| Title of Invention | A CHIMERIC MONOCLONAL ANTIBODY |
|---|---|
| Abstract | ABSTRACT 2017/CHENP/2004 "A CHIMERIC MONOCLONAL ANTIBODY" A chemeric, humanized or human monoclonal anybody that binds to C020, the antibody having a light chain variable region CDR1 comprslng a sequence RASSSVSVIH (SEQ ID NO 1), CDR2 comprising a sequence ATSNLAS (SEQ 10 NO 4), and CDR3 comprising a sequence QQWTSNPPT (SEQ ID NO S)- end the antibody having a heavy chain variable region CDR1 comprising a sequence SYNMH (SEQ ID NO 8): CDR2 comprising a sequence AIYPGNGDT5YNQKFKG (SEQ ID NO 9). and CDR3 compnsing a sequence STVYGGDWYFDV (SEO ID NO: 10) or a sequence WYYSNSVWyFDV (SEQ ID NO. 13) |
| Full Text | BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to humanize4 chimeric and human anti-CD20 antibodies, particularly monoclonal antibodies (mAbs) therapeutic and diagnostic conjugates of humanized, chimeric and human anti-CD20 antibodies and methods of treating B cell lymphomas and leukemias and various autoimmune diseases using humanized, chimeric and human anti-CD20 antibodies. The present invention relates to antibody fusion proteins or ftagments thereof eonq>rising at least two anti-CD20 mAbs or fragments thereof or at least one anti-CD2Q MAb or fra^ent thereof and at least one second MAb or fragment thereof, other than the antiCD20 MAb or fragment diereof. The humanized, chimeric and human anti--CD20 mAbs, fr'^ments thereof, antibody fiision proteins thereof or fragments thereof may be administered alone, as a therapeutic conjugate or in combination with a therapeutic immimoconjugate, with other naked antibodies, or with therapeutic agents or as a diagnostic conji^ate. The present invMition relates to DNA sequences encoding humaziized, chimeric and human anti-CD20 antibodies, and antibody fusion proteins, vectors and host cells containing the DNA sequences, and methods of makir^ the humaiuzed, chimeric and human anti'CD20 antibodies. 2. Background The immune system of vertebrates consists of a number of organs and cell types which have evolved to accurately recognize foreign antigens, specifically bind to, and eliminate/destroy such foreign antigens. Lymphocytes, amongst others, are critical to the immune system. Lymphocytes are divided into two major sub-populations, T cells and B cells. Although inter-dependent, T cells are largely responsible for cell-mediated irorauni^ and B cells are largely responsible for antibody production (humoral immunity). In humans, each B cell can produce an enormous number of antibody molecules. Such antibody production typically ceases (or substantially decreases) when a foreign antigen has been neutralized. Occasionally, however, proliferation of a particular B cell will continue unabated and may result in a cancer known as a B cell lymphoma. B-cell lymphomas, such as the B-ceU subtype of non-Hodgkin's lymphoma, are significant contributors to cancer mortality. The response of B-cell mahgnancies to various forms of treatment is mixed. For example, in cases in which adequate chnical staging of non-Hodgkiu's lymphoma is possible, field radiation therapy can provide satisfactory treatment. Still, about one-half of the patients die from the disease. Devesaetal.J. Nat'lCancerlnst. 79:701(1987). The majority of chronic lymphocytic leukemias are of B-cell lineage. Freedman, Hematol. Oncol CUn. North Am. 4-AQ5 (1990). This type of B-ceU malignancy is the most common leukemia in the Western world. Goodman et al. Leukemia and Lymphoma 22:1 (1996). The natural history of chronic lymphocytic leukemia falls into several phases. In the early phase, chronic lymphocytic leukemia is an indolent disease, characterized by the accumulation of small mature fimctionally-incompetent malignant B-cells having a lengthened life span. Eventually, the doubling time of the malignant B-cells decreases and patients become increasingly symptomatic. While treatment can provide symptomatic relief, the overall survival of the patients is only minimally affected. The late stages of chronic lymphocytic