine marker sequence provides a convenient means to purify the proteins of the present invention. The nucleic acid of the present invention - excluding the coding sequence - is optionally a vector, adapter, or linker for cloning and/or expression of a polynucleotide of the present invention. Additional sequences can be added to such cloning and/or expression sequences to optimize their function in cloning and/or expression, to aid in isolation of the polynucleotide, or to improve the introduction of the polynucleotide into a cell. Use of cloning vectors, expression vectors, adapters, and linkers is well known in the art. (See, e-g., Ausubel, supra; or Sambrook, supra) Recombinant Methods for Constructing Nucleic Adds The isolated nucleic acid compositions of this invention, such as RNA, cDNA, genomic DNA, or any combinab on feereof, can be obtained from biological sources using any number of cloning methodologies known to those of skill in the art In some embodiments, oligonucleotide probes mat selectively hybridize, under stringent conditions, to the polynucleotides of the present invention are used to identify fee desired sequence in a cDNA or genomic DNA library. The isolation of RNA, and construction of cDNA and genomic libraries, is well known to those of ordinary skill in the art (See, eg., Ausubel, supra; or Sambrook, supra) Nucleic Acid Screening and Isolation Methods A cDN A or genomic library can be screened using a probe based upon the sequence of a polynucleotide of the present invention, such as those disclosed herein. Probes can be used to hybridize with genomic DNA or cDNA sequences to isolate homologous genes in the same or different organisms. Those of skill in the art will appreciate mat various degrees of stringency of hybridization can be e mployed in the assay; and either fee hybridization or fee wash medium can be stringent As the conditions for hybridization become more stringent, there must be a greater degree of complementarity between fee probe and the target for duplex formation to occur. The degree of stringency can be controlled by one or more of temperature, ionic strength, pH and the presence of a partially denaturing solvent such as formamide. For example, fee stringency of hybridization is conveniently varied by changing the polarity of fee reactant solution through, for example, manipulation of fee concentration of formamide within the range of 0% to 50%. The degree of complementarity (sequence identity) required for detectable binding will vary in accordance with fee stringency of fee hybridization medium and/or wash medium. The degree of complementarity will optimally be 100%, or 90-100%, or any range or viilue therein. However, it should be understood feat minor sequence variations in the probes and primers can be compensated for by reducing fee stringency of the hybridization and/or wash medium. Method;; of amplification of RNA or DNA are well known in the art and can be used according to the present invention without undue experimentation, based on the teaching and guidance presented herein. Known methods of DNA or RNA amplification include, but are not limited to, polymerase chain reaction (PCR) and related amplification processes (see, e.g., U.S. Patent Nos. 4,683,195, 4,683,202,4,300,159,4,965,188, to Mullis, et al.; 4,795,699 and 4,921,794 to Tabor, et al; 5,142,033 to Innis; 5,122,464 to Wilson, et al.; 5,091,310 to lnnis; 5,066,584 to Gyllensten, et al; 4,889,818 to Gelfand, et al; 4,994,370 to Silver, et al; 4,766,067 to Biswas; 4,656,134 to Ringold) and RNA mediated amplification that uses anti-sense RNA to the target sequence as a template for double- stranded DNA synthesis (U.S. Patent No. 5,130,238 to Malek, et al, with the tradename NASBA), the entire contents of which references are incorporated herein by reference. (See, e.g., Ausubel, supra; or Sambrook, supra.) For instance, polymerase chain reaction (PCR) technology can be used to amplify the sequences of polynucleotides of the present invention and related genes direcdy from genomic DNA or cDNA libraries. PCR and other in vitro amplification methods can also be useful, for example, to clone nucleic acid sequences that code for proteins to be expressed, to make nucleic acids to use as probes for detecting the presence of the desired mRNA in samples, for nucleic acid sequencing, or for other purposes. Examples of techniques sufficient to direct persons of skill through in vitro amplification methods are [bund in Berger, supra, Sambrook, supra, and Ausubel, supra, as well as Mullis, et al., U.S. Patent No. 4,683,202 (1987); and Innis, et al., PCR Protocols A Guide to Methods and Applications, Eds., Academic Press Inc., San Diego, CA (1990). Commercially available kits for genomic PCR amplification are known in the ait. See, e.g., Advantage-GC Genomic PCR Kit (Clontech). The T4 gene 32 protein (Boehringer Miinnheim) can be used to improve yield of long PCR products. Synthetic Methods for Constructing Nucleic Adds The isolated nucleic acids of the present invention can also be prepared by direct chemical s ynthesis by known methods (see, e.g., Ausubel, et al., supra). Chemical synthesis generally produces a smgle-stranded oligonucleotide, which can be converted into double-stranded DNA by hybridization with a complementary sequence, or by polymerization with a DNA polymerase using the single strand as a template. One of skill in the art will recognize that while chemical synthesis of DNA can be Hrnited to sequences of about 100 or more bases, longer sequences can be obtained by the ligation of shorter sequences. Recombinant Expression Cassettes The present invention further provides recombinant expression cassettes comprising a nucleic ac id of the present invention. A nucleic acid sequence of the present invention, for example, a cDNA or a genomic sequence encoding an Ig derived protein or specified portion or variant of the present invention, can be used to construct a recombinant expression cassette that can be introduced into at least one desired host cell. A recombinant expression cassette will typically comprise a polynucleotide of die present invention operably linked to transcriptional initiation regulatory sequences that will direct the transcription of die polynucleotide in the intended host cell. Both heterologous and non-heterologous (i .e., endogenous) promoters can be employed to direct expression of the nucleic acids of the present invention. In some embodiments, isolated nucleic acids mat serve as promoter, enhancer, or other elements can be introduced in the appropriate position (upstream, downstream or in intron) of a non-heterologous form of a poly nucleotide of the present invention so as to up or down regulate expression of a polynucleotide of the present invention. For example, endogenous promoters can be altered in vivo or in vitro by mutation, deletion and/or substitution. A polynucleotide of the present invention can be expressed in either sense or anti-sense orientation as desired. It will be appreciated that control of gene expression in either sense or anti-sense orientation can have a direct impact on the observable characteristics. Another method of suppression is sense suppression. Introduction of nucleic acid configured in tiie sense orientation has been shown to be an effective means by which to block the transcription of target genes. A variety of cross-linking agents, alkylating agents and radical generating species as pendant groups on polynucleotides of the present invention can be used to bind, label, detect and/or cleave nucleic acids. Knorre, et al., Biochirnie 67:785-789 (1985); Vlassov, et al., Nucleic Acids Res. 14:4065-4076 (1986); Iverson and Dervan, J. Am. Chem. Soc. 109:1241-1243 (1987); Meyer, et al., J. Am. Chem. Soc. 111:8517-8519 (1989); Lee, et al., Biochemistry 27:3197-3203 (1988); Home, et al., J. Am. Chem. Soc. 112:2435-24:17 (1990); Webb and Matteucci, J. Am. Chem. Soc. 108:2764-2765 (1986); Nucleic Acids Res. 14:7661 7674 (1986); Feteritz, et al., J. Am. Chem. Soc. 113:4000 (1991). Various compounds to bind, detect, label, and/or cleave nucleic acids are known in the art See, for example, U.S. Patent Nos. 5,543,507; 5,672,593; 5,484,908; 5,256,648; and 5,681941, each entirely incorporated herein by reference. Vectors And Host Cells The present invention also relates to vectors that include isolated nucleic acid molecules of the present invention, host cells that are genetically engineered with the recombinant vectors, and the production of at least one IL-23p40 Ig derived protein or specified portion or variant by recombinant techniques, as is well known in the art. See, e.g., Sambrook, et al., supra; Ausubel, et al., supra, each entirely incorporated herein by reference. The polynucleotides can optionally be joined to a vector containing a selectable marker for propagation in a host. Generally, a plasmid vector is introduced in a precipitate, such as a calcium phosphate precipitate, or in a complex with a charged lipid. If the vector is a virus, it can be packaged in vitro using an appropriate packaging cell line and then transduced into host cells. The DNA insert should be operatively linked to an appropriate promoter. The expression constructs will further contain sites for transcription initiation, termination and, in the transcribed region, a ribosome binding site for translation. The coding portion of the mature transcripts expressed by the constructs will preferably include a translation initiating at the beginning and a termination codon (e.g., UAA, UGA or UAG) appropriately positioned at the end of the raRNA to be translated, with UAA and UAG preferred for mammalian or eukaryotic cell expression. Expression vectors will preferably but optionally include at least one selectable marker. Such markers include, e.g., but not limited to, methotrexate (MTX), dihydrofolate reductase (DHFR, US Pat.Nos. 4,399,216; 4,634,665; 4,656,134; 4,956,288; 5,149,636; 5,179,017, ampicillin, neomycin (G418), mycophenolic acid, or glutanrine synthetase (GS, US PatNos. 5,122,464; 5,770,359; 5.827,739) resistance for eukaryotic cell culture, and tetracycline or ampicillin resistance genes for culturing in e. Coli and other bacteria or prokaryotics (the above patents are entirely incorporated hereby by reference). Appropriate culture mediums and conditions for the above-described host cells are known in the art. Suitable vectors will be readily apparent to the skilled artisan. Introduction of a vector construct into a host cell can be effected by calcium phosphate transfection, DEAE-dextran mediated transfection, canonic lipid-mediated transfection, electroporation, transduction, infection or other known methods. Such methods ate described in the art, such as Sambrook, supra. Chapters 1-4 and 16-18; Ausubel, supra, Chapters 1,9,13,15,16. At least one Ig derived protein or specified portion or variant of the present invention can be expressed in a modified form, such as a flision protein, and can include not only secretion signals, but aJso additional heterologous functional regions. For instance, a region of additional amino acids, particularly charged amino acids, can be added to the N-terminus of an Ig derived protein or specified portion or variant to improve stability and persistence in the host cell, daring purification, or during subsequent handling and storage. Also, peptide moieties can be added to an Ig derived protein or specified portion or variant of the present invention to facilitate purification. Such regions can be removed prior to final preparation of an Ig derived protein or at least one fragment thereof. Such methods are described in many standard laboratory manuals, such as Sambrook, supra, Chapters 17 29-17.42 and .18.1-18.74; Ausubel, supra, Chapters 16,17 and 18. Those of ordinary skill in the art are knowledgeable in the numerous expression systems available for expression of a nucleic acid encoding a protein of the present invention. Alternatively, nucleic acids of the present invention can be expressed in a host cell by turning on (by manipulation) in a host cell that contains endogenous DNA encoding an Ig derived protein or specified portion or variant of the present invention. Such methods are well known in the art, e.g., as described in US patent Nos. 5,580,734,5,641,670,5,733,746, and 5,733,761, entirely incorporated herein by reference. IIusirative of cell cultures useful for the production of the Ig derived proteins, specified portions or vsaiants thereof, are mammalian cells. Mammalian cell systems often will be in the form of monolayers of cells although mammalian cell suspensions or bioreactors can also be used. A number of suitable host cell lines capable of expressing intact glycosylated proteins have been developed in fee art, and include the COS-1 (e.g., ATCC CRL1650), COS-7 (e.g., ATCC CRL651), HEK293, BHK21 (e.g., ATCC CRL-10), CHO (e.g., ATCC CRL1610) and BSC-1 (e.g., ATCC CRL-26) cell lines, Cos-7 cells, CHO cells, hep G2 cells, P3X63Ag8.653, SP2/0-Agl4, 293 cells, HeLa cells and the like, which are readily available from, for example, American Type Culture Collection, Manassas, Va. Preferred host cells include cells of lymphoid origin such as myeloma and lymphoma cells. Particularly preferred host cells are P3X63Ag8.653 cells (ATCC Accession Number CRL-1580) and SP2/0-Agl4 cells (ATCC Accession Number CRL-1851). In a particularly preferred embodiment, the recombinant cell is a P3X63Ab8.653 or a SP2/D-Agl4 cell. Expression vectors for these cells can include one or more of the following expression control sequences, such as, but not limited to, an origin of replication; a promoter (e.g., late or early SV40 promoters, the CMV promoter (US PatNos. 5,168,062; 5,385,839), an HSV tk promoter, a pgk (phosphoglycerate kinase) promoter, an EF-1 alpha promoter (US PatNo. 5,266,491), at least one human immunoglobulin promoter, an enhancer, and/or processing information sites, such as ribosome binding sites, RNA splice sites, polyadenylation sites (e.g., an SV40 large T Ag poly A addition site), and transcriptional terminator sequences. See, e.g., Ausubel et al., supra; Sambrook, et aL, supra. Other cells useful for production of nucleic acids or proteins of the present invention are known and/or available, for instance, from the American Type Culture Collection Catalogue of Cell Lines and Hybridomas i www.atcc.org) or other known or commercial sources. When eukaryotic host cells are employed, polyadenlyation or transcription terminator sequences arc typically incorporated into the vector. An example of a terminator sequence is the polyadenlyation sequence from the bovine growth hormone gene. Sequences for accurate splicing of the transcript can a Iso be included. An example of a splicing sequence is the VP1 intron from SV40 (Sprague, et al., J. Virol. 45:773-781 (1983)). Additionally, gene sequences to control replication in the host cell can be incorporated into the vector, as known in the art. Purification of an Ig derived protein or Specified Portion or Variant Thereof An IL-23p40 Ig derived protein or specified portion or variant can be recovered and purified from recombinant cell cultures by well-known methods including, but not limited to, protein A purification, ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. High peiformance liquid chromatography ("HPLC") can also be employed for purification. See e.g., Colbgan, Current Protocols in Immunology, or Current Protocols in Protein Science, John Wiley & Sons. NY, NY, (1997-2003), e.g., Chapters 1,4,6,8,9,10, each entirely incorporated herein by reference. Ig derived proteins or specified portions or variants of the present invention include naturally purified products, products of chemical synthetic procedures, and products produced by recombinant techniques from a eukaryotic host, including, for example, yeast, higher plant, insect and mammalian cells. Depending upon the host employed in a recombinant production procedure, the Ig derived protem or specified portion or variant of the present invention can be giycosylated or can be non- glycosylated, with glycosylated preferred. Such methods are described in many standard laboratory manuals, such as Sambrook, supra, Sections 17.37-17.42; Ausubel, supra, Chapters 10,12,13,16,18 and 20, Coliigan, Protein Science, supra, Chapters 12-14, all entirely incorporated herein by reference. IL-23P40 Ig DERIVED PROTEINS, FRAGMENTS AND/OR VARIANTS The isolated Ig derived proteins of the present invention comprise an Ig derived protein or specified portion or variant encoded by any one of the polynucleotides of the present invention, as discussed more fully herein, or any isolated or prepared Ig derived protein or specified portion or variant thereof. Preferably, the human Ig derived protein or antigen-binding fragment binds human IL-23p40 proteins or fragments and, thereby substantially neutralizes the biological activity of the protein. An Ig derived protein, or specified portion or variant thereof, that partially or preferably substantially neu tralizes at least one biological activity of at least one IL23p40 protein or fragment can bind the protem or fragment and thereby inhibit activities mediated through the binding of IL-23p40 to at least one lL-23p40 receptor or through other IL-23p40-dependent or mediated mechanisms. As used herein, the term "neutralizing Ig derived protein" refers to an Ig derived protein mat can inhibit human p40 or pl9 protem or fragment related-dependent activity by about 20-120%, preferably, by at least about 60,70,80,90,91,92,93,94,95,96,97,98,99,100% or more depending on the assay. The capacity of anti-human E^23p40 Ig derived protein or specified portion or variant to inhibit human BL-:'.3p40 related-dependent activity is preferably assessed by at least one suitable EL-23p40 Ig derived protein or protein assay, as described herein and/or as known in the art A human Ig derived prott an or specified portion or variant of the invention can be of any class (IgG, IgA, IgM, IgE, IgD, etc.) or isotype and can comprise a kappa or lambda light chain. In one embodiment, the human Ig derived protein or specified portion or variant comprises an IgG heavy chain or defined fragment, for example, at least one of isotypes, IgGl, IgG2, IgG3 or IgG4. Ig derived proteins of mis type can be prepared by emplo} ing a transgenic mouse or other trangenic non-human mammal comprising at least one human light chain (e.g., IgG, IgA and IgM (e.g., yl, Y2. Y3. Y4 transgenes as described herein and/oi as known in she art. In another embodiment, the anti-human IL-23p40 Ig derived protein or specified portion or variant thereof comprises an IgGl heavy chain and an IgGl Mght chain. At least one Ig derived protein or specified portion or variant of the invention binds at least one spmfied epitope specific to at least one IL-23p40 protein, subunit, fragment, portion or any combination thereof. The at least one epitope can comprise at least one Ig derived protein binding region that comprises at least one portion of said protein, which epitope is preferably comprised of at least one extracellular soluble, hydrophillic, external or cytoplasmic portion of said protein. As non- limiting examples, (a) a IL-23p40 Ig derived protein or specified portion or variant specifically binds at least one epitope comprising at least 1-3, to the entire amino acid sequence, selected from the group consisting of at least one p40 subunit of human IL-23. The at least one specified epitope can comprise any combination of at least one amino acid of the p40 subunit of a human interieukin-23, such as, but not limited to, 1,2,3,4,5,6,7,8,9,10,11,12,13 or 14 amino acids of at least one of, 1- 10,10-20, 20-30,30-40,40-50,50-60,60-70,70-80,80-90,90-100,100-110,110-120,120-130,130- 140,140 150,150-160,160-170,170-180,180-190,190-200,200-210,210-220,220-230,230-240, 240-250, 250-260, 260-270,280-290,290-300,300-306, 1-7,14-21,29-52, 56-73, 83-93,96-105, 156-175, 194-204,208-246,254-273,279-281, or 289-300 of SEQ ID NO:l. Generally, the human Ig derived protein or antigen-binding fragment of the present invention will comprise an antigen-binding region that comprises at least one human complementarity determining region (CDR1, CDR2 and CDR3) or variant of at least one heavy chain variable region and at least one human complementarity determining region (CDR1, CDR2 and CDR3) or variant of at least one light chain variable region. As a non-limiting example, the Ig derived protein or antigen- binding portion or variant can comprise at least one of the heavy chain CDR3, and/or a light chain CDR3. In a particular embodiment, the Ig derived protein or antigen-binding fragment can have an antigen-binding region that comprises at least a portion of at least one heavy chain CDR (i.e., CDR1, CDR2 and/or CDR3) having the amino acid sequence of the corresponding CDRs 1,2 and/or 3. In another particular embodiment, the Ig derived protein or antigen-binding portion or variant can have an antigen-binding region that comprises at least a portion of at least one light chain CDR (i.e., CDR1, GDR2 and/or CDR3) having the amino acid sequence of the corresponding CDRs 1,2 and/or 3. Such Ig derived proteins can be prepared by chemically joining together the various portions (e.g., CDRs, framework) of the Ig derived protein using conventional techniques, by preparing and expressing a (i.e., one or more) nucleic acid molecule that encodes the Ig derived protein using conventional techniques of recombinant DNA technology or by using any other suitable method. The anti-IL-23p40 Ig derived protein can comprise at least one of a heavy or light chain variable region having a defined amino acid sequence. For example, in a preferred embodiment, the ann-IL-23p40 Ig derived protein comprises at least one of at least one heavy chain variable region and/or at least one light chain variable region. Human Ig derived proteins that bind to human IL- 23p40 proteins; or fragments and that comprise a defined heavy or light chain variable region can be prepared using suitable methods, such as phage display (Katsube, Y., et al, bit J Mol. Med, 1(5):863- 868 (1998)) or mediods that employ transgenic animals, as known in the art and/or as described herein. For example, a transgenic mouse, comprising a functionally rearranged human immunoglobulin heavy chain transgene and a transgene comprising DNA from a human Immunoglobulin light chain locus that can undergo functional rearrangement, can be immunized with human IL-23p40 proteins or fragments thereof to elicit the production of Ig derived proteins. If dssired, the Ig derived protein producing cells can be isolated and hybridomas or other immortalized Ig; derived protein-producing cells can be prepared as described herein and/or as known in the art. Alternatively, the Ig derived protein, specified portion or variant can be expressed using the encoding nucleic acid or portion thereof in a suitable host cell. The invention also relates to Ig derived proteins, antigen-binding fragments, immunoglobulin chains and CDRs comprising amino acids in a sequence that is substantially the same as an amino acid sequence described herein. Preferably, such Ig derived proteins or antigen-binding fragments and Ig derived proteins comprising such chains or CDRs can bind human IL-23p40 proteins or fragments with high affinity (e.g., KD less man or equal to about 109 M). Amino acid sequences that are substantially the same as the sequences described herein include sequences comprising conservative amino acid substitutions, as well as amino acid deletions and/or insertions. A conservat ve amino acid substitution refers to the replacement of a first amino acid by a second amino acid that has chemical and/or physical properties (e.g., charge, structure, polarity, hydrophobicity/hydrophilicity) that are similar to those of the first amino acid. Conservative substitutions include replacement of one amino acid in a group by another within the same group as in the following groups: lysine (K), arginine (R) and histidine (H); aspartate (D) and glutamate (E); asparagine (N), glutamine (Q), serine (S), threonine (T), tyrosine (Y), K, R, H, D and E; alanine (A), valine (V), leucine (L), isoleucine (I), proline (P), phenylalanine (F), tryptophan (W), methionine (M), cysteine (C) and glycine (G); F, W and Y; C, S and T. Amino Acid Codes The amino acids that make up IL-23p40 Ig derived proteins or specified portions or variants of the present invention are often abbreviated. The amino acid designations can be indicated by designating the amino acid by its single letter code, its three letter code, name, or three nucleotide codon(s) as in well understood in the art (see Alberts, B., et al., Molecular Biology of The Cell, Third Ed., Garland Publishing, Inc., New York, 1994): An IL-23p40 Ig derived protein or specified portion or variant of the present invention can include one or more amino acid substitutions, deletions or additions, either from natural mutations or human manipulation, as specified herein. Of course, the number of amino acid substitutions a skilled artisan would make depends on many factors, including those described above. Generally speaking, the number of amino acid substitutions, insertions or deletions for any given IL-23p40 polypeptide will not be more than 40,30, 20,19,18,17, 16,15,14,13,12,11,10, 9,8,7,6,5,4,3,2,1, such as 1-30 or any range or value Therein, as specified herein. Amino acids in an IL-23p40 Ig derived protein or specified portion or variant of the present invention that are essential for function can be identified by methods known in the art, such as site- directed mutagenesis or alanine-scanning mutagenesis (e.g., Ausubel, supra, Chapters 8,15; Cunningham and Wells, Science 244:1081-1085 (1989)). The latter procedure introduces single alanine mutations at every residue in the molecule. The resulting mutant molecules are then tested for biological activity, such as, but not limited to, at least one IL-23p40 neutralizing activity. Sites that aie critical for Ig derived protein or specified portion or variant binding can also be identified by structural analysis, such as crystallization, nuclear magnetic resonance or photoaffinity labeling (Smith, et al., J. Mol. Biol. 224:899-904 (1992) and de Vos, et al., Science 255:306-312 (1992)). The Ig derived proteins or specified portions or variants of the present invention, or specified variants thereof, can comprise any number of contiguous amino acid residues from an Ig derived protein or specified portion or variant of the present invention, wherein mat number is selected from the group of integers consisting of from 10-100% of the number of contiguous residues in an EL-23p40 Ig derived pnrtein or specified portion or variant. Optionally, this subsequence of contiguous amino acids is at least ab)ur 10,20, 30,40,50,60,70, 80,90,100,110,120,130,140,150,160,170,180,190,200,210,220, 23(), 240,250 or more amino acids in length, or any range or value therein. Further, the number of such sut»sequences can be any integer selected from the group consisting of from 1 to 20, such as at least 2,3, 4, or 5. As those of skill will appreciate, the present invention includes at least one biologically active Ig derived protein or specified portion or variant of the present invention. Biologically active Ig derived pro: eins or specifi preferably at least 50%, 60%, or 70%, and most preferably at least 80%, 90%, or 95%-1000% of that of the native (non-synthetic), endogenous or related and known Ig derived protein or specified portion or variant Methods of assaying and quantifying measures of enzymatic activity and substrate specificity, are well known to those of skill in the art. In another aspect, the invention relates to human Ig derived proteins and antigen-binding fragments, as described herein, which are modified by the covalent attachment of an organic moiety. Such modification can produce an Ig derived protein or antigen-binding fragment with improved pharmacokinetic properties (e.g., increased in vivo serum half-life). The organic moiety can be a linear or branched hydrophilic polymeric group, fatty acid group, or fatty acid ester group. In particular embodiments, the hydrophilic polymeric group can have a molecular weight of about 800 to about 120,000 Daltons and can be a polyalkane glycol (e.g., polyethylene glycol (PEG), {olypropylene glycol (PPG)), carbohydrate polymer, amino acid polymer or polyvinyl pyrolidone, and the fatty acid or fatty acid ester group can comprise from about eight to about forty carbon atoms. The modified Ig derived proteins and antigen-binding fragments of the invention can comprise one or more organic moieties that are covalendy bonded, directly or indirectly, to the Ig derived protein or specified portion or variant. Each organic moiety that is bonded to an Ig derived protein or antigen-binding fragment of the invention can independently be a hydrophilic polymeric group, a fatty acid group or a fatty acid ester group. As used herein, the term "fatty acid" encompasses mono-carboxylic acids and di-carboxylic acids. A "hydrophilic polymeric group," as the term is used herein, refers to an organic polymer that is more soluble in water than in octane. For example, polylysine is more soluble in water than in octane. Thus, an Ig derived protein modified by the covalent attachment of polylysine is encompassed by the invention. Hydrophilic polymers suitable for modifying Ig derived proteins of the invention can be linear or branched and include, for example, polyalkane glycols (e.g., PEG, monomethoxy-polyethylene glycol (mPEG), PPG and the Iil.e), carbohydrates (e.g., dextran, cellulose, oligosaccharides, polysaccharides and the like), polymers of hydrophilic amino acids (e.g., polylysine, polyargmine, polyaspartate and the like), polyalkane oxides (e.g., polyethylene oxide, polypropylene oxide and the like) and polyvinyl pyrolidone. Preferably, the hydrophilic polymer that modifies the Ig derived protein of the invention has a molecular weight of about 800 to about 150,000 Daltons as a separate molecular entity. For example, PEG,ooo and PEG2o,ooo. wherein the subscript is the average molecular weight of the polymer in Daltons, can be used. The hydrophilic polymeric group can be substituted with one to about six alkyl, fatty acid or fati y acid ester groups. Hydrophilic polymers that are substituted with a fatty acid or fatty acid ester group can be prepared by employing suitable methods. For example, a polymer comprising an amine group can be coupled to a carboxylate of the fatty acid or fatty acid ester, and an activated carboxylate (e.j,., activated with N, N-carbonyl diimidazole) on a fatty acid or fatty acid ester can be coupled to a hyclroxyl group on a polymer. Fatty acids and fatty acid esters suitable for modifying Ig derived proteins of the invention can be saturated or can contain one or more units of uasaturation. Fatty acids that are suitable for modifying Ig derived proteins of the invention include, for example, n-dodecanoate (Clz, laurate), n- tetradecanoaie (C!4, myristate), n-octadecanoate (C„, stearate), n-eicosanoate (Qo, arachidate), n- docosanoate (C22, behenate), n-triacontanoate (C30), n-tetracontanoate (C«), c«-A9-octadecanoate (Cis, oleate), all cw-A5,8,ll,14-eicosatetraenoate (CM, arachidonate), octanedioic acid, tetradecanedioic acid, octadecanedioic acid, docosanedioic acid, and the like. Suitable fatty acid esters include mono-esters of dicarboxylic acids mat comprise a linear or branched lower alkyl group. The lower alkyl group can comprise from one to about twelve, preferably, one to about six, carbon atoms. The modified human Ig derived proteins and antigen-binding fragments can be prepared using suitable methods, such as by reaction with one or more modifying agents. A "modifying agent" as the 1 erm is used herein, refers to a suitable organic group (e.g., hydrophilic polymer, a fatty acid, a fatty acid ester) that comprises an activating group. An "activating group" is a chemical moiety or functional group that can, under appropriate conditions, react with a second chemical group thereby forming a covalent bond between (he modifying agent and the second chemical group. For example, a mine-reactive activating groups include electrophilic groups such as tosylate, mesylate, halo (chloro, bromo, fluoro, iodo), N-hydroxysuccinimidyl esters (NHS), and the like. Activating groups that can react with thiols include, for example, maleimide, iodoacetyl, acrylolyl, pyridyl disulfides, S-thiol-2- n tiobenzoic acid thiol (TNB-thiol), and the like. An aldehyde functional group can be coupled to amine- or hydrazide-containing molecules, and an azide group can react with a trivalent phosphorous gioup to form phosphoraraidate or phosphorimide linkages. Suitable methods to introduce activating groups into molecules are known in the art (see, for example, Hermanson, G. T., Bioconjugate Teclmiques, Academic Press: San Diego, CA (1996)). An activating group can be bonded directly to the; organic group (e.g., hydrophilic polymer, fatty acid, fatty acid ester), or through a linker moiety, for example, a divalent Ci-Cl2 group wherein one or more carbon atoms can be replaced by a h& eroatom such as oxygen, nitrogen or sulfur. Suitable linker moieties include, for example, let methylene glycol, -(CH2)r, -NH-tCH^-NH-, -(CH2)2NH- and -CHJ-O-CHJ-CHT-O-CHZ-CHZ-O- CH-NH-. Modifying agents that comprise a linker moiety can be produced, for example, by reacting a niono-Boc-alkyldiamine (e.g., mono-Boc-ethylenediamine, mono-Boc-diarninohexane) with a fatty acid in the presence of l-ethyI-3-(3-dimethylaminopropyl) carbodiimide (EDC) to form an amide borid between the free amine and the fatty acid carboxylate. The Boc protecting group can be removed from the product by treatment with trifluoroacetic acid (TFA) to expose a primary amine that can be coupled to another carboxylate as described, or can be reacted with maleic anhydride and the resu king product cyclized to produce an activated maleimido derivative of the fatty acid. (See, for example, Thompson, et al, WO 92/16221, the entire teachings of which are incorporated herein by reference.) The modified Ig derived proteins of the invention can be produced by reacting a human Ig derived protein or antigen-binding fragment with a modifying agent. For example, the organic moieties can be bonded to the Ig derived protein in a non-site specific manner by employing an amine-reactive modifying agent, for example, an NHS ester of PEG. Modified human Ig derived proteins or antigen-binding fragments can also be prepared by reducing disulfide bonds (e.g., intra- cliain disulfide bonds) of an Ig derived protein or antigen-binding fragment. The reduced Ig derived protein or antigen-binding fragment can then be reacted with a thiol-reactive modifying agent to produce the modified Ig derived protein of the invention. Modified human Ig derived proteins and antigen-binding fragments comprising an organic moiety that is bonded to specific sites of an Ig derived protein or specified portion or variant of the present invention can be prepared using suitable methods, such as reverse proteolysis (Fisch et al., Bioconjugate Chem., 3:147-153 (1992); Werlen et al.,Bioconjugate Chem., 5:411-417 (1994); Kumaran etal. Protein Set 6(10):2233-2241 (1997); Itoh et al, Bioorg. Chem., 24(1): 59-68 (1996); Capellas et al, Biotechnol Bioeng., 56(4):456-463 (1997)), and die methods described in Hermanson, G. T., Bioconjugate Techniques, Academic Press: San Diego, CA (1996). [L-23P40 IG DERIVED PROTEIN OR SPECIFIED PORTION OR VARIANT COMPOSITIONS The present invention also provides at least one EL-23p40 Ig derived protein or specified xirtion or variant composition comprising at least one, at least two, at least three, at least four, at least :!lve, at least six or more IL-23p40 Ig derived proteins or specified portions or variants thereof, as described herein and/or as known in the art that are provided in a non-naturally occurring composition, mixture or form. Such compositions comprise non-naturally occurring compositions comprising at least one or two full length, C- and/or N-terminally deleted variants, domains, fragments, or specified variants, of the IL-23p40 Ig derived protein amino acid sequence, or specified fragments, domains or variants thereof. Such composition percentages are by weight, volume, c oncentration, molarity, or molality as liquid or dry solutions, mixtures, suspension, emulsions or c olloids, as known in the art or as described herein. EL-23p40 Ig derived protein or specified portion or variant compositions of the present invention can further comprise at least one of any suitable auxiliary, such as, but not limited to, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant or the like. Phiirmaceutically acceptable auxiliaries are preferred. Non-limiting examples of, and methods of preparing such sterile solutions are well known in the art, such as, but limited to, Gennaro, Ed., Remington's Phartnaceutical Sciences, 18 Edition, Mack Publishing Co. (Easton, PA) 1990. Pharmaceutically acceptable carriers can be routinely selected that are suitable for the mode of administration, solubility and/or stability of the IL-23p40 composition as well known in the art or as described herein. Pharmaceutical excipients and additives useful in the present composition include, but are not limited to, proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including monosaccharides, di-, tri-, tetra-, and oligosaccharides; derivatized sugars, such as alditols, aldonic acids, esterified sugars and the like; and polysaccharides or sugar polymers), which can be present singly or in combination, comprising alone or in combination 1-99.99% by weight or volume. Exemplary protein excipients include serum albumin, such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Representative amino acid/Ig derived protein or specified portion or variant components, which can also function in a buffering capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like. One preferred amino acid is glycine. Carbohydrate excipients suitable for use in the invention include, for example, monosaccharides, such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; ^saccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitcl, lactitol, xylitol sorbitol (glucitol), myoinositol and the like. Preferred carbohydrate excipients for use in the present invention are mannitol, trehalose, and raffinose. IL-23p40 Ig derived protein compositions can also include a buffer or a pH adjusting agent; typically, the buffer is a salt prepared from an organic acid or base. Representative buffers include organic acid salts, such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; Tris, tromethamine hydrochloride, or phosphate buffers. ]'referred buffers for use in the present compositions are organic acid salts, such as citrate. Additionally, the IL-23p40 Ig derived protein or specified portion or variant compositions of the invention can include polymeric excipients/additives such as polyvinylpyrrolidones, ficolls (a polymeric sugar), dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl-P-cyclodextrin), polyethylene glycols, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic ugents, surfactants (e.g., polysorbates such as 'TWEEN 20" and 'TWEEN 80"), lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol), and chelating agents (e.g., EDTA). These and additional known pharmaceutical excipients and/or additives suitable for use in the IL-23p40 compositions according to the invention are known in the art, e.g., as listed in "Remington: The Science & Practice of Pharmacy", 19th ed., Williams & Williams, (1995), and in the "Physician's Desk Reference", 52nd ed.. Medical Economics, Montvale, NJ (1998), the disclosures of which are entirely incorporated herein by reference. Preferrred carrier or excipient materials are carbohydrates (is.g., saccharides and alditols) and buffers (e.g., citrate) or polymeric agents. Formulations As noted above, the invention provides for stable formulations, which preferably comprise a phosphate buffer with saline or a chosen salt, preserved solutions and formulations containing a preservative, as well as multi-use preserved formulations suitable for pharmaceutical or veterinary use, comprising at least one IL-23p40 Ig derived protein or specified portion or variant in a pharmaceutically acceptable formulation. Preserved formulations contain at least one known preservative or optionally selected from the group consisting of at least one phenol, m-cresol, p- cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkylparaben (methyl, ethyl, propyl, butyl and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, or mixtures thereof in an aqueous diluent Any suitable concentration or mixture can be used as known in the art, such as 0.001-5%, or any range or value therein, such as, but not limited to 0.001,0.003, 0.005, 0.009,0.01,0.02,0.03,0.05,0.09,0.1,0.2,0.3,0.4., 0.5, 0.6,0.7.0.8,0.9,1.0,1.1,1.2,1.3, 1.4,1.5,1.6,1.7,1.8,1.9,2.0,2.1,2.2,2.3,2.4,2.5,2.6, 2.7,2.8,2.9,3.0,3.1,3.2, 3.3,3.4,3.5, 3.6, 3.7,3.8, 3.9,4.0,4.3,4.5,4.6,4.7,4.8,4.9, or any range or value therein. Non-limiting examples include, no preservative, 0.1-2% m-cresol (e.g., 0.2,0.3.0.4,0.5,0.9,1.0%), 0.1-3% benzyl alcohol (e.g.. Oil, 0.9,1.1., 1.5,1.9,2.0,2.5%), 0.001-0.5% thimerosal (e.g., 0.005,0.01), 0.001-2.0% phenol (e.g., 0.05,0.25,0.28,0.5,0.9,1.0%), 0.0005-1.0% alkylparaben(s) (e.g., 0.00075,0.0009,0.001, 0.002,0.005,0.0075,0.009,0.01,0.02,0.05,0.075,0.09,0.1,0.2. 0.3,0.5,0.75,0.9,1.0%), and the like. As noted above, the invention provides an article of manufacture, comprising packaging material and at least one vial comprising a solution of at least one EL-23p40 Ig derived protein or specified portion or variant with me prescribed buffers and/or preservatives, optionally, in an aqueous diluent, wherein said packaging material comprises a label that indicates that such solution can be held over a period of 1,2,3,4,5,6,9,12,18,20,24,30,36,40,48,54,60,66,72 hours or greater. The invention further comprises an article of manufacture, comprising packaging material, a first vial comprising lyophilized at least one IL-23p40 Ig derived protein or specified portion or variant, and a second vial comprising an aqueous diluent of prescribed buffer or preservative, wherein said packaging material comprises a label that instructs a patient to reconstitute the at least one IL-23p40 Ig derived protein or specified portion or variant in the aqueous diluent to form a solution mat can be held over a period of twenty-four hours or greater. The at least one IL-23p40Ig derived protein or specified portion or variant used in accordance with the present invention can be produced by recombinant means, including from mammalian cell or transgenic preparations, or can be purified from other biological sources, as described herein or as known in the art. The range of at least one IL-23p40 Ig derived protein or specified portion or variant in the product of the present invention includes amounts yielding upon reconstitution, if in a wet/dry system, i concentrations from about 1.0 jtg/ml to about 1000 mg/ml, although lower and higher concentrations are operable and are dependent on the intended delivery vehicle, e.g., solution formulations will differ from transdermal patch, pulmonary, transmucosal, or osmotic or micro pump methods. Preferably, the aqueous diluent optionally further comprises a pharmaceutical] y acceptable preservative. Preferred preservatives include those selected from the group consisting of phenol, m- cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkylparaben (methyl, ethyl, propyl, butyl and the like), benzalkonium chloride, benzemonium chloride, sodium dehydroacetate and thimerosal, or mixtures thereof. The concentration of preservative used in the formulation is a concentration sufficient to yield an anti-microbial effect Such concentrations are dependent on the preservative selected and are readily determined by the skilled artisan. Other excipients, e.g., isotonicity agents, buffers, antioxidants, and preservative enhancers, can be optionally and preferably added to the diluent. An isotonicity agent, such as glycerin, is commonly used at known concentrations. A physiologically tolerated buffer is preferably added to provide improved pH control. The formulations can cover a wide range of pHs, such as from about pH 4 to about pH 10, and preferred ranges from about pH 5 to about pH 9, and a most preferred range of about 6.0 to about 8.0. Preferably, the formulations of the present invention have pH between about 6.8 and about 7.8. Preferred buffers include phosphate buffers, most preferably, sodium phosphate, particularly phosphate buffered saline (PBS). Other additives, such as a pharmaceutically acceptable solubilizers like Tween 20 (polyoxyethylene (20) sorbitan roonolaurate), Tween 40 (polyoxyethylene (20) sorbitan monopalmitate), Tween 80 (polyoxyethylene (20) sorbitan monooleate), Pluronic F68 (polyoxyethylene polyoxypropylene block copolymers), and PEG (polyethylene glycol) or non-ionic surfactants, such as polysorbate 20 or 80 or poloxamer 184 or 188, Pluronic® polyls, other block co- polymers, and chelators, such as EDTA and EGTA, can optionally be added to the formulations or compositions to reduce aggregation. These additives are particularly useful if a pump or plastic container is used to administer the formulation. The presence of pharmaceutically acceptable surfactant mitigates the propensity for the protein to aggregate. The formulations of the present invention can be prepared by a process which comprises mixing at least one EL-23p40 Ig derived protein or specified portion or variant and a preservative selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkylparaben, (methyl, ethyl, propyl, butyl and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal or mixtures thereof in an aqueous diluen t. Mixing tli e at least one IL-23p40 Ig derived protein or specified portion or variant and preservative in an aqueous diluent is carried out using conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, a measured amount of at least one IL- 23p40 Ig derived protein or specified portion or variant in buffered solution is combined with the desired preservative in a buffered solution in quantities sufficient to provide the protein and preservative at the desired concentrations. Variations of this process would be recognized by one of ordinary skill in the art. For example, the order the components are added, whether additional additives are used, the temperature and pH at which the formulation is prepared, are all factors that may be optimized for the concentration and means of administration used. The claimed formulations can be provided to patients as clear solutions or as dual vials comprising a vial of lyophilized (at least one) TL-23p40 Ig derived protein or specified portion or variant that is reconstituted with a second vial containing water, a preservative and/or excipients, preferably, a phosphate buffer and/or saline and a chosen salt, in an aqueous diluent Either a single solution vial or dual vial requiring reconstitution can be reused multiple times and can suffice for a single or multiple cycles of patient treatment and thus can provide a more convenient treatment regimen than currently available. The present claimed articles of manufacture are useful for administration over a period of immediately to twenty-four hours or greater. Accordingly, the presently claimed articles of manufacture offer significant advantages to the patient Formulations of the invention can optionally be safely stored at temperatures of from about 2°C to about 40°C and retain the biologically activity of the protein for extended periods of time, thus allowing a package label indicating that the solution can be held and/or used over a period of 6,12,18,24,36,48,72, or 96 hours or greater. If preserved diluent is used, such label can include use up to 1-12 months, one-half, one and a half, and/or two years. The solutions of at least one IL-23p40 Ig derived protein or specified portion or variant in the invention can be prepared by a process that comprises mixing at least one Ig derived protein or specified portion or variant in an aqueous diluent Mixing is carried out using conventional dissolution and mixing procedures. To prepare a suitable diluent, for example, a measured amount of at least one Ig; derived protein or specified portion or variant in water or buffer is combined in quantities sufficient to provide the protein and optionally a preservative or buffer at the desired concentrations. Variations of this process would be recognized by one of ordinary skill in the art. For example, the order the components are added, whether additional additives are used, the temperature and pH at which the formulation is prepared, are all factors that may be optimized for the concentration and means of administration used. The claimed products can be provided to patients as clear solutions or as dual vials comprising a vial of lyophilized (at least one) IL-23p40 Ig derived protein or specified portion or variant that is reconstituted with a second vial containing the aqueous diluent Either a single solution vial or dual vial requiring reconstitution can be reused multiple times and can suffice for a single or multiple cycles of patient treatment and thus provides a more convenient treatment regimen than currently available. The claimed products can be provided indirectly to patients by providing to pharmacies, clinics, or other such institutions and facilities, clear solutions or dual vials comprising a vial of lyophilized (at least one) IL-23p40 Ig derived protein or specified portion or variant that is reconstituted with a second vial containing the aqueous diluent. The clear solution in this case can be up to one liter or even larger in size, providing a large reservoir from which smaller portions of the at least one Ig derived protein or specified portion or variant solution can be retrieved one or multiple times for transfer into smaller vials and provided by the pharmacy or clinic to their customers and/or patients. Recognized devices comprising these single vial systems include those pen-injector devices for delivery of a solution such as BD Pens, BD Autojector. Humaject®'NovoPen, B-DPen, AutoPen®, and OptiPen®, GenotropinPen®, Genotronorm Pen, Huroatro Pen, Reco-Pen. Roferon Pen, Biojector. Iject, J-tip Needle-Free Injector®, Intraject®, Medi-Ject, e.g., as made or developed by Becton Dickenson (Franklin Lakes, NJ, www.bectondickenson.com), Disetronic (Burgdorf, Switzerland, www.disetronic.com; Bioject, Portland, Oregon (www.bioject.com); National Medical Products , Weston Medical (Peterborough, UK, www.weston-medical.com), Medi-Ject Corp (Minneapolis, MN, www.mediject.com). Recognized devices comprising a dual vial system include those pen-injector systems for reconstituting a lyophilized drug in a cartridge for delivery of the reconstituted solution, such as the HumatroPen. The products presently claimed include packaging material. The packaging material provides;, in addition to the information required by the regulatory agencies, the conditions under which the product can be used. The packaging material of the present invention provides instructions to the patient to reconstitute the at least one IL-23p40 Ig derived protein or specified portion or variant in the aqueous diluent to form a solution and to use the solution over a period of 2-24 hours or greater for the two vial, wet/dry, product For the single vial, solution product, the label indicates that such solution can be used over a period of 2-24 hours or greater. The presently claimed products are useful for human pharmaceutical product use. The formulations of the present invention can be prepared by a process mat comprises mixing at least one IL-23p40 Ig derived protein or specified portion or variant and a selected buffer, preferably, a phosphate buffer containing saline or a chosen salt Mixing the at least one Ig derived protein or specified portion or variant and buffer in an aqueous diluent is carried out using conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, a measured amount of at least one Ig derived protein or specified portion or variant in water or buffer is combined with the desired buffering agent in water in quantities sufficient to provide the protein and buffer at the desired concentrations. Variations of this process would be recognized by one of ordinary skill in the art. For example, the order the components are added, whether additional additives are used, the temperature and pH at which the formulation is prepared, are all factors that can be optimized for the concentration and means of administration used. The claimed stable or preserved formulations can be provided to patients as clear solutions or as dual vials comprising a vial of lyophilized at least one IL-23p40 Ig derived protein or specified portion or variant that is reconstituted with a second vial containing a preservative or buffer and excipients in an aqueous diluent. Either a single solution vial or dual vial requiring reconstitution can be reused multiple times and can suffice for a single or multiple cycles of patient treatment and thus provides a more convenient treatment regimen than currently available. At least one IL-23p40 Ig derived protein or specified portion or variant in either the stable or preserved formulations or solutions described herein, can be administered to a patient in accordance with the present invention via a variety of delivery methods including SC or EM injection; transdermal, pulmonary, transmucosal, implant, osmotic pump, cartridge, micro pump, or other means appreciated by the skilled artisan, as well-known in the art. Therapeutic Applications The present invention also provides a method for modulating 04 treating IL-23p40 conditions or diseases, in a cell, tissue, organ, animal, or patient including, but not limited to, at least one of rheumatoid arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, gastric ulcer, seronegative arthropathies, osteoarthritis, inflammatory bowel disease, ulcerative colitis, systemic lupus erythematosis, antiphospholipid syndrome, iridocyclitis/uveitis/optic neuritis, idiopathic pulmonary fibrosis, systemic vasculitis/wegener's granulomatosis, sarcoidosis, orchitis/vasectomy reversal procedures, allergic/atopic diseases, asthma, allergic rhinitis, eczema, allergic contact dermatitis, allergic conjunctivitis, hypersensitivity pneumonitis, transplants, organ transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis syndrome, gram positive sepsis, gram negative sepsis, culture negative sepsis, fungal sepsis, neutropenic fever, urosepsis, meningococcemia, trauma/hemorrhage, bums, ionizing radiation exposure, acute pancreatitis, adult respiratory distress syndrome, rheumatoid arthritis, alcohol-induced hepatitis, chronic inflammatory pathologies, sarcoidosis, Crohn's pathology, sickle cell anemia, diabetes, nephrosis, atopic diseases, hypersensitity reactions, allergic rhinitis, hay fever, perennial rhinitis, conjunctivitis, endometriosis, asthma, urticaria, systemic anaphalaxis, dermatitis, pernicious anemia, hemolytic disesease, thrombocytopenia, graft rejection of any organ or tissue, kidney translplant rejection, heart transplant rejection, liver transplant rejection, pancreas transplant rejection, lung transplant rejection, bone marrow transplant (BMT) rejection, skin allograft rejection, cartilage transplant rejection, bone graft rejection, small bowel transplant rejection, fetal thymus implant rejection, parathyroid transplant rejection, xenograft rejection of any organ or tissue, allograft rejection, anti-receptor hypersensitivity reactions, Graves disease, Raynoud's disease, type B insulin-resistant diabetes, asthma, myasthenia gravis, antibody-meditated cytotoxicity, type EI hypersensitivity reactions, systemic lupus erythematosus, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes syndrome, antiphospholipjd syndrome, pemphigus, scleroderma, mixed connective tissue disease, idiopathic Addison's disease, diabetes meJlitus, chronic active hepatitis, primary billiary cirrhosis, vitiligo, vasculitis, post-MI cardiotomy syndrome, type IV hypersensitivity, contact dermatitis, hypersensitivity pneumonitis, allograft rejection, granulomas due to intracellular organisms, drug sensitivity, metabolic/idiopathic, Wilson's disease, hemachromatosis, alpha-1-antitrypsin deficiency, diabetic retinopathy, hashirnoto's thyroiditis, osteoporosis, hypothalmic-pituitary-adrenal axis evaluation, primary biliary cirrhosis, thyroiditis, encephalomyelitis, cachexia, cystic fibrosis, neonatal chronic lung disease, chronic obstructive pulmonary disease (COPD), familial hematophagocytic lymphohistiocytosis, dermatologic conditions, psoriasis, alopecia, nephrotic syndrome, nephritis, glomerular nephritis, acute renal failure, hemodialysis, uremia, toxicity, preeclampsia, okt3 therapy, anti-cd3 therapy, cytokine therapy, chemotherapy, radiation therapy (e.g., including but not limited to, asthenia, anemia, cachexia, and the like), chronic salicylate intoxication, acute or chronic bacterial infection, acute and chronic parasitic or infectious processes, including bacterial, viral and fungal infections, HIV infection/HIV neuropathy, meningitis, hepatitis (e.g.. A, B or C, or the like), septic arthritis, peritonitis, pneumonia, epiglottitis, e. Coli 0157:h7, hemolytic uremic syndrome/mrombolytic thrombocytopenic purpura, malaria, dengue hemorrhagic fever, leishmaniasis, leprosy, toxic shock syndrome, streptococcal myositis, gas gangrene, mycobacterium tuberculosis, mycobacterium avium intracellulare, Pneumocystis carinii pneumonia, pelvic inflammatory disease, orchitis/epidydimitis, legioneUa, lyme disease, influenza a, epstein-barr virus, vital-associated hemaphagocytic syndrome, vital encephalitis/aseptic meningitis, neurodegenerative diseases, multiple sclerosis, migraine headache, AIDS dementia complex, demyelinating diseases, such as multiple sclerosis and acute transverse myelitis; extrapyramidal and cerebellar disorders, such as lesions of the corticospinal system; disorders of me basal ganglia or cerebellar disorders; hyperkinetic movement disorders, such as Huntington's Chorea and senile chorea; drug-induced movement disorders, such as those induced by drugs which block CNS dopamine receptors; hypokinetic movement disorders, such as Parkinson's disease; Progressive supranucleo Palsy; structural lesions of the cerebellum; spinocerebellar degenerations, such as spinal ataxia, Friedreich's ataxia, cerebellar cortical degenerations, multiple systems degenerations (Mencel, Dejerine-Thomas, Shi-Drager, and Machado-Joseph); systemic disorders (Refsum's disease, abetalipoprotemia, ataxia, telangiectasia, and mitochondrial multi-system disorder); demyelinating core disorders, such as multiple sclerosis, acute transverse myelitis; and disorders of the motor unit, such as neurogenic muscular atrophies (anterior horn cell degeneration, sur.h as amyotrophic lateral sclerosis, infantile spinal muscular atrophy and juvenile spinal muscular atrophy); Alzheimer's disease; Down's Syndrome in middle age; Diffuse Lewy body disease; Senile Dementia of Lewy body type; Wernicke-Korsakoff syndrome; chronic alcoholism; Creutrfeldt-Jakob disease; Subacute sclerosing panencephalitis, Hallerrprden-Spatz disease; and Dementia pugilistica, neurotrauniatic injury (e.g., but not limited to, spinal cord injury, brain injury, concussion, and repetitive concussion), pain, inflammatory pain, autism, depression, stroke, cognitive disorders, epilepsy, arid the like. Such a method can optionally comprise administering an effective amount of at least one composition or pharmaceutical composition comprising at least one IL-23p40 Ig derived protein or specified portion or variant to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy. Any method of the present invention can comprise administering an effective amount of a composition or pharmaceutical composition comprising at least one IL-23p40 Ig derived protein or specified portion or variant to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy. Such a method can optionally further comprise co-administration or c ombination therapy for treating such immune diseases, wherein the administering of said at least one IL-23p40 Ig derived protein, specified portion or variant thereof, further comprises administering, before concurrently, and/or after, at least one selected from at least one multiple sclerosis therapeutic (including but not limited to, beta-interferon la and beta-interferon lb (e.g., Avonex™, Rcbif™, Betaseon™), glutiramer acetate (e.g., Copaxone), cyclophasphamide, azathioprine, glucocorticosieroids, methotrexate, Paclitaxel, 2-chlorodeoxyadenosine, mitoxantrone, IL-10, TGBb, CM, CD52, antegren, CD11, CD18, TNFtdpha, IL-1, IL-2, and/or CD4 antibody or antibody receptor fusion, interferon alpha, immunoglobulin, Lismide (Requirumax™), insulin-like growth factor-1 fIGF-1), elprodil, pirfenidone, oral myelin, or compounds that act on one or more of at least one of: autoimmune suppression of myelin destruction, immune regulation, activation, proliferation, migration and/or suppressor cell function of T-cells, inhibition of T cell receptor/peptide/MHC-II i nteraction, Induction of T cell anergy, deletion of autoreactive T cells, reduction of trafficking across Wood brain barrier, alteration of balance of pro-inflammatory (Thl) and immunomodulatory (Th2) cytokines, inhibition of matrix metalloprotease inhibitors, neuroprotection, reduction of gliosis, promotion of re-myelination), TNF antagonist (e.g., but not limited to, a TNF Ig derived protein or fragment, a soluble TNF receptor or fragment, fusion proteins thereof, or a small molecule TNF antagonist), an antirheumatic, a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSABD), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an antimicrobial (e.g., aminoglycoside, an antifungal, an antiparasitic, an antiviral, a carbapenem, cephalosporin, a flurorquinolone, a macrolide, a penicillin, a sulfonamide, a tetracycline, another antimicrobial), an antipsoriatic, a corticosteriod, an anabolic steroid, an EL-23p40 agent, a mineral, a nutritional, a thyroid agent, a vitamin, a calcium related hormone, an antidiarrheal, an antitussive, an antiemetic, an antiulcer, a laxative, an anticoagulant, an erythropoietin (e.g., epoetin alpha), a filgrastim (e.g., G-CSF, Neupogen), a sargramostim (GM-CSF, Leukine), an immunization, an immunoglobulin, an immunosuppressive (e.g., basiliximab, cyclosporine, daclizumab), a growth hormone, a hormone replacement drug, an estrogen receptor modulator, a mydriatic, a cycloplegic, an allyJating agent, an antimetabolite, a mitotic inhibitor, a radiopharmaceutical, an antidepressant, an antimatiic agent, an antipsychotic, an anxiolytic, a hypnotic, a sympathomimetic, a stimulant, donepezil, tacrine, an asthma medication, a beta agonist, an inhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn, an epinephrine or analog, domase alpha (Pulmozyme), a cytokine or a cytokine antagonist. Suitable dosages are well known in the art. See, e.g., Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, CT (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, C'A (2000), each of which references are entirely incorporated herein by reference. TNF antagonists suitable for compositions, combination therapy, co-administration, devices and/or methods of the present invention (further comprising at least one antibody, specified portion and variant thereof, of the present invention), include, but are not limited to, anti-TNF Ig derived proteins, antigen-binding fragments thereof, and receptor molecules which bind specifically to TNF; compounds which prevent and/or inhibit TNF synthesis, TNF release or its action on target cells, such as thalidomide, tenidap, phosphodiesterase inhibitors (e.g., pentoxifylline and rolipram), A2b adenosine receptor agonists and A2b adenosine receptor enhancers; compounds which prevent and/or inhibit TNF receptor signalling, such as mitogen activated protein (MAP) kinase inhibitors; compounds which block and/or inhibit membrane TNF cleavage, such as metalloproteinase inhibitors; compounds which block and/or inhibit TNF activity, such as angiotensin converting enzyme (ACE) inhibitors (e.g., captopril); and compounds which block and/or inhibit TNF production and/or synthesis, such as MAP kinase inhibitors. As used herein, a "tumor necrosis factor Ig derived protein," "TNF Ig derived protein," "TNFoc Ig derived protein," or fragment and the like decreases, blocks, inhibits, abrogates or interferes with TNFa activity in vitro, in situ and/or preferably in vivo. For example, a suitable TNF human Ig derived protein of the present invention can bind TNFa and includes anti-TNF Ig derived proteins, antigen-binding fragments thereof, and specified mutants or domains thereof that bind specifically to TNFa. A suitable TNF antibody or fragment can also decrease block, abrogate, interfere, prevent and/or inhibit TNF RNA, DNA or protein synthesis, TNF release, TNF receptor signaling, membrane TNF cleavage, TNF activity, TNF production and/or synthesis. Chimeric Ig derived protein cA2 consists of. the antigen binding variable region of the high- affinity neutralizing mouse anti-human TNFa IgGl Ig derived protein, designated A2, and the constant regions of a human IgGl, kappa immunoglobulin. The human IgGl Fc region improves allogeneic Ig derived protein effector function, increases the circulating serum half-life and decreases the immunogenicity of the Ig derived protein. The avidity and epitope specificity of the chimeric Ig derived protein cA2 is derived from the variable region of the murine Ig derived protein A2. In a particular embodiment, a preferred source for nucleic acids encoding the variable region of the murine [g derived protein A2 is the A2 hybridoma cell line. Chimeric A2 (cA2) neutralizes the cytotoxic effect of both natural and recombinant human TNFα in a dose dependent manner. From binding assays of chimeric Ig derived protein cA2 and recombinant human TNFa, the affinity constant of chimeric Ig derived protein cA2 was calculated to be 1.04xl0^M-1. Preferred methods for determining monoclonal Ig derived protein specificity and affinity by competitive inhibition can be found in Harlow, et al, Ig derived proteins: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1988; Colligan etal., eds., Current Protocols in Immunology, Greene Publishing Assoc, and Wiley Interscience, New York, (1992-2003); Kozbor et ah, Immunol Today, 4:72-79 (1983); Ausubel et al, eds. Current Protocols in Molecular Biology, Wiley Interscience, New York (1987-2003); and Muller, Metlu Enzymol, 92:589-601 (1983), which references are entirely incorporated herein by reference. In a particular embodiment, murine monoclonal Ig derived protein A2 is produced by a cell line designated cl34A. Chimeric Ig derived protein cA2 is produced by a cell line designated cl68A. Additional examples of monoclonal anti-TNF Ig derived proteins mat can be used in me present invention are described in the art (see, e.g., U.S. Patent No. 5,231,024; Moller, A. et al., Cytokine 2(3):162-169 (1990); U.S. Application No. 07/943,852 (filed September 11,1992); Rathjen et al., International Publication No. WO 91/02078 (published February 21,1991); Rubin etal, EPO Patent Publication No. 0 218 868 (published April 22,1987); Yone et al., EPO Patent Publication No. 0 288 088 (October 26,1988); Liang, et al., Biochan. Biophys. Res. Comm. 757:847-854 (1986); Meager, etal.., Hybridoma 6:305-311 (1987); Fendly etal., Hybridoma 6:359-369 (1987); Bringman, etal, Hybridoma 6:489-507 (1987); and Hirai, etal., J. Immunol. Metfu 96:57-62 (1987), which references are entirely incorporated herein by reference). TNF Receptor Molecules Preferred TNF receptor molecules useful in the present invention are those that bind TNFa with high affinity (see, e.g., Feldmann etal.. International Publication No. WO 92/07076 (published April 30,1992); Schall et al, Cett 67:361-370 (1990); and Loetscher et al., CeU 61:351-359 (1990), which references are entirely incorporated herein by reference) and optionally possess low iramunogenicity. In particular, the 55 kDa (p55 TNF-R) and the 75 kDa (p75 TNF-R) TNF cell surface receptors are useful in the present invention. Truncated forms of these receptors, comprising the extracellular domains (BCD) of the receptors or functional portions thereof (see, e.g., Corcoran et al, Eur. J. Biochem. 225:831-840 (1994)), are also useful in the present invention. Truncated forms of the TNF receptors, comprising the ECD, have been detected in urine and serum as 30 kDa and 40 kDa TNFa inhibitory binding proteins (Engelmann, H. et al, J. Biol Client. 265:1531-1536 (1990)). TNF receptor mul timeric molecules and TNF immunoreceptor fusion molecules, and derivatives and fragments or portions thereof, are additional examples of TNF receptor molecules which are useful in the methods and compositions of the present invention. The TNF receptor molecules which can be used in the invention are characterized by their ability to treat patients for extended periods with good to excellent alleviation of symptoms and low toxicity. Low immunogenicity and/or high affinity, as well as other undefined properties, may contribute to the therapeutic results achieved. TNF receptor multimeric molecules useful in the present invention comprise all or a functional portion of the ECD of two or more TNF receptors linked via one or more polypeptide linkers or other nonpeptide linkers, such as polyethylene glycol (PEG). The multimeric molecules can further comprise a signal peptide of a secreted protein to direct expression of die multimeric molecule. These multimeric molecules and methods for their production have been described in U.S. Application No. 08/437,533 (filed May 9,1995), the contents of which are entirely incorporated herein by reference. TNF immunoreceptor fusion molecules useful in the methods and compositions of the present invention comprise at least one portion of one or more immunoglobulin molecules and all or a functional portion of one or more TNF receptors. These immunoreceptor fusion molecules can be assembled as monomers, or hetero- or homo-multimers. The immunoreceptor fusion molecules can also be monovalent or multivalent An example of such a TNF immunoreceptor fusion molecule is TNF receptor/IgG fusion protein. TNF immunoreceptor fusion molecules and methods for then- production have been described in the art (Lesslauer etal., Eur. J. Immunol 27:2883-2886 (1991); Ashkenazd etal., Proc. Nad. Acad. Set USA 58:10535-10539 (1991); Peppel etal., J. Exp. Med. 174:1483-1489 (1991); Rolls etal., Proc. Natl. Acad Set. USA 97:215-219 (1994); Butler etal., Cytokine 6(6):616-623 (1994); Baker et al., Eur. J. Immunol 24:2040-2048 (1994); Beutler et al., U S. Patent No. 5,447,851; and U.S. Application No. 08/442,133 (filed May 16,1995), each of which references are entirely incorporated herein by reference). Methods for producing immunoreceptor fusion molecules can also be found in Capon et al., US. Patent No. 5,116,964; Capon et al, U.S. Patent No. 5,225,538; and Capon et al.. Nature 337:525-531 (1989), which references are entirely incorporated herein by reference. A functional equivalent, derivative, fragment or region of TNF receptor molecule refers to the portion of the TNF receptor molecule, or the portion of the TNF receptor molecule sequence which encodes TNF receptor molecule, that is of sufficient size and sequences to functionally resemble TNF receptor molecules that can be used in the present invention (e.g., bind TNFa with high affinity and I>ossess low immunogenicity). A functional equivalent of TNF receptor molecule also includes modified TNF receptor molecules that functionally resemble TNF receptor molecules that can be used ; n the present invention (e.g., bind TNFa with high affinity and possess low immunogenicity). For (sxample, a functional equivalent of TNF receptor molecule can contain a "SILENT" codon or one or more amino acid substitutions, deletions or additions (e.g., substitution of one acidic amino acid for iinother acidic amino acid; or substitution of one codon encoding the same or different hydrophobic amino acid for another codon encoding a hydrophobic amino acid). See Ausubel et al.. Current Protocols in Molecular Biology\ Greene Publishing Assoc, and Wiley-Interscience, New York (1987- 2003). Cytokines include any known cytokine. See, e.g., CopewithCytokines.com. Cytokine antagonists include, but are not limited to, any Ig derived protein, fragment or mimetic, any soluble receptor, fragment or mimetic, any small molecule antagonist, or any combination thereof. Therapeutic Treatments. Any method of the present invention can comprise a method for treating an BL-23p40 mediated disorder, comprising administering an effective amount of a composition or pharmaceutical composition comprising at least one !L-23p40 Ig derived protein or specified portion or variant to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy. Typically, treatment of pathologic conditions is effected by administering an effective amount or dosage of at bast one IL-23p40 Ig related protein composition diat total, on average, a range from at least about 0.01 to 500 milligrams of at least one IL-23p40 Ig derived protein or specified portion or variant /kilogram of patient per dose, and, preferably, from at least about 0.1 to 100 milligrams Ig derived protein or specified portion or variant/kilogram of patient per single or multiple administration, depending upon the specific activity of the Ig protein contained in the composition. Alternatively, the effective serum concentration can comprise 0.1-5000 Mg/ml serum concentration per single or multiple adminstration. Suitable dosages are known to medical practitioners and will, of course, depend upon the particular disease state, specific activity of die composition being administered, and the particular patient undergoing treatment. In some instances, to achieve the desired therapeutic amount, it can be necessary ro provide for repeated administration, ie., repeated individual administrations of a particular monitored or metered dose, where the individual administrations are repeated until the desired daily dose or effect is achieved. Preferred doses can optionally include 0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1,2,3,4,5,6,7,8, 9,10,11,12,13,14,15,16,17,18,19,20,21, 22,23,24,25,26,27,28,29,30,31,32,33,34,35, 36, 37, 38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,62,63,64,65, 66, 67,68,69,70,71,72,73,74,75,76,77,78,79,80, 81,82,83,84,85, 86,87,88,89,90,91.92,93, 94, 95,96,97,98,99 and/or 100 mg/kg/administration, or any range, value or fraction thereof, or to achieve a serum concentration of 0.1,0.5,0.9,1.0,1.1,1.2,1.5,1.9,2.0, 2.5,2.9,3.0,3.5,3.9,4.0,4.5, 4.9,5.0,55,5.9. 6.0,6.5,6.9,7.0,7.5,7.9,8.0,8.5,8.9,9.0,9.5,9.9,10,10.5,10.9,11,11.5,11.9,20, i::.5,12.9,13.0, 13.5,13.9,14.0,14.5,4.9,5.0,5.5., 5.9,6.0,6.5,6.9,7.0,7.5,7.9,8.0,8.5,8.9,9.0,9.5, 9.5,10,10.5,10.9,11,11.5,11.9,12,12.5,12.9,13.0,13.5,13.9,14,14.5,15,15.5,15.9,16,16.5,16.9, 17, 17.5,17.9,18,18.5,18.9,19,19.5,19.9,20,20.5,20.9, 21,22,23, 24,25,26,27, 28,29,30,35,40, 45,50,55,60, 65,70,75,80, 85,90,96,100,200, 300,400,500,600,700, 800,900,1000,1500,2000, 2500,3000,3500,4000,4500, and/or 5000 μg/ml serum concentration per single or multiple administration, or any range, value or fraction thereof. Alternatively, the dosage administered can vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; age, health, and weight of the recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired. Usually, a dosage of active ingredient can be about 0.1 to 100 milligrams per kilogram of body weight. Ordinarily, 0.1 to 50, and preferably 0.1 to 10 milligrams per kilogram per administration or in sustained release form is effective to obtain desired results. As a non-limiting example, treatment of humans or animals can be provided as a one-time or periodic dosage of at least one Ig derived protein or specified portion or variant of the present invention 0.1 to 100 mg/kg, such as 0.5,0.9,1.0,1.1,1.5,2,3,4,5,6,7,8,9,10,11,12,13,14,15, 16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,40,45,50,60,70,80,90 or 100 mg/kg, per day, on at least one of day 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21, 22,23, 24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39, or 40, or, alternatively or additionally, at ieast one of week 1,2, 3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25, 26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49.50,51, or 52, or, alternatively or additionally, at least one of 1,2,3,4,5,6„ 7, 8, 9,10,11,12,13,14,15,16, 17,18,19, or 20 years, or any combination thereof, using single, infusion or repeated doses. Dosage forms (composition) suitable for internal administration generally contain from about 0.1 milligram to about 500 milligrams of active ingredient per unit or container. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.5-99.999% by weight based on the total weight of the composition. For parenteral administration, the Ig derived protein or specified portion or variant can be formulated as a solution, suspension, emulsion or lyophilized powder in association, or separately provided, with a pharmaceutically acceptable parenteral vehicle. Examples of such vehicles are water, saline, Ringer's solution, dextrose solution, and 1-10% human serum albumin. Liposomes and nonaqueous vehicles, such as fixed oils, may also be used. The vehicle or lyophilized powder may contain additives that maintain isotonicity (e.g., sodium chloride, mannitol) and chemical stability (e.g., buffers and preservatives). The formulation is sterilized by known or suitable techniques. Suitable pharmaceutical carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field. Alternative Administration Many known and developed modes of can be used according to the present invention for administering pharmaceuu'cally effective amounts of at least one IL-23p40 Ig derived protein or specified portion or variant according to the present invention. While pulmonary administration is used in the following description, other modes of administration can be used according to me present invention with suitable results. IL-23p40 Ig derived proteins of the present invention can be delivered in a carrier, as a solution, emulsion, colloid, or suspension, or as a dry powder, using any of a variety of devices and methods suitable for administration by inhalation or other modes described here within or known in the art. Parenteral Formulations and Administration Formulations for parenteral administration can contain as common excipients sterile water or saline, polyalkylene glycols, such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like. Aqueous or oily suspensions for injection can be prepared by using an appropriate emulsifier or humidifier and a suspending agent, according to known mediods. Agents for injection can be non-toxic, non-orally administrable diluting agents, such as an aqueous solution or a sterile injectable solution or suspension in a solvent. As the usable vehicle or solvent, water, Ringer's solution, isotonic saline, etc. are allowed; as an ordinary solvent, or suspending solvent, sterile involatile oil can be used. For these purposes, any kind of in volatile oil and fatty acid can be used, including natural or synthetic or semisynthetic fatty oils or fatty acids; natural or synthetic or semisynthtetic mono- or di- or tri-glycerides. Parental administration is known in the art and includes, tut is not limited to, conventional means of injections, a gas pressured needle-less injection device as described in U.S. Pat. No. 5,851,198, and a laser perforator device as described in U.S. Pat No. 5 839,446 entirely incorporated herein by reference. Alternative Delivery The invention further relates to the administration of at least one IL-23p40 Ig derived protein or specified portion or variant by parenteral, subcutaneous, intramuscular, intravenous, bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermal means. An anti-IL-23p40 Ig derived protein or spiiafied portion or variant composition can be prepared for use for parenteral (subcutaneous, intramuscular or intravenous) administration, particularly in the form of liquid solutions or suspensions; for use in vaginal or rectal administration particularly in semisolid forms, such as creams and suppositories; for buccal, or sublingual administration, particularly in the form of tablets or capsules; or intranasally, particularly in the form of powders, nasal drops or aerosols or certain agents; or transdermally, particularly in the form of a gel, ointment, lotion, suspension or patch delivery sysrem with chemical enhancers, such as dimethyl sulfoxide, to either modify the skin structure or to increase the drug concentration in the transdermal patch (Junginger, et al. In "Drug Permeation Enhancement"; Hsieh, D. S., Eds., pp. 59-90 (Marcel Dekker, Inc. New York 1994, entirely incorporated herein by reference), or with oxidizing agents that enable the application of formulations containing proteins and peptides onto the skin (WO 98/53847), or applications of electric fields to create transient transport pathways such as electroporation, or to increase the mobility of charged drugs through the skin such as iontophoresis, or application of ultrasound, such as sonophoresis (U.S. Pat. Nos. 4,309,989 and 4,767,402) (the above publications and patents being entirely incorporated herein by reference). Pulmonary/Nasal Administration For pulmonary administration, preferably, at least one IL-23p40 Ig derived protein or specified portion or variant composition is delivered in a particle size effective for reaching the lower airways of the lung or sinuses. According to the invention, at least one EL-23p40 Ig derived protein or specified portion or variant can be delivered by any of a variety of inhalation or nasal devices known in the art for administration of a therapeutic agent by inhalation. These devices capable of depositing acrosolized formulations in the sinus cavity or alveoli of a patient include metered dose inhalers, nebulizers, dry powder generators, sprayers, and the like. Other devices suitable for directing the pulmonary or nasal administration of Ig derived protein or specified portion or variants are also known in the art. All such devices can use formulations suitable for the administration for the dispensing of Ig derived protein or specified portion or variant in an aerosol. Such aerosols can be comprised of either solutions (both aqueous and non aqueous) or solid particles. Metered dose inhalers, like the Ventolin® metered dose inhaler, typically use a propellent gas and require actuation during inspiration (See, e.g., WO 94/16970, WO 98/35888). Dry powder inhalers like Turbuhaler™ (Astra), Rotahaler (Glaxo), Diskus* (Glaxo), Spiros™ inhaler (Dura), devices marketed by Inhale Therapeutics, and the Spinhaler* powder inhaler (Fisons), use bream-actuation of a mixed powder (US 4668218 Astra, EP 237507 Astra, WO 97/25086 Glaxo, WO 94/08552 Dura, US 5458135 Inhale, WO 94/06498 Fisons, entirely incorporated herein by reference). Nebulizers, like AERx™ Aradigm, the Ultravent* nebulizer (Mallinckrodt), and the Acorn II® nebulizer (Marquest Medical Products) (US 5404871 Aradigm, WO 97/22376), the above references entirely incorporated herein by reference, produce aerosols from solutions, while metered dose inhalers, dry powder inhalers, etc. generate small particle aerosols. These specific examples of commercially available inhalation devices are intended to be representative of specific devices suitable for the practice of mis invention, and are not intended as limiting the scope of the invention. Preferably, a composition comprising at least one IL-23p40 Ig derived protein or specified portion or variant is delivered by a dry powder inhaler or a sprayer. There are several desirable features of an inhalation device for administering at least one Ig derived protein or specified portion or variant of the present invention. For example, delivery by the inhalation device is advantageously reliable, reproducible, and accurate. The inhalation device can optionally deliver small dry particles, e.g., less than about 10 μm, preferably, about 1-5 μm, for good respirability. Administration of IL-23p40 Ig derived protein or specified portion or variant Compositions as a Spray A spray including IL-23p40 Ig derived protein or specified portion or variant composition protein can be produced by forcing a suspension or solution of at least one IL-23p40 Ig derived protein or specified portion or variant through a nozzle under pressure. The nozzle size and configuration, the applied pressure, and die liquid feed rate can be chosen to achieve the desired output and particle size. An electrospray can be produced, for example, by an electric field in connection with a capillary or nozzle feed. Advantageously, particles of at least one IL-23p40 Ig derived protein or specified portion or variant composition protein delivered by a sprayer have a particle size less than about 10 uxn, preferably, in the range of about 1 μm to about 5 μm, and, most preferably, about 2 μm to about 3 urn. Formulations of at least one IL-23p40 Ig derived protein or specified portion or variant composition protein suitable for use with a sprayer typically include Ig derived protein or specified portion or variant composition protein in an aqueous solution at a concentration of about 0.1 mg to about 100 mg of at least one IL-23p40 Ig derived protein or specified portion or variant composition protein per ml of solution or mg/gm, or any range or value therein, e.g., but not united to, 0.1,0.2., 0.3,0.4,0.5, 0.6,0.7,0.8,0.9,1, 2,3,4, 5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20, 21, 22, 23,24,25,26, 27,28,29,30,40,45,50,60,70,80,90 or 100 mg/ml or mg/gm The formulation can include agents; such as an excipient, a buffer, an isotonicity agent, a preservative, a surfactant, and, preferably, zinc. The formulation can also include an excipient or agent for stabilization of the Ig derived protein or specified portion or variant composition protein, such as a buffer, a reducing agent, a bulk protein, or a carbohydrate. Bulk proteins useful in formulating Ig derived protein or specified portion or variant composition proteins include albumin, prolamine, or die like. Typical carbohydrates useful in formulating Ig derived protein or specified portion or variant composition proteins include sucrose, mannitol, lactose, trehalose, glucose, or the like. The Ig derived protein or specified portion or variant composition protein formulation can also include a surfactant, which can reduce or prevent surface-induced aggregation of the Ig derived protein or specified portion or variant composition protein caused by atomization of the solution in forming an aerosol. Various conventional surfactants can be employed, such as polyoxyemylene fatty acid esters and alcohols, and polyoxyethylone sorbitol fatty acid esters. Amounts will generally range between 0.001 and 14% by weight of the formulation. Especially preferred surfactants for purposes of this invention are polyoxyethylene sorbitan monooleate, polysorbate 80, polysorbate 20, or the like. Additional agents known in the art for formulation of a protein such as IL-23p40 Ig derived proteins, or specified portions or variants, can also be included in die formulation. Administration of EL-23p40 Ig derived protein or specified portion or variant compositions by a Nebulizer Ig derived protein or specified portion or variant composition protein can be administered by a nebulizer, such as a jet nebulizer or an ultrasonic nebulizer. Typically, in a jet nebulizer, a compressed air source is used to create a high-velocity air jet through an orifice. As the gas expands beyond the nozzle, a low-pressure region is created, which draws a solution of Ig derived protein or specified portion or variant composition protein through a capillary tube connected to a liquid reservoir. The liquid stream from the capillary tube is sheared into unstable filaments and droplets as it exits the tube, creating the aerosol. A range of configurations, flow rates, and baffle types can be employed to achieve the desired performance characteristics from a given jet nebulizer. In an ultrasonic nebulizer, high-frequency electrical energy is used to create vibrational, mechanical energy, typically employing a piezoelectric transducer. This energy is transmitted to the formulation of Ig derived protein or specified portion or variant composition protein either directly or through a coupling fluid, creating an aerosol including the Ig derived protein or specified portion or variant composition protein. Advantageously, particles of Ig derived protein or specified portion or variant composition protein delivered by a nebulizer have a particle size less than about 10 \xm, preferably, in the range of about 1 μrn to about S μm, and, most preferably, about 2 μm to about 3 urn. Formulations of at least one IL-23p40 Ig derived protein or specified portion or variant suitable for use with a nebulizer, either jet or ultrasonic, typically include a concentration of about 0.1 mg to about 100 mg of at least one IL-23p40 Ig derived protein or specified portion or variant protein per ml of solution. The formulation can include agents, such as an excipient, a buffer, an isotonicity agent, a preservative, a surfactant, and, preferably, zinc. The formulation can also include an excipient or agent for stabilization of the at least one IL-23p40 Ig derived protein or specified portion or variant composition protein, such as a buffer, a reducing agent, a bulk protein, or a carbohydrate. Bulk proteins useful in formulating at least one EL-23p40 Ig derived protein or specified portion or variant composition proteins include albumin, protamine, or the like. Typical carbohydrates useful in formulating at least one EL-23p40 Ig derived protein or specified portion or variant include sucrose, mannitol, lactose, trehalose, glucose, or the like. The at least one IL23p40 Ig derived protein or specified portion or variant formulation can also include a surfactant, which can reduce or prevent surface-induced aggregation of the at least one IL-23p40 Ig derived protein or specified portion or variant caused by atomization of the solution in forming an aerosol. Various conventional surfactants can be employed, such as polyoxyethylene fatty acid esters and alcohols, and polyoxyethylene sorbital fatty acid esters. Amounts will generally range between 0.001 and 49b by weight of the formulation. Especially preferred surfactants for purposes of this invention are polyoxyethylene soibitan mono- oleate, polysorbate 80, polysorbate 20, or the like. Additional agents known in the art for formulation of a protein, such as Ig derived protein or specified portion or variant protein, can also be included in the formulation. Administration of IL-23p40 Ig derived protein or specified portion or variant compositions By A Metered Dose Inhaler In a metered dose inhaler (MDI), a propellant, at least one IL-23p40 Ig derived protein or specified portion or variant, and any excipients or other additives are contained in a canister as a mixture including a liquefied compressed gas. Actuation of the metering valve releases the mixture as an aerosol, preferably, containing particles in the size range of less than about 10 μm, preferably, about 1 μm to about 5μm, and, most preferably, about 2 um to about 3 fun. The desired aerosol particle size can be obtained by employing a formulation of Ig derived protein or specified portion or variant composition protein produced by various methods known to those of skill in the art, including jet-milling, spray drying, critical point condensation, or the like. Preferred metered dose inhalers include those manufactured by 3M or Glaxo and employing a hydrofluorocarbon propellant Formulations of at least one EL-23p40 Ig derived protein or specified portion or variant for use with a metered-dose inhaler device will generally include a finely divided powder containing at least one IL-23p40 Ig derived protein or specified portion or variant as a suspension in a non-aqueous medium, for example, suspended in a propellant with the aid of a surfactant. The propellant can be any conventional material employed for this purpose, such as chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane, dichlorodifluorornethane, dichlorotetrafluoroethanol and 1,1,1,2-tetrafluoroethane, HFA-134a (hydrofluroalkane-134a), HFA-227 (hydrofluroalkane-227), or the like. Preferably, the propellant is a hydrofluorocarbon. The surfactant can be chosen to stabilize the at least one IL-23p40 Ig derived protein or specified portion or variant as a suspension in the propellant, to protect the active agent against chemical degradation, and the like. Suitable surfactants include soibitan trioleate, soya lecithin, oleic acid, or the like. In some cases, solution aerosols are preferred using solvents, such as ethanol. Additional agents known in the art for formulation of a protein can also be included in the formulation. One of ordinary skill in the art will recognize that the methods of the current invention can be achieved by pulmonary administration of at least one -IL23p40 Ig derived protein or specified portion or variant compositions via devices not described herein. Oral Formulations and Administration Formulations for oral administration rely on the co-administration of adjuvants (e.g., resorcinols and nonionic surfactants, such as polyoxyethylene oleyl ether and n- hexadecyl polyethylene ether) to increase artificially the permeability of the intestinal walls, as well as the co-administration of enzymatic inhibitors (e.g., pancreatic trypsin inhibitors, diisopropylfluorophosphate (DFF) and trasylol) to inhibit enzymatic degradation. The active constituent compound of the solid-type dosage form for oral administration can be mixed with at least one additive, including sucrose, lactose, cellulose, mannitol, trehalose, raffinose, maltitol, dextran, starches, agar, arginates, chitins, chitosans, pectins, gum tragacanth, gum arabic, gelatin, coUagen, casein, albumin, synthetic or semisynthetic polymer, and glyceride. These dosage forms can also contain other type(s) of additives, e.g., inactive diluting agent, lubricant, such as magnesium stearate, paraben, preserving agent, such as sorbic acid, ascorbic acid, .alpha-tocopherol, antioxidant, such as cysteine, disintegrator, binder, thickener, buffering agent, sweetening agent, flavoring agent, perfuming agent, etc. Tablets and pills can be further processed into enteric-coated preparations. The liquid preparations for oral administration include emulsion, syrup, elixir, suspension and solution preparations allowable for medical use. These preparations may contain inactive diluting agents ordinarily used in said field, e.g., water. liposomes have also been described as drug delivery systems for insulin and heparin (U.S. Pat. No. 4,239,754). More recently, microspheres of artificial polymers of mixed amino acids (proteinoids) have been used to deliver pharmaceuticals (U.S. Pat. No. 4,925,673). Furthermore, carrier compounds described in U.S. Pat No. 5,879,681 and UJS. Pat. No. 5,5,871,753 are used to deliver biologically active agents orally are known in the art Mucosal Formulations and Administration For absorption through mucosal surfaces, compositions and methods of administering at least one IL-23p40 Ig derived protein or specified portion or variant include an emulsion comprising a plurality of submicron particles, a mucoadhesive macromolecule, abioactive peptide, and an aqueous continuous phase, which promotes absorption through mucosal surfaces by achieving mucoadhesion of the emulsion particles (U.S. Pat. Nos. 5,514,670). Mucous surfaces suitable for application of the emulsions of the present invention can include corneal, conjunctival, buccal, sublingual, nasal, vaginal, pulmonary, stomachic, intestinal, and rectal routes of administration. Formulations for vaginal or rectal administration, e.g., suppositories, can contain as excipients, for example, polyalkyleneglycols, vaseline, cocoa butter, and the like. Formulations for intranasal administration can be solid and contain as excipients, for example, lactose or can be aqueous or oily solutions of nasal drops. For buccal administration excipients include sugars, calcium stearate, magnesium stearate, pregelinatined starch, and the like (U.S. Pat. Nos. 5,849,695). Transdermal Formulations and Administration For transdermal administration, die at least one IL-23p40 Ig derived protein or specified portion or variant is encapsulated in a delivery device, such as a liposome or polymeric nanopardcles, microparticle, microcapsule, or microspheres (referred to collectively as microparticles unless otherwise stated). A number of suitable devices are known, including microparticles made of synthetic polymers, such as polyhydroxy acids, such as polylactic acid, polyglycolic acid and copolymers thereof, polyorthoesters, polyanhydrides, and polyphosphazenes, and natural polymers, such as collagen, polyamino acids, albumin and other proteins, alginate and other polysaccharides, and combinations thereof (U.S. Pat. Nos. 5,814,599). Prolonged Administration and Formulations It can be sometimes desirable to deliver the compounds of the present invention to the subject over prolonged periods of time, for example, for periods of one week to one year from a single administration. Various slow release, depot or implant dosage forms can be utilized. For example, a dosage form can contain a pharmaceutically acceptable non-toxic salt of the compounds mat has a low degree of solubility in body fluids, for example, (a) an acid addition salt with a polybasic acid, such as phosphoric acid, sulfuric acid, citric acid, tartaric acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene mono- or di-sulfonic acids, polygalacturonic acid, and the like; (b) a salt with a polyvalent metal cation such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium and the like, or with an organic cation formed from e.g., N.N'- dibenzyl-eth) lenediamine or ethylenediamine; or (c) combinations of (a) and (b) e.g., a zinc tannate salt. Additionally, the compounds of die present invention or, preferably, a relatively insoluble salt such as those just described, can be formulated in a gel, for example, an aluminum monostearate gel with, e.g. sesame oil, suitable for injection. Particularly preferred salts are zinc salts, zinc tannate salts, pamoate salts, and the like. Another type of slow release depot formulation for injection would contain the compound or salt dispersed for encapsulated in a slow degrading, non-toxic, non-antigenic polymer, such as a polylactic acid/polyglycolic acid polymer, for example, as described in U.S. Pat. No 3,773,919. The compounds or, preferably, relatively insoluble salts such as those described above can also be formulated in cholesterol matrix silastic pellets, particularly for use in animals. Additional slow release, depot or implant formulations, e.g., gas or liquid liposomes are known in the literature (U.S. Pat. Nos. 5.770,222 and "Sustained and Controlled Release Drug Delivery Systems", J. R. Robinson ed.. Marcel Dekker, Inc., N.Y., 1978). Having generally described the invention, the same will be more readily understood by reference to the following examples, which are provided by way of illustration and are not intended as limiting. Examples of the Invention Example 1: Generation, Clothing and Expression of an anti-IL-23p40 hummoglobulin derived protein i Mammalian Cells Anti-IL-23p40 Ig derived proteins am generated using known method such as murine or transgenic mice expressing human antibodies that are immunized with human IL-23, and for which B cells are isolated, cloned and selected for specificity and inhibtting activity for IL-23 (preferably with little or no inhibition of IL-12 activity) using known methods and assays, e.g as known in the art and references to IL-23 proteins, IL-23 assays and IL-12 assays, entirely incorporaledhentn by reference, as as known in me art). Alternatively, portions of the IL-12 betal receptor are cloned and fused with antibody fragments to generate receptor fusion proteins mat Mode bindmg of 11^23 to h^ receptors but which do not inhibit binding of IL-I2 to its receptors, as known in me art Clones expressing IL-23p40 specific antibodies or fusion proteins, such as anti-IL-23p40Ig derived proteins of me present invention, are selected so tb^ they neutralires or inhibft at least one lL- 23 activity and which do not substantially inhibit at least one IL-12 activity. The heavy chain, light chain CDRs, variable regkms, or variabk and constant regions are cloned and pot into appropriate expression vectors. A typical mammahan expression vector contains at least one promoter element, which mediates the fadtiation of tnmscrintion of mRNA, the Ig derived protein or specified portion or variant coding sequence, and signals required for me termination of transcription and polyadenyiation of the transcript Additional elements include enhancers, Kozak sequences and intervening seqoenoes flanked by donor and acceptor sites for RNAspticing. Highly effcient trancription can be achieved with early and late promotes from SV40,the long terminal repeats (LTRS) from Retroviruses, e.g, RSV, HTLVL HTVI and the early promoter of the cytomegalovirus (CMV). However, cellular elements can also be used (eg., the human actin promoter). Suitable expression vectors for use in practicing the present invention include, for example, vectors, such as pIRESlneo, pRetro-Off, pRetro-On, PLXSN, or pLNCX (clonetech Labs, Palo Alto, CA), pcDNA3.1 (+/-), pcDNA/Zeo (4/-) or pcDNA3.1/Hygro (4/-) (invitrogen), PSVL and PMSG (Pharmacia, Uppsala, Sweden), pRSVcat (ATCC 371S2), pSV2dhfir (ATOC 37146) and pBC12MI(ATCC 67109). Mammalian host cells that could be used include human Hela 293, H9 and Jurkat cells, mouse NIH3T3 and C127 ceDs, Cos 1, Cos 7 and CV 1, quail QC1-3 cells, mouse L cells and Chinese hamster ovary (CHO) cells. Alternatively, the gene can be expressed in stable cell lines that contain ate gene integrated into a chromosome. The co-transfection with a selectable marker, such as dhfir, gpt, neomycin, or hygromycin, allows die identification and isolation of the transfected cells. The transfocted gene can also be amplified to express large amounts of the encoded Ig derived protein or specified portion or variant The DHFR (dihydrofolate reductase) marker is useful to develop cell lines that carry several hundred or even several thousand copies of the gene of interest. Another useful selection marker is the enzyme glutamine synthase (GS) (Murphy, et al., Biochem. J. 227:277-279 (1991); Bebbington, et al., Bio/Technology 10:1(59-175 (1992)). Using these markers, the mammalian cells are grown in selective medium and me cells with the highest resistance are selected. These cell lines contain the amplified gene(s) integrated into a chromosome. Chinese hamster ovary (CHO) and NSO cells are often used for the production of Ig derived protein or specified portion or variants. Cloning and Expression in CHO Cells The vector pC4 is used for the expression of IL-23p40 Ig derived protein or specified portion or variant Plasmid pC4 is a derivative of the plasmid pSV2-dhfr (ATCC Accession No. 37146). The plasmid contains me mouse DHFR gene under control of die SV40 early promoter. Chinese hamster ovary- or other cells lacking dihydrofolate activity that are transfected with these plasmids can be selected by growing the cells in a selective medium (e.g., alpha minus MEM, Life Technologies, Gaimersburg, MD) supplemented with me chemotherapeutic agent methotrexate. The amplification of the DHFR genes in cells resistant to methotrexate (MTX) has been well documented (see, e.g., F. W. Alt, et al.. J. Biol. Chem. 253:1357-1370 (1978); J. L. Hamlin and C. Ma, Biochem. et Biophys. Acta 1097:107-143 (1990); and M. J. Page and M. A. Sydenham, Biotechnology 9:64-68 (1991)). Cells grown in increasing concentrations of MTX develop resistance to the drug by overproducing die target enzyme:, DHFR, as a result of amplification of the DHFR gene. If a second gene is linked to the DHFR gene, it is usually co-amplified and over-expressed. It is known in the art that mis approach can be used to develop cell lines carrying more man 1,000 copies of the amplified gene(s). Subsequently, when the methotrexate is withdrawn, cell lines are obtained mat contain the amplified gene integrated into one or more chromosome(s) of the host cell. The plasmid pC4 (and also pCl) contains for expressing die gene of interest the strong promoter of the long terminal repeat (LTR) of the Rous Sarcoma Virus (Cullen, et al., Molec. Cell. Biol. 5:438-447 (1985)) plus a fragment isolated from the enhancer of the immediate early gene of human cytomegalovirus (CMV) (Boshart, et al., Cell 41:521-530 (1985)). Downstream of the promoter are BamHL Xbal, and Asp718 restriction enzyme cleavage sites that allow integration of the genes; the multiple cloning sites facilitate cloning of the gene of interest Behind these cloning sites, the plasmid contains the 3' intron and polyadenylation site and termination signal of the rat preproinsulin gene. Other high efficiency promoters can also be used for the expression, e.g., the human b-actin promoter, the SV40 early or late promoters or the long terminal repeats from other retroviruses, e.g., HTV and HTLVI. Clontech's Tet-Off and Tet-On gene expression systems and similar systems can be used to express the IL-23p40 in a regulated way in mammalian cells (M. Gossen, and H. Bujard, Proc. Nad. Acad. Sci. USA 89:5547-5551 (1992)). For the polyadenylation of the mRNA, other signals, e.g., from die human growth hormone or globin genes, can be used as well. Stable cell lines carrying a gene of interest integrated into the chromosomes can also be selected upon co-transfection with a selectable marker, such as gpt, G418 or hygromycin. It is advantageous to use moie than one selectable marker in the beginning, e.g., G418 plus methotrexate. The plasmid pC4 is digested with restriction enzymes and then dephosphorylated using calf intestinal phosphatase by procedures known in the art The vector is then isolated from a.1% agarose gel. The DNA sequence encoding the complete IL-23p40 Ig derived protein or specified portion or variant i s used, corresponding to HC and LC variable regions of an IL-23p40 Ig derived protein of the present invention, according to known method steps. Isolated nucleic acid encoding a suitable human constant region (i.e., HC and LC regions) is also used in this construct (e.g., as provided in vector pl351). The' isolated variable and constant region encoding DNA and the dephosphorylated vector are then ligated with T4 DNA ligase. E. coli HB101 or XL-1 Blue cells are then transformed and bacteria are identified that contain the fragment inserted into plasmid pC4 using, for instance, restriction enzyme analysis. Chinese hamster ovary (CHO) cells lacking an active DHFR gene are used for transfection. 5 ug of the expression plasmid pC4 is cotransfected with 0 .5 fig of the plasmid pSV2-neo using lipofectin. The plasmid pSV2neo contains a dominant selectable marker, the neo gene from Tn5 encoding an enzyme mat confers resistance to a group of antibiotics including G418. The cells are seeded in alpha minus MEM supplemented with 1 ug /ml G418. After 2 days, the cells are trypsinized and seeded in hybridoma cloning plates (Greiner, Germany) in alpha minus MEM supplemented with 10,25, or 50 ng/ml of methotrexate plus 1 ug /ml G418. After about 10-14 days, single clones are trypsinized and then seeded in 6-well petri dishes or 10 ml flasks using different concentrations of methotrexate (50 nM, 100 nM, 200 nM, 400 nM, 800 nM). Clones growing at the highest concentrations of methotrexate are then transferred to new 6-well plates containing even higher concentrations of methotrexate (1 mM, 2 mM, 5 mM, 10 mM, 20 mM). The same procedure is repeated until clones are obtained that grow at a concentration of 100 - 200 mM. Expression of the desired gene product is analyzed, for instance, by SDS-PAGE and Western blot or by reverse phase HPLC analysis. The completely human anti-IL-23p40 protein Ig derived proteins are further characterized. Several of generated Ig derived proteins are expected to have affinity constants between 1x10* and 11012. Such high affinities of these fully human monoclonal Ig derived proteins make mem suitable for therapeutic applications in IL-23p40 protein-dependent diseases, pathologies or related conditions. Example 2: Comparison of the therapeutic efficacy of auti-IL-12p35 and anti-IL-12/23p40 antibodies in murine experimental autoimmune encephalomyelitis (EAE) Summary: This set of studies was performed to investigate the therapeutic efficacy of IH2 or IL-12/23 specific neutralization in a mouse model for multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Neutralizing rat anti-mouse monoclonal antibodies (mAbs) specific for the p35 subunit of IL-12 or the p40 subunit, that is shared between IL-12 and IL-23, were administered either prior to disease induction, prior to disease onset, or after disease was ongoing. In all cases, only anti-p40 antibody demonstrated therapeutic potential. These data suggest that JL-23 is the predominant contributor to disease pathogenesis in this autoimmune model. Abbreviations: EL Interleukin mAb Monoclonal antibody EAE Experimental autoimmune encephalomyelitis Th T helper cell IFNy Interferon gamma cs Clinical score MBP Myelin basic protein PK Pharmacokinetics Introduction: Biologically active IL-12 exists as a heterodimer comprised of 2 covalently linked subunits of 35 (p35) and 40 (p40) kilo Daltons. Several lines of evidence have demonstrated that IL-12 can induce robust Thl immune responses that are characterized by production of JJFNy md IL~2 from CD4+ T cells. Inappropriate Thl responses, and thus IL-12 expression, are believed to correlate with many immune-mediated inflammatory diseases, such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, insulin-dependent diabetes mellitus, and uveitis. In animal models, IL-12 neutralization was shown to ameliorate an autoimmune disease. However, these studies neutralized IL-12 through its p40 subunit The description of IL-23, a heterodimeric cytokine that shares the p40 subunit, made it important to determine whether previous findings were due to IL- 12 or IL-23 activity. Therefore, the p35 and p40 specific neutralization were compared in a mouse model of autoimmunity, experimental autoimmune encephalomyelitis (EAE). Neutralizing antibodies specific for EL-12p35 had no effect on EAE progression. In contrast, neutralization of both IL-12 and H.-23 with an anti-p40 mAb suppressed clinical signs of EAE whether antibody was administered before or after Thl differentiation. Our data suggests that the activity of anti-p40 treatment in EAE is based solely on neutralization of IL-23. Methods and Materials: Mice: Female C3H/HEB/FEJ mice (Jackson Laboratories, Bar Harbor, ME) were used in pharmacokinetic analyses. For EAE studies, female B10.PL (H-2") mice were obtained from the Jackson Laboratories, and were used between 6-8 weeks of age. All animals were maintained according to IACUC guidelines under approved protocols. Antibodies: C17.8 (rat anti-mouse IL-12/23p40, IgG2a), and C18.2 (rat and mouse IL-12p35, IgG2a) hybridomas were provided by Dr. Giorgio Trinehieri and the Wistar Institute (Philadelphia, PA). Ascites was generated at Harlan Byproducts (Indianapolis, IN) and purified by protein G affinity. Serum PK of rat anti-mouse antibodies: Female C3H/HEB/FEJ mice, approximately 20-25 grams, were individually weighed and treated with a single 5 mg/kg intraperitoneal dose of 12SI labeled antibody (C17.8, C18.2), with a constant dose volume/mouse of 10 mL/kg. Retro-orbital bleeds were taken from anesthetized mice at 30 minutes, 6 and 24 hours, 4, 7, 11 and 18 days. Blood samples were allowed to stand at room temperature for at least 30 minutes, but no longer than 1 hour, and were men centrifuged at approximately 2,300-3,500 rpm for 10-15 minutes. Approximately 50 uL aliquots of each serum sample were counted for 12SI using a LKB Compugamma 1282 counter (Wallac, Gaithersburg, MD). 10 mL aliquots of the injectates were also counted. The average fraction of injected counts at each time point was calculated and multiplied by the total mg of antibody injected to determine the total nig remaining in the serum at each time point Data is shown as the mean mg of mAb in the sera +/- s.d. with 5-10 animals in each group. EAR Induction and Scoring: For EAE induction, female B10.PL mice were injected subcutaneously over four sites on the back with a total of 100 \|il of CFA (containing 200 Mg Mycobacterium tuberculosis Jamaica strain) combined with 200 (ig guinea pig-MBP (Sigma). Mice also received 200 ng pertussis toxin (List Biological, Campbell, CA) i.p. in 0.2 ml PBS at the time of immunization and 48 hours later. Mice received i.p. injections of C17.8 (anti-IL-12p40) or C18.2 (anti-IL-12p35) monoclonal antibodies diluted to 100 mg/kg (C18.2) or 20 mg/kg (C17.8) in PBS, on indicated days. Control mice received PBS or Rat IgG (Biosource) at 20 mg/kg in PBS. Animals that demonstrated clinical signs (cs) were scored as follows: limp tail or waddling gait with tail tonicity 1, waddling gait with limp tail (ataxia) 2, ataxia with partial limb paralysis 2.5, full paralysis of one limb 3, full paralysis of one limb with partial paralysis of second limb 3.5, full paralysis of two limbs 4, moribund 4.5, death 5. Animals that scored a 5 were not included in the mean daily cs analysis for the rest of the experiment Daily cs are averaged for the group, and mean incidence, day of onset, highest acute cs, cumulative cs, cs/day, number of relapses and relapse severity ± sem are described. Mean cumulative cs per group was calculated by averaging the sum of daily clinical scores for individual animals. Cs/day was calculated by dividing the cumulative cs by die number of days the animal remained in the study. To determine the mean day of onset, animals not developing EAE were not included in the analysis. To determine the mean highest cs, mice not developing EAE were assigned a value of "0" and included in the analysis. Relapses were defined by .ii full point drop in clinical score sustained for at least 2 observed days followed by a full point increase in clin ical score sustained for at least 2 observed days. Results and Discussion: Anti-p35 and Anti-p40 antibodies have identical pharmacokinetics To establish the clearance rates of anti-p40 and anti-p35 antibodies, normal mice were injected with a single 5 mg/kg dose of 125I labeled antibodies and circulating levels were measured for 11 days post antibody administration. Anti-p35 and anti-p40 had overlapping pharmacokinetics, demonstrating that clearance rates are identical in normal mice (2). The expected clearance rate of each mAb is approximately 7-10 days. Although this is a single dose PK study, these data support once weekly dosing for in vivo studies. Only anti-p40 treatment prior to EAE induction is protective. To determine the relative roles of IL-12 and 1L-23 in an autoimmune disease, a murine model for multiple sclerosis, relapsing experimental autoimmune encephalomyelitis (EAE), was used. Upon EAE induction with myelin basic protein (MBP) in adjuvant, B10.PL mice typically exhibit an initial episode of paralysis (acute disease), then recover either partially or completely and progress through multiple relapses and/or chronic EAR It has long been assumed that EAE is dependent upon IL-12 expression since IL-12 is believed to be a primary mediator of ThO to Thl differentiation. However, to distinguish the potential role of IL-23 in EAE induction, neutralizing concentrations of anti-p40 (IL-12 and IL-23) or anti-p35 (IL-12 only) antibodies were established one day prior to immunization for EAE (Day -1). Onset of disease can vary between animals; therefore, treatment was repeated 7 and 14 days later to ensure that anti-p35 and IL-p40 antibodies were present during Thl differentiation. Several in vitro neutralization studies have demonstrated that the anti-40 mAb is 5 times more effective in neutralizing IL-12 than the anti-p35 mAb (data not shown). Therefore, the dose of anti-p35 mAb was adjusted to be 5 fold higher than anti-p40 in all EAE experiments. In two separate experiments, mice treated with Rat IgG isotype control antibody (20 mg/kg) or anti-p35 (100 mg/kg) did not demonstrate protection from disease. It is important to note that peripheral administration of a non-specific control antibody (Rat IgG) did not alter the clinical course of disease when compared to non-treated mice with EAE. In both studies, mice treated with anti-p40 mAb (20 mg/kg) exhibited nearly complete inhibition of EAE clinical signs. Remarkably, suppression of disease extended beyond the expected rate of antibody clearance through 70 days post EAE induction. In each experiment, only one animal treated with anti-p40 exhibited two consecutive days of EAE clinical signs, and each demonstrated a late onset and significantly lower acute clinical scores, cumulative clinical scores, and no relapses in disease (Table 1). These results demonstrated that neutralisation of EL-12 and EL-23 through the shared p40 subunit provided nearly complete protection from EAE. In contrast, specific neutralization of IL-12 only via anti-p35 was ineffective. These data strongly suggest that EAE is not mediated by EL-12. Only and-p40 treatment just prior to disease onset is protective. Although prophylactic treatment completely protected mice from EAE, it remained to be determined if EL-12 specific neutralization would be protective once the Thl population was established in vivo. Therefore, in a separate set of experiments, mice were treated with either a control antibody (Rat IgG), anti-p35, or anti-p40 monoclonal antibodies ten days after EAE induction, but prior to disease onset. Since typical immune responses occur within 7 days, this time point should be effective to reflect the effects of anti-IL-12 or anti-IL-23 mAbs on differentiated Thl cells. EAE onset can vary between animals; therefore, treatment was repeated 7 and 14 days later to ensure that anti-p35 and anti-p40 antibodies were present during the onset of disease. In two separate experiments, mice treated with isotype control antibody (20 mg/kg) or anti-p35 (100 mg/kg) were not protected from disease, when compared to untreated EAE mice. However, mice treated with anti-p40 mAb (20 mg/kg) were significantly protected from EAE. As shown in the previously described studies, disease suppression was observed well beyond the time required for clearance of peripherally administered antibody through day 70 post EAE induction. Considering that antibody was not administered until after Thl differentiation (day 10), it was not surprising that disease incidence, day of onset, and the highest clinical score during acute EAE were not different in any group (Table 2). However, in both experiments, mice receiving anti-p40 exhibited significandy lower cumulative clinical scores, clinical scores per day, and relapse severity. Only anti-p40 treatment durinE established EAE is protective. The most difficult, but clinically relevant, hurdle for any therapy is to suppress established disease. Therefore, another set of experiments was performed in which mice were immunized for EAE, then divided into treatment groups once disease was ongoing. Approximately 30 days post BAE induction, mice had progressed through the acute phase of disease. At this time, animals were divided into groups with comparable cumulative and daily clinical scores. Treatment was repeated 7 and 14 days later to ensure that antibodies were available in neutralizing concentrations during the iransition from acute to chronic or remitting-relapsing disease. Only anti-p40 treatment (20 mg/kg) ameliorated disease when compared to either isotype control antibody (20 mg/kg) or anti-p35 (100 mg/kg) treated animals. Disease suppression was observed through day 80 post EAE induction. In I roth experiments, analysis from the first day of treatment through day 80 demonstrated that mice receiving anti-p40 exhibited lower cumulative clinical scores, clinical scores per day, and the least highest clinical score post treatment. These data suggest that not only is IL-23 likely to mediate Thl differentiation (Table 1) and EAE induction (Table 2), but IL-23 also contributes to the effector phase of chronic autoimmune responses (Table 3). Therefore, anti-p40 treatment can offer therapy at any lime in the progression of autoimmune disease. Mice were divided into 3 treatment groups with comparable disease severity once EAE was established (approximately day 30). Clinical scores were analyzed from the first day of treatment through 80 days post EAE induction. Data is shown as the mean per group ± s.e.m. Conclusions The understanding of the role of IL-12 in immune function has been based on studies of the {40 subunit of EL-12. Therefore, a side-by-side comparison of neutralization of the IL-12 specific p35 subunit versus, the p40 subunit shared between IL-12 and IL-23 in an animal model of autoimmune disease was conducted. Neutralization via anti-p40 significantly inhibited EAE when mAb was administered at any time point However, IL-12 specific neutralization was completely ineffective. Therefore, our data shows that IL-12 only partially contributes to this autoimmune model and mat IL- '.'3 is expected be the more prominent mediator of autoimmune T cell responses. Example 3: IL-23 mediates experimental autoimmune encephalomyelitis Materials and Methods Animals: Female C3Heb/FeJ and B10.PL mice (Jackson Laboratories, Bar Harbor, ME) and female C :5 7BL/6 mice (Charles River Laboratories, Raleigh NC) between 6-8 weeks of age were used and maintained according to IACUC guidelines under approved protocols. Antibodies Rat monoclonal antibodies to mouse IL-23 were developed at Centocor (Malvern, PA). Negative rat IgG (from Biosource, Camarillo, CA) was used as a control. Neutralizing rat anti-mouse p40 (C17.8), and rat anti-mouse IL-12 (C18.2) antibodies were provided by Dr. Giorgio Trmchieri and the Wistar Institute (Philadelphia, PA). Ascites was generated at Harlan Bioproducts (Indianapolis, IN) and antibodies were purified by protein G affinity chromatography. Cytokines Recombinant murine IL-12 was obtained from R&D Systems (Minneapolis, MN). Recombinant hlFN-y and human IL-2 were obtained from Peprotech (Rocky Hill, NJ). Murine IL-23 was generated using transient transfection technology and Immobilized Metal Affinity Chromatography (IMAC). Briefly, separate expression constructs for murine p40 and murine pl9-His were co-transfeeted into HEK 293E cells using Lipofectamine 2000 (Invitrogen, Carlsbad, CA) as suggested by the manufacturers instructions. Alternatively, a linked IL-23 construct was generated as described and transfection of HEK293E cells was performed. Twenty-fours hours post-transfection, the growth medium was replaced with serum-free 293 SPMII (Invitrogen) and left to condition for 5 days, The media was then removed, centrifuged, and processed by IMAC using TALON resin (BD Biosciences, Palo Alto, CA). His-tagged proteins were eluted with 150 mM EDTA, then dialyzed against PBS, concentrated, filtered, and stored at -80°C. Bioactivity of both co-transfected and linked IL-23 was verified by splenocyte IL-17 protein production as described below. EL -12and IL-23 ELISA Murine IL-12 and murine IL-23 (1 ug/ml) were coated overnight on Nunc Maxisorp plates in PBS. After the plates were washed and blocked, rat anti-mouse p40, rat anti-mouse EL-12, and rat anti-mouse IL-23 antibodies were titrated and allowed to bind for 2 hours. Bound protein was detected using 1:10,000 HRP-conjugated goat anti-rat IgG antibody (from Jackson Immuno Research, West Grove, PA) followed by substrate. Data is shown as the mean optical density of replicate wells. IL-12 Neutralization Non- adherent human peripheral blood mononuclear cells (PBMC) were cultured for four days with 5 μg/ml PHA (Lectin, Phaseolus vulgaris, Sigma, St. Louis, MO) in complete RPMM640 (Invitrogen) with 10% heat-inactivated fetal bovine serum (JRH, Lenexa, KS), 1% L-glutamine (JRH), 100 Units/ml penicillin and 100 μg/ml streptomycin (Invitrogen). Cells were harvested, washed, then cultured with rhIL-2 (10 units/ml) in the presence of murine IL-12 (1 ng/ml) either alone or pre-incubated with tested antibodies for 22 hours. Supematants were analyzed for human XFNy protein levels by luminescence immunoassay using anti-IFNy antibodies generated at Centocor. IL-23 Neutralization Single cell suspensions were prepared from spleens of C57BL/6 mice. 2xl06 cells/ml were cultured in complete RPMI with 10 U/ml rhIL-2 (Peprotech) and 1 ng/ml mouse IL-23, either alone or pre-incubated with tested antibodies for 3 days. Supematants were collected and analyzed for IL-17 protein by ELIS A (R&D Systems) per the manufacturer's instructions. EAE Analysis Female B10.PL mice were injected s.c. over four sites on the back with a total of 100 ul of complete Freunds adjuvant (CFA) combined with 200 μg guinea pig-myelin basic protein (MBP) (Sigma). Mice also received 200 ng pertussis toxin (List Biological, Campbell, CA) i.p. in 0.2 ml PBS at die time of immunization and 48 hours later. Mice received i.p. injections of anti-p40, anti-EL- 12, or anti-IL-23 monoclonal antibodies diluted to 100 mg/kg (anti-IL-12), 20 mg/kg (anti-p40, anti- IL-23), or 50 mg/kg (anti-IL-23) in PBS, on indicated days. Control mice were either not treated or received Rat IgG (Biosource, Camarillo, CA) at 20 mg/kg in PBS. Animals that demonstrated clinical signs (cs) were scored as follows: limp tail or waddling gait with tail tonicity 1, waddling gait with limp tail (ataxia) 2, ataxia with partial limb paralysis 2.5, full paralysis of one limb 3, full paralysis of one limb with partial paralysis of second limb 3.5, full paralysis of two limbs 4, moribund 4.5, death 5. Scores for animals that were sacrificed or scored a 5 were not included in the mean daily cs analysis for the rest of the experiment. Daily cs are averaged for the group, and incidence, mortality, day of onset, highest acute cs, cumulative cs, cs/day, number of relapses and relapse severity ± sem are described. Mean cumulative cs per group was calculated by averaging the sum of daily clinical scores for individual animals. Cs/day was calculated by dividing the cumulative cs by the number of days the animal remained in the study. To determine the mean day of onset, animals not developing EAE were not included in the analysis. To determine the mean highest icute cs, mice that never developed EAE were assigned a value of "0" and included in the group mean. Relapses were defined by a full point drop in clinical score sustained for at least 2 observed days followed by a full point increase in clinical score sustained for at least 2 observed days. r To determine the mean number of relapses per group, mice not demonstrating a defined relapse were assigned a value of "0" and included in the group mean. To determine the mean relapse severity, the highest clinical score of each relapse event was averaged and animals mat did not relapse were not included in the analysis. For ex vivo EAE analysis, spleens and peripheral lymph nodes (inguinal, axillary, brachial, and cervical) were harvested from each animal on days 10,17, 24, or 32 post EAE induction. Single cell suspensions (5 x lOVwell) were prepared from individual animals, washed twice, men cultured in vitro in RPMI complete for 72 hours with 40 μg/ml MBP, 5 μg/ml ConA, or media alone and proliferation was measured using ATPLite (Perkin Elmer, Boston, MA). Data is represented as a stimulation index, which is the mean proliferation to MBP divided by the mean proliferation to media alone. Splenocytes and lymph node cells were also cultured at 4 x 106 cells/ml with 40 μg/ml MBP or media alone for 48 hours and supernatants were tested for IFNy, IL-17, EL-4, IL-5, and IL-10 proteins by ELISA, according to the manufacturer instructions (R&D Systems). Even though minimal cytokine levels were detected in media-only cultures, those values were subtracted from the levels found in MBP-stimulated cultures so that the data presented represents only antigen-specific cytokine production. For histopathologic examination and ranking, mouse brains and spinal columns were fixed in 10% buffered formalin by emersion. After fixation, the brains were sliced coronally into 4 segments. Spinal columns were decalcified in 5% EDTA and men sliced sagitally into 5 segments. The tissues were processed and embedded in paraffin using routine methods. Tissue blocks were sectioned at 5 jim, and stained with hematoxylin and eosin (H&E) or Luxol Blue-Cresyl Echt Violet (Poly Scientific, Bay Shore, NT). Additional sections were stained immunohistochemically for glial fibrillary acidic protein (GFAP) (BioGenex, San Ramon, CA). Sections were blinded and ranked based on the extent of inflammation. Brains and spinal cords were analyzed separately. Results IL-23 specific neutralization ameliorates EAE To confirm that neutralization of only IL-23 will provide effective therapy for EAE, monoclonal antibodies to mouse IL-23 were generated. As shown in Figure 1A, an antibody specific for mouse IL-23 that demonstrated no reactivity with mouse TL-12 was identified. Subsequent studies have shown that the anti-EL-12 and anti-EL-23 antibodies do not cross react even when 100 ng/ml of the opposite cytokine is present. As shown in Figure IB, the anti-EL-23 specific antibody binds to the p40 subunit of IL-23 and does not bind to the pl9 subunit. Accordingly, it is EL-23p40 specific. Since it was recently shown mat IL-23 will induce EL-17 production, these antibodies were tested for their ability to neutralize IL-23 bioactivity. As shown in Figure 1C, the EL-23 specific antibody inhibits IL-17 production with similar potency as anti-p40. In contrast, the anti-EL-12 antibody demonstrated no effect on EL-17 levels. Lastly, to confirm that the anti-EL-23 antibody does not interfere with IL-12 function, the antibodies' ability to inhibit IFNY production in T cell cultures was tested. As previously demonstrated, anti-IL-12 and anti-p40 inhibited IFNY production, however, the anti-EL 23 antibody had no effect on IFNy levels (Figure ID). Therefore, a neutralizing anti- mouse IL-23 antibody that does not bind EL-12 or inhibit IL-12 mediated responses has been developed. The anti-IL-23 and anti-p40 antibodies were compared for w v/'w inhibition of EAE. In two separate experiments, mice were treated with either a control antibody, anti-p40, or anti-IL-23 ten days after EAE induction, which is prior to disease onset. Mice treated with anti-IL-23 demonstrated clinical suppression of EAE comparable to that of anti-p40 treated animals (Figure IE). Mice receiving anti-p40 or anti-IL-23 exhibited a later day of onset, reduced severity of acute disease and subsequent relapses, and lower clinical scores per day (Table 4). These results confirm that IL-23, rather than IL-12, is responsible for EAE even in mice that have not been genetically manipulated. EL-23 neutralization prevents EAE pomology in the CNS EAE. presents as an ascending bind limb paralysis and is therefore scored for severity by deficits in motor function. However, the cause of mis impairment can only be observed by assessing pathology within the brain and spinal cord. Therefore, a separate study was performed in which mice were immunized for EAE, then treated with control Rat IgG, anti-IL-12, anti-p40, or anti-IL-23 antibodies on days 10 and 17, and sacrificed on days 17 and 24 by cardiac perfusion. Brains and spinal cords were analyzed for cellular infiltration by H&E and demyelination by Luxol Fast Blue. Sections were blinded and ranked from least to most severe, then correlated to the clinical score of the animal on the day of sacrifice. As shown in Figure 2A, the severity of spinal cord pathology correlated with the clinical score severity, whereas brain pathology did not This is not surprising since clinical scoring is defined by motor ability, which is primarily a measurement of spinal cord function. Histopathology rankings were then sub-divided into treatment groups to assess differences after 2 in vivo antibody treatments (day 24). All treatment groups, including anti-IL-12, had lower pathology rankings man the Rat IgG treated control animals (Figure 2B). However, it is important to note that with treatment paradigms that are initiated 10 days post EAE induction, clinical protection with anti-p40 or anti-IL-23 is not typically observed until day 30 or later (Figure ID). Regardless, there were remarkable differences in spinal cord inflammation, demyelination, and astrocyte gliosis when the Rat IgG control and anti-EL- 23 groups were compared. These data confirm that the clinical protection that is observed after anti- D-23 therapy is a result of partial protection from CNS pathology. As discussed above, for treatment paradigms that are initiated 10 days post EAE induction, clinical protection with anti-p40 or anti-IL-23 is not typically observed until day 30 or later (Figure ID). Therefore, day 24 may be too early to detect differences in CNS pathology between treatment groups. Regardless, there are remarkable differences in spinal cord inflammation and demyelination when the Rat IgG control and anti-IL-23 groups are compared. These data confirm that the clinical :cross sections using a monomorphic grid. Inflammation and demyelination in the brain is expressed as present (+) or absent (-). Table 2. EAE clinical scores with IL-12 and IL-23 neutralization after Th1 differentiation. a clinical score (cs) b cumulative cs Mice were treated on days 10,17, and 24 and clinical scores were analyzed from day 0 through 70 days post EAE induction. Data is shown as the mean per group ± s.e.m. Table 3. EAE clinical scores with IL-12 and IL-23 neutralization during established EAE. Pre-Tx From first treatment through 80 days post EAE induction Novel anti-IL-23p40 specific human Ig derived proteins, including, without limitation, antibodies, fusion proteins, and mimetibodies, isolated nucleic acids that encode the anti- IL-2340 Ig derived proteins, vectors, host cells, transgenic animals or plants, and methods of making and using thereof, are useful for therapeutic compositions, methods and devices. Preferably, the anti-IL-23p40 specific human Ig derived proteins do not bind the p40 subunit of IL-12 and, thus, do not neutralize IL-12 related activity.