leukemia are characterized by significant anemia and/or thrombocytopenia. At this point, the median survival is less tl^n tvyo years. Foon et al, Annals Lit. Medicine 113:525 (1990). Due to the very low rate of cellular proUferation, chronic lymphocytic leukemia is resistant to cytotoxic drug treatment. Traditional methods of treating B-cell malignancies, including chemother^y and radiotherapy, have limited utility due to toxic side effects. The use of monoclonal antibodies to direct radionuclides, toxins, or other therapeutic agents offers the possibility tiiat such agents can be delivered selectively to tumor sites, thus limiting toxicity to normal tissues. Also, flie presence of B-cell antigens on these B-cell malignancies makes them optimal targets for therapy witii unconjugated B-cell antibodies, such as against CD19, CD20, CD2I, CD23, and CD22 markers on B-cells. HLA-DR and other antigens may sMve as targets for nonr^ and malignant B-cells, although they are also expressed on other cell tvoes. Further, certain MUCl. MUC2. MUC3, and ^^JC4 antigens, preferably MUCl, are also expressed in different hematopoietic malignancies, including B-cell tumors expressing CD20 and other B-cell markers. Still other antigen tai^ets, such as those ^sociated with the vascular endothelium of tumors, including tenascin, vascular endothelium growth factor (VEGF), and placental grow& factor (PIGF), as well as other categories of antigens associated with B-cell malignancies, such as oncogene products, are also suitable targets for said complementaiy antibodies for use in the present invention. B cells comprise cell surface proteins which can be utilized as markers for differentiation and identification. One such human B-cell marker is the human B lymphocyte-restricted differentiation antigen Bp35, referred to as CD20. CD20 is expressed during early pre-B cell development and remains until plasma cell differentiation. CD20 is expressed on both normal B cells and malignant B cells whose abnormal growth can lead to B-cell lymphomas. Antibodies against the CD20 antigen have been investigated for the therapy of B-cell lymphomas. For example, a chimeric aiiti-CD20 antibody, desigMted as "IDEC-C2B8," has activity against B-cell lymphomas when provided as unconjugated antibodies at repeated injections of doses exceeding 500 mg per injection. Maloney et al. Blood 84:2A57 (1994); Loi^o, Curr. Opin. Oncol. 5:353 (1996). About 50 percent of non-Hodgkin's patients, having the low-grade indolent form, treated with this regimen showed responses. Therapeutic responses have also been obtained usii^ '^'l-labeled BI anti-CD20 murine monoclonal antibody when provided as repeated doses exceeding 600 mg per iigection. Kaminski et al, N. Engl. J. Med. 329:459 (1993); Press et al. N. Engl J. Med 329:1219 (1993); Press etal, lancet 346:336 (1995). However, these antibodies, whether provided as unconjugated forms or radiolabeled forms, have not shown high rates of objective and durable responses in patients with the more prevalent and lethal form of B-cell lymphoma, the intermediate or aggressive type. Thraefore, a need existe to develop an immuaothetapy for B-cell malignancies that achieves a therapeutic response of significant duration. Additional stui^es targeting CD20 surfece antigen have been demonstrated using an anti-CD20 mtuine monoclonal antibody, IF5, which was administered by continiious intravenous infiision to B cell lymphoma patients. Extremely high levels (>2 grams) of 1F5 were reportedly required to deplete circulating tumor ceils, and the results were described as being "transient." Press et al., "Monocloiml Antibody 1F5 (Anti-CD20) Serotherapy of Human B-Cell Lymphomas." Blood 69/2:5B4-591 (1987). However, a potential problem with this approach is that non-human monoclonal antibodies (e.g., murine monoclonal antibodies) typically lack human effector fimctionality, i.e., they are unable to mediate complement- One approach that has improved the ability of murine monoclonal antibodies to be effective in the treatment of B-cell