Full Text

FIELD OF THE INVENTION
The present invention relates to at least one IL-23p40 specific human Ig derived protein or
fragment thereof, encoding and complementary nucleic acids, host cells, and methods of making and
using thereof, including therapeutic formulations, administration and devices.
BACKGROUND OF THE INVENTION
Interleukin-23 (IL-23) is the name given to a factor that is composed of the p40 subunit of IL-
12 (IL-12beta, IL-12-p40) and another protein of 19 kDa, designated pl9. pl9 is structurally related
to DL6, G-CSF, and the p35 subunit of IL-12. Like IL-12 p35, IL-23 pl9 cannot be secreted as a
monomer and has not demonstrated biological function. Rather, each subunit must partner with p40
to be expressed by antigen presenting cells (APC) and mediate biologic effects. The active complex
is secreted by dendritic cells after cell activation. Mouse memory T-cells (CD4 (+)CD45 Rb(low))
proliferate in response to IL-23 but not in response to IL-12. Human IL23 has been shown to
stimulate the production of IFN-gamma by PHA blast T-cells and memory T-cells. It also induces
proliferation of both cell types. Human monocyte-derived macrophages produce IL23 in response to
virus infection (Sendai virus but not Influenza A virus).
IL-23 binds to the beta-1 subunit but not to the beta-2 subunit of the IL-12 receptor, activating
one of the STAT proteins, STAT-4, in PHA blast T-cells. The EL-23 receptor consists of a receptor
chain, tenned IL-23R, and the beta-1 subunit of the DL-12 receptor. The human IL-23R gene is on
human chromosome 1 within 150 kb of the gene encoding EL-12Rbeta2. EL-23 activates the same
signaling molecules as EL-12: JAK2, Tyk2, and STAT-1, STAT-3, STAT-4, and STAT-5. STAT-4
activation is substantially weaker and different DNA-binding STAT complexes form in response to
IL-23 compared with IL-12. IL-23R associates constirutively with JAK2 and in a ligand-dependent
manner with STAT-3.
Expression of pl9 in transgenic mice leads to ranting, systemic inflammation, infertility, and
death before 3 months of age. The animals show high serum concentrations of the pro-inflammatory
cytokines TNF-alpha and IL1 The number of circulating neutrophils is increased. Acute phase
proteins are expressed constitutively. Animals expressing pl9 specifically in the liver do not show
these abnormalities. Expression of p19 is most likely due to hematopoietic cells as bone marrow
transplantation of cells expressing pl9 causes the same phenotype as that observed in the transgenic
animals.
Biologically active DL-12 exists as a heterodimer comprised of 2 covalently linked subunits of
35 (p35) and 40 (p40) kD. IL-12 acts by binding to both the IL-12beta 1 and beta 2 receptor proteins

and thereby induces signaling in a cell presenting both of these receptors. Several lines of evidence
have demonstrated that IL-12 can induce robust Thl immune responses that are characterized by
production of IFNy and IL-2 from CD4+T cells.
IL-12 is produced by APCs in response to a variety of pathogens. One example is the
protozoan parasite Leishnaiiia major, which has been used as an in vivo model for defining factors
involved in T cell development. Resistant strains of mice developed Thl responses characterized by
robust IFNy production. In contrast, susceptible mice demonstrate a Th2 cytokine profile most often
described by IL-4, IL-5, and IL-10 production. It was shown that EL-12 could restore immune
function in susceptible mice and administration of a neutralizing anti-p40 antibody resulted in disease
onset in otherwise resistant strains. This change in disease susceptibility was associated with a
reversal of T cell cytokine profiles. Therefore, IL-12 has been identified as a critical parameter in
defining Thl differentiation.
Inappropriate Thl responses, and thus IL-12 expression, are believed to correlate with many
immune-mediated inflammatory diseases and disorders, such as multiple sclerosis, rheumatoid
arthritis, inflammatory bowel disease, insulin-dependent diabetes mellitus, and uveitis. In animal
models, IL-12 neutralization through its p40 subunit was shown to ameliorate immune-mediated
inflammatory diseases. For example, administration of recombinant IL-12 exacerbated EAE, and
reatment with neutralizing anti-p40 antibodies inhibited EAE onset or relapses. In addition, IL-12
p40+mice are completely resistant to EAE even though mice deficient in other pro-inflammatory
cytokines, such as IFN, TNFα, or LTα, remain susceptible. IL-12 p35+mice are fully susceptible to
HAE, which suggests that alternative p40 cytokines, such as IL-23, are responsible for such diseases.
The role of IL-23 in EAE and collagen-induced arthritis (CIA) has been recendy confirmed in studies
using p19+ mice. These animals demonstrated complete resistance to disease induction, similar to
p40+mice.
Non-human, chimeric, polyclonal (e.g., anti-sera) and/or monoclonal antibodies
(Mabs) and fragments (e.g., proteolytic digestion products thereof) are potential therapeutic
agents that are being developed in some cases to attempt to treat certain diseases. However,
such antibodies ihat comprise non-human portions elicit an immune response when
administered to humans. Such an immune response can result in an immune complex-
mediated clearance of the antibodies from the circulation, and make repeated administration
unsuitable for therapy, thereby reducing the therapeutic benefit to the patient and limiting the
readmininistration of the Ig derived protein. For example, repeated adrninistration of antibodies
comprising non-human portions can lead to serum sickness and/or anaphalaxis. In order to
avoid these and other such problems, a number of approaches have been taken to reduce the
iminunogenicity of such antibodies and portions thereof, including chimerization and

"humanization," as well known in the art These approaches have produced antibodies having
reduced immunogenicity, but with other less disirable properties.
Accordingly, there is a need to provide anti-IL-23p40 antibodies or specified portions or
variants, nucleic acids, host cells, compositions, and methods of making and using thereof, that
overcome one more of these problems.
SUMMARY OF THE INVENTION
The present invention provides immunoglobulin (Ig) derived proteins that are specific for the
p40 subunit of IL-23 and which preferably do not bind to the p40 subunit of IL-12 ("anti-IL-23p40 Ig
derived protein" or uIL-23p40 Ig derived protein"). Such Ig derived proteins including antibody and
antagonist or receptor fusion proteins that block the binding of IL-23 to at least one of its receptors
(e.g., but not limited to, IL-23 receptor and/or IL-12 beta 1 receptor) by binding to the p40 subunit of
IL-23. Preferably, such anti-lL-23p40 Ig derived proteins do not bind and/or inhibit binding of IL-12
to one or more of its receptors, e.g., but not limited to IL-12 beta 1 receptor and/or IL-12 beta 2
receptor. The present invention further provides compositions, formulations, methods, devices and
uses of such anti-IL-23p40 Ig derived proteins, including for therapeutic and diagnostic uses.
In a further embodiment, the present invention provides Ig derived proteins that selectively
inhibit IL-23 related activities, and optionally further do not inhibit IL-12 specific activities that are
mediated by ±e binding of IL-12 to one or more of its receptors (e.g., but not limited to, IL-12 beta 1
receptor, or D.-12 beta 2 receptor).
In another embodiment, the present invention provides Ig derived proteins that inhibit IL-23
activity in antigen presenting cells (APCs), such as but not limited to, macrophages, microglia,
mcsangial phagocytes, synovial A cells, stem cell precursors, Langerhans cells, Kuppfer cells,
dendritic cells, B cells, and the like. Such APC's can be present in different tissues, e.g., but not
limited to, skin, epidermis, liver, spleen, brain, spinal cord, thymus, bone marrow, joint synovial fluid,
idneys, blood, and the like. Such APC's can also be limited to outside or inside the blood brain
barrier.
In a further embodiment, the present invention provides Ig derived proteins that are suitable
for treating at least one IL-23 related condition by blocking IL-23 binding to one or more of its
receptors, and optionally where the Ig derived proteins do not block IL-12 binding to one or more of
its receptors.
The present invention thus provides isolated anti-IL-23p40 human Ig derived proteins (Ig
derived proteins), including immunoglobulins, receptor fusion proteins, cleavage products and other
specified portion;: and variants thereof, as well as anti-IL-23p40 Ig derived protein compositions,
enc oding or complementary nucleic acids, vectors, host cells, compositions, formulations, devices,
transgenic animal 5, transgenic plants, and methods of making and using thereof, as described and
enabled herein, in combination with what is known in the art Such anti-IL-23p40 Ig derived proteins

act as antagonists to IL-23p40 proteins and thus are useful for treating IL-23p40 pathologies. IL-
23p40 proteins include, but are not limited to, IL-23 and IL-12, particularly, the p40 subunit of IL-23
and IL-12, as well as the p35 subunit of IL-12 or pl9 subunit of IL-23.
The present invention also provides at least one isolated IL-23p40 Ig derived protein or
specified portion or variant as described herein and/or as known in die art.
The present invention provides, in one aspect, isolated nucleic acid molecules comprising,
complementary, or hybridizing to, a polynucleotide encoding specific IL-23p40 Ig derived proteins or
specified portions or variants thereof, comprising at least one specified sequence, domain, portion or
variant thereof. The present invention further provides recombinant vectors comprising said isolated
EL-23p40 Ig derived protein nucleic acid molecules, host cells containing such nucleic acids and/or
recombinant vectors, as well as methods of making and/or using such Ig derived protein nucleic acids,
vectors and/or host cells.
At least one Ig derived protein or specified portion or variant of the invention binds at least
one specified epitope specific to at least one IL-23p40 protein, subunit, fragment, portion or any
combination thereof. The at least one epitope can comprise at least one Ig derived protein binding
region that comprises at least one portion of said protein, which epitope is preferably comprised of at
least one extracellular, soluble, hydrophillic, external or cytoplasmic portion of said protein. Non-
limiting examples include 1,2,3,4,5,6,7,8,9,10,11,12,13 or 14 amino acids of at least one of, 1-
10,10-20,20-30,30-40,40-50,50-60,60-70,70-80,80-90,90-100,100-110,110-120,120-130,130-
140,140-150,150-160,160-170,170-180,180-190,190-200,200-210,210-220,220-230.230-240,
240-250,250-260,260-270, 280-290, 290-300, 300-306,1-7,14-21, 29-52,56-73, 83-93, 96-105,
156-175,194-204,208-246,254-273, 279-281, or 289-300 of SBQ ED NO:l, the human p40 subunit
(306 amino acids).
The at least one Ig derived protein or specified portion or variant can optionally comprise at
least one specified portion of at least one CDR (e.g., CDR1, CDR2 or CDR3 of the heavy or light
chain variable region) and/or at least one framework region. The at least one Ig derived protein or
specified portion or variant amino acid sequence can further optionally comprise at least one specified
substitution, insertion or deletion.
The present invention also provides at least one composition comprising (a) an isolated IL-
23p40 Ig derived protein or specified portion or variant encoding nucleic acid and/or Ig derived
protein as described herein; and (b) a suitable carrier or diluent. The carrier or diluent can optionally
be pharmaceutically acceptable, according to known methods. The composition can optionally
further comprise at least one further compound, protein or composition.
The present invention also provides at least one method for expressing at least one IL-23p40
Ig derived protein or specified portion or variant in a host cell, comprising culturing a host cell as
described herein and/or as known in the art under conditions wherein at least one IL-23p40 Ig derived
protein or specified portion or variant is expressed in detectable and/or recoverable amounts.

The present invention further provides at least one IL-23p40 Ig derived protein, specified
portion or variant in a method or composition, when administered in a therapeutically effective
amount, for modulation, for treating or reducing the symptoms of immune, neurological, and related
disorders, such as, but not limited to, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid
arthritis, systemic onset juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondilitis, gastric
ulcer, seronegative arthropathies, osteoarthritis, inflammatory bowel disease, ulcerative colitis,
systemic lupus erythematosis, antiphospholipid syndrome, iridocyclitis/uveitis/optic neuritis,
idiopathic pulmonary fibrosis, systemic vasculitis/Wegener's granulomatosis, sarcoidosis,
orchitis/vasectomy reversal procedures, allergic/atopic diseases, asthma, allergic rhinitis, eczema,
allergic contact dermatitis, allergic conjunctivitis, hypersensitivity pneumonitis, transplants, organ
transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis
syndrome, gram positive sepsis, gram negative sepsis, culture negative sepsis, fungal sepsis,
neutropenic fever, urosepsis, meningococcemia, trauma/hemorrhage, burns, ionizing radiation
exposure, ac ute pancreatitis, adult respiratory distress syndrome, rheumatoid arthritis, alcohol-induced
hepatitis, chronic inflammatory pathologies, sarcoidosis, Crohn's pathology, sickle cell anemia,
diabetes, nephrosis, atopic diseases, hypersensitity reactions, allergic rhinitis, hay fever, perennial
rhinitis, conjunctivitis, endometriosis, asthma, urticaria, systemic anaphalaxis, dermatitis, pernicious
anemia, hemolytic disesease, thrombocytopenia, graft rejection of any organ or tissue, kidney
translplant rejection, heart transplant rejection, liver transplant rejection, pancreas transplant rejection,
lung transplant rejection, bone marrow transplant (BMT) rejection, skin allograft rejection, cartilage
transplant rejection, bone graft rejection, small bowel transplant rejection, fetal thymus implant
rejection, parathyroid transplant rejection, xenograft rejection of any organ or tissue, allograft
rejection, anti receptor hypersensitivity reactions. Graves disease, Raynoud's disease, type B insulin-
resistant diabetes, asthma, myasthenia gravis, antibody-meditated cytotoxicity, type III
tiypersensitivily reactions, systemic lupus erythematosus, POEMS syndrome (polyneuropathy,
organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome),
polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes syndrome,
iintiphospholipid syndrome, pemphigus, scleroderma, mixed connective tissue disease, idiopathic
Addison's disease, diabetes mellitus, chronic active hepatitis, primary Miliary cirrhosis, vitiligo,
vasculitis, post-MI cardiotomy syndrome, type IV hypersensitivity, contact dermatitis,
hypersensitivity pneumonitis, allograft rejection, granulomas due to intracellular organisms, drug
sensitivity, metabolic/idiopathic, Wilson's disease, hemachromatosis, alpha-1-antitrypsin deficiency,
diabetic retinopathy, hashimoto's thyroiditis, osteoporosis, hypothalamic-pituitary-adrenal axis
evaluation, primary biliary cirrhosis, thyroiditis, encephalomyelitis, cachexia, cystic fibrosis, neonatal
clironic lung disease, chronic obstructive pulmonary disease (COPD), familial hematophagocytic
Iymphohistiocytosis, dermatologic conditions, psoriasis, alopecia, nephrotic syndrome, nephritis,
glomerular nephritis, acute renal failure, hemodialysis, uremia, toxicity, preeclampsia, okt3 therapy,

anti-cd3 therapy, cytokine therapy, chemotherapy, radiation therapy (e.g., including but not limited to,
asthenia, anemia, cachexia, and the like), chronic salicylate intoxication, acute or chronic bacterial
infection, acute and chronic parasitic or infectious processes, including bacterial, viral and fungal
infections, HIV infection/HIV neuropathy, meningitis, hepatitis (e.g., A, B or C, or the like), septic
arthritis, peritonitis, pneumonia, epiglottitis, e. Coli 0157:h7, hemolytic uremic
syndrome/thrombolytic thrombocytopenic purpura, malaria, dengue hemorrhagic fever, leishmaniasis,
leprosy, toxic shock syndrome, streptococcal myositis, gas gangrene, mycobacterium tuberculosis,
mycobacterium avium intracellulare, Pneumocystis carinii pneumonia, pelvic inflammatory disease,
orchitis/epidydimitis, legionella, lyme disease, influenza a, epstein-barr virus, vital-associated
hemaphagoeytic syndrome, vital encephalitis/aseptic meningitis, neurodegenerative diseases, multiple
sclerosis, migraine headache, AIDS dementia complex, demyelinatmg diseases, such as multiple
sclerosis and acute transverse myelitis; extrapyramidal and cerebellar disorders, such as lesions of the
corticospinal system; disorders of die basal ganglia; hyperkinetic movement disorders, such as
Huntington's Chorea and senile chorea; drug-induced movement disorders, such as those induced by
drugs which block CNS dopamine receptors; hypokinetic movement disorders, such as Parkinson's
disease; Progressive supranucleo Palsy; structural lesions of the cerebellum; spinocerebellar
degenerations, such as spinal ataxia, Friedreich's ataxia, cerebellar cortical degenerations, multiple
systems degenerations (Mencel, Dejerine-Thomas, Shi-Drager, and Machado-Joseph); systemic
disorders (Refsum's disease, abetalipoprotemia, ataxia, telangiectasia, and mitochondrial multisystem
disorder); demyelinating core disorders, such as multiple sclerosis, acute transverse myelitis; and
disorders of the motor unit, such as neurogenic muscular atrophies (anterior horn cell degeneration,
such as amyotrophic lateral sclerosis, infantile spinal muscular atrophy and juvenile spinal muscular
atrophy); Alzheimer's disease; Down's Syndrome in middle age; Diffuse Lewy body disease; Senile
Dementia of Lewy body type; Wernicke-Korsakoff syndrome; chronic alcoholism; Creutzfeldt-Jakob
disease; Subacute sclerosing panencephalitis, Hallerrorden-Spatz disease; and Dementia pugilistica,
neurotraumalic injury (e.g., but not limited to, spinal cord injury, brain injury, concussion, and
repetitive concussion), pain, inflammatory pain, autism, depression, stroke, cognitive disorders,
epilepsy, and the like, as needed in many different conditions, such as but not limited to, prior to,
subsequent to, or during a related disease or treatment condition, as known in the art.
The present invention further provides at least one IL-23p40 Ig derived protein, specified
portion or variant in a method or composition, when administered in a therapeutically effective
amount, for modulation, for treating or reducing the symptoms of at least one IL-23p40 disease in a
cell, tissue, organ, animal or patient and/or, as needed in many different conditions, such as but not
limited to, prior to, subsequent to, or during a related disease or treatment condition, as known in me
art and/or as described herein.

The present invention also provides at least one composition, device and/or method of
delivery of a therapeutically or propfaylactically effective amount of at least one IL-23p40 Ig derived
protein or specified portion or variant, according to the present invention.
The present invention also provides at least one isolated IL-23p40 Ig derived protein,
comprising at least one immnuoglobulin complementarity determining region (GDR) or at least one
ligand binding region (LBR) that specifically binds at least one IL-23p40 protein, wherein (a) said IL-
23p40 Ig derived protein specifically binds at least one epitope comprising at least 1-3, to the entire
amino acid sequence, selected from the group consisting of the p40 subunit of a human interleukin-23
(1-306 of SEQ ID NO:l), such as but not limited to, 1,2,3,4,5,6,7,8,9,10,11,12,13 or 14amino
acids of at least one of, 1-10,10-20,20-30,30-40,40-50,50-60,60-70,70-80,80-90,90-100,100-
110,110-120,120-130,130-140,140-150,150-160,160-170,170-180,180-190,190-200,200-210,
210-220,220-230,230-240,240-250,250-260,260-270,280-290,290-300,300-306,1-7,14-21,29-
52,56-73,83-93,96-105,156-175,194-204,208-246,254-273,279-281, or 289-300 of SEQ ID
NO:l. In a preferred embodiment, the anti-human IL-23p40 Ig derived protein binds IL-23p40 with
an affinity of at least 10"9 M, at least 10"10 M, at least 10'" M, or at least 10"12 M. In another preferred
embodiment, the human Ig derived protein substantially neutralizes at least one activity of at least one
ID-23p40 protein or receptor.
The invention also provides at least one isolated IL-23p40 human Ig derived protein encoding
nucleic acid, comprising a nucleic acid that hybridizes under stringent conditions, or has at least 95%
identity, to a nucleic acid encoding a IL-23p40 Ig derived protein. The invention further provides an
isolated EL-22 p40 human Ig derived protein, comprising an isolated human Ig derived protein
encoded by such a nucleic acid. The invention further provides a IL-23p40 human Ig derived protein
encoding nucleic acid composition, comprising such an isolated nucleic acid and a carrier or diluent.
The invention further provides an Ig derived protein vector, comprising such a nucleic acid, wherein
t he vector optionally further comprises at least one promoter selected from the group consisting of a
late or early SV40 promoter, a CMV promoter, an HSV tk promoter, a pgk (phosphoglycerate kinase)
promoter, a human immunoglobulin promoter, or an EF-1 alpha promoter. Such a vector can optionally
f urther comprise at least one selection gene or portion thereof selected from at least one of
methotrexate (MTX), dihydrofolate reductase (DHFR), green fluorescent protein (GFP), neomycin
(G418), or glutamine synthetase (GS). The invention further comprises a mammalian host cell
comprising such an isolated nucleic acid, optionally, wherein said host cell is at least one selected
from COS-1, COS-7, HEK293, BHK21, CHO, BSC-1, Hep G2,653, SP2/0,293, HeLa, myeloma, or
lymphoma cells, or any derivative, immortalized or transformed cell thereof.
The invention also provides at least one method for producing at least one EL-23p40 human Ig
derived protein, comprising translating such a nucleic acid or an endogenous nucleic acid that
hybridizes therei.o under stringent conditions, under conditions in vitro, in vivo or in situ, such that the
IL-23p40 humar Ig derived protein is expressed in detectable or recoverable amounts.

The invention also provides at least one EL-23p40 human Ig derived protein composition,
comprising at least one isolated IL-23p40 human Ig derived protein and a carrier or diluent, optionally
further wherein said carrier or diluent is pharmaceutically acceptable, and/or further comprising at
least one compound or protein selected from at least one of a TNF antagonist, an antirheumatic, a
muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an
anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a
corticosteriod, an anabolic steroid, an IL-23p40 agent, a mineral, a nutritional, a thyroid agent, a
vitamin, a calcium related hormone, an anndiarrheal, an antitussive, an antiemetic, an antiulcer, a
laxative, an anticoagulant, an erythropoietin, a filgrastim, a sargramostim, an immunization, an
immunoglobulin, an immunosuppressive, a growth hormone, a hormone replacement drug, an
estrogen receptor modulator, a mydriatic, a cyclopkgic, an alkylating agent, an antimetabolite, a
mitotic inhibitor, a radiopharmaceutical, an antidepressant, an antimanic agent, an antipsychotic, an
anxiolytic, a hypnotic, a sympamomimetic, a stimulant, donepeztl, tacrine, an asthma medication, a
beta agonist, an inhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn, an epinephrine
or analog, dornase alpha, a cytokine, and a cytokine antagonist
The present invention also provides at least one method for treating a IL-23p40 condition in a
cell, tissue, organ or animal, comprising contacting or administering an immune related- or infectious
related-condition modulating effective amount of at least one EL-23p40 human Ig derived protein
with, or 1:0, said cell, tissue, organ or animal, optionally wherein said animal is a primate, optionally, a
monkey or a human. The method can further optionally include wherein said effective amount is
0.001-100 mg/kilogram of said cells, tissue, organ or animal. Such a method can further include
wherein said contacting or said administrating is by at least one mode selected from intravenous,
intramuscular, bolus, intraperitoneal, subcutaneous, respiratory, inhalation, nasal, vaginal, rectal,
buccal, sublingual, intranasal, subdermal, and transdermal. Such a method can further comprise
administering, prior, concurrently or after said (a) contacting or administering, at least one
composition comprising a therapeutically effective amount of at least one compound or protein
selected from at least one of a TNF antagonist, an antirheumatic, a muscle relaxant, a narcotic, a non-
steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anethetic, a
neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteriod, an anabolic steroid, an EL-
23p40 agent, a mineral, a nutritional, a thyroid agent, a vitamin, a calcium related hormone, an
anndiarrheal, an antitussive, an antiemetic, an antiulcer, a laxative, an anticoagulant, an
erythropoietin, a filgrastim, a sargramostim, an immunization, an immunoglobulin, an
immunosuppressive, a growth hormone, a hormone replacement drug, an estrogen receptor modulator,
a mydriatic, a cycloplegic, an alkylating agent, an antimetabolite, a mitotic inhibitor, a
radiopharmaceutical, an antidepressant, antimanic agent, an antipsychotic, an anxiolytic, a hypnotic, a
sympathomimetic, a stimulant, donepezil, tacrine, an asthma medication, a beta agonist, an inhaled

steroid, a. leukotriene inhibitor, a memylxanthine, a cromolyn, an epinephrine or analog, domase
alpha, a cytokine, and a cytokine antagonist.
The present invention also provides at least one medical device, comprising at least one IL-
23p40 human Ig derived protein, wherein said device is suitable to contacting or adrninisterting said at
least one IL-23p40 human Ig derived protein by at least one mode selected from intravenous,
intramuscular, bolus, intraperitoneal, subcutaneous, respiratory, inhalation, nasal, vaginal, rectal,
buccal, sublingual, intranasal, subdermal, or transdermal.
The present invention also provides at least one human immunoglobulin light chain IL-23p40
protein, comprising at least one portion of a variable region comprising at least one human Ig derived
protein fragment of the invention.
The: present invention also provides at least one human immunoglobulin heavy chain or
portion thereof, comprising at least one portion of a variable region comprising at least one IL-23p40
human Ig derived protein fragment
The invention also includes at least one human Ig derived protein, wherein said human Ig
derived protein binds the same epitope or antigenic region as an IL-23p40 human Ig derived protein.
The invention also includes at least one formulation comprising at least one IL-23p40 human
Ig derived protein, and at least one selected from sterile water, sterile buffered water, or at least one
preservative selected from me group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol,
benzyl alcohol, alkylparaben, benzalkonium chloride, benzethonium chloride, sodium dehydroacetate
and thimerosal, or mixtures thereof in an aqueous diluent, optionally, wherein die concentration of EL-
23p40 human Ig derived protein is about 0.1 mg/ml to about 100 mg/ml, further comprising at least
one isotonicity agent or at least one physiologically acceptable buffer.
The invention also includes at least one formulation comprising at least one IL-23p40 human
lg derived protein in lyophilized form in a first container, and an optional second container
comprising at least one of sterile water, sterile buffered water, or at least one preservative selected
from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol,
alkylparaben, benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal,
o; • mixtures thereof in an aqueous diluent, optionally further wherein me concentration of IL-23p40
human Ig derived protein is reconsitituted to a concentration of about 0.1 mg/ml to about 500 mg/ml,
further comprising an isotonicity agent, or further comprising a physiologically acceptable buffer.
The invention further provides at least one method of treating at least one IL-23p40 mediated
condition, comprising administering to a patient in need thereof a formulation of the invention.
The invention also provides at least one article of manufacture for human pharmaceutical use,
comprising packaging material and a container comprising a solution or a lyophilized form of at least
one IL-23p40 human Ig derived protein of the invention, optionally further wherein said container is a
glass or plastic container having a stopper for multi-use administration, optionally further wherein
said container is a blister pack, capable of being punctured and used in intravenous, intramuscular,

bolus, intraperitoneal, subcutaneous, respiratory, inhalation, nasal, vaginal, rectal, buccal, sublingual,
intranasal, subdermal, or transdermal administration; said container is a component of a intravenous,
intramuscular, bolus, intraperitoneal, subcutaneous, respiratory, inhalation, nasal, vaginal, rectal,
buccal, sublingual, intranasal, subdermal, or transdermal delivery device or system; said container is a
component of an injector or pen-injector device or system for intravenous, intramuscular, bolus,
intraperitoneal, subcutaneous, respiratory, inhalation, nasal, vaginal, rectal, buccal, sublingual,
intranasal, subdermal, or transdermal.
The invention further provides at least one method for preparing a formulation of at least one
IL-23p40 human Ig derived protein of the invention, comprising admixing at least one IL-23p40
human Ig derived protein in at least one buffer containing saline or a salt.
The invention also provides at least one method for producing at least one IL-23p40 human Ig
derived protein of the invention, comprising providing a host cell, transgenic animal, transgenic plant
or plant cell capable of expressing in recoverable amounts said human Ig derived protein, optionally
further wheiein said host cell is a mammalian cell, a plant cell or a yeast cell; said transgenic animal is
a mammal; said transgenic mammal is selected from a goat, a cow, a sheep, a horse, and a non-human
primate.
The invention further provides at least one transgenic animal or plant expressing at least one
human Ig derived protein of the invention.
The invention further provides at least one IL-23p40 human Ig derived protein produced by a
method of the invention.
The invention further provides at least one method for treating at least one IL-23p40 mediated
disorder, comprising at least one of (a) administering an effective amount of a composition or
pharmaceutical composition comprising at least one IL-23p40 human Ig derived protein to a cell,
tissue, organ, animal or patient in need of such modulation, treatment or therapy; and further
administering, before concurrently, and/or after said administering in (a) above, at least one selected
from at least one of an immune related therapeutic, a TNF antagonist, an antirheumatic, a muscle
relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a
sedative, 2 local anesthetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a
corticosteriod, an anabolic steroid, a neurological agent, a mineral, a nutritional, a thyroid agent, a
vitamin, a calcium related hormone, an antidiarrheal, an antitussive, an antiemetic, an antiulcer, a
laxative, an anticoagulant, an erythropoietin, a filgrastim, a sargramostim, an immunizing agent, an
immunoglobulin, an immunosuppressive, a growth hormone, a hormone replacement drug, an
estrogen receptor modulator, a mydriatic, a cycloplegic, an alkylating agent, an antimetabolite, a
mitotic inhibitor, a radiopharmaceutical, an antidepressant, antimanic agent, an antipsychotic, an
anxiolytic, a hypnotic, a sympathomimetic, a stimulant, adonepezil, a tacrine, an asthma medication, a
beta agonist, an inhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn, an epinephrine
or analog, a domase alpha, or a cytokine and a cytokine antagonist.

The present invention further provides any invention described herein and is not limited to
any particular description, embodiment or example provided herein.
BRIEF DESCRIPTION FIGURES
Figure 1A is a graph showing the specificity of the anti-IL-23 antibody for IL-23.
Figure IB is a graph showing die specificity of me anti-IL-23 antibody for the IL-23 p40 subunit
Figure 1C is a graph showing the effect of antibodies on IL-17 levels.
Figure ID is a graph showing the effect of antibodies on JFNv levels.
Figure IE is a graph showing the clinical suppression of EAE by the antibodies.
Figure 2A is a graph showing the correlation of brain and spinal cord pathology with the clinical
score severity.
Figure 2B is a graph showing the histopatbology rankings of the antibodies.
Figure 3A is a graph showing T cell response to myelin basic protein in the presence of antibodies.
Figure 3B is a graph showing IFNy levels in the presence of antibodies.
Figure 3C is a graph showing EL-17 levels in the presence of antibodies.
Figure 3D is a graph showing IL-5 levels in the presence of antibodies.
Figure 3E is a graph showing IL-10 levels in the presence of antibodies.
DESCRIPTION OF THE INVENTION
The present invention provides immunoglobulin (Ig) derived proteins that are specific for the
p40 subunit of IL-23 and which preferably do not bind to the p40 subunit of IL-12. Such Ig derived
proteins including antibody and receptor fusion proteins that block the binding of EL-23 to at least one
of its receptors (e.g., but not limited to, IL-23 receptor and/or IL-12 bete 1 receptor) by binding to the
p40 subunit of IL-23. Preferably, such anti-IL-23p40 Ig derived proteins do not bind and/or inhibit
binding of IL-12 to one or more of its receptors, e.g., but not limited to IL-12 beta 1 receptor and/or
IL-12 beta 2 receptor. The present invention further provides compositions, formulations, methods,
devices and uses of such anti-IL-23p40 Ig derived proteins, including for therapeutic and diagnostic
USiS.
The present invention also provides Ig derived proteins mat selectively inhibit IL-23 related
activities, and optionally further does not inhibit IL-12 specific activities that are mediated by the
binding of IL-12 to one or more of its receptors (e.g., but not limited to, IL-12 beta 1 receptor, or IL-
12 beta 2 receptor).
The present invention further provides Ig derived proteins that ate suitable for treating at least
one IL-23 related condition by blocking IL-23 binding to one or more of its receptors, and optionally
where me Ig derived proteins do not block IL-12 binding to one or more of its receptors.

The present invention also provides Ig derived proteins that inhibit IL-23 activity in antigen
presenting cells (APCs), such as but not limited to, macrophages, microglia, mesangutl phagocytes,
synovial A cells, stem cell precursors, Langerhans cells, Kuppfer cells, dendritic cells, B cells, and the
like. Such APC's can be present in different tissues, e.g., but not limited to. skin, epidermis, liver,
spleen, brain, spinal cord, thymus, bone marrow, joint synovial fluid, kidneys, blood, and the like.
Such AI'C's can also be limited to outside or inside the blood brain barrier.
The present invention provides isolated, recombinant and/or synthetic IL-23p40 Ig derived
proteins or specified portions or variants, as well as compositions and encoding nucleic acid
molecules; comprising at least one polynucleotide encoding at least one IL-23p40 Ig derived protein.
Such Ig derived proteins or specified portions or variants of the present invention comprise specific
full length Ig derived protein sequences, domains, fragments and specified variants thereof, and
methods of making and using said nucleic acids and Ig derived proteins or specified portions or
variants, including therapeutic compositions, methods and devices.
As used herein, a "anti-IL-23p40 Ig derived protein," "anti-IL-23p40 Ig derived protein
portion," "anti-IL-23p40 Ig derived protein fragment," "anti-IL-23p40 Ig derived protein variant" "IL-
23p40 Ig derived protein," "IL-23p40 Ig derived protein portion," or "IL-23p40 Ig derived protein
fragment" and/or "IL-23p40 Ig derived protein variant" and the like decreases, blocks, inhibits,
abrogates or interferes with IL-23p40 protein activity, binding or IL-23p40 protein receptor activity or
binding in vitro, in situ and/or preferably in vivo. As used herein, "IL-12p40" refers to the p40
subunit of IL-23, as well as active portions, fragments, isoforms, splice variants, and the like, as
known in the art
For example, a suitable IL-23p40 Ig derived protein, specified portion or variant of the
present invention can bind at least one IL-23p40 protein or receptor and includes anti-IL-23p40 Ig
derived proteins, antigen-binding fragments thereof, and specified portions, variants or domains
thereof that bind specifically to IL-23p4G. A suitable IL-23p40 Ig derived protein, specified portion,
or variant can also decrease block, abrogate, interfere, prevent and/or inhibit IL-23p40 protein RNA,
DMA or protein synthesis, IL-23p40 protein release, IL-23p40 protein or receptor signaling,
membrane IL-23p40 protein cleavage, IL-23 related activity, IL-23p40 protein production and/or
synthesis, e.g., as described herein or as known in the art.
Anti-IL-23p40 Ig derived proteins (also termed anti~IL-23p4G Ig derived proteins) useful in
the methods and compositions of me present invention are characterized by high affinity binding to
IL-23p40 proteins, and optionally and preferably having low toxicity. In particular, an Ig derived
protein, specified fragment or variant of the invention, where the individual components, such as the
variable region, constant region and framework, individually and/or collectively, optionally and
preferably possess low immunogenicity, is useful in the present invention. The Ig derived proteins
that can be used in the invention are optionally characterized by their ability to treat patients for
extended periods w.th good to excellent alleviation of symptoms and low toxicity. Low

immunogenicity and/or high affinity, as well as other suitable properties, may contribute to the
therapeutic results achieved "Low immunogenicity" is defined herein as raising significant HAHA,
HACA or HAMA responses in less than about 75%, or preferably less than about 50% of the patients
treated and/or raising low titres in the patient treated Qess than about 300, preferably less than about
100 measured with a double antigen enzyme immunoassay) (Elliott et al.. Lancet 344:1125-1127
(1994), each of the above references entirely incorporated herein by reference.
Utility
The isolated nucleic acids of the present invention can be used for production of at least one IL-
23p40 Ig derived protein, fragment or specified variant thereof, which can be used to effect in an cell,
tissue, organ or animal (including mammals and humans), to modulate, treat, alleviate, help prevent
the incidence of, or reduce the symptoms of, at least one IL-23p40 condition.
Such a method can comprise administering an effective amount of a composition or a
pharmaceutical composition comprising at least one anti-IL-23p40 Ig derived protein or specified
portion or variant to a cell, tissue, organ, animal or patient in need of such modulation, treatment,
alleviation, prevention, or reduction in symptoms, effects or mechanisms. The effective amount can
comprise an amount of about 0.001 to 500 mg/kg per single or multiple administration, or to achieve a
serum concentration of 0.01-5000 ug/ml serum concentration per single or multiple adminstration, or
any effective range or value therein, as done and determined using known methods, as described
herein or known in the relevant arts.
Citations
All publications or patents cited herein are entirely incorporated herein by reference, whether
or not specifically designated accordingly, as they show the state of the art at the time of die present
invention and/or to provide description and enablement of the present invention. Publications refer to
any sci entific or patent publications, or any other information available in any media format,
including all recorded, electronic or printed formats. The following references are entirely
incorporated herein by reference: Ausubel, et al., ed., Current Protocols in Molecular Biology, John
Wiley & Sons, Inc., NY, NY (1987-2003); Sambrook, et al., Molecular Cloning: A Laboratory
Manual, 2nd Edition, Cold Spring Harbor, NY (1989); Harlow and Lane, Ig derived proteins, a
Laboratory Manual, Cold Spring Harbor, NY (1989); Colligan, et al., eds., Current Protocols in
Immunology, John Wiley & Sons, Inc., NY (1994-2003); Colligan et al., Current Protocols in Protein
Science, John Wiley & Sons, NY, NY, (1997-2003).
Ig derived proteins of the Present Invention
The term "Ig derived protein" is intended to encompass Ig derived proteins, digestion
fragments, specified portions and variants thereof, including Ig derived protein mimetics or