disorders has been to conjugate a radioactive label or chemotherapeutic E^ent to the antibody, such that the label or agent is localized at the tumor site. For example, the above-referenced IF5 antibody and other B-cell antibodies have beai labeled with '^'l and were reportedly evaluated for biodistiibution in two patients. See Eary, J. F. et al., "Imaging and Treatment of B-Cell Lymphoma" J. Nuc. Med. 31/8:1257-1268 (1990); see also, Press, O. W. et al, "Treatment of Refiactory Non-Hodgkin's Lymphoma with Radiolabeled MB-1 (Anti-CD37) Antibody" J. Clin. Chic. 7/8:1027-1038 (1989) (mdication that one patient treated with '^^I-labeled IF-5 achieved a partial response); Goldenberg, D. M. et al, "Targeting, Dosimetry and Radioimmunotherapy of B-Cell Lymphomas with '^'l-Labeled LL2 Monoclonal Antibody" J. Clin. Oncol 9/4:548-564 (1991) (three of . eight patients receivmg multiple injections reported to have developed a HAMA response to this CD22 murine antibody); Appelbaum, F. R. "Radiolabeled Monoclonal Antibodies in the Treataient of Non-Hodgkin's Lymphoma" Hem/Oncol Climes o/N. A. 5/5:1013-1025 (1991) (review article); Press, O. W. et al "Radiolabeled-Antibody Therapy of B-CeU Lymphoma with Autologous Bone Marrow Support." New England Journal o/Medicine 329/17: 1219-12223(1993) (" 'Mabeled anti-CD20 antibody IF5 and B1); and Kaininski, M. G. et al "Radioimmunotherapy of B-Cell Lymphoma with ["'l] Anti-B 1 (Anti-CD20) Antibody". NEJM329n:459 (1993) ("'l-Iabeled anti-CD20 antibody Bl; hereinafter "Kammski"); PCT published application WO 92/07466 (antibodies conjugated to chemotherapeutic ^ents such as doxorubicin or mitomycin). Howevw, these approaches have not eliminated the obstacles associated with using murine antibodies, despite the fact that many patients witti lymphoma who have received prior aggressive cytotoxic chemotherapy are immune suppressed, thus having lower HAMA rates than lymphoma patients who have not been heavily pretreated. Autoimmune diseases are a class of diseases associated with B-cell disorders. Examples include immune-mediated thrombocytopeiuas, such as acute idiopathic thrombocytopenic purpura and chronic idiopathic thrombocytopenic piupura, myasthenia gravis, Ivqjus uephritis, lupus erythematosus, and rheimiatoid arthritis. The most common treatments are corticosteroids and cytotoxic drugs, which can be very toxic. "Hiese drugs also suppress ttie entire immune system, can result in serious infection, and have adverse affects on the bone marrow, liver and kidneys. Other therapeutics that have been used to treat Class HI autoimmune diseases to date have been directed against T-cells and macroph^es. There is a need for more effective methods of treating autoimmune diseases, particularly Class III autoimmune diseases. To address the many issues related to B-cell disorders and their treatment, the present invention provides humanized, chimeric and human anti-CD20 monoclonal antibodies with the same complementarity determining regions (CDRs) that bind to the CD20 antigen of the present invention used alone, conjugated to a therapeutic agent or in combination with other treataient modahties, for the treatment of B cell lymphomas and leukemias aod autoimmune disorders in humans and other mammals without the adverse responses associated with using murine antibodies. SUMMARY OF THE INVENTION Accordii^ly, the present invention provides humanized, chimeric and human anti-CD20 antibodies that bind to a human B cell marker, referred to as CD20, which is usefiil for the treatment and diagnosis of B-cell disorders, such as B-cell malignancies and autoimmune diseases. The present invention further provides methods of treatment of mammalian subjects, such as humans or domestic animals, with one or more humanized, chimeric and human CD20 antibodies, alone, as an antibody fiision protein, as a therapeutic conjugate alone or as part of an antibody fusion protein, in combination, or as a multimodal ther^y, widi other antibodies, other therqwutic agents or immunomodulators or as an immunoconjugate