comprising portions of Ig derived proteins that mimic the structure and/or function of an antibody or
specified fragment or portion thereof, including single chain Ig derived proteins and fragments
thereof, and is also intended to encompass proteins mat contain miitaetics to therapeutic proteins,
antibodies, arid digestioi fragments, specified portions and variants thereof, wherein the protein
comprises at least one functional EL-23p40 protein ligand binding region (LBR) that optionally
replaces at least one complementarity determing region (CDR) of the antibody from which the Ig-
derived protein, portion or variant is derived. Such IL-23p40 IgG derived proteins, specified portions
or variants include those that mimic the structure and/or function of at least one IL-23p40 protein
antagonist, such as an IL-23p40 protein antibody or receptor or ligahd protein, or fragment or analog.
Functional fragments include antigen-binding fragments that bind to human IL-23p40 proteins or
fragments thereof. For example, Ig derived protein fragments capable of binding to human IL-23p40
proteins or fragments thereof, including, but not limited to, Fab (e.g., by papain digestion), Fab' (e.g.,
by pepsin digestion and partial reduction) and F(ab')2 (e.g., by pepsin digestion), facb (e.g., by
plasmin digestion), pFc' (e.g., by pepsin or plasmin digestion), Fd (e.g., by pepsin digestion, partial
reduction and reaggregation), Fv or scFv (e.g., by molecular biology techniques) fragments, are
encompassed by the invention (see, e.g., Colligan, Immunology, supra).
Such fragments can be produced by enzymatic cleavage, synthetic or recombinant techniques,
as known in the art and/or as described herein. Ig derived proteins can also be produced in a variety
of truncated forms using Ig derived protein genes in which one or more stop codons have been
introduced upstream of the natural stop site. For example, a chimeric gene encoding a F(abr)2 heavy
chain portion c an be designed to include DNA sequences encoding the CH1 domain and/or hinge
region of the heavy chain. The various portions of Ig derived proteins can be joined together
chemically by conventional techniques, or can be prepared as a contiguous protein using genetic
engineering techniques. For example, a nucleic acid encoding the variable and constant regions of a
human Ig derived protein chain can be expressed to produce a contiguous protein. See, e.g., Colligan,
Immunology, supra, sections 2.8 and 2.10, for fragmentation and Ladner etal, U.S. Patent No.
4,946,778 and Bird, R.E. et al, Science, 242:423-426 (1988), regarding single chain Ig derived
proteins, each of which publications are entirely incorporated herein by reference.
As used herein, the term "human Ig derived protein" refers to an Ig derived protein in which
i ubstantially every part of the protein (e.g., CDR, LBR, framework, CL, CHdomains (e.g., CH1, CH2,
CH3), hinge, (VL, VH)) is substantially non-immunogenic, with only minor sequence changes or
variations. Such changes or variations optionally and preferably retain or reduce the immunogenicity
in humans relative to non-modified human Ig derived proteins. Thus, a human Ig derived protein is
distinct from a chimeric or humanized Ig. It is pointed out that a hurflan Ig derived protein can be
produced by a non-human animal or prokaryotic or eukaryotic cell that is capable of expressing
functionally rea rranged human immunoglobulin (e.g., heavy chain anoVor light chain) genes. Further,
v/hen a human ig derived protein is a single chain Ig derived protein, it can comprise a linker peptide

that is not found in native human Ig derived proteins. For example, an Fv can comprise a linker
peptide, such as two to about eight glycine or other amino acid residues, which connects the variable
region of the heavy chain and the variable region of the light chain. Such linker peptides are
considered to be of human origin. IL-23p40 Ig derived proteins mat comprise at least one IL-23p40
protein ligand or receptor thereof can be designed against an appropriate ligand, such as isolated
and/or IL-23p40 protein, or a portion thereof (including synthetic molecules, such as synthetic
peptides). Preparation of such IL-23p40 Ig derived proteins are performed using known techniques to
identify and characterize ligand binding regions or sequences of at least one IL-23p40 protein or
portion thereof.
Human Ig derived proteins that are specific for the p40 subunit can be raised against an
appropriate immunogenic antigen, such as isolated IL-23 protein or a portion thereof (including
synthetic molecules, such as synthetic peptides). Preparation of immunogenic antigens, and
monoclonal Ig derived protein production can be performed using any suitable technique. A variety
of methods have been described (see e.g., Kohler etaL, Nature, 256:495-497 (197S) and Eur. J.
Immunol 6:511-519 (1976); Milstein et al. Nature 266:550-552 (1977); Koprowski et al, U.S.
Patent No. 4,172,124; Harlow, E. and D. Lane, 1988, Ig derived proteins: A Laboratory Manual,
(Cold Spring Harbor Laboratory: Cold Spring Harbor, NY); Current Protocols In Molecular Biology,
Vol. 2 (e.g., Supplement 27, Summer "94), Ausubel, F.M. et al., Eds., (John Wiley & Sons: New
York, NY), Chapter 11, (1991-2003)), each of which is entirely incorporated herein by reference.
Generally, a hybridoma is produced by fusing a suitable immortal cell line (e.g., a myeloma cell line
such as, but not limited to, Sp2/0, Sp2/0-AG14, NSO, NS1, NS2, AE-1, L.5, >243, P3X63Ag8.653,
Sp2 SA3, Sp2 MAI, Sp2 SSI, Sp2 SA5, U937, MLA 144, ACT IV, MOLT4, DA-1, JURKAT,
WEffl, K-562, COS, RAJL NIH 3T3, HL-60, MLA 144, NAMAIWA, NEURO 2A, or the like, or
heteromylomas, fusion products thereof, or any cell or fusion cell derived therefrom, or any other
suitable cell line as known in the art, see, e.g., www.atcc.org. www.lifetech.com., and the like, each of
which is entirely incorporated herein by reference) with Ig derived protein, producing cells, such as,
but not limited to, isolated or cloned spleen cells, or any other cells expressing heavy or light chain
constant or variable or framework or CDR sequences, either as endogenous or heterologous nucleic
acid, as recombinant or endogenous, viral, bacterial, algal, prokaryotic, amphibian, insect, reptilian,
fish, mammalian, rodent, equine, ovine, goat, sheep, primate, eukaryotic, genomic DNA, cDNA,
rDNA, mitochondrial DNA orRNA, chloroplast DNA orRNA, hnRNA, mRNA, tRNA, single,
double or triple stranded, hybridized, and the like or any combination thereof. See, e.g., Ausubel,
supra, and Colligan, Immunology, supra, chapter 2, each entirely incorporated herein by reference.
Ig derived protein producing cells can be obtained from the peripheral blood or, preferably the
spleen or lymph nodes, of humans or other suitable animals that have been immunized with the
antigen of interest. Any other suitable host cell can also be used for expressing heterologous or
endogenous nucleic acid encoding an Ig derived protein, specified fragment or variant thereof, of the

present invention. The fused cells (hybridomas) or recombinant cells can be isolated using selective
culture conditions or other suitable known methods, and cloned by limiting dilution or cell sorting, or
other known methods. Cells which produce Ig derived proteins with the desired specificity can be
selected by a suitable assay (e.g., ELISA).
Other suitable methods of producing or isolating antibodies of the requisite specificity can be
used, including, but not limited to, methods that select recombinant antibody from a peptide or protein
library (e.g., but not limited to, a bacteriophage, ribosome, oligonucleotide, RNA, cDNA, or the like,
display library; e.g., as available from Cambridge antibody Technologies, Cambridgeshire, UK;
MorphoSys, Martinsreid/Planegg, DE; Biovation, Aberdeen, Scotland, UK; Biolnvent, Lund,
Sweden; Dyax Corp., Enzon, Affymax/Biosite; Xoma, Berkeley, CA; Ixsys. See, e.g., EP 368,684,
PCT/GB91/01134; PCT/GB92/01755; PCT/GB92/002240; PCT/GB92/0O883; PCT/GB93/00605; US
08/350260(5/12/94); PCT/GB94A)1422; PCT/GB94/02662; PCT/GB97/01835; (CAT/MRC);
WO90/14443; WO90/14424; WO90/14430; PCT/US94/1234; W092/18619; WO96/07754; (Scripps);
W096713583, WO97/08320 (MorphoSys); WO95/16027 (Biolnvent); WO88/06630; WO90/3809
(Dyax); US 4,704,692 (Enzon); PCT/US91/02989 (Affymax); WO89/06283; EP 371 998; EP 550
400; (Xoma); EP 229 046; PCT/US91/07149 (Ixsys); or stochastically generated peptides or proteins -
US 5723323,5763192,5814476,5817483,5824514,5976862, WO 86/05803, EP 590 689 (Ixsys,
now Applied Molecular Evolution (AME), each entirely incorporated herein by reference) or that rely
upon immunization of transgenic animals (e.g., SCID mice, Nguyen et al., Microbiol. Immunol.
41:901-907 (1997); Sandhu et al., Crit Rev. Biotechnol. 16:95-118 (1996); Eren et al., Immunol.
93:154-161 (1998), each entirely incorporated by reference as well as related patents and applications)
that are capable of producing a repertoire of human antibodies, as known in the art and/or as described
herein. Such techniques, include, but are.not limited to, ribosome display (Hanes et al., Proc. Nad.
Acad. Sci. USA, 94:4937-4942 (May 1997); Hanes et al., Proc. Nad. Acad. Sci. USA, 95:14130-
14135 (Nov. 1998)); single cell antibody producing technologies (e.g., selected lymphocyte antibody
method ("SLAM") (US pat. No. 5,627,052, Wen et al., J. Immunol. 17:887-892 (1987); Babcook et
al., Proc. Natl. Acad. Sci. USA 93:7843-7848 (1996)); gel microdroplet and flow cytometry (Powell
et al., Biotechnol. 8:333-337 (1990); One Cell Systems, Cambridge, MA; Gray et al., J. Imm. Meth.
182:155-163 (1995); Kenny et al., Bio/Technol. 13:787-790 (1995)); B-cell selection (Steenbakkers et
al., Molec. Biol. Reports 19:125-134 (1994); Jonak et al., Progress Biotech, Vol. 5, In Vitro
Immunization in Hybridoma Technology, Borrebaeck, ed., Elsevier Science Publishers B.V.,
Amsterdam, Netherlands (1988)). each of which is entirely incorporated herein by reference.
Methods for humanizing non-human Ig derived proteins can also be used and are well known
in the art. Generally, a humanized antibody has one or more amino acid residues introduced into it
from a source which is non-human. These non-human amino acid residues are often referred to as
"import" residues, which are typically taken from an "import" variable domain. Humanization can be
essentially performed following the method of Winter and co-workers (Jones et al., Nature 321:522

(1986); Riechmann et al., Nature 332:323 (1988); Verhoeyen et al., Science 239:1534 (1988), each of
which is entirely incorporated herein by reference), by substituting rodent CDRs or CDR sequences
for the corresponding sequences of a human antibody. Accordingly, such "humanized" Ig derived
proteir s are chimeric Ig derived proteins (Cabilly et al., supra), wherein substantially less than an
intact human variable domain has been substituted by the corresponding sequence from a non-human
species. In practice, humanized Ig derived proteins are typically human Ig derived proteins in which
some CDR residues and possibly some FR residues are substituted by residues from analogous sites in
rodent Ig derived proteins.
The choice of human variable domains, bom light and heavy, to be used in making the
humanized Ig derived proteins can be used to reduce antigenicity. According to the so-called "best-
fit" method, the sequence of the variable domain of a rodent antibody is screened against the entire
library of known human variable-domain sequences. The human sequence which is closest to that of
the rodent is then accepted as the human framework (FR) for the humanized antibody (Sims et al., J.
Immunol. 151:2296 (1993); Chothia and Lesk, J. Mol. Biol. 196:901 (1987), each of which is entirely
incorporated herein by reference). Another method uses a particular framework derived from the
consensus sequence of all human Ig derived proteins of a particular subgroup of light or heavy chains.
The same framework can be used for several different humanized Ig derived proteins (Carter et al.,
Proc. Natl. Acad. Sci. U.SA. 89:4285 (1992); Presta et al., J. Immunol. 151:2623 (1993), each of
which is entirely incorporated herein by reference).
Ig derived proteins can also optionally be humanized with retention of high affinity for the
antigen and other favorable biological properties. To achieve this goal, according to a preferred
method, humanized Ig derived proteins are prepared by a process of analysis of the parental sequences
and various conceptual humanized products using three-dimensional models of die parental and
humanized sequences. Three-dimensional immunoglobulin models are commonly available and are
familiar to those skilled in the art Computer programs are available which illustrate and display
probable three-dimensional conformational structures of selected candidate immunoglobulin
sequences. Inspection of these displays permits analysis of the likely role of the residues in the
functioning of the candidate immunoglobulin sequence, i.e., the analysis of residues that influence the
ability of the candidate immunoglobulin to bind its antigen. In this way, FR residues can be selected
and combined from the consensus and import sequences so that the desired antibody characteristic,
such as increased affinity for the target antigen(s), is achieved. In general, the CDR residues are
directly and most substantially involved in influencing antigen binding.
Human monoclonal Ig derived proteins can be made by the hybridoma method. Human
myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal Ig
derived proteins have been described, for example, by Kozbor, J. Immunol. 133:3001 (1984); Brodeur
st al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker,
Inc., New York, 1987); and Boemer et al., J. Immunol. 147:86 (1991% each of which is entirely

incorporated herein by reference.
Alternatively, phage display technology and, as presented above, can be used to produce
human Ig derived proteins and antibody fragments in vitro, from immunoglobulin variable (V)
domain gene repertoires from unimmunized donors. According to one none limiting example of this
technique, antibody V domain genes are cloned in-frame into either a major or minor coat protein
gene of a filamentous bacteriophage, such as M13 or fd, and displayed as functional antibody
fragments on the surface of the phage particle. Because the filamentous particle contains a single-
stranded DNA copy of the phage genome, selections based on die functional properties of the
antibody also result in selection of the gene encoding die antibody exhibiting those properties. Thus,
the phage mimics some of the properties of the B-cell. Phage display can be performed in a variety of
formats; for their review see, e.g., Johnson et al., Current Opinion in Structural Biology 3:564 (1993),
each of which is entirely incorporated herein by reference. Several sources of V-gene segments can
be used for phage display. Clackson et al., Nature 352:624 (1991) isolated a diverse array of anti-
oxazolone Ig derived proteins from a small random combinatorial library of V genes derived from the
spleens of immunized mice. A repertoire of V genes from unimmunized human donors can be
constructed and Ig derived proteins to a diverse array of antigens (including self-antigens) can be
isolated essentially following the techniques described by Marks et al., J. Mol. Biol. 222:581 (1991),
or Griffith et al., EMBO J. 12:725 (1993), each of which is entirely incorporated herein by reference.
In a natural immune response, antibody genes accumulate mutations at a high rate (somatic
hypermutation). Some of the changes introduced will confer higher affinity, and B cells displaying
high-affinity surface immunoglobulin are preferentially replicated and differentiated during
subsequent antigen challenge. This natural process can be mimicked by employing the technique
known as "chain shuffling" (Marks et al., Bio/Technol. 10:779 (1992)). In this method, the affinity of
"primary" human Ig derived proteins obtained by phage display can be improved by sequentially
replacing the heavy and light chain V region genes with repertoires of naturally occurring variants
(repertoires) of V domain genes obtained from unimmunized donors. This technique allows die
production of Ig derived proteins and antibody fragments with affinities in the nM range. A strategy
for making very large phage antibody repertoires has been described by Waterhouse et al., Nucl.
Acids Res. 21:2265 (1993). Gene shuffling can also be used to derive human Ig derived proteins from
rodent Ig derived proteins, where the human antibody has similar affinities and specificities to the
starting rodent antibody. According to this method, which is also referred to as "epitope imprinting,"
the heavy or light chain V domain gene of rodent Ig derived proteins obtained by phage display
technique is replaced with a repertoire of human V domain genes, creating rodent-human chimeras.
Selection with antigen results in isolation of human variable capable of restoring a functional antigen-
binding site, i.e., the epitope governs (imprints) the choice of partner. When the process is repeated in
order to replace the remaining rodent V domain, a human antibody is obtained (see PCT WO
93/06213, published 1 April 1993). Unlike traditional humanization of rodent Ig derived proteins by

CDR grafting, this technique provides completely human Ig derived proteins, which have no
framework or CDR residues of rodent origin.
Bispecific Ig derived proteins can also be used that are monoclonal, preferably human or
humanized. Ig derived proteins mat have binding specificities for at least two different antigens. In
die present case, one of the binding specificities is for at least one IL-23p40 protein, the other one is
for any other antigen. For example, bispecific Ig derived proteins specifically binding a IL-23p40
protein and. at least one neurotrophic factor, or two different types of IL-23p40 polypeptides are
within the scope of the present invention.
Methods for making bispecific Ig derived proteins are known in the art Traditionally, the
recombinant production of bispecific Ig derived proteins is based on the co-expression of two
immunoglobulin heavy chain-light chain pairs, where me two heavy chains have different specificities
(Milstein and Cuello, Nature 305:537 (1983)). Because of the random assortment of immunoglobulin
heavy and light chains, these hybridomas (quadromas) produce a potential mixture of 10 different
antibody molecules, of which only one has the correct bispecific structure. The purification of the
correct molecule, which is usually done by affinity chromatography steps, is rather cumbersome, and
the product yields are low. Similar procedures are disclosed in WO 93/D8829 published 13 May
1993, and in Traunecker et al., EMBO J. 10:3655 (1991), entirely incorporated herein by referece.
According to a different and more preferred approach, antibody-variable domains with the
desired binding specificities (antibody-antigen combining sites) are fused to immunoglobulin
constant-domain sequences. The fusion preferably is with an immunoglobulin heavy-chain constant
domain, comprising at least part of the hinge, the second heavy chain constant region (C.sub.H 2), and
the third heavy chain constant region (C.sub.H 3). It is preferred to have the first heavy-chain
constant region (C.sub.H 1), containing the site necessary for light-chain binding, present in at least
one of the fusions. DNAs encoding the immunoglobulin heavy chain fusions and, if desired, the
immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into
a suitable host organism. This provides for great flexibility in adjusting the mutual proportions of the
three polypeptide fragments in embodiments when unequal ratios of the three polypeptide chains used
in the construction provide the optimum yields. It is, however, possible to insert the coding sequences
for two or all three polypeptide chains in one expression vector when the production of at least two
polypeptide chains in equal ratios results in high yields or when the ratios are of no particular
significance. In a preferred embodiment of this approach, the bispecific Ig derived proteins are
composed of a hybrid immunoglobulin heavy chain with a first binding specificity in one arm, and a
hybrid immunoglobulin heavy chain-light chain pair (providing a second binding specificity) in the
other aim. This asymmetric structure facilitates the separation of the desired bispecific compound
from unwanted immunoglobulin chain combinations, as the presence of an immunoglobulin light
chain in only one half of the bispecific molecule provides for a facile way of separation. For further
details of generating bispecific Ig derived proteins, see, for example, Suresh et al., Methods in

Enzymology 121:210 (1986).
Heteroconjugate Ig derived proteins are also within the scope of the present invention.
Heteroconjugate Ig derived proteins are composed of two covalently joined Ig derived proteins. Such
Ig derived proteins have, for example, been proposed to target immune system cells to unwanted cells
(U.S. Pat No. 4,676,980), and for treatment of HIV infection (WO 91/00360; WO 92/00373; and EP
03089). Heteroconjugate Ig derived proteins can be made using any convenient cross-linking
methods. Suitable cross-linking agents are well known in the art, and are disclosed in U.S. Pat No.
4,676,980, along with a number of cross-linking techniques.
In a preferred embodiment, at least one anti-IL-23p40 Ig derived protein or specified portion
or variant of the present invention is produced by a cell line, a mixed cell line, an immortalized cell or
clonal population of immortalized cells. Immortalized IL-23p40 producing cells can be produced
using suitable methods, for example, fusion of a human Ig derived protein-producing cell and a
heteromyeloma or immortalization of an activated human B cell via infection with Epstein Barr virus
(Niedbala et al, Hybridoma, 77(3):299-304 (1998); Zanella et aL, J Immunol Methods, /Jd(2):205-
215 (1992); Gustafsson et aL, Hum Ig derived proteins Hybridomas, 2(1)26-32 (1991)). Preferably,
the human anti-human IL-23p40 proteins or fragments or specified portions or variants is generated
by immunization of a transgenic animal (e.g., mouse, rat, hamster, non-human primate, and the like)
capable of producing a repertoire of human Ig derived proteins, as described herein and/or as known
in the art. Cells that produce a human anti-IL-23p40 Ig derived protein can be isolated from such
animals and immortalized using suitable methods, such as the methods described herein.
Transgenic mice that can produce a repertoire of human Ig derived proteins that bind to
human antigens can be produced by known methods (e.g., but not limited to, U.S. Pat Nos:
5,770,428,5,569,825,5,545,806,5,625,126,5,625,825,5,633,425,5,661,016 and 5,789,650 issued to
Lonberg et al.; Jakobovits et al WO 98/50433, Jakobovits et al WO 98/24893, Lonberg et al WO
!>8/24884, Lonberg et al WO 97/13852, Lonberg et al WO 94/25S85, Kncherlapate et al WO
y6/34096, Kucheriapate et al EP 0463 151 Bl, Kucherlapate et al. EP 0710 719 Al, Surani et al US.
Pat. No. 5,545,807, Bruggemann et al. WO 90/04036, Bruggemann et al EP 0438 474 Bl, Lonberg et
ci EP 0814 259 A2, Lonberg ef aL GB 2 272 440 A, Lonberg et al. Nature 368:856-859 (1994),
Taylor et aL. Int. Immunol 6(4)579-591 (1994), Green et aL Nature Genetics 7:13-21 (1994), Mendez
et al, Nature Gemtics 15:146-156 (1997), Taylor et al, Nucleic Acids Research 20(23):6287-6295
(J 992), Tuaillo:i et al. Proc Natl Acad Sci USA 90(8)3720-3724 (1993), Lonberg et al. hit Rev
Ivmuuwl 13(l):65-93 (1995) and Hshwald etal, Nat Biotechnol 14(7):845-851 (1996), which are
each entirely incorporated herein by reference). Generally, these mice comprise at least one transgene
comprising DNA from at least one human immunoglobulin locus that is functionally rearranged, or
which can undergo functional rearrangement. The endogenous immunoglobulin loci in such mice can
be disrupted or deleted to eliminate the capacity of the animal to produce Ig derived proteins encoded
b> endogenous genes.

The term "functionally rearranged," as used herein refers to a segment of DNA from an
immunoglobulin locus that has undergone V(D)J recombination, thereby producing an
immunoglobulin gene that encodes an immunoglobulin chain (e.g., heavy chain, light chain), or any
portion thereof. A functionally rearranged immunoglobulin gene can be directly or indirectly
identified using suitable methods, such as, for example, nucleotide sequencing, hybridization (e.g.,
Southern blotting. Northern blotting) using probes that can anneal to coding joints between gene
segments or enzymatic amplification of immunoglobulin genes (e.g., polymerase chain reaction) with
primers that can anneal to coding joints between gene segments. Whether a cell produces an Ig
derived protein comprising a particular variable region or a variable region comprising a particular
sequence (e.g., at least one CDR sequence) can also be determined using suitable methods. In one
example, mRNA can be isolated from an Ig derived protein-producing cell (e.g., a hybridoma or
recombinant cell or other suitable source) and used to produce cDNA encoding the Ig derived protein
or specified portion or variant thereof. The cDNA can be cloned and sequenced or can be amplified
(e.g., by polymerase chain reaction or other known and suitable methods) using a first primer that
anneals specifically to a portion of the variable region of interest (e.g., CDR, coding joint) and a
second primer that anneals specifically to non-variable region sequences (e.g., CH1, VH).
Screening Ig derived protein or specified portion or variants for specific binding to similar
proteins or fragments can be conveniently achieved using peptide display libraries. This method involves
(he screening of large collections of peptides for individual members having the desired function or
structure. Ig derived protein screening of peptide display libraries is well known in the art The displayed
peptide sequences can be from 3 to 5000 or more amino acids in length, frequently from 5-100 amino
acids long, and often from about 8 to 25 amino acids long. In addition to direct chemical synthetic
methods for generating peptide libraries, several recombinant DNA methods have been described. One
type involves the display of a peptide sequence on the surface of a bacteriophage or cell. Each
bacteriophage or cell contains the nucleotide sequence encoding the particular displayed peptide
sequence. Such methods are described in PCT Patent Publication Nos. 91/17271,91/18980,91/19818,
and 93/08278. Other systems for generating libraries of peptides have aspects of both in vitro chemical
synthesis and recombinant methods. See, PCT Patent Publication Nos. 92/05258,92/14843, and
96/19256. Sea also, U.S. Patent Nos. 5,658,754; and 5,643,768. Peptide display libraries, vector, and
screening kits are commercially available from such suppliers as Invitrogen (Carlsbad, CA), and
Cambridge Ig derived protein Technologies (Cambridgeshire, UK). See, e.g., U.S. Pat. Nos. 4704692,
4939666,494(5778,5260203,5455030,5518889,5534621,5656730,5763733,5767260,5856456,
assigned to Enzon; 5223409,5403484,5571698,5837500, assigned to Dyax, 5427908,5580717,
assigned to Af fymax; 5885793, assigned to Cambridge Ig derived protein Technologies; 5750373,
assigned to Genentech, 5618920,5595898,5576195,5698435,5693493,5698417, assigned to Xoma,
Colligan, supra; Ausubel, supra; or Sambrook, supra, each of the above patents and publications entirely
incorporated herein by reference.

Ig derived proteins, specified portions and variants of the present invention can also be
prepared using at least one EL-23p40 Ig derived protein or specified portion or variant encoding
nucleic acid to provide transgenic animals or mammals, such as goats, cows, horses, sheep, and the
like, that produce such Ig derived proteins or specified portions or variants in their milk. Such
animals can be provided using known methods. See, e.g., but not limited to, US patent nos.
5,827,690; 5,849,992; 4,873,316; 5,849,992; 5,994,616; 5,565,362; 5,304,489, and the like, each of
which is entirely incorporated herein by reference.
Ig derived proteins, specified portions and variants of the present invention can additionally
be prepared using at least one IL-23p40 Ig derived protein or specified portion or variant encoding
nucleic acid to provide transgenic plants and cultured plant cells (e.g., but not limited to, tobacco and
maize) that produce such Ig derived proteins, specified portions or variants in the plant parts or in
cells cultured therefrom. As a non-limiting example, transgenic tobacco leaves expressing
recombinant proteins have been successfully used to provide large amounts of recombinant proteins,
e.g., using art inducible promoter. See, e.g., Cramer et al., Curr. Top. Microbol. Immunol. 240:95-118
(1999) and references cited therein. Also, transgenic maize have been used to express mammalian
proteins at commercial production levels, with biological activities equivalent to those produced in
other recombinant systems or purified from natural sources. See, e.g., Hood et al., Adv. Exp. Med.
Biol. 464:127-147 (1999) and references cited therein. Ig derived proteins have also been produced in
large amount;; from transgenic plant seeds including Ig derived protein fragments, such as single chain
Ig derived proteins (scFv's), including tobacco seeds and potato tubers. See, e.g., Conrad et al., Plant
Mol. Biol. 38:101-109 (1998) and reference cited therein. Thus, Ig derived proteins, specified
portions and variants of the present invention can also be produced using transgenic plants, according
to known methods. See also, e.g., Fischer et al., Biotechnol. Appl. Biochem. 30:99-108 (Oct., 1999),
Ma et al., Trends Biotechnol. 13:522-7 (1995); Ma et al., Plant Physiol. 109:341-6 (1995); Wbitelam
:t al., Biochem. Soc. Trans. 22:940-944 (1994); and references cited therein. Each of the above
references is entirely incorporated herein by reference.
The Ig derived proteins of the invention can bind human IL-23p40 proteins or fragments with
a. wide range of affinities (KD)- In a preferred embodiment, at least one human mAb of the present
invention can optionally bind human IL-23p40 proteins or fragments with high affinity. For example,
a human mAb can bind human EL-23p40 proteins or fragments with a KD equal to or less than about
10 ' M or, more preferably, with a KD equal to or less than about 0.1-9.9 (or any range or value
therein) X 10"lc M, 10"", 10'12,10"13or any range or value therein.
The affinity or avidity of an Ig derived protein for an antigen can be determined
experimentally using any suitable method. (See, for example, Berzofsky, et al., "Ig derived protein-
Antigen Interactions," In Fundamental Immunology, Paul, W. E., Ed., Raven Press: New York, NY
(1984); Kuby, Janis Immunology, W. H. Freeman and Company: New York, NY (1992); and methods
described herein). The measured affinity of a particular Ig derived protein-antigen interaction can

vary if measured under different conditions (e.g., salt concentration, pH). Thus, measurements of
affinity and other antigen-binding parameters (e.g., KD, Ka, Kd) are preferably made with standardized
solutions of ]g derived protein and antigen, and a standardized buffer, such as the buffer described
herein.
Nucleic Acid Molecules
Using the information provided herein, a nucleic acid molecule of the present invention
encoding at least one IL-23p40 Ig derived protein or specified portion or variant can be obtained using
methods described herein or as known in die art
Nucleic acid molecules of the present invention can be in me form of RNA, such as mRNA,
hnRNA, tRNA or any other form, or in the form of DNA, including, but not limited to, cDNA and
genomic DNA obtained by cloning or produced synthetically, or any combinations thereof. The DNA
can be triple-si randed, double-stranded or single-stranded, or any combination thereof. Any portion
of at least one strand of the DNA or RNA can be the coding strand, also known as the sense strand, or
; t can be the non-coding strand, also referred to as the anti-sense strand.
Isolated nucleic acid molecules of die present invention can include nucleic acid molecules
c omprising an open reading frame (ORF), optionally with one or more introns, e.g., but not limited to,
jit least one specified portion of at least one CDR, as CDR1, CDR2 and/or CDR3 of at least one heavy
chain or light chain, respectively; nucleic acid molecules comprising the coding sequence for a IL-
23p40 Ig derived protein or specified portion or variant; and nucleic acid molecules which comprise a
nucleotide sequence substantially different from those described above but which, due to the
degeneracy of die genetic code, still encode at least one IL-23p40 Ig derived protein as described
h'irein and/or as known in the art. Of course, the genetic code is well known in the art. Thus, it
would be routine for one skilled in the art to generate such degenerate nucleic acid variants that code
for specific EL-23p40 Ig derived protein or specified portion or variants of the present invention. See,
e.g., Ausubel, et al., supra, and such nucleic acid variants are included in the present invention.
As indicated herein, nucleic acid molecules of the present invention which comprise a nucleic
acid encoding a IL-23p40 Ig derived protein or specified portion or variant can include, but are not
limited to, those encoding the amino acid sequence of an Ig derived protein fragment, by itself; the
coding sequence for the entire Ig derived protein or a portion thereof; the coding sequence for an Ig
derived protein, fragment or portion, as well as additional sequences, such as the coding sequence of
at east one signal leader or fusion peptide, with or without the aforementioned additional coding
secfuonces, such as at least one intron, together with additional, non-coding sequences, including but
noi limited to, non-coding 5' and 3' sequences, such as the transcribed, non-translated sequences that
play a role in transcription, mRNA processing, including splicing and polyadenylation signals (for
example - ribosome binding and stability of mRNA); an additional coding sequence that codes for
additional amino acids, such as those that provide additional functionalities. Thus, the sequence

encoding an Ig derived protein or specified portion or variant can be fused to a marker sequence, such
as a sequence encoding a peptide that facilitates purification of the fused Ig derived protein or
specified portion or variant comprising an Ig derived protein fragment or portion.
Polynucleotides Which Selectively Hybridize to a Polynucleotide as Described Herein
The present invention provides isolated nucleic acids that hybridize under selective hybridization
conditions to a polynucleotide encoding a IL-23p40 Ig derived protein of the present invention. Thus, the
polynucleotides of this embodiment can be used for isolating, detecting, and/or quantifying nucleic acids
comprising such polynucleotides. For example, polynucleotides of the present invention can be used to
identify, isolate, or amplify partial or full-length clones in a deposited library. In some embodiments, the
polynucleotides are genomic or cDNA sequences isolated, or otherwise complementary to, a cDNA from
a human or mammalian nucleic acid library.
Preferably, the cDNA library comprises at least 80% full-length sequences, preferably, at least
J'i5% or 90% fud-lengm sequences, and, more preferably, at least 95% full-length sequences. The cDNA
libraries can be normalized to increase the representation of rare sequences. Low or moderate stringency
hybridization conditions are typically, but not exclusively, employed with sequences having a reduced
sequence identity relative to complementary sequences. Moderate and high stringency conditions can
optionally be employed for sequences of greater identity. Low stringency conditions allow selective
h ybridization of sequences having about 70% sequence identity and can be employed to identify
orthologous or paralogous sequences.
Optionally, polynucleotides of this invention will encode at least a portion of an Ig derived
protein or specified portion or variant encoded by the polynucleotides described herein. The
polynucleotides of this invention embrace nucleic acid sequences that can be employed for selective
hybridization to a polynucleotide encoding an Ig derived protein or specified portion or variant of the
present invention. See, e.g., Ausubel, supra; Colligan, supra, each entirely incorporated herein by
reference.
Construction of Nucleic Adds
The isolated nucleic acids of the present invention can be made using (a) recombinant methods,
(b) synthetic techniques, (c) purification techniques, or combinations thereof, as well-known in the art
The nucleic acids can conveniently comprise sequences in addition to a polynucleotide of the
present invention. For example, a multi-cloning site comprising one or more endonuclease restriction
sites can be inserted into the nucleic acid to aid in isolation of the polynucleotide. Also, translatable
sequences can be inserted to aid in the isolation of the translated polynucleotide of the present invention.
For example, a hexa-histidine marker sequence provides a convenient means to purify the proteins of the
present invention. The nucleic acid of the present invention - excluding the coding sequence - is

optionally a vector, adapter, or linker for cloning and/or expression of a polynucleotide of the present
invention.
Additional sequences can be added to such cloning and/or expression sequences to optimize their
function in cloning and/or expression, to aid in isolation of the polynucleotide, or to improve the
introduction of the polynucleotide into a cell. Use of cloning vectors, expression vectors, adapters, and
linkers is well known in the art. (See, e-g., Ausubel, supra; or Sambrook, supra)
Recombinant Methods for Constructing Nucleic Adds
The isolated nucleic acid compositions of this invention, such as RNA, cDNA, genomic DNA, or
any combinab on feereof, can be obtained from biological sources using any number of cloning
methodologies known to those of skill in the art In some embodiments, oligonucleotide probes mat
selectively hybridize, under stringent conditions, to the polynucleotides of the present invention are used
to identify fee desired sequence in a cDNA or genomic DNA library. The isolation of RNA, and
construction of cDNA and genomic libraries, is well known to those of ordinary skill in the art (See, eg.,
Ausubel, supra; or Sambrook, supra)
Nucleic Acid Screening and Isolation Methods
A cDN A or genomic library can be screened using a probe based upon the sequence of a
polynucleotide of the present invention, such as those disclosed herein. Probes can be used to hybridize
with genomic DNA or cDNA sequences to isolate homologous genes in the same or different organisms.
Those of skill in the art will appreciate mat various degrees of stringency of hybridization can be
e mployed in the assay; and either fee hybridization or fee wash medium can be stringent As the
conditions for hybridization become more stringent, there must be a greater degree of complementarity
between fee probe and the target for duplex formation to occur. The degree of stringency can be
controlled by one or more of temperature, ionic strength, pH and the presence of a partially denaturing
solvent such as formamide. For example, fee stringency of hybridization is conveniently varied by
changing the polarity of fee reactant solution through, for example, manipulation of fee concentration of
formamide within the range of 0% to 50%. The degree of complementarity (sequence identity) required
for detectable binding will vary in accordance with fee stringency of fee hybridization medium and/or
wash medium. The degree of complementarity will optimally be 100%, or 90-100%, or any range or
viilue therein. However, it should be understood feat minor sequence variations in the probes and primers
can be compensated for by reducing fee stringency of the hybridization and/or wash medium.
Method;; of amplification of RNA or DNA are well known in the art and can be used
according to the present invention without undue experimentation, based on the teaching and
guidance presented herein.
Known methods of DNA or RNA amplification include, but are not limited to, polymerase
chain reaction (PCR) and related amplification processes (see, e.g., U.S. Patent Nos. 4,683,195,

4,683,202,4,300,159,4,965,188, to Mullis, et al.; 4,795,699 and 4,921,794 to Tabor, et al; 5,142,033
to Innis; 5,122,464 to Wilson, et al.; 5,091,310 to lnnis; 5,066,584 to Gyllensten, et al; 4,889,818 to
Gelfand, et al; 4,994,370 to Silver, et al; 4,766,067 to Biswas; 4,656,134 to Ringold) and RNA
mediated amplification that uses anti-sense RNA to the target sequence as a template for double-
stranded DNA synthesis (U.S. Patent No. 5,130,238 to Malek, et al, with the tradename NASBA), the
entire contents of which references are incorporated herein by reference. (See, e.g., Ausubel, supra; or
Sambrook, supra.)
For instance, polymerase chain reaction (PCR) technology can be used to amplify the sequences
of polynucleotides of the present invention and related genes direcdy from genomic DNA or cDNA
libraries. PCR and other in vitro amplification methods can also be useful, for example, to clone nucleic
acid sequences that code for proteins to be expressed, to make nucleic acids to use as probes for detecting
the presence of the desired mRNA in samples, for nucleic acid sequencing, or for other purposes.
Examples of techniques sufficient to direct persons of skill through in vitro amplification methods are
[bund in Berger, supra, Sambrook, supra, and Ausubel, supra, as well as Mullis, et al., U.S. Patent No.
4,683,202 (1987); and Innis, et al., PCR Protocols A Guide to Methods and Applications, Eds., Academic
Press Inc., San Diego, CA (1990). Commercially available kits for genomic PCR amplification are
known in the ait. See, e.g., Advantage-GC Genomic PCR Kit (Clontech). The T4 gene 32 protein
(Boehringer Miinnheim) can be used to improve yield of long PCR products.
Synthetic Methods for Constructing Nucleic Adds
The isolated nucleic acids of the present invention can also be prepared by direct chemical
s ynthesis by known methods (see, e.g., Ausubel, et al., supra). Chemical synthesis generally produces a
smgle-stranded oligonucleotide, which can be converted into double-stranded DNA by hybridization with
a complementary sequence, or by polymerization with a DNA polymerase using the single strand as a
template. One of skill in the art will recognize that while chemical synthesis of DNA can be Hrnited to
sequences of about 100 or more bases, longer sequences can be obtained by the ligation of shorter
sequences.
Recombinant Expression Cassettes
The present invention further provides recombinant expression cassettes comprising a nucleic
ac id of the present invention. A nucleic acid sequence of the present invention, for example, a cDNA or a
genomic sequence encoding an Ig derived protein or specified portion or variant of the present invention,
can be used to construct a recombinant expression cassette that can be introduced into at least one desired
host cell. A recombinant expression cassette will typically comprise a polynucleotide of die present
invention operably linked to transcriptional initiation regulatory sequences that will direct the
transcription of die polynucleotide in the intended host cell. Both heterologous and non-heterologous