linked to at least one Uier^eutic agent, therapeutic radionuclide or immimomodulator. These humanized, chimeric and human CD20 antibodies can also be used as a diagnostic imaging agent alone, in combination with otiier diagnostic imaging agents, and/or in conjunction with therapeutic ^pUcations. The present invention additionally is directed to anti-CD20 mAbs or fragments fliereof that contain specific murine CDRs or a combination of murine CDRs from more than one murine or chimeric anti-CD20 MAb that have specificity for CD20. These mAbs can be humanized, chimeric or human anti-CD20 mAbs. The present invention is also directed to antibody iiision proteins comprising at least two anti-CD20mAbs or figments thereof or a first MAb comprising an anti-CD20niAbs or fragments tiiereof and a second MAb. The present invention is fijrther directed to a therapeutic or diagnostic conjugates of the anti-CD20 mAbs or fragments thereof or antibody fusion proteins of the anti-CD20 mAbs or other mAbs or fragments thereof bound to at least one therapeutic agent or at least one diagnostic agent. Antibody fusion proteins wi& multiple tiierapeutic agents of the same or different type are encompassed by the present invention. The present invention is additiondiy directed to a method of using the anti-CD20 mAbs or fragments tho^of or antibody fiosion proteins thereof or fragments thereof for therapy, either alone, in combination with each other, as the antibody component of a therapeutic immunoconjugate witii one or more tiierapeutic agents or each administered in combination with one or more ther^Kutic agaits or with an immunoconjugate with one or more therapeutic agents. The present invention finder is directed to a method of using ttie auti-CD20 mAbs or fragments thereof or antibody fiision proteins thereof or fragments thereof as a diagnostic bound to one or more diagnostic agents. The present invention additionally is directed to a method of pretargetmg a cell in a patients suffering from a B-cell lymphoma or leukemia or an autoimmune disease using an antibocfy fixsion protem or fragment thereof of the present invention. BRIEF DESCRIPTION OF THE FIGURES Figure 1 discloses the V gene sequences cloned by RT-PCR from a hybridoma cell line prodiicing a murine anti-CD20, and the dedticed amino acid sequences of the variable light figure 1 A) and heavy chain (Figure IB) of the A20 antibody, designated as A20Vk and A20A/H, respectively. Underlined arrows indicate the sequences of the PCR primers used for cloning. The putative CDR region sequences, as defined by the Kabat numbering scheme, are shown in bold and underlined. Amino acid sequences are given as single-letter codes below die corresponding nucleotide sequence. The Kabat numbering scheme was used for amino acid residues. Amino acid residues numbered by a letter represent the insertion residue according to Kabat, and have the same number as that of the previous residue. For example, residues 82,82A, 82B and 82C in Figure IB are indicated as 82 A, B, and C, respectively,. Figure 2 discloses die Vk, the variable light chain, and the VH, the variable heavy ch^ sequences of cA20, a chimeric anti-CD20 antibody. The CDR region sequences are shown in bold and underlined. The amino acid residues and the nucleotides are numbered sequentially and same numbering system is used for humanized V sequences. The light chain variable region is shown in Fig. 2A and the heavy chain variable region is shown in Fig. 2B. The numbering system is the same as for Figure 1. The restriction sites used for constructing cA20 are underlined. Figure 3 shows a comparison of the binding affinities of the chuneric A20 (cA20), and murine A20, (A20), in a cell surface competitive binding assay against ^^^I-iabJed A20. Increasing concentrations of cA20 blocked the binding of radiolabeled A20 to Raji cells (as depicted by closed circles) in a comparable manner as tliat of murine A20 (depicted by closed diamonds). Figure 4 compares the amino acid sequences of the variable heavy chain (VH) and