(i .e., endogenous) promoters can be employed to direct expression of the nucleic acids of the present
invention.
In some embodiments, isolated nucleic acids mat serve as promoter, enhancer, or other elements
can be introduced in the appropriate position (upstream, downstream or in intron) of a non-heterologous
form of a poly nucleotide of the present invention so as to up or down regulate expression of a
polynucleotide of the present invention. For example, endogenous promoters can be altered in vivo or in
vitro by mutation, deletion and/or substitution.
A polynucleotide of the present invention can be expressed in either sense or anti-sense
orientation as desired. It will be appreciated that control of gene expression in either sense or anti-sense
orientation can have a direct impact on the observable characteristics.
Another method of suppression is sense suppression. Introduction of nucleic acid configured in
tiie sense orientation has been shown to be an effective means by which to block the transcription of
target genes.
A variety of cross-linking agents, alkylating agents and radical generating species as pendant
groups on polynucleotides of the present invention can be used to bind, label, detect and/or cleave nucleic
acids. Knorre, et al., Biochirnie 67:785-789 (1985); Vlassov, et al., Nucleic Acids Res. 14:4065-4076
(1986); Iverson and Dervan, J. Am. Chem. Soc. 109:1241-1243 (1987); Meyer, et al., J. Am. Chem. Soc.
111:8517-8519 (1989); Lee, et al., Biochemistry 27:3197-3203 (1988); Home, et al., J. Am. Chem. Soc.
112:2435-24:17 (1990); Webb and Matteucci, J. Am. Chem. Soc. 108:2764-2765 (1986); Nucleic Acids
Res. 14:7661 7674 (1986); Feteritz, et al., J. Am. Chem. Soc. 113:4000 (1991). Various compounds to
bind, detect, label, and/or cleave nucleic acids are known in the art See, for example, U.S. Patent Nos.
5,543,507; 5,672,593; 5,484,908; 5,256,648; and 5,681941, each entirely incorporated herein by
reference.
Vectors And Host Cells
The present invention also relates to vectors that include isolated nucleic acid molecules of
the present invention, host cells that are genetically engineered with the recombinant vectors, and the
production of at least one IL-23p40 Ig derived protein or specified portion or variant by recombinant
techniques, as is well known in the art. See, e.g., Sambrook, et al., supra; Ausubel, et al., supra, each
entirely incorporated herein by reference.
The polynucleotides can optionally be joined to a vector containing a selectable marker for
propagation in a host. Generally, a plasmid vector is introduced in a precipitate, such as a calcium
phosphate precipitate, or in a complex with a charged lipid. If the vector is a virus, it can be packaged
in vitro using an appropriate packaging cell line and then transduced into host cells.
The DNA insert should be operatively linked to an appropriate promoter. The expression
constructs will further contain sites for transcription initiation, termination and, in the transcribed
region, a ribosome binding site for translation. The coding portion of the mature transcripts expressed

by the constructs will preferably include a translation initiating at the beginning and a termination
codon (e.g., UAA, UGA or UAG) appropriately positioned at the end of the raRNA to be translated,
with UAA and UAG preferred for mammalian or eukaryotic cell expression.
Expression vectors will preferably but optionally include at least one selectable marker. Such
markers include, e.g., but not limited to, methotrexate (MTX), dihydrofolate reductase (DHFR, US
Pat.Nos. 4,399,216; 4,634,665; 4,656,134; 4,956,288; 5,149,636; 5,179,017, ampicillin, neomycin
(G418), mycophenolic acid, or glutanrine synthetase (GS, US PatNos. 5,122,464; 5,770,359;
5.827,739) resistance for eukaryotic cell culture, and tetracycline or ampicillin resistance genes for
culturing in e. Coli and other bacteria or prokaryotics (the above patents are entirely incorporated
hereby by reference). Appropriate culture mediums and conditions for the above-described host cells
are known in the art. Suitable vectors will be readily apparent to the skilled artisan. Introduction of a
vector construct into a host cell can be effected by calcium phosphate transfection, DEAE-dextran
mediated transfection, canonic lipid-mediated transfection, electroporation, transduction, infection or
other known methods. Such methods ate described in the art, such as Sambrook, supra. Chapters 1-4
and 16-18; Ausubel, supra, Chapters 1,9,13,15,16.
At least one Ig derived protein or specified portion or variant of the present invention can be
expressed in a modified form, such as a flision protein, and can include not only secretion signals, but
aJso additional heterologous functional regions. For instance, a region of additional amino acids,
particularly charged amino acids, can be added to the N-terminus of an Ig derived protein or specified
portion or variant to improve stability and persistence in the host cell, daring purification, or during
subsequent handling and storage. Also, peptide moieties can be added to an Ig derived protein or
specified portion or variant of the present invention to facilitate purification. Such regions can be
removed prior to final preparation of an Ig derived protein or at least one fragment thereof. Such
methods are described in many standard laboratory manuals, such as Sambrook, supra, Chapters
17 29-17.42 and .18.1-18.74; Ausubel, supra, Chapters 16,17 and 18.
Those of ordinary skill in the art are knowledgeable in the numerous expression systems
available for expression of a nucleic acid encoding a protein of the present invention.
Alternatively, nucleic acids of the present invention can be expressed in a host cell by turning on
(by manipulation) in a host cell that contains endogenous DNA encoding an Ig derived protein or
specified portion or variant of the present invention. Such methods are well known in the art, e.g., as
described in US patent Nos. 5,580,734,5,641,670,5,733,746, and 5,733,761, entirely incorporated herein
by reference.
IIusirative of cell cultures useful for the production of the Ig derived proteins, specified portions
or vsaiants thereof, are mammalian cells. Mammalian cell systems often will be in the form of
monolayers of cells although mammalian cell suspensions or bioreactors can also be used. A number of
suitable host cell lines capable of expressing intact glycosylated proteins have been developed in fee art,
and include the COS-1 (e.g., ATCC CRL1650), COS-7 (e.g., ATCC CRL651), HEK293, BHK21

(e.g., ATCC CRL-10), CHO (e.g., ATCC CRL1610) and BSC-1 (e.g., ATCC CRL-26) cell lines, Cos-7
cells, CHO cells, hep G2 cells, P3X63Ag8.653, SP2/0-Agl4, 293 cells, HeLa cells and the like, which
are readily available from, for example, American Type Culture Collection, Manassas, Va. Preferred
host cells include cells of lymphoid origin such as myeloma and lymphoma cells. Particularly
preferred host cells are P3X63Ag8.653 cells (ATCC Accession Number CRL-1580) and SP2/0-Agl4
cells (ATCC Accession Number CRL-1851). In a particularly preferred embodiment, the
recombinant cell is a P3X63Ab8.653 or a SP2/D-Agl4 cell.
Expression vectors for these cells can include one or more of the following expression control
sequences, such as, but not limited to, an origin of replication; a promoter (e.g., late or early SV40
promoters, the CMV promoter (US PatNos. 5,168,062; 5,385,839), an HSV tk promoter, a pgk
(phosphoglycerate kinase) promoter, an EF-1 alpha promoter (US PatNo. 5,266,491), at least one human
immunoglobulin promoter, an enhancer, and/or processing information sites, such as ribosome binding
sites, RNA splice sites, polyadenylation sites (e.g., an SV40 large T Ag poly A addition site), and
transcriptional terminator sequences. See, e.g., Ausubel et al., supra; Sambrook, et aL, supra. Other cells
useful for production of nucleic acids or proteins of the present invention are known and/or available, for
instance, from the American Type Culture Collection Catalogue of Cell Lines and Hybridomas
i www.atcc.org) or other known or commercial sources.
When eukaryotic host cells are employed, polyadenlyation or transcription terminator sequences
arc typically incorporated into the vector. An example of a terminator sequence is the polyadenlyation
sequence from the bovine growth hormone gene. Sequences for accurate splicing of the transcript can
a Iso be included. An example of a splicing sequence is the VP1 intron from SV40 (Sprague, et al., J.
Virol. 45:773-781 (1983)). Additionally, gene sequences to control replication in the host cell can be
incorporated into the vector, as known in the art.
Purification of an Ig derived protein or Specified Portion or Variant Thereof
An IL-23p40 Ig derived protein or specified portion or variant can be recovered and purified
from recombinant cell cultures by well-known methods including, but not limited to, protein A
purification, ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange
chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography,
affinity chromatography, hydroxylapatite chromatography and lectin chromatography. High
peiformance liquid chromatography ("HPLC") can also be employed for purification. See e.g.,
Colbgan, Current Protocols in Immunology, or Current Protocols in Protein Science, John Wiley &
Sons. NY, NY, (1997-2003), e.g., Chapters 1,4,6,8,9,10, each entirely incorporated herein by
reference.
Ig derived proteins or specified portions or variants of the present invention include naturally
purified products, products of chemical synthetic procedures, and products produced by recombinant
techniques from a eukaryotic host, including, for example, yeast, higher plant, insect and mammalian

cells. Depending upon the host employed in a recombinant production procedure, the Ig derived
protem or specified portion or variant of the present invention can be giycosylated or can be non-
glycosylated, with glycosylated preferred. Such methods are described in many standard laboratory
manuals, such as Sambrook, supra, Sections 17.37-17.42; Ausubel, supra, Chapters 10,12,13,16,18
and 20, Coliigan, Protein Science, supra, Chapters 12-14, all entirely incorporated herein by reference.
IL-23P40 Ig DERIVED PROTEINS, FRAGMENTS AND/OR VARIANTS
The isolated Ig derived proteins of the present invention comprise an Ig derived protein or
specified portion or variant encoded by any one of the polynucleotides of the present invention, as
discussed more fully herein, or any isolated or prepared Ig derived protein or specified portion or variant
thereof.
Preferably, the human Ig derived protein or antigen-binding fragment binds human IL-23p40
proteins or fragments and, thereby substantially neutralizes the biological activity of the protein. An
Ig derived protein, or specified portion or variant thereof, that partially or preferably substantially
neu tralizes at least one biological activity of at least one IL23p40 protein or fragment can bind the
protem or fragment and thereby inhibit activities mediated through the binding of IL-23p40 to at least
one lL-23p40 receptor or through other IL-23p40-dependent or mediated mechanisms. As used
herein, the term "neutralizing Ig derived protein" refers to an Ig derived protein mat can inhibit human
p40 or pl9 protem or fragment related-dependent activity by about 20-120%, preferably, by at least
about 60,70,80,90,91,92,93,94,95,96,97,98,99,100% or more depending on the assay. The
capacity of anti-human E^23p40 Ig derived protein or specified portion or variant to inhibit human
BL-:'.3p40 related-dependent activity is preferably assessed by at least one suitable EL-23p40 Ig
derived protein or protein assay, as described herein and/or as known in the art A human Ig derived
prott an or specified portion or variant of the invention can be of any class (IgG, IgA, IgM, IgE, IgD,
etc.) or isotype and can comprise a kappa or lambda light chain. In one embodiment, the human Ig
derived protein or specified portion or variant comprises an IgG heavy chain or defined fragment, for
example, at least one of isotypes, IgGl, IgG2, IgG3 or IgG4. Ig derived proteins of mis type can be
prepared by emplo} ing a transgenic mouse or other trangenic non-human mammal comprising at least
one human light chain (e.g., IgG, IgA and IgM (e.g., yl, Y2. Y3. Y4 transgenes as described herein
and/oi as known in she art. In another embodiment, the anti-human IL-23p40 Ig derived protein or
specified portion or variant thereof comprises an IgGl heavy chain and an IgGl Mght chain.
At least one Ig derived protein or specified portion or variant of the invention binds at least
one spmfied epitope specific to at least one IL-23p40 protein, subunit, fragment, portion or any
combination thereof. The at least one epitope can comprise at least one Ig derived protein binding
region that comprises at least one portion of said protein, which epitope is preferably comprised of at
least one extracellular soluble, hydrophillic, external or cytoplasmic portion of said protein. As non-
limiting examples, (a) a IL-23p40 Ig derived protein or specified portion or variant specifically binds

at least one epitope comprising at least 1-3, to the entire amino acid sequence, selected from the group
consisting of at least one p40 subunit of human IL-23. The at least one specified epitope can
comprise any combination of at least one amino acid of the p40 subunit of a human interieukin-23,
such as, but not limited to, 1,2,3,4,5,6,7,8,9,10,11,12,13 or 14 amino acids of at least one of, 1-
10,10-20, 20-30,30-40,40-50,50-60,60-70,70-80,80-90,90-100,100-110,110-120,120-130,130-
140,140 150,150-160,160-170,170-180,180-190,190-200,200-210,210-220,220-230,230-240,
240-250, 250-260, 260-270,280-290,290-300,300-306, 1-7,14-21,29-52, 56-73, 83-93,96-105,
156-175, 194-204,208-246,254-273,279-281, or 289-300 of SEQ ID NO:l.
Generally, the human Ig derived protein or antigen-binding fragment of the present invention
will comprise an antigen-binding region that comprises at least one human complementarity
determining region (CDR1, CDR2 and CDR3) or variant of at least one heavy chain variable region
and at least one human complementarity determining region (CDR1, CDR2 and CDR3) or variant of
at least one light chain variable region. As a non-limiting example, the Ig derived protein or antigen-
binding portion or variant can comprise at least one of the heavy chain CDR3, and/or a light chain
CDR3. In a particular embodiment, the Ig derived protein or antigen-binding fragment can have an
antigen-binding region that comprises at least a portion of at least one heavy chain CDR (i.e., CDR1,
CDR2 and/or CDR3) having the amino acid sequence of the corresponding CDRs 1,2 and/or 3. In
another particular embodiment, the Ig derived protein or antigen-binding portion or variant can have
an antigen-binding region that comprises at least a portion of at least one light chain CDR (i.e., CDR1,
GDR2 and/or CDR3) having the amino acid sequence of the corresponding CDRs 1,2 and/or 3. Such
Ig derived proteins can be prepared by chemically joining together the various portions (e.g., CDRs,
framework) of the Ig derived protein using conventional techniques, by preparing and expressing a
(i.e., one or more) nucleic acid molecule that encodes the Ig derived protein using conventional
techniques of recombinant DNA technology or by using any other suitable method.
The anti-IL-23p40 Ig derived protein can comprise at least one of a heavy or light chain
variable region having a defined amino acid sequence. For example, in a preferred embodiment, the
ann-IL-23p40 Ig derived protein comprises at least one of at least one heavy chain variable region
and/or at least one light chain variable region. Human Ig derived proteins that bind to human IL-
23p40 proteins; or fragments and that comprise a defined heavy or light chain variable region can be
prepared using suitable methods, such as phage display (Katsube, Y., et al, bit J Mol. Med, 1(5):863-
868 (1998)) or mediods that employ transgenic animals, as known in the art and/or as described
herein. For example, a transgenic mouse, comprising a functionally rearranged human
immunoglobulin heavy chain transgene and a transgene comprising DNA from a human
Immunoglobulin light chain locus that can undergo functional rearrangement, can be immunized with
human IL-23p40 proteins or fragments thereof to elicit the production of Ig derived proteins. If
dssired, the Ig derived protein producing cells can be isolated and hybridomas or other immortalized
Ig; derived protein-producing cells can be prepared as described herein and/or as known in the art.

Alternatively, the Ig derived protein, specified portion or variant can be expressed using the encoding
nucleic acid or portion thereof in a suitable host cell.
The invention also relates to Ig derived proteins, antigen-binding fragments, immunoglobulin
chains and CDRs comprising amino acids in a sequence that is substantially the same as an amino
acid sequence described herein. Preferably, such Ig derived proteins or antigen-binding fragments
and Ig derived proteins comprising such chains or CDRs can bind human IL-23p40 proteins or
fragments with high affinity (e.g., KD less man or equal to about 10*9 M). Amino acid sequences that
are substantially the same as the sequences described herein include sequences comprising
conservative amino acid substitutions, as well as amino acid deletions and/or insertions. A
conservat ve amino acid substitution refers to the replacement of a first amino acid by a second amino
acid that has chemical and/or physical properties (e.g., charge, structure, polarity,
hydrophobicity/hydrophilicity) that are similar to those of the first amino acid. Conservative
substitutions include replacement of one amino acid in a group by another within the same group as in
the following groups: lysine (K), arginine (R) and histidine (H); aspartate (D) and glutamate (E);
asparagine (N), glutamine (Q), serine (S), threonine (T), tyrosine (Y), K, R, H, D and E; alanine (A),
valine (V), leucine (L), isoleucine (I), proline (P), phenylalanine (F), tryptophan (W), methionine (M),
cysteine (C) and glycine (G); F, W and Y; C, S and T.
Amino Acid Codes
The amino acids that make up IL-23p40 Ig derived proteins or specified portions or variants
of the present invention are often abbreviated. The amino acid designations can be indicated by
designating the amino acid by its single letter code, its three letter code, name, or three nucleotide
codon(s) as in well understood in the art (see Alberts, B., et al., Molecular Biology of The Cell, Third
Ed., Garland Publishing, Inc., New York, 1994):

An IL-23p40 Ig derived protein or specified portion or variant of the present invention can
include one or more amino acid substitutions, deletions or additions, either from natural mutations or
human manipulation, as specified herein.
Of course, the number of amino acid substitutions a skilled artisan would make depends on
many factors, including those described above. Generally speaking, the number of amino acid
substitutions, insertions or deletions for any given IL-23p40 polypeptide will not be more than 40,30,
20,19,18,17, 16,15,14,13,12,11,10, 9,8,7,6,5,4,3,2,1, such as 1-30 or any range or value
Therein, as specified herein.
Amino acids in an IL-23p40 Ig derived protein or specified portion or variant of the present
invention that are essential for function can be identified by methods known in the art, such as site-
directed mutagenesis or alanine-scanning mutagenesis (e.g., Ausubel, supra, Chapters 8,15;
Cunningham and Wells, Science 244:1081-1085 (1989)). The latter procedure introduces single
alanine mutations at every residue in the molecule. The resulting mutant molecules are then tested for
biological activity, such as, but not limited to, at least one IL-23p40 neutralizing activity. Sites that
aie critical for Ig derived protein or specified portion or variant binding can also be identified by
structural analysis, such as crystallization, nuclear magnetic resonance or photoaffinity labeling
(Smith, et al., J. Mol. Biol. 224:899-904 (1992) and de Vos, et al., Science 255:306-312 (1992)).
The Ig derived proteins or specified portions or variants of the present invention, or specified
variants thereof, can comprise any number of contiguous amino acid residues from an Ig derived protein
or specified portion or variant of the present invention, wherein mat number is selected from the group of
integers consisting of from 10-100% of the number of contiguous residues in an EL-23p40 Ig derived
pnrtein or specified portion or variant. Optionally, this subsequence of contiguous amino acids is at least
ab)ur 10,20, 30,40,50,60,70, 80,90,100,110,120,130,140,150,160,170,180,190,200,210,220,
23(), 240,250 or more amino acids in length, or any range or value therein. Further, the number of such
sut»sequences can be any integer selected from the group consisting of from 1 to 20, such as at least 2,3,
4, or 5.
As those of skill will appreciate, the present invention includes at least one biologically active Ig
derived protein or specified portion or variant of the present invention. Biologically active Ig derived
pro: eins or specifi
preferably at least 50%, 60%, or 70%, and most preferably at least 80%, 90%, or 95%-1000% of that of
the native (non-synthetic), endogenous or related and known Ig derived protein or specified portion or
variant Methods of assaying and quantifying measures of enzymatic activity and substrate specificity,
are well known to those of skill in the art.
In another aspect, the invention relates to human Ig derived proteins and antigen-binding
fragments, as described herein, which are modified by the covalent attachment of an organic moiety.
Such modification can produce an Ig derived protein or antigen-binding fragment with improved
pharmacokinetic properties (e.g., increased in vivo serum half-life). The organic moiety can be a
linear or branched hydrophilic polymeric group, fatty acid group, or fatty acid ester group. In
particular embodiments, the hydrophilic polymeric group can have a molecular weight of about 800 to
about 120,000 Daltons and can be a polyalkane glycol (e.g., polyethylene glycol (PEG),
{olypropylene glycol (PPG)), carbohydrate polymer, amino acid polymer or polyvinyl pyrolidone,
and the fatty acid or fatty acid ester group can comprise from about eight to about forty carbon atoms.
The modified Ig derived proteins and antigen-binding fragments of the invention can
comprise one or more organic moieties that are covalendy bonded, directly or indirectly, to the Ig
derived protein or specified portion or variant. Each organic moiety that is bonded to an Ig derived
protein or antigen-binding fragment of the invention can independently be a hydrophilic polymeric
group, a fatty acid group or a fatty acid ester group. As used herein, the term "fatty acid"
encompasses mono-carboxylic acids and di-carboxylic acids. A "hydrophilic polymeric group," as
the term is used herein, refers to an organic polymer that is more soluble in water than in octane. For
example, polylysine is more soluble in water than in octane. Thus, an Ig derived protein modified by
the covalent attachment of polylysine is encompassed by the invention. Hydrophilic polymers
suitable for modifying Ig derived proteins of the invention can be linear or branched and include, for
example, polyalkane glycols (e.g., PEG, monomethoxy-polyethylene glycol (mPEG), PPG and the
Iil.e), carbohydrates (e.g., dextran, cellulose, oligosaccharides, polysaccharides and the like), polymers
of hydrophilic amino acids (e.g., polylysine, polyargmine, polyaspartate and the like), polyalkane
oxides (e.g., polyethylene oxide, polypropylene oxide and the like) and polyvinyl pyrolidone.
Preferably, the hydrophilic polymer that modifies the Ig derived protein of the invention has a
molecular weight of about 800 to about 150,000 Daltons as a separate molecular entity. For example,
PEG,ooo and PEG2o,ooo. wherein the subscript is the average molecular weight of the polymer in
Daltons, can be used.
The hydrophilic polymeric group can be substituted with one to about six alkyl, fatty acid or
fati y acid ester groups. Hydrophilic polymers that are substituted with a fatty acid or fatty acid ester
group can be prepared by employing suitable methods. For example, a polymer comprising an amine
group can be coupled to a carboxylate of the fatty acid or fatty acid ester, and an activated carboxylate
(e.j,., activated with N, N-carbonyl diimidazole) on a fatty acid or fatty acid ester can be coupled to a
hyclroxyl group on a polymer.

Fatty acids and fatty acid esters suitable for modifying Ig derived proteins of the invention
can be saturated or can contain one or more units of uasaturation. Fatty acids that are suitable for
modifying Ig derived proteins of the invention include, for example, n-dodecanoate (Clz, laurate), n-
tetradecanoaie (C!4, myristate), n-octadecanoate (C„, stearate), n-eicosanoate (Qo, arachidate), n-
docosanoate (C22, behenate), n-triacontanoate (C30), n-tetracontanoate (C«), c«-A9-octadecanoate
(Cis, oleate), all cw-A5,8,ll,14-eicosatetraenoate (CM, arachidonate), octanedioic acid,
tetradecanedioic acid, octadecanedioic acid, docosanedioic acid, and the like. Suitable fatty acid
esters include mono-esters of dicarboxylic acids mat comprise a linear or branched lower alkyl group.
The lower alkyl group can comprise from one to about twelve, preferably, one to about six, carbon
atoms.
The modified human Ig derived proteins and antigen-binding fragments can be prepared using
suitable methods, such as by reaction with one or more modifying agents. A "modifying agent" as the
1 erm is used herein, refers to a suitable organic group (e.g., hydrophilic polymer, a fatty acid, a fatty
acid ester) that comprises an activating group. An "activating group" is a chemical moiety or
functional group that can, under appropriate conditions, react with a second chemical group thereby
forming a covalent bond between (he modifying agent and the second chemical group. For example,
a mine-reactive activating groups include electrophilic groups such as tosylate, mesylate, halo (chloro,
bromo, fluoro, iodo), N-hydroxysuccinimidyl esters (NHS), and the like. Activating groups that can
react with thiols include, for example, maleimide, iodoacetyl, acrylolyl, pyridyl disulfides, S-thiol-2-
n tiobenzoic acid thiol (TNB-thiol), and the like. An aldehyde functional group can be coupled to
amine- or hydrazide-containing molecules, and an azide group can react with a trivalent phosphorous
gioup to form phosphoraraidate or phosphorimide linkages. Suitable methods to introduce activating
groups into molecules are known in the art (see, for example, Hermanson, G. T., Bioconjugate
Teclmiques, Academic Press: San Diego, CA (1996)). An activating group can be bonded directly to
the; organic group (e.g., hydrophilic polymer, fatty acid, fatty acid ester), or through a linker moiety,
for example, a divalent Ci-Cl2 group wherein one or more carbon atoms can be replaced by a
h& eroatom such as oxygen, nitrogen or sulfur. Suitable linker moieties include, for example,
let methylene glycol, -(CH2)r, -NH-tCH^-NH-, -(CH2)2NH- and -CHJ-O-CHJ-CHT-O-CHZ-CHZ-O-
CH-NH-. Modifying agents that comprise a linker moiety can be produced, for example, by reacting
a niono-Boc-alkyldiamine (e.g., mono-Boc-ethylenediamine, mono-Boc-diarninohexane) with a fatty
acid in the presence of l-ethyI-3-(3-dimethylaminopropyl) carbodiimide (EDC) to form an amide
borid between the free amine and the fatty acid carboxylate. The Boc protecting group can be
removed from the product by treatment with trifluoroacetic acid (TFA) to expose a primary amine that
can be coupled to another carboxylate as described, or can be reacted with maleic anhydride and the
resu king product cyclized to produce an activated maleimido derivative of the fatty acid. (See, for

example, Thompson, et al, WO 92/16221, the entire teachings of which are incorporated herein by
reference.)
The modified Ig derived proteins of the invention can be produced by reacting a human Ig
derived protein or antigen-binding fragment with a modifying agent. For example, the organic
moieties can be bonded to the Ig derived protein in a non-site specific manner by employing an
amine-reactive modifying agent, for example, an NHS ester of PEG. Modified human Ig derived
proteins or antigen-binding fragments can also be prepared by reducing disulfide bonds (e.g., intra-
cliain disulfide bonds) of an Ig derived protein or antigen-binding fragment. The reduced Ig derived
protein or antigen-binding fragment can then be reacted with a thiol-reactive modifying agent to
produce the modified Ig derived protein of the invention. Modified human Ig derived proteins and
antigen-binding fragments comprising an organic moiety that is bonded to specific sites of an Ig
derived protein or specified portion or variant of the present invention can be prepared using suitable
methods, such as reverse proteolysis (Fisch et al., Bioconjugate Chem., 3:147-153 (1992); Werlen et
al.,Bioconjugate Chem., 5:411-417 (1994); Kumaran etal. Protein Set 6(10):2233-2241 (1997); Itoh
et al, Bioorg. Chem., 24(1): 59-68 (1996); Capellas et al, Biotechnol Bioeng., 56(4):456-463
(1997)), and die methods described in Hermanson, G. T., Bioconjugate Techniques, Academic Press:
San Diego, CA (1996).
[L-23P40 IG DERIVED PROTEIN OR SPECIFIED PORTION OR VARIANT
COMPOSITIONS
The present invention also provides at least one EL-23p40 Ig derived protein or specified
xirtion or variant composition comprising at least one, at least two, at least three, at least four, at least
:!lve, at least six or more IL-23p40 Ig derived proteins or specified portions or variants thereof, as
described herein and/or as known in the art that are provided in a non-naturally occurring
composition, mixture or form. Such compositions comprise non-naturally occurring compositions
comprising at least one or two full length, C- and/or N-terminally deleted variants, domains,
fragments, or specified variants, of the IL-23p40 Ig derived protein amino acid sequence, or specified
fragments, domains or variants thereof. Such composition percentages are by weight, volume,
c oncentration, molarity, or molality as liquid or dry solutions, mixtures, suspension, emulsions or
c olloids, as known in the art or as described herein.
EL-23p40 Ig derived protein or specified portion or variant compositions of the present
invention can further comprise at least one of any suitable auxiliary, such as, but not limited to,
diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant or the like.
Phiirmaceutically acceptable auxiliaries are preferred. Non-limiting examples of, and methods of
preparing such sterile solutions are well known in the art, such as, but limited to, Gennaro, Ed.,
Remington's Phartnaceutical Sciences, 18* Edition, Mack Publishing Co. (Easton, PA) 1990.
Pharmaceutically acceptable carriers can be routinely selected that are suitable for the mode of

administration, solubility and/or stability of the IL-23p40 composition as well known in the art or as
described herein.
Pharmaceutical excipients and additives useful in the present composition include, but are not
limited to, proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including
monosaccharides, di-, tri-, tetra-, and oligosaccharides; derivatized sugars, such as alditols, aldonic
acids, esterified sugars and the like; and polysaccharides or sugar polymers), which can be present
singly or in combination, comprising alone or in combination 1-99.99% by weight or volume.
Exemplary protein excipients include serum albumin, such as human serum albumin (HSA),
recombinant human albumin (rHA), gelatin, casein, and the like. Representative amino acid/Ig
derived protein or specified portion or variant components, which can also function in a buffering
capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine,
lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like. One preferred
amino acid is glycine.
Carbohydrate excipients suitable for use in the invention include, for example,
monosaccharides, such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like;
^saccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as
raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol,
xylitol, maltitcl, lactitol, xylitol sorbitol (glucitol), myoinositol and the like. Preferred carbohydrate
excipients for use in the present invention are mannitol, trehalose, and raffinose.
IL-23p40 Ig derived protein compositions can also include a buffer or a pH adjusting agent;
typically, the buffer is a salt prepared from an organic acid or base. Representative buffers include
organic acid salts, such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid,
succinic acid, acetic acid, or phthalic acid; Tris, tromethamine hydrochloride, or phosphate buffers.
]'referred buffers for use in the present compositions are organic acid salts, such as citrate.
Additionally, the IL-23p40 Ig derived protein or specified portion or variant compositions of
the invention can include polymeric excipients/additives such as polyvinylpyrrolidones, ficolls (a
polymeric sugar), dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl-P-cyclodextrin),
polyethylene glycols, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic
ugents, surfactants (e.g., polysorbates such as 'TWEEN 20" and 'TWEEN 80"), lipids (e.g.,
phospholipids, fatty acids), steroids (e.g., cholesterol), and chelating agents (e.g., EDTA).
These and additional known pharmaceutical excipients and/or additives suitable for use in the
IL-23p40 compositions according to the invention are known in the art, e.g., as listed in "Remington:
The Science & Practice of Pharmacy", 19th ed., Williams & Williams, (1995), and in the "Physician's
Desk Reference", 52nd ed.. Medical Economics, Montvale, NJ (1998), the disclosures of which are
entirely incorporated herein by reference. Preferrred carrier or excipient materials are carbohydrates
(is.g., saccharides and alditols) and buffers (e.g., citrate) or polymeric agents.

Formulations
As noted above, the invention provides for stable formulations, which preferably comprise a
phosphate buffer with saline or a chosen salt, preserved solutions and formulations containing a
preservative, as well as multi-use preserved formulations suitable for pharmaceutical or veterinary
use, comprising at least one IL-23p40 Ig derived protein or specified portion or variant in a
pharmaceutically acceptable formulation. Preserved formulations contain at least one known
preservative or optionally selected from the group consisting of at least one phenol, m-cresol, p-
cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde,
chlorobutanol, magnesium chloride (e.g., hexahydrate), alkylparaben (methyl, ethyl, propyl, butyl and
the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, or
mixtures thereof in an aqueous diluent Any suitable concentration or mixture can be used as known
in the art, such as 0.001-5%, or any range or value therein, such as, but not limited to 0.001,0.003,
0.005, 0.009,0.01,0.02,0.03,0.05,0.09,0.1,0.2,0.3,0.4., 0.5, 0.6,0.7.0.8,0.9,1.0,1.1,1.2,1.3,
1.4,1.5,1.6,1.7,1.8,1.9,2.0,2.1,2.2,2.3,2.4,2.5,2.6, 2.7,2.8,2.9,3.0,3.1,3.2, 3.3,3.4,3.5, 3.6,
3.7,3.8, 3.9,4.0,4.3,4.5,4.6,4.7,4.8,4.9, or any range or value therein. Non-limiting examples
include, no preservative, 0.1-2% m-cresol (e.g., 0.2,0.3.0.4,0.5,0.9,1.0%), 0.1-3% benzyl alcohol
(e.g.. Oil, 0.9,1.1., 1.5,1.9,2.0,2.5%), 0.001-0.5% thimerosal (e.g., 0.005,0.01), 0.001-2.0% phenol
(e.g., 0.05,0.25,0.28,0.5,0.9,1.0%), 0.0005-1.0% alkylparaben(s) (e.g., 0.00075,0.0009,0.001,
0.002,0.005,0.0075,0.009,0.01,0.02,0.05,0.075,0.09,0.1,0.2. 0.3,0.5,0.75,0.9,1.0%), and the
like.
As noted above, the invention provides an article of manufacture, comprising packaging
material and at least one vial comprising a solution of at least one EL-23p40 Ig derived protein or
specified portion or variant with me prescribed buffers and/or preservatives, optionally, in an aqueous
diluent, wherein said packaging material comprises a label that indicates that such solution can be
held over a period of 1,2,3,4,5,6,9,12,18,20,24,30,36,40,48,54,60,66,72 hours or greater.
The invention further comprises an article of manufacture, comprising packaging material, a first vial
comprising lyophilized at least one IL-23p40 Ig derived protein or specified portion or variant, and a
second vial comprising an aqueous diluent of prescribed buffer or preservative, wherein said
packaging material comprises a label that instructs a patient to reconstitute the at least one IL-23p40
Ig derived protein or specified portion or variant in the aqueous diluent to form a solution mat can be
held over a period of twenty-four hours or greater.
The at least one IL-23p40Ig derived protein or specified portion or variant used in accordance
with the present invention can be produced by recombinant means, including from mammalian cell or
transgenic preparations, or can be purified from other biological sources, as described herein or as
known in the art.
The range of at least one IL-23p40 Ig derived protein or specified portion or variant in the
product of the present invention includes amounts yielding upon reconstitution, if in a wet/dry system,
i

concentrations from about 1.0 jtg/ml to about 1000 mg/ml, although lower and higher concentrations
are operable and are dependent on the intended delivery vehicle, e.g., solution formulations will differ
from transdermal patch, pulmonary, transmucosal, or osmotic or micro pump methods.
Preferably, the aqueous diluent optionally further comprises a pharmaceutical] y acceptable
preservative. Preferred preservatives include those selected from the group consisting of phenol, m-
cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkylparaben (methyl, ethyl, propyl, butyl and
the like), benzalkonium chloride, benzemonium chloride, sodium dehydroacetate and thimerosal, or
mixtures thereof. The concentration of preservative used in the formulation is a concentration
sufficient to yield an anti-microbial effect Such concentrations are dependent on the preservative
selected and are readily determined by the skilled artisan.
Other excipients, e.g., isotonicity agents, buffers, antioxidants, and preservative enhancers,
can be optionally and preferably added to the diluent. An isotonicity agent, such as glycerin, is
commonly used at known concentrations. A physiologically tolerated buffer is preferably added to
provide improved pH control. The formulations can cover a wide range of pHs, such as from about
pH 4 to about pH 10, and preferred ranges from about pH 5 to about pH 9, and a most preferred range
of about 6.0 to about 8.0. Preferably, the formulations of the present invention have pH between
about 6.8 and about 7.8. Preferred buffers include phosphate buffers, most preferably, sodium
phosphate, particularly phosphate buffered saline (PBS).
Other additives, such as a pharmaceutically acceptable solubilizers like Tween 20
(polyoxyethylene (20) sorbitan roonolaurate), Tween 40 (polyoxyethylene (20) sorbitan
monopalmitate), Tween 80 (polyoxyethylene (20) sorbitan monooleate), Pluronic F68
(polyoxyethylene polyoxypropylene block copolymers), and PEG (polyethylene glycol) or non-ionic
surfactants, such as polysorbate 20 or 80 or poloxamer 184 or 188, Pluronic® polyls, other block co-
polymers, and chelators, such as EDTA and EGTA, can optionally be added to the formulations or
compositions to reduce aggregation. These additives are particularly useful if a pump or plastic
container is used to administer the formulation. The presence of pharmaceutically acceptable
surfactant mitigates the propensity for the protein to aggregate.
The formulations of the present invention can be prepared by a process which comprises
mixing at least one EL-23p40 Ig derived protein or specified portion or variant and a preservative
selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl
alcohol, alkylparaben, (methyl, ethyl, propyl, butyl and the like), benzalkonium chloride,
benzethonium chloride, sodium dehydroacetate and thimerosal or mixtures thereof in an aqueous
diluen t. Mixing tli e at least one IL-23p40 Ig derived protein or specified portion or variant and
preservative in an aqueous diluent is carried out using conventional dissolution and mixing
procedures. To prepare a suitable formulation, for example, a measured amount of at least one IL-
23p40 Ig derived protein or specified portion or variant in buffered solution is combined with the
desired preservative in a buffered solution in quantities sufficient to provide the protein and

preservative at the desired concentrations. Variations of this process would be recognized by one of
ordinary skill in the art. For example, the order the components are added, whether additional
additives are used, the temperature and pH at which the formulation is prepared, are all factors that
may be optimized for the concentration and means of administration used.
The claimed formulations can be provided to patients as clear solutions or as dual vials
comprising a vial of lyophilized (at least one) TL-23p40 Ig derived protein or specified portion or
variant that is reconstituted with a second vial containing water, a preservative and/or excipients,
preferably, a phosphate buffer and/or saline and a chosen salt, in an aqueous diluent Either a single
solution vial or dual vial requiring reconstitution can be reused multiple times and can suffice for a
single or multiple cycles of patient treatment and thus can provide a more convenient treatment
regimen than currently available.
The present claimed articles of manufacture are useful for administration over a period of
immediately to twenty-four hours or greater. Accordingly, the presently claimed articles of
manufacture offer significant advantages to the patient Formulations of the invention can optionally
be safely stored at temperatures of from about 2°C to about 40°C and retain the biologically activity
of the protein for extended periods of time, thus allowing a package label indicating that the solution
can be held and/or used over a period of 6,12,18,24,36,48,72, or 96 hours or greater. If preserved
diluent is used, such label can include use up to 1-12 months, one-half, one and a half, and/or two
years.
The solutions of at least one IL-23p40 Ig derived protein or specified portion or variant in the
invention can be prepared by a process that comprises mixing at least one Ig derived protein or
specified portion or variant in an aqueous diluent Mixing is carried out using conventional
dissolution and mixing procedures. To prepare a suitable diluent, for example, a measured amount of
at least one Ig; derived protein or specified portion or variant in water or buffer is combined in
quantities sufficient to provide the protein and optionally a preservative or buffer at the desired
concentrations. Variations of this process would be recognized by one of ordinary skill in the art. For
example, the order the components are added, whether additional additives are used, the temperature
and pH at which the formulation is prepared, are all factors that may be optimized for the
concentration and means of administration used.
The claimed products can be provided to patients as clear solutions or as dual vials
comprising a vial of lyophilized (at least one) IL-23p40 Ig derived protein or specified portion or
variant that is reconstituted with a second vial containing the aqueous diluent Either a single solution
vial or dual vial requiring reconstitution can be reused multiple times and can suffice for a single or
multiple cycles of patient treatment and thus provides a more convenient treatment regimen than
currently available.
The claimed products can be provided indirectly to patients by providing to pharmacies,
clinics, or other such institutions and facilities, clear solutions or dual vials comprising a vial of

lyophilized (at least one) IL-23p40 Ig derived protein or specified portion or variant that is
reconstituted with a second vial containing the aqueous diluent. The clear solution in this case can be
up to one liter or even larger in size, providing a large reservoir from which smaller portions of the at
least one Ig derived protein or specified portion or variant solution can be retrieved one or multiple
times for transfer into smaller vials and provided by the pharmacy or clinic to their customers and/or
patients.
Recognized devices comprising these single vial systems include those pen-injector devices
for delivery of a solution such as BD Pens, BD Autojector*. Humaject®'NovoPen*, B-D*Pen,
AutoPen®, and OptiPen®, GenotropinPen®, Genotronorm Pen*, Huroatro Pen*, Reco-Pen*. Roferon
Pen*, Biojector*. Iject*, J-tip Needle-Free Injector®, Intraject®, Medi-Ject*, e.g., as made or
developed by Becton Dickenson (Franklin Lakes, NJ, www.bectondickenson.com), Disetronic
(Burgdorf, Switzerland, www.disetronic.com; Bioject, Portland, Oregon (www.bioject.com); National
Medical Products , Weston Medical (Peterborough, UK, www.weston-medical.com), Medi-Ject Corp
(Minneapolis, MN, www.mediject.com). Recognized devices comprising a dual vial system include
those pen-injector systems for reconstituting a lyophilized drug in a cartridge for delivery of the
reconstituted solution, such as the HumatroPen*.
The products presently claimed include packaging material. The packaging material
provides;, in addition to the information required by the regulatory agencies, the conditions under
which the product can be used. The packaging material of the present invention provides instructions
to the patient to reconstitute the at least one IL-23p40 Ig derived protein or specified portion or variant
in the aqueous diluent to form a solution and to use the solution over a period of 2-24 hours or greater
for the two vial, wet/dry, product For the single vial, solution product, the label indicates that such
solution can be used over a period of 2-24 hours or greater. The presently claimed products are useful
for human pharmaceutical product use.
The formulations of the present invention can be prepared by a process mat comprises mixing
at least one IL-23p40 Ig derived protein or specified portion or variant and a selected buffer,
preferably, a phosphate buffer containing saline or a chosen salt Mixing the at least one Ig derived
protein or specified portion or variant and buffer in an aqueous diluent is carried out using
conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, a
measured amount of at least one Ig derived protein or specified portion or variant in water or buffer is
combined with the desired buffering agent in water in quantities sufficient to provide the protein and
buffer at the desired concentrations. Variations of this process would be recognized by one of
ordinary skill in the art. For example, the order the components are added, whether additional
additives are used, the temperature and pH at which the formulation is prepared, are all factors that
can be optimized for the concentration and means of administration used.

The claimed stable or preserved formulations can be provided to patients as clear solutions or
as dual vials comprising a vial of lyophilized at least one IL-23p40 Ig derived protein or specified
portion or variant that is reconstituted with a second vial containing a preservative or buffer and
excipients in an aqueous diluent. Either a single solution vial or dual vial requiring reconstitution can
be reused multiple times and can suffice for a single or multiple cycles of patient treatment and thus
provides a more convenient treatment regimen than currently available.
At least one IL-23p40 Ig derived protein or specified portion or variant in either the stable or
preserved formulations or solutions described herein, can be administered to a patient in accordance
with the present invention via a variety of delivery methods including SC or EM injection;
transdermal, pulmonary, transmucosal, implant, osmotic pump, cartridge, micro pump, or other means
appreciated by the skilled artisan, as well-known in the art.
Therapeutic Applications
The present invention also provides a method for modulating 04 treating IL-23p40 conditions
or diseases, in a cell, tissue, organ, animal, or patient including, but not limited to, at least one of
rheumatoid arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis,
psoriatic arthritis, ankylosing spondylitis, gastric ulcer, seronegative arthropathies, osteoarthritis,
inflammatory bowel disease, ulcerative colitis, systemic lupus erythematosis, antiphospholipid
syndrome, iridocyclitis/uveitis/optic neuritis, idiopathic pulmonary fibrosis, systemic
vasculitis/wegener's granulomatosis, sarcoidosis, orchitis/vasectomy reversal procedures,
allergic/atopic diseases, asthma, allergic rhinitis, eczema, allergic contact dermatitis, allergic
conjunctivitis, hypersensitivity pneumonitis, transplants, organ transplant rejection, graft-versus-host
disease, systemic inflammatory response syndrome, sepsis syndrome, gram positive sepsis, gram
negative sepsis, culture negative sepsis, fungal sepsis, neutropenic fever, urosepsis,
meningococcemia, trauma/hemorrhage, bums, ionizing radiation exposure, acute pancreatitis, adult
respiratory distress syndrome, rheumatoid arthritis, alcohol-induced hepatitis, chronic inflammatory
pathologies, sarcoidosis, Crohn's pathology, sickle cell anemia, diabetes, nephrosis, atopic diseases,
hypersensitity reactions, allergic rhinitis, hay fever, perennial rhinitis, conjunctivitis, endometriosis,
asthma, urticaria, systemic anaphalaxis, dermatitis, pernicious anemia, hemolytic disesease,
thrombocytopenia, graft rejection of any organ or tissue, kidney translplant rejection, heart transplant
rejection, liver transplant rejection, pancreas transplant rejection, lung transplant rejection, bone
marrow transplant (BMT) rejection, skin allograft rejection, cartilage transplant rejection, bone graft
rejection, small bowel transplant rejection, fetal thymus implant rejection, parathyroid transplant
rejection, xenograft rejection of any organ or tissue, allograft rejection, anti-receptor hypersensitivity
reactions, Graves disease, Raynoud's disease, type B insulin-resistant diabetes, asthma, myasthenia
gravis, antibody-meditated cytotoxicity, type EI hypersensitivity reactions, systemic lupus
erythematosus, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal

gammopathy, and skin changes syndrome), polyneuropathy, organomegaly, endocrinopathy,
monoclonal gammopathy, skin changes syndrome, antiphospholipjd syndrome, pemphigus,
scleroderma, mixed connective tissue disease, idiopathic Addison's disease, diabetes meJlitus, chronic
active hepatitis, primary billiary cirrhosis, vitiligo, vasculitis, post-MI cardiotomy syndrome, type IV
hypersensitivity, contact dermatitis, hypersensitivity pneumonitis, allograft rejection, granulomas due
to intracellular organisms, drug sensitivity, metabolic/idiopathic, Wilson's disease, hemachromatosis,
alpha-1-antitrypsin deficiency, diabetic retinopathy, hashirnoto's thyroiditis, osteoporosis,
hypothalmic-pituitary-adrenal axis evaluation, primary biliary cirrhosis, thyroiditis,
encephalomyelitis, cachexia, cystic fibrosis, neonatal chronic lung disease, chronic obstructive
pulmonary disease (COPD), familial hematophagocytic lymphohistiocytosis, dermatologic conditions,
psoriasis, alopecia, nephrotic syndrome, nephritis, glomerular nephritis, acute renal failure,
hemodialysis, uremia, toxicity, preeclampsia, okt3 therapy, anti-cd3 therapy, cytokine therapy,
chemotherapy, radiation therapy (e.g., including but not limited to, asthenia, anemia, cachexia, and the
like), chronic salicylate intoxication, acute or chronic bacterial infection, acute and chronic parasitic
or infectious processes, including bacterial, viral and fungal infections, HIV infection/HIV
neuropathy, meningitis, hepatitis (e.g.. A, B or C, or the like), septic arthritis, peritonitis, pneumonia,
epiglottitis, e. Coli 0157:h7, hemolytic uremic syndrome/mrombolytic thrombocytopenic purpura,
malaria, dengue hemorrhagic fever, leishmaniasis, leprosy, toxic shock syndrome, streptococcal
myositis, gas gangrene, mycobacterium tuberculosis, mycobacterium avium intracellulare,
Pneumocystis carinii pneumonia, pelvic inflammatory disease, orchitis/epidydimitis, legioneUa, lyme
disease, influenza a, epstein-barr virus, vital-associated hemaphagocytic syndrome, vital
encephalitis/aseptic meningitis, neurodegenerative diseases, multiple sclerosis, migraine headache,
AIDS dementia complex, demyelinating diseases, such as multiple sclerosis and acute transverse
myelitis; extrapyramidal and cerebellar disorders, such as lesions of the corticospinal system;
disorders of me basal ganglia or cerebellar disorders; hyperkinetic movement disorders, such as
Huntington's Chorea and senile chorea; drug-induced movement disorders, such as those induced by
drugs which block CNS dopamine receptors; hypokinetic movement disorders, such as Parkinson's
disease; Progressive supranucleo Palsy; structural lesions of the cerebellum; spinocerebellar
degenerations, such as spinal ataxia, Friedreich's ataxia, cerebellar cortical degenerations, multiple
systems degenerations (Mencel, Dejerine-Thomas, Shi-Drager, and Machado-Joseph); systemic
disorders (Refsum's disease, abetalipoprotemia, ataxia, telangiectasia, and mitochondrial multi-system
disorder); demyelinating core disorders, such as multiple sclerosis, acute transverse myelitis; and
disorders of the motor unit, such as neurogenic muscular atrophies (anterior horn cell degeneration,
sur.h as amyotrophic lateral sclerosis, infantile spinal muscular atrophy and juvenile spinal muscular
atrophy); Alzheimer's disease; Down's Syndrome in middle age; Diffuse Lewy body disease; Senile
Dementia of Lewy body type; Wernicke-Korsakoff syndrome; chronic alcoholism; Creutrfeldt-Jakob
disease; Subacute sclerosing panencephalitis, Hallerrprden-Spatz disease; and Dementia pugilistica,

neurotrauniatic injury (e.g., but not limited to, spinal cord injury, brain injury, concussion, and
repetitive concussion), pain, inflammatory pain, autism, depression, stroke, cognitive disorders,
epilepsy, arid the like. Such a method can optionally comprise administering an effective amount of
at least one composition or pharmaceutical composition comprising at least one IL-23p40 Ig derived
protein or specified portion or variant to a cell, tissue, organ, animal or patient in need of such
modulation, treatment or therapy.
Any method of the present invention can comprise administering an effective amount of a
composition or pharmaceutical composition comprising at least one IL-23p40 Ig derived protein or
specified portion or variant to a cell, tissue, organ, animal or patient in need of such modulation,
treatment or therapy. Such a method can optionally further comprise co-administration or
c ombination therapy for treating such immune diseases, wherein the administering of said at least one
IL-23p40 Ig derived protein, specified portion or variant thereof, further comprises administering,
before concurrently, and/or after, at least one selected from at least one multiple sclerosis therapeutic
(including but not limited to, beta-interferon la and beta-interferon lb (e.g., Avonex™, Rcbif™,
Betaseon™), glutiramer acetate (e.g., Copaxone), cyclophasphamide, azathioprine,
glucocorticosieroids, methotrexate, Paclitaxel, 2-chlorodeoxyadenosine, mitoxantrone, IL-10, TGBb,
CM, CD52, antegren, CD11, CD18, TNFtdpha, IL-1, IL-2, and/or CD4 antibody or antibody receptor
fusion, interferon alpha, immunoglobulin, Lismide (Requirumax™), insulin-like growth factor-1
fIGF-1), elprodil, pirfenidone, oral myelin, or compounds that act on one or more of at least one of:
autoimmune suppression of myelin destruction, immune regulation, activation, proliferation,
migration and/or suppressor cell function of T-cells, inhibition of T cell receptor/peptide/MHC-II
i nteraction, Induction of T cell anergy, deletion of autoreactive T cells, reduction of trafficking across
Wood brain barrier, alteration of balance of pro-inflammatory (Thl) and immunomodulatory (Th2)
cytokines, inhibition of matrix metalloprotease inhibitors, neuroprotection, reduction of gliosis,
promotion of re-myelination), TNF antagonist (e.g., but not limited to, a TNF Ig derived protein or
fragment, a soluble TNF receptor or fragment, fusion proteins thereof, or a small molecule TNF
antagonist), an antirheumatic, a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug
(NSABD), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an
antimicrobial (e.g., aminoglycoside, an antifungal, an antiparasitic, an antiviral, a carbapenem,
cephalosporin, a flurorquinolone, a macrolide, a penicillin, a sulfonamide, a tetracycline, another
antimicrobial), an antipsoriatic, a corticosteriod, an anabolic steroid, an EL-23p40 agent, a mineral, a
nutritional, a thyroid agent, a vitamin, a calcium related hormone, an antidiarrheal, an antitussive, an
antiemetic, an antiulcer, a laxative, an anticoagulant, an erythropoietin (e.g., epoetin alpha), a
filgrastim (e.g., G-CSF, Neupogen), a sargramostim (GM-CSF, Leukine), an immunization, an
immunoglobulin, an immunosuppressive (e.g., basiliximab, cyclosporine, daclizumab), a growth
hormone, a hormone replacement drug, an estrogen receptor modulator, a mydriatic, a cycloplegic, an
allyJating agent, an antimetabolite, a mitotic inhibitor, a radiopharmaceutical, an antidepressant, an

antimatiic agent, an antipsychotic, an anxiolytic, a hypnotic, a sympathomimetic, a stimulant,
donepezil, tacrine, an asthma medication, a beta agonist, an inhaled steroid, a leukotriene inhibitor, a
methylxanthine, a cromolyn, an epinephrine or analog, domase alpha (Pulmozyme), a cytokine or a
cytokine antagonist. Suitable dosages are well known in the art. See, e.g., Wells et al., eds.,
Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, CT (2000); PDR
Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma
Linda, C'A (2000), each of which references are entirely incorporated herein by reference.
TNF antagonists suitable for compositions, combination therapy, co-administration, devices
and/or methods of the present invention (further comprising at least one antibody, specified portion
and variant thereof, of the present invention), include, but are not limited to, anti-TNF Ig derived
proteins, antigen-binding fragments thereof, and receptor molecules which bind specifically to TNF;
compounds which prevent and/or inhibit TNF synthesis, TNF release or its action on target cells, such
as thalidomide, tenidap, phosphodiesterase inhibitors (e.g., pentoxifylline and rolipram), A2b
adenosine receptor agonists and A2b adenosine receptor enhancers; compounds which prevent and/or
inhibit TNF receptor signalling, such as mitogen activated protein (MAP) kinase inhibitors;
compounds which block and/or inhibit membrane TNF cleavage, such as metalloproteinase inhibitors;
compounds which block and/or inhibit TNF activity, such as angiotensin converting enzyme (ACE)
inhibitors (e.g., captopril); and compounds which block and/or inhibit TNF production and/or
synthesis, such as MAP kinase inhibitors.
As used herein, a "tumor necrosis factor Ig derived protein," "TNF Ig derived protein,"
"TNFoc Ig derived protein," or fragment and the like decreases, blocks, inhibits, abrogates or
interferes with TNFa activity in vitro, in situ and/or preferably in vivo. For example, a suitable TNF
human Ig derived protein of the present invention can bind TNFa and includes anti-TNF Ig derived
proteins, antigen-binding fragments thereof, and specified mutants or domains thereof that bind
specifically to TNFa. A suitable TNF antibody or fragment can also decrease block, abrogate,
interfere, prevent and/or inhibit TNF RNA, DNA or protein synthesis, TNF release, TNF receptor
signaling, membrane TNF cleavage, TNF activity, TNF production and/or synthesis.
Chimeric Ig derived protein cA2 consists of. the antigen binding variable region of the high-
affinity neutralizing mouse anti-human TNFa IgGl Ig derived protein, designated A2, and the
constant regions of a human IgGl, kappa immunoglobulin. The human IgGl Fc region improves
allogeneic Ig derived protein effector function, increases the circulating serum half-life and decreases
the immunogenicity of the Ig derived protein. The avidity and epitope specificity of the chimeric Ig
derived protein cA2 is derived from the variable region of the murine Ig derived protein A2. In a
particular embodiment, a preferred source for nucleic acids encoding the variable region of the murine
[g derived protein A2 is the A2 hybridoma cell line.

Chimeric A2 (cA2) neutralizes the cytotoxic effect of both natural and recombinant human
TNFα in a dose dependent manner. From binding assays of chimeric Ig derived protein cA2 and
recombinant human TNFa, the affinity constant of chimeric Ig derived protein cA2 was calculated to
be 1.04xl0^M-1. Preferred methods for determining monoclonal Ig derived protein specificity and
affinity by competitive inhibition can be found in Harlow, et al, Ig derived proteins: A Laboratory
Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1988; Colligan etal.,
eds., Current Protocols in Immunology, Greene Publishing Assoc, and Wiley Interscience, New York,
(1992-2003); Kozbor et ah, Immunol Today, 4:72-79 (1983); Ausubel et al, eds. Current Protocols
in Molecular Biology, Wiley Interscience, New York (1987-2003); and Muller, Metlu Enzymol,
92:589-601 (1983), which references are entirely incorporated herein by reference.
In a particular embodiment, murine monoclonal Ig derived protein A2 is produced by a cell
line designated cl34A. Chimeric Ig derived protein cA2 is produced by a cell line designated cl68A.
Additional examples of monoclonal anti-TNF Ig derived proteins mat can be used in me
present invention are described in the art (see, e.g., U.S. Patent No. 5,231,024; Moller, A. et al.,
Cytokine 2(3):162-169 (1990); U.S. Application No. 07/943,852 (filed September 11,1992); Rathjen
et al., International Publication No. WO 91/02078 (published February 21,1991); Rubin etal, EPO
Patent Publication No. 0 218 868 (published April 22,1987); Yone et al., EPO Patent Publication No.
0 288 088 (October 26,1988); Liang, et al., Biochan. Biophys. Res. Comm. 757:847-854 (1986);
Meager, etal.., Hybridoma 6:305-311 (1987); Fendly etal., Hybridoma 6:359-369 (1987); Bringman,
etal, Hybridoma 6:489-507 (1987); and Hirai, etal., J. Immunol. Metfu 96:57-62 (1987), which
references are entirely incorporated herein by reference).
TNF Receptor Molecules
Preferred TNF receptor molecules useful in the present invention are those that bind TNFa
with high affinity (see, e.g., Feldmann etal.. International Publication No. WO 92/07076 (published
April 30,1992); Schall et al, Cett 67:361-370 (1990); and Loetscher et al., CeU 61:351-359 (1990),
which references are entirely incorporated herein by reference) and optionally possess low
iramunogenicity. In particular, the 55 kDa (p55 TNF-R) and the 75 kDa (p75 TNF-R) TNF cell
surface receptors are useful in the present invention. Truncated forms of these receptors, comprising
the extracellular domains (BCD) of the receptors or functional portions thereof (see, e.g., Corcoran et
al, Eur. J. Biochem. 225:831-840 (1994)), are also useful in the present invention. Truncated forms
of the TNF receptors, comprising the ECD, have been detected in urine and serum as 30 kDa and 40
kDa TNFa inhibitory binding proteins (Engelmann, H. et al, J. Biol Client. 265:1531-1536 (1990)).
TNF receptor mul timeric molecules and TNF immunoreceptor fusion molecules, and derivatives and
fragments or portions thereof, are additional examples of TNF receptor molecules which are useful in
the methods and compositions of the present invention. The TNF receptor molecules which can be

used in the invention are characterized by their ability to treat patients for extended periods with good
to excellent alleviation of symptoms and low toxicity. Low immunogenicity and/or high affinity, as
well as other undefined properties, may contribute to the therapeutic results achieved.
TNF receptor multimeric molecules useful in the present invention comprise all or a
functional portion of the ECD of two or more TNF receptors linked via one or more polypeptide
linkers or other nonpeptide linkers, such as polyethylene glycol (PEG). The multimeric molecules
can further comprise a signal peptide of a secreted protein to direct expression of die multimeric
molecule. These multimeric molecules and methods for their production have been described in U.S.
Application No. 08/437,533 (filed May 9,1995), the contents of which are entirely incorporated
herein by reference.
TNF immunoreceptor fusion molecules useful in the methods and compositions of the present
invention comprise at least one portion of one or more immunoglobulin molecules and all or a
functional portion of one or more TNF receptors. These immunoreceptor fusion molecules can be
assembled as monomers, or hetero- or homo-multimers. The immunoreceptor fusion molecules can
also be monovalent or multivalent An example of such a TNF immunoreceptor fusion molecule is
TNF receptor/IgG fusion protein. TNF immunoreceptor fusion molecules and methods for then-
production have been described in the art (Lesslauer etal., Eur. J. Immunol 27:2883-2886 (1991);
Ashkenazd etal., Proc. Nad. Acad. Set USA 58:10535-10539 (1991); Peppel etal., J. Exp. Med.
174:1483-1489 (1991); Rolls etal., Proc. Natl. Acad Set. USA 97:215-219 (1994); Butler etal.,
Cytokine 6(6):616-623 (1994); Baker et al., Eur. J. Immunol 24:2040-2048 (1994); Beutler et al.,
U S. Patent No. 5,447,851; and U.S. Application No. 08/442,133 (filed May 16,1995), each of which
references are entirely incorporated herein by reference). Methods for producing immunoreceptor
fusion molecules can also be found in Capon et al., US. Patent No. 5,116,964; Capon et al, U.S.
Patent No. 5,225,538; and Capon et al.. Nature 337:525-531 (1989), which references are entirely
incorporated herein by reference.
A functional equivalent, derivative, fragment or region of TNF receptor molecule refers to the
portion of the TNF receptor molecule, or the portion of the TNF receptor molecule sequence which
encodes TNF receptor molecule, that is of sufficient size and sequences to functionally resemble TNF
receptor molecules that can be used in the present invention (e.g., bind TNFa with high affinity and
I>ossess low immunogenicity). A functional equivalent of TNF receptor molecule also includes
modified TNF receptor molecules that functionally resemble TNF receptor molecules that can be used
; n the present invention (e.g., bind TNFa with high affinity and possess low immunogenicity). For
(sxample, a functional equivalent of TNF receptor molecule can contain a "SILENT" codon or one or
more amino acid substitutions, deletions or additions (e.g., substitution of one acidic amino acid for
iinother acidic amino acid; or substitution of one codon encoding the same or different hydrophobic
amino acid for another codon encoding a hydrophobic amino acid). See Ausubel et al.. Current

Protocols in Molecular Biology\ Greene Publishing Assoc, and Wiley-Interscience, New York (1987-
2003).
Cytokines include any known cytokine. See, e.g., CopewithCytokines.com. Cytokine
antagonists include, but are not limited to, any Ig derived protein, fragment or mimetic, any soluble
receptor, fragment or mimetic, any small molecule antagonist, or any combination thereof.
Therapeutic Treatments.
Any method of the present invention can comprise a method for treating an BL-23p40
mediated disorder, comprising administering an effective amount of a composition or pharmaceutical
composition comprising at least one !L-23p40 Ig derived protein or specified portion or variant to a
cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy.
Typically, treatment of pathologic conditions is effected by administering an effective amount or
dosage of at bast one IL-23p40 Ig related protein composition diat total, on average, a range from at least
about 0.01 to 500 milligrams of at least one IL-23p40 Ig derived protein or specified portion or variant
/kilogram of patient per dose, and, preferably, from at least about 0.1 to 100 milligrams Ig derived protein
or specified portion or variant/kilogram of patient per single or multiple administration, depending upon
the specific activity of the Ig protein contained in the composition. Alternatively, the effective serum
concentration can comprise 0.1-5000 Mg/ml serum concentration per single or multiple adminstration.
Suitable dosages are known to medical practitioners and will, of course, depend upon the particular
disease state, specific activity of die composition being administered, and the particular patient
undergoing treatment. In some instances, to achieve the desired therapeutic amount, it can be necessary
ro provide for repeated administration, ie., repeated individual administrations of a particular monitored
or metered dose, where the individual administrations are repeated until the desired daily dose or effect is
achieved.
Preferred doses can optionally include 0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1,2,3,4,5,6,7,8,
9,10,11,12,13,14,15,16,17,18,19,20,21, 22,23,24,25,26,27,28,29,30,31,32,33,34,35, 36,
37, 38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,62,63,64,65,
66, 67,68,69,70,71,72,73,74,75,76,77,78,79,80, 81,82,83,84,85, 86,87,88,89,90,91.92,93,
94, 95,96,97,98,99 and/or 100 mg/kg/administration, or any range, value or fraction thereof, or to
achieve a serum concentration of 0.1,0.5,0.9,1.0,1.1,1.2,1.5,1.9,2.0, 2.5,2.9,3.0,3.5,3.9,4.0,4.5,
4.9,5.0,55,5.9. 6.0,6.5,6.9,7.0,7.5,7.9,8.0,8.5,8.9,9.0,9.5,9.9,10,10.5,10.9,11,11.5,11.9,20,
i::.5,12.9,13.0, 13.5,13.9,14.0,14.5,4.9,5.0,5.5., 5.9,6.0,6.5,6.9,7.0,7.5,7.9,8.0,8.5,8.9,9.0,9.5,
9.5,10,10.5,10.9,11,11.5,11.9,12,12.5,12.9,13.0,13.5,13.9,14,14.5,15,15.5,15.9,16,16.5,16.9,
17, 17.5,17.9,18,18.5,18.9,19,19.5,19.9,20,20.5,20.9, 21,22,23, 24,25,26,27, 28,29,30,35,40,
45,50,55,60, 65,70,75,80, 85,90,96,100,200, 300,400,500,600,700, 800,900,1000,1500,2000,

2500,3000,3500,4000,4500, and/or 5000 μg/ml serum concentration per single or multiple
administration, or any range, value or fraction thereof.
Alternatively, the dosage administered can vary depending upon known factors, such as the
pharmacodynamic characteristics of the particular agent, and its mode and route of administration;
age, health, and weight of the recipient; nature and extent of symptoms, kind of concurrent treatment,
frequency of treatment, and the effect desired. Usually, a dosage of active ingredient can be about 0.1
to 100 milligrams per kilogram of body weight. Ordinarily, 0.1 to 50, and preferably 0.1 to 10
milligrams per kilogram per administration or in sustained release form is effective to obtain desired
results.
As a non-limiting example, treatment of humans or animals can be provided as a one-time or
periodic dosage of at least one Ig derived protein or specified portion or variant of the present
invention 0.1 to 100 mg/kg, such as 0.5,0.9,1.0,1.1,1.5,2,3,4,5,6,7,8,9,10,11,12,13,14,15,
16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,40,45,50,60,70,80,90 or 100 mg/kg, per
day, on at least one of day 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21, 22,23,
24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39, or 40, or, alternatively or additionally, at
ieast one of week 1,2, 3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,
26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49.50,51, or
52, or, alternatively or additionally, at least one of 1,2,3,4,5,6„ 7, 8, 9,10,11,12,13,14,15,16,
17,18,19, or 20 years, or any combination thereof, using single, infusion or repeated doses.
Dosage forms (composition) suitable for internal administration generally contain from about
0.1 milligram to about 500 milligrams of active ingredient per unit or container. In these
pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about
0.5-99.999% by weight based on the total weight of the composition.
For parenteral administration, the Ig derived protein or specified portion or variant can be
formulated as a solution, suspension, emulsion or lyophilized powder in association, or separately
provided, with a pharmaceutically acceptable parenteral vehicle. Examples of such vehicles are
water, saline, Ringer's solution, dextrose solution, and 1-10% human serum albumin. Liposomes and
nonaqueous vehicles, such as fixed oils, may also be used. The vehicle or lyophilized powder may
contain additives that maintain isotonicity (e.g., sodium chloride, mannitol) and chemical stability
(e.g., buffers and preservatives). The formulation is sterilized by known or suitable techniques.
Suitable pharmaceutical carriers are described in the most recent edition of Remington's
Pharmaceutical Sciences, A. Osol, a standard reference text in this field.

Alternative Administration
Many known and developed modes of can be used according to the present invention for
administering pharmaceuu'cally effective amounts of at least one IL-23p40 Ig derived protein or
specified portion or variant according to the present invention. While pulmonary administration is
used in the following description, other modes of administration can be used according to me present
invention with suitable results.
IL-23p40 Ig derived proteins of the present invention can be delivered in a carrier, as a
solution, emulsion, colloid, or suspension, or as a dry powder, using any of a variety of devices and
methods suitable for administration by inhalation or other modes described here within or known in
the art.
Parenteral Formulations and Administration
Formulations for parenteral administration can contain as common excipients sterile water or
saline, polyalkylene glycols, such as polyethylene glycol, oils of vegetable origin, hydrogenated
naphthalenes and the like. Aqueous or oily suspensions for injection can be prepared by using an
appropriate emulsifier or humidifier and a suspending agent, according to known mediods. Agents
for injection can be non-toxic, non-orally administrable diluting agents, such as an aqueous solution
or a sterile injectable solution or suspension in a solvent. As the usable vehicle or solvent, water,
Ringer's solution, isotonic saline, etc. are allowed; as an ordinary solvent, or suspending solvent,
sterile involatile oil can be used. For these purposes, any kind of in volatile oil and fatty acid can be
used, including natural or synthetic or semisynthetic fatty oils or fatty acids; natural or synthetic or
semisynthtetic mono- or di- or tri-glycerides. Parental administration is known in the art and includes,
tut is not limited to, conventional means of injections, a gas pressured needle-less injection device as
described in U.S. Pat. No. 5,851,198, and a laser perforator device as described in U.S. Pat No.
5 839,446 entirely incorporated herein by reference.
Alternative Delivery
The invention further relates to the administration of at least one IL-23p40 Ig derived protein
or specified portion or variant by parenteral, subcutaneous, intramuscular, intravenous, bolus, vaginal,
rectal, buccal, sublingual, intranasal, or transdermal means. An anti-IL-23p40 Ig derived protein or
spiiafied portion or variant composition can be prepared for use for parenteral (subcutaneous,
intramuscular or intravenous) administration, particularly in the form of liquid solutions or
suspensions; for use in vaginal or rectal administration particularly in semisolid forms, such as creams
and suppositories; for buccal, or sublingual administration, particularly in the form of tablets or
capsules; or intranasally, particularly in the form of powders, nasal drops or aerosols or certain agents;
or transdermally, particularly in the form of a gel, ointment, lotion, suspension or patch delivery
sysrem with chemical enhancers, such as dimethyl sulfoxide, to either modify the skin structure or to

increase the drug concentration in the transdermal patch (Junginger, et al. In "Drug Permeation
Enhancement"; Hsieh, D. S., Eds., pp. 59-90 (Marcel Dekker, Inc. New York 1994, entirely
incorporated herein by reference), or with oxidizing agents that enable the application of formulations
containing proteins and peptides onto the skin (WO 98/53847), or applications of electric fields to
create transient transport pathways such as electroporation, or to increase the mobility of charged
drugs through the skin such as iontophoresis, or application of ultrasound, such as sonophoresis (U.S.
Pat. Nos. 4,309,989 and 4,767,402) (the above publications and patents being entirely incorporated
herein by reference).
Pulmonary/Nasal Administration
For pulmonary administration, preferably, at least one IL-23p40 Ig derived protein or
specified portion or variant composition is delivered in a particle size effective for reaching the lower
airways of the lung or sinuses. According to the invention, at least one EL-23p40 Ig derived protein or
specified portion or variant can be delivered by any of a variety of inhalation or nasal devices known
in the art for administration of a therapeutic agent by inhalation. These devices capable of depositing
acrosolized formulations in the sinus cavity or alveoli of a patient include metered dose inhalers,
nebulizers, dry powder generators, sprayers, and the like. Other devices suitable for directing the
pulmonary or nasal administration of Ig derived protein or specified portion or variants are also
known in the art. All such devices can use formulations suitable for the administration for the
dispensing of Ig derived protein or specified portion or variant in an aerosol. Such aerosols can be
comprised of either solutions (both aqueous and non aqueous) or solid particles. Metered dose
inhalers, like the Ventolin® metered dose inhaler, typically use a propellent gas and require actuation
during inspiration (See, e.g., WO 94/16970, WO 98/35888). Dry powder inhalers like Turbuhaler™
(Astra), Rotahaler* (Glaxo), Diskus* (Glaxo), Spiros™ inhaler (Dura), devices marketed by Inhale
Therapeutics, and the Spinhaler* powder inhaler (Fisons), use bream-actuation of a mixed powder
(US 4668218 Astra, EP 237507 Astra, WO 97/25086 Glaxo, WO 94/08552 Dura, US 5458135 Inhale,
WO 94/06498 Fisons, entirely incorporated herein by reference). Nebulizers, like AERx™ Aradigm,
the Ultravent* nebulizer (Mallinckrodt), and the Acorn II® nebulizer (Marquest Medical Products)
(US 5404871 Aradigm, WO 97/22376), the above references entirely incorporated herein by
reference, produce aerosols from solutions, while metered dose inhalers, dry powder inhalers, etc.
generate small particle aerosols. These specific examples of commercially available inhalation
devices are intended to be representative of specific devices suitable for the practice of mis invention,
and are not intended as limiting the scope of the invention. Preferably, a composition comprising at
least one IL-23p40 Ig derived protein or specified portion or variant is delivered by a dry powder
inhaler or a sprayer. There are several desirable features of an inhalation device for administering at
least one Ig derived protein or specified portion or variant of the present invention. For example,
delivery by the inhalation device is advantageously reliable, reproducible, and accurate. The

inhalation device can optionally deliver small dry particles, e.g., less than about 10 μm, preferably,
about 1-5 μm, for good respirability.
Administration of IL-23p40 Ig derived protein or specified portion or variant Compositions as a
Spray
A spray including IL-23p40 Ig derived protein or specified portion or variant composition
protein can be produced by forcing a suspension or solution of at least one IL-23p40 Ig derived
protein or specified portion or variant through a nozzle under pressure. The nozzle size and
configuration, the applied pressure, and die liquid feed rate can be chosen to achieve the desired
output and particle size. An electrospray can be produced, for example, by an electric field in
connection with a capillary or nozzle feed. Advantageously, particles of at least one IL-23p40 Ig
derived protein or specified portion or variant composition protein delivered by a sprayer have a
particle size less than about 10 uxn, preferably, in the range of about 1 μm to about 5 μm, and, most
preferably, about 2 μm to about 3 urn.
Formulations of at least one IL-23p40 Ig derived protein or specified portion or variant
composition protein suitable for use with a sprayer typically include Ig derived protein or specified
portion or variant composition protein in an aqueous solution at a concentration of about 0.1 mg to
about 100 mg of at least one IL-23p40 Ig derived protein or specified portion or variant composition
protein per ml of solution or mg/gm, or any range or value therein, e.g., but not united to, 0.1,0.2.,
0.3,0.4,0.5, 0.6,0.7,0.8,0.9,1, 2,3,4, 5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20, 21, 22,
23,24,25,26, 27,28,29,30,40,45,50,60,70,80,90 or 100 mg/ml or mg/gm The formulation can
include agents; such as an excipient, a buffer, an isotonicity agent, a preservative, a surfactant, and,
preferably, zinc. The formulation can also include an excipient or agent for stabilization of the Ig
derived protein or specified portion or variant composition protein, such as a buffer, a reducing agent,
a bulk protein, or a carbohydrate. Bulk proteins useful in formulating Ig derived protein or specified
portion or variant composition proteins include albumin, prolamine, or die like. Typical
carbohydrates useful in formulating Ig derived protein or specified portion or variant composition
proteins include sucrose, mannitol, lactose, trehalose, glucose, or the like. The Ig derived protein or
specified portion or variant composition protein formulation can also include a surfactant, which can
reduce or prevent surface-induced aggregation of the Ig derived protein or specified portion or variant
composition protein caused by atomization of the solution in forming an aerosol. Various
conventional surfactants can be employed, such as polyoxyemylene fatty acid esters and alcohols, and
polyoxyethylone sorbitol fatty acid esters. Amounts will generally range between 0.001 and 14% by
weight of the formulation. Especially preferred surfactants for purposes of this invention are
polyoxyethylene sorbitan monooleate, polysorbate 80, polysorbate 20, or the like. Additional agents

known in the art for formulation of a protein such as IL-23p40 Ig derived proteins, or specified
portions or variants, can also be included in die formulation.
Administration of EL-23p40 Ig derived protein or specified portion or variant compositions by a
Nebulizer
Ig derived protein or specified portion or variant composition protein can be administered by
a nebulizer, such as a jet nebulizer or an ultrasonic nebulizer. Typically, in a jet nebulizer, a
compressed air source is used to create a high-velocity air jet through an orifice. As the gas expands
beyond the nozzle, a low-pressure region is created, which draws a solution of Ig derived protein or
specified portion or variant composition protein through a capillary tube connected to a liquid
reservoir. The liquid stream from the capillary tube is sheared into unstable filaments and droplets as
it exits the tube, creating the aerosol. A range of configurations, flow rates, and baffle types can be
employed to achieve the desired performance characteristics from a given jet nebulizer. In an
ultrasonic nebulizer, high-frequency electrical energy is used to create vibrational, mechanical energy,
typically employing a piezoelectric transducer. This energy is transmitted to the formulation of Ig
derived protein or specified portion or variant composition protein either directly or through a
coupling fluid, creating an aerosol including the Ig derived protein or specified portion or variant
composition protein. Advantageously, particles of Ig derived protein or specified portion or variant
composition protein delivered by a nebulizer have a particle size less than about 10 \xm, preferably, in
the range of about 1 μrn to about S μm, and, most preferably, about 2 μm to about 3 urn.
Formulations of at least one IL-23p40 Ig derived protein or specified portion or variant
suitable for use with a nebulizer, either jet or ultrasonic, typically include a concentration of about 0.1
mg to about 100 mg of at least one IL-23p40 Ig derived protein or specified portion or variant protein
per ml of solution. The formulation can include agents, such as an excipient, a buffer, an isotonicity
agent, a preservative, a surfactant, and, preferably, zinc. The formulation can also include an
excipient or agent for stabilization of the at least one IL-23p40 Ig derived protein or specified portion
or variant composition protein, such as a buffer, a reducing agent, a bulk protein, or a carbohydrate.
Bulk proteins useful in formulating at least one EL-23p40 Ig derived protein or specified portion or
variant composition proteins include albumin, protamine, or the like. Typical carbohydrates useful in
formulating at least one EL-23p40 Ig derived protein or specified portion or variant include sucrose,
mannitol, lactose, trehalose, glucose, or the like. The at least one IL23p40 Ig derived protein or
specified portion or variant formulation can also include a surfactant, which can reduce or prevent
surface-induced aggregation of the at least one IL-23p40 Ig derived protein or specified portion or
variant caused by atomization of the solution in forming an aerosol. Various conventional surfactants
can be employed, such as polyoxyethylene fatty acid esters and alcohols, and polyoxyethylene sorbital
fatty acid esters. Amounts will generally range between 0.001 and 49b by weight of the formulation.

Especially preferred surfactants for purposes of this invention are polyoxyethylene soibitan mono-
oleate, polysorbate 80, polysorbate 20, or the like. Additional agents known in the art for formulation
of a protein, such as Ig derived protein or specified portion or variant protein, can also be included in
the formulation.
Administration of IL-23p40 Ig derived protein or specified portion or variant compositions By
A Metered Dose Inhaler
In a metered dose inhaler (MDI), a propellant, at least one IL-23p40 Ig derived protein or
specified portion or variant, and any excipients or other additives are contained in a canister as a
mixture including a liquefied compressed gas. Actuation of the metering valve releases the mixture as
an aerosol, preferably, containing particles in the size range of less than about 10 μm, preferably,
about 1 μm to about 5μm, and, most preferably, about 2 um to about 3 fun. The desired aerosol
particle size can be obtained by employing a formulation of Ig derived protein or specified portion or
variant composition protein produced by various methods known to those of skill in the art, including
jet-milling, spray drying, critical point condensation, or the like. Preferred metered dose inhalers
include those manufactured by 3M or Glaxo and employing a hydrofluorocarbon propellant
Formulations of at least one EL-23p40 Ig derived protein or specified portion or variant for
use with a metered-dose inhaler device will generally include a finely divided powder containing at
least one IL-23p40 Ig derived protein or specified portion or variant as a suspension in a non-aqueous
medium, for example, suspended in a propellant with the aid of a surfactant. The propellant can be
any conventional material employed for this purpose, such as chlorofluorocarbon, a
hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane,
dichlorodifluorornethane, dichlorotetrafluoroethanol and 1,1,1,2-tetrafluoroethane, HFA-134a
(hydrofluroalkane-134a), HFA-227 (hydrofluroalkane-227), or the like. Preferably, the propellant is a
hydrofluorocarbon. The surfactant can be chosen to stabilize the at least one IL-23p40 Ig derived
protein or specified portion or variant as a suspension in the propellant, to protect the active agent
against chemical degradation, and the like. Suitable surfactants include soibitan trioleate, soya
lecithin, oleic acid, or the like. In some cases, solution aerosols are preferred using solvents, such as
ethanol. Additional agents known in the art for formulation of a protein can also be included in the
formulation.
One of ordinary skill in the art will recognize that the methods of the current invention can be
achieved by pulmonary administration of at least one -IL23p40 Ig derived protein or specified portion
or variant compositions via devices not described herein.