variable light chain (Vk) of human antibodies, and chimeric and htmianzied anti-CD20 antibodies. Figure 4A compares the amino acid sequences of the variable heavy chain (VH) of the human antibodies, EU and NEWM (FR4 only), the chimeric antibody, (cA20VH) and two humanized antibodies, (hA30VHl and hA20VH2) and Figure 4B compares the amino acid sequences of the variable light chain (Vk) of the hximan antibody, (REIVk), a chimeric antibody, (cA20Vk), and a humanized antibody, (hA20Vk). Dots indicate that tlK residues in A20 are identical to the correspondir^ residue in the human antibody. The CDRs aie identified as a boxed region. The Kabat numbering scheme was used to number the amino acid residues. Figure 5 discloses the nucleotide sequences of hA20 hght chain V genes, (hA20Vk) (Figure 5A), and heavy cham V genes, hA20VHl (Figure 5B) and hA20VH2 (Figure 5C), as well as the adjacent flanking sequences of flie VKpBR2 (Figure 5A) and VHpBS2 (Figures 5B and 5C) staging vectors, respectively. The non-transiated nucleotide sequences are showQ in lowercase. Hie restriction sites used for subcloning are imderlined and indicated. The secretion signal peptide sequence is indicated by a double underline. Numbering of Vk and VH amino acid residues is same as that in Figin^ 2. Figure 6 shows the results of a cell surface competitive binding assay to compare the binding activity of two hiunanized A20 antibodies, (hA20-l and hA20-2), with that of A20, cA20 and a chimeric anti-CD20 MAb, c2B8. Figure 6A shows hA20-l (closed triangles) and hA20-2 (closed circles) and tiie murine anti-CD20 antibody, A20 (closed squares) competed equally well for the binding of '^^I-A20 to Raji cells. Figure 6B shows hA20-l (closed cycles), cA20 (closed squares) and c2B8 (closed diamonds) competed equally well for the binding of '^I-c2B8 to Raji cells. Figure 7 discloses the constant region of a hum«i. igu i vv,rt-mnge) (Figure 7A) and the constant region of a human ks^pa chain (Ck) (Figure 7B). Figure 8 is a competitive cell surfece bmding assay. Ag-binding specificity and affinity studies ofhumanized anti-CD20 Abs (cA20, hA20, and clF5, purified by affinity chromatography on a Protein A column) were evaluated by a cell surface competitive bindi:^ assay with murine 2B8 and ntuximab (IDEC Pharmaceuticals Corp., San Diego, CA). Figure 8 (A) is a comparison of the binding activities of cA20 (square), hA20-l (triangle) and hA20-l (circle) with that of m2B8 (diamond); figure 8 (B) compares of the binding activities of cA20 (square), clF5 (triangle) and ntuximab (diamond). Figure 9 is a study comparing the binding activities of hA20 with oAer anti-CD20 Abs, including ntuximab and murine Bl, by a cell surface competitive binding assay. A constant amount (100,000 cpm, -10 ICiAg) of '^^I-labeled rituximab was incubated with Raji cells in the presence of varying concentrations (0,2-700 nM) of competing Abs, hA20 (triangle), mBl (Downward triangle) or rituximab (square) at 4'Cforl-2h. Figure 10 depicts die cytotoxic effect of crossUnked hA20 and other CD20 Abs on cultured lymphoma cells. Total cell and viable cell cell populations were measured by (A) trypan blue staining and cell counting or (B) MTT assay. Figure 11 isagraphof in vivo therapy studies with various auri-CD20and other Abs. Raji cells administered i.v. to SCID mice, to create a Raji lymphoma model of disseminated disease. Figure 12 is a graph depicting in vivo therapy with liA20 and hLL2. Raji cells administered i.v. to SCID mice, to create a Raji lymphoma model of disseminated disease. DETAILED DESCRIPTION OF THE INVENTION 1, Overview As discussed above, anti-CD20 antibodies that are unconjugated or labeled with a thenqpeutic radionnchde, have tailed to provide high rntra of objective and lasting responses in patients with intennediate or aggressive forms of B-cell lymphoma. The present invention provides a humanized, a chimeric and a human anti-CD20 antibody and antibody fiision proteins thereof usefiU for treatment of mammaUan subjects, humans and domestic animals, alone, as