Oral Formulations and Administration
Formulations for oral administration rely on the co-administration of adjuvants (e.g.,
resorcinols and nonionic surfactants, such as polyoxyethylene oleyl ether and n-
hexadecyl polyethylene ether) to increase artificially the permeability of the intestinal walls, as well as
the co-administration of enzymatic inhibitors (e.g., pancreatic trypsin inhibitors,
diisopropylfluorophosphate (DFF) and trasylol) to inhibit enzymatic degradation. The active
constituent compound of the solid-type dosage form for oral administration can be mixed with at least
one additive, including sucrose, lactose, cellulose, mannitol, trehalose, raffinose, maltitol, dextran,
starches, agar, arginates, chitins, chitosans, pectins, gum tragacanth, gum arabic, gelatin, coUagen,
casein, albumin, synthetic or semisynthetic polymer, and glyceride. These dosage forms can also
contain other type(s) of additives, e.g., inactive diluting agent, lubricant, such as magnesium stearate,
paraben, preserving agent, such as sorbic acid, ascorbic acid, .alpha-tocopherol, antioxidant, such as
cysteine, disintegrator, binder, thickener, buffering agent, sweetening agent, flavoring agent,
perfuming agent, etc.
Tablets and pills can be further processed into enteric-coated preparations. The liquid
preparations for oral administration include emulsion, syrup, elixir, suspension and solution
preparations allowable for medical use. These preparations may contain inactive diluting agents
ordinarily used in said field, e.g., water. liposomes have also been described as drug delivery
systems for insulin and heparin (U.S. Pat. No. 4,239,754). More recently, microspheres of artificial
polymers of mixed amino acids (proteinoids) have been used to deliver pharmaceuticals (U.S. Pat.
No. 4,925,673). Furthermore, carrier compounds described in U.S. Pat No. 5,879,681 and UJS. Pat.
No. 5,5,871,753 are used to deliver biologically active agents orally are known in the art
Mucosal Formulations and Administration
For absorption through mucosal surfaces, compositions and methods of administering at least
one IL-23p40 Ig derived protein or specified portion or variant include an emulsion comprising a
plurality of submicron particles, a mucoadhesive macromolecule, abioactive peptide, and an aqueous
continuous phase, which promotes absorption through mucosal surfaces by achieving mucoadhesion
of the emulsion particles (U.S. Pat. Nos. 5,514,670). Mucous surfaces suitable for application of the
emulsions of the present invention can include corneal, conjunctival, buccal, sublingual, nasal,
vaginal, pulmonary, stomachic, intestinal, and rectal routes of administration. Formulations for
vaginal or rectal administration, e.g., suppositories, can contain as excipients, for example,
polyalkyleneglycols, vaseline, cocoa butter, and the like. Formulations for intranasal administration
can be solid and contain as excipients, for example, lactose or can be aqueous or oily solutions of
nasal drops. For buccal administration excipients include sugars, calcium stearate, magnesium
stearate, pregelinatined starch, and the like (U.S. Pat. Nos. 5,849,695).

Transdermal Formulations and Administration
For transdermal administration, die at least one IL-23p40 Ig derived protein or specified
portion or variant is encapsulated in a delivery device, such as a liposome or polymeric nanopardcles,
microparticle, microcapsule, or microspheres (referred to collectively as microparticles unless
otherwise stated). A number of suitable devices are known, including microparticles made of
synthetic polymers, such as polyhydroxy acids, such as polylactic acid, polyglycolic acid and
copolymers thereof, polyorthoesters, polyanhydrides, and polyphosphazenes, and natural polymers,
such as collagen, polyamino acids, albumin and other proteins, alginate and other polysaccharides,
and combinations thereof (U.S. Pat. Nos. 5,814,599).
Prolonged Administration and Formulations
It can be sometimes desirable to deliver the compounds of the present invention to the subject
over prolonged periods of time, for example, for periods of one week to one year from a single
administration. Various slow release, depot or implant dosage forms can be utilized. For example, a
dosage form can contain a pharmaceutically acceptable non-toxic salt of the compounds mat has a low
degree of solubility in body fluids, for example, (a) an acid addition salt with a polybasic acid, such as
phosphoric acid, sulfuric acid, citric acid, tartaric acid, tannic acid, pamoic acid, alginic acid,
polyglutamic acid, naphthalene mono- or di-sulfonic acids, polygalacturonic acid, and the like; (b) a
salt with a polyvalent metal cation such as zinc, calcium, bismuth, barium, magnesium, aluminum,
copper, cobalt, nickel, cadmium and the like, or with an organic cation formed from e.g., N.N'-
dibenzyl-eth) lenediamine or ethylenediamine; or (c) combinations of (a) and (b) e.g., a zinc tannate
salt. Additionally, the compounds of die present invention or, preferably, a relatively insoluble salt
such as those just described, can be formulated in a gel, for example, an aluminum monostearate gel
with, e.g. sesame oil, suitable for injection. Particularly preferred salts are zinc salts, zinc tannate
salts, pamoate salts, and the like. Another type of slow release depot formulation for injection would
contain the compound or salt dispersed for encapsulated in a slow degrading, non-toxic, non-antigenic
polymer, such as a polylactic acid/polyglycolic acid polymer, for example, as described in U.S. Pat.
No 3,773,919. The compounds or, preferably, relatively insoluble salts such as those described
above can also be formulated in cholesterol matrix silastic pellets, particularly for use in animals.
Additional slow release, depot or implant formulations, e.g., gas or liquid liposomes are known in the
literature (U.S. Pat. Nos. 5.770,222 and "Sustained and Controlled Release Drug Delivery Systems",
J. R. Robinson ed.. Marcel Dekker, Inc., N.Y., 1978).
Having generally described the invention, the same will be more readily understood by
reference to the following examples, which are provided by way of illustration and are not intended as
limiting.

Examples of the Invention
Example 1: Generation, Clothing and Expression of an anti-IL-23p40 hummoglobulin derived
protein i Mammalian Cells
Anti-IL-23p40 Ig derived proteins am generated using known method such as murine or
transgenic mice expressing human antibodies that are immunized with human IL-23, and for which B
cells are isolated, cloned and selected for specificity and inhibtting activity for IL-23 (preferably with
little or no inhibition of IL-12 activity) using known methods and assays, e.g as known in the art and
references to IL-23 proteins, IL-23 assays and IL-12 assays, entirely incorporaledhentn by reference,
as as known in me art). Alternatively, portions of the IL-12 betal receptor are cloned and fused with
antibody fragments to generate receptor fusion proteins mat Mode bindmg of 11^23 to h^ receptors but
which do not inhibit binding of IL-I2 to its receptors, as known in me art
Clones expressing IL-23p40 specific antibodies or fusion proteins, such as anti-IL-23p40Ig
derived proteins of me present invention, are selected so tb^ they neutralires or inhibft at least one lL-
23 activity and which do not substantially inhibit at least one IL-12 activity.
The heavy chain, light chain CDRs, variable regkms, or variabk and constant regions are
cloned and pot into appropriate expression vectors. A typical mammahan expression vector contains
at least one promoter element, which mediates the fadtiation of tnmscrintion of mRNA, the Ig derived
protein or specified portion or variant coding sequence, and signals required for me termination of
transcription and polyadenyiation of the transcript Additional elements include enhancers, Kozak
sequences and intervening seqoenoes flanked by donor and acceptor sites for RNAspticing. Highly
effcient trancription can be achieved with early and late promotes from SV40,the long terminal
repeats (LTRS) from Retroviruses, e.g, RSV, HTLVL HTVI and the early promoter of the
cytomegalovirus (CMV). However, cellular elements can also be used (eg., the human actin
promoter). Suitable expression vectors for use in practicing the present invention include, for
example, vectors, such as pIRESlneo, pRetro-Off, pRetro-On, PLXSN, or pLNCX (clonetech Labs,
Palo Alto, CA), pcDNA3.1 (+/-), pcDNA/Zeo (4/-) or pcDNA3.1/Hygro (4/-) (invitrogen), PSVL and
PMSG (Pharmacia, Uppsala, Sweden), pRSVcat (ATCC 371S2), pSV2dhfir (ATOC 37146) and
pBC12MI(ATCC 67109). Mammalian host cells that could be used include human Hela 293, H9 and
Jurkat cells, mouse NIH3T3 and C127 ceDs, Cos 1, Cos 7 and CV 1, quail QC1-3 cells, mouse L cells
and Chinese hamster ovary (CHO) cells.
Alternatively, the gene can be expressed in stable cell lines that contain ate gene integrated
into a chromosome. The co-transfection with a selectable marker, such as dhfir, gpt, neomycin, or
hygromycin, allows die identification and isolation of the transfected cells.
The transfocted gene can also be amplified to express large amounts of the encoded Ig derived
protein or specified portion or variant The DHFR (dihydrofolate reductase) marker is useful to
develop cell lines that carry several hundred or even several thousand copies of the gene of interest.

Another useful selection marker is the enzyme glutamine synthase (GS) (Murphy, et al., Biochem. J.
227:277-279 (1991); Bebbington, et al., Bio/Technology 10:1(59-175 (1992)). Using these markers,
the mammalian cells are grown in selective medium and me cells with the highest resistance are
selected. These cell lines contain the amplified gene(s) integrated into a chromosome. Chinese
hamster ovary (CHO) and NSO cells are often used for the production of Ig derived protein or
specified portion or variants.
Cloning and Expression in CHO Cells
The vector pC4 is used for the expression of IL-23p40 Ig derived protein or specified portion
or variant Plasmid pC4 is a derivative of the plasmid pSV2-dhfr (ATCC Accession No. 37146). The
plasmid contains me mouse DHFR gene under control of die SV40 early promoter. Chinese hamster
ovary- or other cells lacking dihydrofolate activity that are transfected with these plasmids can be
selected by growing the cells in a selective medium (e.g., alpha minus MEM, Life Technologies,
Gaimersburg, MD) supplemented with me chemotherapeutic agent methotrexate. The amplification
of the DHFR genes in cells resistant to methotrexate (MTX) has been well documented (see, e.g., F.
W. Alt, et al.. J. Biol. Chem. 253:1357-1370 (1978); J. L. Hamlin and C. Ma, Biochem. et Biophys.
Acta 1097:107-143 (1990); and M. J. Page and M. A. Sydenham, Biotechnology 9:64-68 (1991)).
Cells grown in increasing concentrations of MTX develop resistance to the drug by overproducing die
target enzyme:, DHFR, as a result of amplification of the DHFR gene. If a second gene is linked to the
DHFR gene, it is usually co-amplified and over-expressed. It is known in the art that mis approach
can be used to develop cell lines carrying more man 1,000 copies of the amplified gene(s).
Subsequently, when the methotrexate is withdrawn, cell lines are obtained mat contain the amplified
gene integrated into one or more chromosome(s) of the host cell.
The plasmid pC4 (and also pCl) contains for expressing die gene of interest the strong
promoter of the long terminal repeat (LTR) of the Rous Sarcoma Virus (Cullen, et al., Molec. Cell.
Biol. 5:438-447 (1985)) plus a fragment isolated from the enhancer of the immediate early gene of
human cytomegalovirus (CMV) (Boshart, et al., Cell 41:521-530 (1985)). Downstream of the
promoter are BamHL Xbal, and Asp718 restriction enzyme cleavage sites that allow integration of the
genes; the multiple cloning sites facilitate cloning of the gene of interest Behind these cloning sites,
the plasmid contains the 3' intron and polyadenylation site and termination signal of the rat
preproinsulin gene. Other high efficiency promoters can also be used for the expression, e.g., the
human b-actin promoter, the SV40 early or late promoters or the long terminal repeats from other
retroviruses, e.g., HTV and HTLVI. Clontech's Tet-Off and Tet-On gene expression systems and
similar systems can be used to express the IL-23p40 in a regulated way in mammalian cells (M.
Gossen, and H. Bujard, Proc. Nad. Acad. Sci. USA 89:5547-5551 (1992)). For the polyadenylation
of the mRNA, other signals, e.g., from die human growth hormone or globin genes, can be used as
well. Stable cell lines carrying a gene of interest integrated into the chromosomes can also be selected

upon co-transfection with a selectable marker, such as gpt, G418 or hygromycin. It is advantageous
to use moie than one selectable marker in the beginning, e.g., G418 plus methotrexate.
The plasmid pC4 is digested with restriction enzymes and then dephosphorylated using calf
intestinal phosphatase by procedures known in the art The vector is then isolated from a.1% agarose
gel.
The DNA sequence encoding the complete IL-23p40 Ig derived protein or specified portion
or variant i s used, corresponding to HC and LC variable regions of an IL-23p40 Ig derived protein of
the present invention, according to known method steps. Isolated nucleic acid encoding a suitable
human constant region (i.e., HC and LC regions) is also used in this construct (e.g., as provided in
vector pl351).
The' isolated variable and constant region encoding DNA and the dephosphorylated vector are
then ligated with T4 DNA ligase. E. coli HB101 or XL-1 Blue cells are then transformed and bacteria
are identified that contain the fragment inserted into plasmid pC4 using, for instance, restriction
enzyme analysis.
Chinese hamster ovary (CHO) cells lacking an active DHFR gene are used for transfection. 5
ug of the expression plasmid pC4 is cotransfected with 0 .5 fig of the plasmid pSV2-neo using
lipofectin. The plasmid pSV2neo contains a dominant selectable marker, the neo gene from Tn5
encoding an enzyme mat confers resistance to a group of antibiotics including G418. The cells are
seeded in alpha minus MEM supplemented with 1 ug /ml G418. After 2 days, the cells are
trypsinized and seeded in hybridoma cloning plates (Greiner, Germany) in alpha minus MEM
supplemented with 10,25, or 50 ng/ml of methotrexate plus 1 ug /ml G418. After about 10-14 days,
single clones are trypsinized and then seeded in 6-well petri dishes or 10 ml flasks using different
concentrations of methotrexate (50 nM, 100 nM, 200 nM, 400 nM, 800 nM). Clones growing at the
highest concentrations of methotrexate are then transferred to new 6-well plates containing even
higher concentrations of methotrexate (1 mM, 2 mM, 5 mM, 10 mM, 20 mM). The same procedure is
repeated until clones are obtained that grow at a concentration of 100 - 200 mM. Expression of the
desired gene product is analyzed, for instance, by SDS-PAGE and Western blot or by reverse phase
HPLC analysis.
The completely human anti-IL-23p40 protein Ig derived proteins are further characterized.
Several of generated Ig derived proteins are expected to have affinity constants between 1x10* and
1*1012. Such high affinities of these fully human monoclonal Ig derived proteins make mem suitable
for therapeutic applications in IL-23p40 protein-dependent diseases, pathologies or related conditions.
Example 2: Comparison of the therapeutic efficacy of auti-IL-12p35 and anti-IL-12/23p40
antibodies in murine experimental autoimmune encephalomyelitis (EAE)

Summary: This set of studies was performed to investigate the therapeutic efficacy of IH2
or IL-12/23 specific neutralization in a mouse model for multiple sclerosis, experimental autoimmune
encephalomyelitis (EAE). Neutralizing rat anti-mouse monoclonal antibodies (mAbs) specific for the
p35 subunit of IL-12 or the p40 subunit, that is shared between IL-12 and IL-23, were administered
either prior to disease induction, prior to disease onset, or after disease was ongoing. In all cases, only
anti-p40 antibody demonstrated therapeutic potential. These data suggest that JL-23 is the
predominant contributor to disease pathogenesis in this autoimmune model.
Abbreviations:
EL Interleukin
mAb Monoclonal antibody
EAE Experimental autoimmune encephalomyelitis
Th T helper cell
IFNy Interferon gamma
cs Clinical score
MBP Myelin basic protein
PK Pharmacokinetics
Introduction: Biologically active IL-12 exists as a heterodimer comprised of 2 covalently
linked subunits of 35 (p35) and 40 (p40) kilo Daltons. Several lines of evidence have demonstrated
that IL-12 can induce robust Thl immune responses that are characterized by production of JJFNy md
IL~2 from CD4+ T cells. Inappropriate Thl responses, and thus IL-12 expression, are believed to
correlate with many immune-mediated inflammatory diseases, such as multiple sclerosis, rheumatoid
arthritis, inflammatory bowel disease, insulin-dependent diabetes mellitus, and uveitis. In animal
models, IL-12 neutralization was shown to ameliorate an autoimmune disease. However, these
studies neutralized IL-12 through its p40 subunit The description of IL-23, a heterodimeric cytokine
that shares the p40 subunit, made it important to determine whether previous findings were due to IL-
12 or IL-23 activity. Therefore, the p35 and p40 specific neutralization were compared in a mouse
model of autoimmunity, experimental autoimmune encephalomyelitis (EAE). Neutralizing antibodies
specific for EL-12p35 had no effect on EAE progression. In contrast, neutralization of both IL-12 and
H.-23 with an anti-p40 mAb suppressed clinical signs of EAE whether antibody was administered
before or after Thl differentiation. Our data suggests that the activity of anti-p40 treatment in EAE is
based solely on neutralization of IL-23.
Methods and Materials:
Mice:
Female C3H/HEB/FEJ mice (Jackson Laboratories, Bar Harbor, ME) were used in
pharmacokinetic analyses. For EAE studies, female B10.PL (H-2") mice were obtained from the
Jackson Laboratories, and were used between 6-8 weeks of age. All animals were maintained
according to IACUC guidelines under approved protocols.

Antibodies:
C17.8 (rat anti-mouse IL-12/23p40, IgG2a), and C18.2 (rat and mouse IL-12p35, IgG2a)
hybridomas were provided by Dr. Giorgio Trinehieri and the Wistar Institute (Philadelphia, PA).
Ascites was generated at Harlan Byproducts (Indianapolis, IN) and purified by protein G affinity.
Serum PK of rat anti-mouse antibodies:
Female C3H/HEB/FEJ mice, approximately 20-25 grams, were individually weighed and
treated with a single 5 mg/kg intraperitoneal dose of 12SI labeled antibody (C17.8, C18.2), with a
constant dose volume/mouse of 10 mL/kg. Retro-orbital bleeds were taken from anesthetized mice at
30 minutes, 6 and 24 hours, 4, 7, 11 and 18 days. Blood samples were allowed to stand at room
temperature for at least 30 minutes, but no longer than 1 hour, and were men centrifuged at
approximately 2,300-3,500 rpm for 10-15 minutes. Approximately 50 uL aliquots of each serum
sample were counted for 12SI using a LKB Compugamma 1282 counter (Wallac, Gaithersburg, MD).
10 mL aliquots of the injectates were also counted. The average fraction of injected counts at each
time point was calculated and multiplied by the total mg of antibody injected to determine the total
nig remaining in the serum at each time point Data is shown as the mean mg of mAb in the sera +/-
s.d. with 5-10 animals in each group.
EAR Induction and Scoring:
For EAE induction, female B10.PL mice were injected subcutaneously over four sites on the
back with a total of 100 |il of CFA (containing 200 Mg Mycobacterium tuberculosis Jamaica strain)
combined with 200 (ig guinea pig-MBP (Sigma). Mice also received 200 ng pertussis toxin (List
Biological, Campbell, CA) i.p. in 0.2 ml PBS at the time of immunization and 48 hours later. Mice
received i.p. injections of C17.8 (anti-IL-12p40) or C18.2 (anti-IL-12p35) monoclonal antibodies
diluted to 100 mg/kg (C18.2) or 20 mg/kg (C17.8) in PBS, on indicated days. Control mice received
PBS or Rat IgG (Biosource) at 20 mg/kg in PBS.
Animals that demonstrated clinical signs (cs) were scored as follows: limp tail or waddling
gait with tail tonicity 1, waddling gait with limp tail (ataxia) 2, ataxia with partial limb paralysis 2.5,
full paralysis of one limb 3, full paralysis of one limb with partial paralysis of second limb 3.5, full
paralysis of two limbs 4, moribund 4.5, death 5. Animals that scored a 5 were not included in the
mean daily cs analysis for the rest of the experiment Daily cs are averaged for the group, and mean
incidence, day of onset, highest acute cs, cumulative cs, cs/day, number of relapses and relapse
severity ± sem are described. Mean cumulative cs per group was calculated by averaging the sum of
daily clinical scores for individual animals. Cs/day was calculated by dividing the cumulative cs by
die number of days the animal remained in the study. To determine the mean day of onset, animals
not developing EAE were not included in the analysis. To determine the mean highest cs, mice not
developing EAE were assigned a value of "0" and included in the analysis. Relapses were defined by
.ii full point drop in clinical score sustained for at least 2 observed days followed by a full point
increase in clin ical score sustained for at least 2 observed days.

Results and Discussion: Anti-p35 and Anti-p40 antibodies have identical pharmacokinetics
To establish the clearance rates of anti-p40 and anti-p35 antibodies, normal mice were
injected with a single 5 mg/kg dose of 125I labeled antibodies and circulating levels were measured for
11 days post antibody administration. Anti-p35 and anti-p40 had overlapping pharmacokinetics,
demonstrating that clearance rates are identical in normal mice (2). The expected clearance rate of
each mAb is approximately 7-10 days. Although this is a single dose PK study, these data support
once weekly dosing for in vivo studies.
Only anti-p40 treatment prior to EAE induction is protective.
To determine the relative roles of IL-12 and 1L-23 in an autoimmune disease, a murine model
for multiple sclerosis, relapsing experimental autoimmune encephalomyelitis (EAE), was used. Upon
EAE induction with myelin basic protein (MBP) in adjuvant, B10.PL mice typically exhibit an initial
episode of paralysis (acute disease), then recover either partially or completely and progress through
multiple relapses and/or chronic EAR It has long been assumed that EAE is dependent upon IL-12
expression since IL-12 is believed to be a primary mediator of ThO to Thl differentiation. However,
to distinguish the potential role of IL-23 in EAE induction, neutralizing concentrations of anti-p40
(IL-12 and IL-23) or anti-p35 (IL-12 only) antibodies were established one day prior to immunization
for EAE (Day -1). Onset of disease can vary between animals; therefore, treatment was repeated 7
and 14 days later to ensure that anti-p35 and IL-p40 antibodies were present during Thl
differentiation. Several in vitro neutralization studies have demonstrated that the anti-40 mAb is 5
times more effective in neutralizing IL-12 than the anti-p35 mAb (data not shown). Therefore, the
dose of anti-p35 mAb was adjusted to be 5 fold higher than anti-p40 in all EAE experiments. In two
separate experiments, mice treated with Rat IgG isotype control antibody (20 mg/kg) or anti-p35 (100
mg/kg) did not demonstrate protection from disease. It is important to note that peripheral
administration of a non-specific control antibody (Rat IgG) did not alter the clinical course of disease
when compared to non-treated mice with EAE. In both studies, mice treated with anti-p40 mAb (20
mg/kg) exhibited nearly complete inhibition of EAE clinical signs. Remarkably, suppression of
disease extended beyond the expected rate of antibody clearance through 70 days post EAE induction.
In each experiment, only one animal treated with anti-p40 exhibited two consecutive days of EAE
clinical signs, and each demonstrated a late onset and significantly lower acute clinical scores,
cumulative clinical scores, and no relapses in disease (Table 1). These results demonstrated that
neutralisation of EL-12 and EL-23 through the shared p40 subunit provided nearly complete protection
from EAE. In contrast, specific neutralization of IL-12 only via anti-p35 was ineffective. These data
strongly suggest that EAE is not mediated by EL-12.
Only and-p40 treatment just prior to disease onset is protective.
Although prophylactic treatment completely protected mice from EAE, it remained to be
determined if EL-12 specific neutralization would be protective once the Thl population was

established in vivo. Therefore, in a separate set of experiments, mice were treated with either a
control antibody (Rat IgG), anti-p35, or anti-p40 monoclonal antibodies ten days after EAE induction,
but prior to disease onset. Since typical immune responses occur within 7 days, this time point should
be effective to reflect the effects of anti-IL-12 or anti-IL-23 mAbs on differentiated Thl cells. EAE
onset can vary between animals; therefore, treatment was repeated 7 and 14 days later to ensure that
anti-p35 and anti-p40 antibodies were present during the onset of disease. In two separate
experiments, mice treated with isotype control antibody (20 mg/kg) or anti-p35 (100 mg/kg) were not
protected from disease, when compared to untreated EAE mice. However, mice treated with anti-p40
mAb (20 mg/kg) were significantly protected from EAE. As shown in the previously described
studies, disease suppression was observed well beyond the time required for clearance of peripherally
administered antibody through day 70 post EAE induction. Considering that antibody was not
administered until after Thl differentiation (day 10), it was not surprising that disease incidence, day
of onset, and the highest clinical score during acute EAE were not different in any group (Table 2).
However, in both experiments, mice receiving anti-p40 exhibited significandy lower cumulative
clinical scores, clinical scores per day, and relapse severity.
Only anti-p40 treatment durinE established EAE is protective.
The most difficult, but clinically relevant, hurdle for any therapy is to suppress established
disease. Therefore, another set of experiments was performed in which mice were immunized for
EAE, then divided into treatment groups once disease was ongoing. Approximately 30 days post
BAE induction, mice had progressed through the acute phase of disease. At this time, animals were
divided into groups with comparable cumulative and daily clinical scores. Treatment was repeated 7
and 14 days later to ensure that antibodies were available in neutralizing concentrations during the
iransition from acute to chronic or remitting-relapsing disease. Only anti-p40 treatment (20 mg/kg)
ameliorated disease when compared to either isotype control antibody (20 mg/kg) or anti-p35 (100
mg/kg) treated animals. Disease suppression was observed through day 80 post EAE induction. In
I roth experiments, analysis from the first day of treatment through day 80 demonstrated that mice
receiving anti-p40 exhibited lower cumulative clinical scores, clinical scores per day, and the least
highest clinical score post treatment. These data suggest that not only is IL-23 likely to mediate Thl
differentiation (Table 1) and EAE induction (Table 2), but IL-23 also contributes to the effector phase
of chronic autoimmune responses (Table 3). Therefore, anti-p40 treatment can offer therapy at any
lime in the progression of autoimmune disease.
Mice were divided into 3 treatment groups with comparable disease severity once EAE was
established (approximately day 30). Clinical scores were analyzed from the first day of treatment
through 80 days post EAE induction. Data is shown as the mean per group ± s.e.m.
Conclusions
The understanding of the role of IL-12 in immune function has been based on studies of the
{40 subunit of EL-12. Therefore, a side-by-side comparison of neutralization of the IL-12 specific p35

subunit versus, the p40 subunit shared between IL-12 and IL-23 in an animal model of autoimmune
disease was conducted. Neutralization via anti-p40 significantly inhibited EAE when mAb was
administered at any time point However, IL-12 specific neutralization was completely ineffective.
Therefore, our data shows that IL-12 only partially contributes to this autoimmune model and mat IL-
'.'3 is expected be the more prominent mediator of autoimmune T cell responses.
Example 3: IL-23 mediates experimental autoimmune encephalomyelitis
Materials and Methods
Animals:
Female C3Heb/FeJ and B10.PL mice (Jackson Laboratories, Bar Harbor, ME) and female
C :5 7BL/6 mice (Charles River Laboratories, Raleigh NC) between 6-8 weeks of age were used and
maintained according to IACUC guidelines under approved protocols.
Antibodies
Rat monoclonal antibodies to mouse IL-23 were developed at Centocor (Malvern, PA).
Negative rat IgG (from Biosource, Camarillo, CA) was used as a control. Neutralizing rat anti-mouse
p40 (C17.8), and rat anti-mouse IL-12 (C18.2) antibodies were provided by Dr. Giorgio Trmchieri
and the Wistar Institute (Philadelphia, PA). Ascites was generated at Harlan Bioproducts
(Indianapolis, IN) and antibodies were purified by protein G affinity chromatography.
Cytokines
Recombinant murine IL-12 was obtained from R&D Systems (Minneapolis, MN).
Recombinant hlFN-y and human IL-2 were obtained from Peprotech (Rocky Hill, NJ). Murine IL-23
was generated using transient transfection technology and Immobilized Metal Affinity
Chromatography (IMAC). Briefly, separate expression constructs for murine p40 and murine pl9-His
were co-transfeeted into HEK 293E cells using Lipofectamine 2000 (Invitrogen, Carlsbad, CA) as
suggested by the manufacturers instructions. Alternatively, a linked IL-23 construct was generated as
described and transfection of HEK293E cells was performed. Twenty-fours hours post-transfection,
the growth medium was replaced with serum-free 293 SPMII (Invitrogen) and left to condition for 5
days, The media was then removed, centrifuged, and processed by IMAC using TALON resin (BD
Biosciences, Palo Alto, CA). His-tagged proteins were eluted with 150 mM EDTA, then dialyzed
against PBS, concentrated, filtered, and stored at -80°C. Bioactivity of both co-transfected and linked
IL-23 was verified by splenocyte IL-17 protein production as described below.
EL -12and IL-23 ELISA
Murine IL-12 and murine IL-23 (1 ug/ml) were coated overnight on Nunc Maxisorp plates in
PBS. After the plates were washed and blocked, rat anti-mouse p40, rat anti-mouse EL-12, and rat
anti-mouse IL-23 antibodies were titrated and allowed to bind for 2 hours. Bound protein was

detected using 1:10,000 HRP-conjugated goat anti-rat IgG antibody (from Jackson Immuno Research,
West Grove, PA) followed by substrate. Data is shown as the mean optical density of replicate wells.
IL-12 Neutralization
Non- adherent human peripheral blood mononuclear cells (PBMC) were cultured for four days
with 5 μg/ml PHA (Lectin, Phaseolus vulgaris, Sigma, St. Louis, MO) in complete RPMM640
(Invitrogen) with 10% heat-inactivated fetal bovine serum (JRH, Lenexa, KS), 1% L-glutamine
(JRH), 100 Units/ml penicillin and 100 μg/ml streptomycin (Invitrogen). Cells were harvested,
washed, then cultured with rhIL-2 (10 units/ml) in the presence of murine IL-12 (1 ng/ml) either alone
or pre-incubated with tested antibodies for 22 hours. Supematants were analyzed for human XFNy
protein levels by luminescence immunoassay using anti-IFNy antibodies generated at Centocor.
IL-23 Neutralization
Single cell suspensions were prepared from spleens of C57BL/6 mice. 2xl06 cells/ml were
cultured in complete RPMI with 10 U/ml rhIL-2 (Peprotech) and 1 ng/ml mouse IL-23, either alone or
pre-incubated with tested antibodies for 3 days. Supematants were collected and analyzed for IL-17
protein by ELIS A (R&D Systems) per the manufacturer's instructions.
EAE Analysis
Female B10.PL mice were injected s.c. over four sites on the back with a total of 100 ul of
complete Freunds adjuvant (CFA) combined with 200 μg guinea pig-myelin basic protein (MBP)
(Sigma). Mice also received 200 ng pertussis toxin (List Biological, Campbell, CA) i.p. in 0.2 ml
PBS at die time of immunization and 48 hours later. Mice received i.p. injections of anti-p40, anti-EL-
12, or anti-IL-23 monoclonal antibodies diluted to 100 mg/kg (anti-IL-12), 20 mg/kg (anti-p40, anti-
IL-23), or 50 mg/kg (anti-IL-23) in PBS, on indicated days. Control mice were either not treated or
received Rat IgG (Biosource, Camarillo, CA) at 20 mg/kg in PBS.
Animals that demonstrated clinical signs (cs) were scored as follows: limp tail or waddling
gait with tail tonicity 1, waddling gait with limp tail (ataxia) 2, ataxia with partial limb paralysis 2.5,
full paralysis of one limb 3, full paralysis of one limb with partial paralysis of second limb 3.5, full
paralysis of two limbs 4, moribund 4.5, death 5. Scores for animals that were sacrificed or scored a 5
were not included in the mean daily cs analysis for the rest of the experiment. Daily cs are averaged
for the group, and incidence, mortality, day of onset, highest acute cs, cumulative cs, cs/day, number
of relapses and relapse severity ± sem are described. Mean cumulative cs per group was calculated by
averaging the sum of daily clinical scores for individual animals. Cs/day was calculated by dividing
the cumulative cs by the number of days the animal remained in the study. To determine the mean
day of onset, animals not developing EAE were not included in the analysis. To determine the mean
highest icute cs, mice that never developed EAE were assigned a value of "0" and included in the
group mean. Relapses were defined by a full point drop in clinical score sustained for at least 2
observed days followed by a full point increase in clinical score sustained for at least 2 observed days.

r
To determine the mean number of relapses per group, mice not demonstrating a defined relapse were
assigned a value of "0" and included in the group mean. To determine the mean relapse severity, the
highest clinical score of each relapse event was averaged and animals mat did not relapse were not
included in the analysis.
For ex vivo EAE analysis, spleens and peripheral lymph nodes (inguinal, axillary, brachial,
and cervical) were harvested from each animal on days 10,17, 24, or 32 post EAE induction. Single
cell suspensions (5 x lOVwell) were prepared from individual animals, washed twice, men cultured in
vitro in RPMI complete for 72 hours with 40 μg/ml MBP, 5 μg/ml ConA, or media alone and
proliferation was measured using ATPLite (Perkin Elmer, Boston, MA). Data is represented as a
stimulation index, which is the mean proliferation to MBP divided by the mean proliferation to media
alone. Splenocytes and lymph node cells were also cultured at 4 x 106 cells/ml with 40 μg/ml MBP or
media alone for 48 hours and supernatants were tested for IFNy, IL-17, EL-4, IL-5, and IL-10 proteins
by ELISA, according to the manufacturer instructions (R&D Systems). Even though minimal
cytokine levels were detected in media-only cultures, those values were subtracted from the levels
found in MBP-stimulated cultures so that the data presented represents only antigen-specific cytokine
production.
For histopathologic examination and ranking, mouse brains and spinal columns were fixed in
10% buffered formalin by emersion. After fixation, the brains were sliced coronally into 4 segments.
Spinal columns were decalcified in 5% EDTA and men sliced sagitally into 5 segments. The tissues
were processed and embedded in paraffin using routine methods. Tissue blocks were sectioned at 5
jim, and stained with hematoxylin and eosin (H&E) or Luxol Blue-Cresyl Echt Violet (Poly
Scientific, Bay Shore, NT). Additional sections were stained immunohistochemically for glial
fibrillary acidic protein (GFAP) (BioGenex, San Ramon, CA). Sections were blinded and ranked
based on the extent of inflammation. Brains and spinal cords were analyzed separately.
Results
IL-23 specific neutralization ameliorates EAE
To confirm that neutralization of only IL-23 will provide effective therapy for EAE,
monoclonal antibodies to mouse IL-23 were generated. As shown in Figure 1A, an antibody specific
for mouse IL-23 that demonstrated no reactivity with mouse TL-12 was identified. Subsequent studies
have shown that the anti-EL-12 and anti-EL-23 antibodies do not cross react even when 100 ng/ml of
the opposite cytokine is present. As shown in Figure IB, the anti-EL-23 specific antibody binds to the
p40 subunit of IL-23 and does not bind to the pl9 subunit. Accordingly, it is EL-23p40 specific.
Since it was recently shown mat IL-23 will induce EL-17 production, these antibodies were
tested for their ability to neutralize IL-23 bioactivity. As shown in Figure 1C, the EL-23 specific
antibody inhibits IL-17 production with similar potency as anti-p40. In contrast, the anti-EL-12
antibody demonstrated no effect on EL-17 levels. Lastly, to confirm that the anti-EL-23 antibody does

not interfere with IL-12 function, the antibodies' ability to inhibit IFNY production in T cell cultures
was tested. As previously demonstrated, anti-IL-12 and anti-p40 inhibited IFNY production, however,
the anti-EL 23 antibody had no effect on IFNy levels (Figure ID). Therefore, a neutralizing anti-
mouse IL-23 antibody that does not bind EL-12 or inhibit IL-12 mediated responses has been
developed. The anti-IL-23 and anti-p40 antibodies were compared for w v/'w inhibition of EAE. In
two separate experiments, mice were treated with either a control antibody, anti-p40, or anti-IL-23 ten
days after EAE induction, which is prior to disease onset. Mice treated with anti-IL-23 demonstrated
clinical suppression of EAE comparable to that of anti-p40 treated animals (Figure IE). Mice
receiving anti-p40 or anti-IL-23 exhibited a later day of onset, reduced severity of acute disease and
subsequent relapses, and lower clinical scores per day (Table 4). These results confirm that IL-23,
rather than IL-12, is responsible for EAE even in mice that have not been genetically manipulated.
EL-23 neutralization prevents EAE pomology in the CNS
EAE. presents as an ascending bind limb paralysis and is therefore scored for severity by
deficits in motor function. However, the cause of mis impairment can only be observed by assessing
pathology within the brain and spinal cord. Therefore, a separate study was performed in which mice
were immunized for EAE, then treated with control Rat IgG, anti-IL-12, anti-p40, or anti-IL-23
antibodies on days 10 and 17, and sacrificed on days 17 and 24 by cardiac perfusion. Brains and
spinal cords were analyzed for cellular infiltration by H&E and demyelination by Luxol Fast Blue.
Sections were blinded and ranked from least to most severe, then correlated to the clinical score of the
animal on the day of sacrifice.
As shown in Figure 2A, the severity of spinal cord pathology correlated with the clinical score
severity, whereas brain pathology did not This is not surprising since clinical scoring is defined by
motor ability, which is primarily a measurement of spinal cord function. Histopathology rankings
were then sub-divided into treatment groups to assess differences after 2 in vivo antibody treatments
(day 24). All treatment groups, including anti-IL-12, had lower pathology rankings man the Rat IgG
treated control animals (Figure 2B). However, it is important to note that with treatment paradigms
that are initiated 10 days post EAE induction, clinical protection with anti-p40 or anti-IL-23 is not
typically observed until day 30 or later (Figure ID). Regardless, there were remarkable differences in
spinal cord inflammation, demyelination, and astrocyte gliosis when the Rat IgG control and anti-EL-
23 groups were compared. These data confirm that the clinical protection that is observed after anti-
D-23 therapy is a result of partial protection from CNS pathology.
As discussed above, for treatment paradigms that are initiated 10 days post EAE induction,
clinical protection with anti-p40 or anti-IL-23 is not typically observed until day 30 or later (Figure
ID). Therefore, day 24 may be too early to detect differences in CNS pathology between treatment
groups. Regardless, there are remarkable differences in spinal cord inflammation and demyelination
when the Rat IgG control and anti-IL-23 groups are compared. These data confirm that the clinical

:cross sections using a monomorphic grid. Inflammation and demyelination in the brain is expressed as present
(+) or absent (-).
Table 2. EAE clinical scores with IL-12 and IL-23 neutralization after Th1 differentiation.

a clinical score (cs)
b cumulative cs
Mice were treated on days 10,17, and 24 and clinical scores were analyzed from day 0 through 70 days
post EAE induction. Data is shown as the mean per group ± s.e.m.
Table 3. EAE clinical scores with IL-12 and IL-23 neutralization during established
EAE.
Pre-Tx* From first treatment through 80 days post EAE induction

Novel anti-IL-23p40 specific human Ig derived proteins, including, without limitation,
antibodies, fusion proteins, and mimetibodies, isolated nucleic acids that encode the anti-
IL-2340 Ig derived proteins, vectors, host cells, transgenic animals or plants, and methods
of making and using thereof, are useful for therapeutic compositions, methods and
devices. Preferably, the anti-IL-23p40 specific human Ig derived proteins do not bind the
p40 subunit of IL-12 and, thus, do not neutralize IL-12 related activity.

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Patent Number

226756

Indian Patent Application Number

2559/KOLNP/2005

PG Journal Number

52/2008

Publication Date

26-Dec-2008

Grant Date

24-Dec-2008

Date of Filing

09-Dec-2005

Name of Patentee

CENTOCOR, INC

Applicant Address

200 GREAT VALLEY PARKWAY MAILCODE RA-1-5, MALVERN, PA 19355

Inventors:

#	Inventor's Name	Inventor's Address
1	JACQUELINE BENSON	5 OAK GLEN DRIVE, MALVERN, PA 19355
2	MARK CUNNINGHAM	716 GARDEN DRIVE, KENNETT SQUARE, PA 19348

PCT International Classification Number

C12N

PCT International Application Number

PCT/US2004/014372

PCT International Filing date

2004-05-06

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/469,366	2003-05-09	U.S.A.