a conjugate or administered in combmation with other tiierapeutic agents, including other naked antibodies and antibody therapeutic conjugates. The anti-CD20 mAbs of the present invention contain specific murine CDRs or a combination of murine CDRs from more than one murine or chimeric anti-CD20 MAb that have specificity for the CD20 antigen. The anti-CD20 mAbs of the present invention are humanized, chimeric or human mAbs and they contain the amino acids of the CDRs of a muriiK anti-CD20 MAb and retain substantially the B-cell and B-cell lymphoma and leukemia cell targeting of the murine anti-CD20 MAb. The CDRs of the light chain variable region of the anti-CD20 MAb comprises CDRl comprismg amino acids RASSSVSYIH, RASSSLSFMH or RASSSVSYMH; CDR2 comprising ammo acids ATSNLAS; and CDR3 comprising ammo acids QQWTSNPPT, HQWSSNPLT or QQSFSNPPT; and the CDRs of the heavy chain variable region of the anti-CD20 MAb comprises CDRl comprising amino acids SYNMH; CDR2 comfHising amino acids AIYPGNGDTSYNQKFKG and CDR3 comprismg amino acids STYYGGDWYFDV, STYYGGDWYFNV, SHYGSNYVDYFDV or WYYSNSYWYFDV. In one embodiment, the humanized and chimeric MAb or fiagment thereof does not contain the CDR3 of the heavy chain variable region comprising STYYGGDWYFNV. More preferably, CDRl of the light cham variable region does not comprise RASSSLSFMH when die CDR3 of the Ught chain variable region con^irises HQWSSNPLT and the CDRS of the heavy chain variable region comprises SHYGSNYVDYFDV. In anodier embodiment, die CDR3 of the light chain variable region does not comprise HQWSSNPLT when CDRl of the light chain variable region comprises RASSSLSFMH and when CDR3 of the heavy chain variable region comprises SHYGSNYVDYFDV. In a fiirther embodiment, the CDR3 of die heavy cham variable region does not comprise SHYGSNYVDYFDV when the CDRl of the light drain variable region comprises ElASSSLSFMH and tiie CDR3 of the light chain variable region comprises HQWSSNPLT. In anodier embodiment, the CDRl of ttie li^t chain variable region does not conqirise RASSSVSYMH wiien die CDR3 of the Ught chain variable region comprises QQSFSNPPT and the CDR3 of the heavy chain variable region comprises WYYSNSYWYFDV. Further, in another embodiment the anti-CQ20 monoclonal antibody (MAb) or fij^jnent thereof does not contain CDR3 of the Ught chain variable region of amino acids QQSFSNPPT when CDRl of the light chain variable region comprises RASSSVSYMH and the CDR3 of the heavy chain variable region comprises WYYSNS'^'WYFDY. Additionally, the anti-CD20 MAb does not contain CDR3 of the heavy chain variable region with amino acids WYYSNSYWYFDV when the CDRl of the light dmin variable region comprises RASSSVSYMH and the CDR3 of the light chmn variable region comprises QQSFSNPPT. In a preferred embodunent, the humanized anti-CD20 (hCD20) monoclonal antibody or antigen-bindii^ fragment thereof comprising the complementarily determining regions (CDRs) of at least one murine anti-CD20 MAb variable region and the framework regions (FRs) of at least one human MAb variable region, wherein said faurtmnized aati-CD20 MAb or fragment thereof renins substantially the B-cell and B-cell lymphoma and leukemia cell targeting of said murine anti-CD20 MAb. The humanized antibody's variable region may comprise a light chain variable region, a heavy chain variable region or a both light and heavy chain variable regions. The humanized antibody or fragment tiiereof may ftirther comprise light and heavy chain constant regions of at least one human antibody. The humanized anti-CD20 MAb or fragment thereof of the present invention conqaises the CDRs of a murirte anti-CD20 MAb and lite frameworit (FR) regions of the light and heavy chain variable regions of a human antibody, while retaining substantially the B-cell, and B-cell lymphoma and leukemia cell targeting of lbs parent murine anti-CD20 MAb, and wherein the CDRs of the ti^t chain variable region of the murine anti-CD20 MAb comprises CDRl comprising amino acids RASSSVSYIH, CDR2 comprising amino acids ATSNLAS and CDR3 comprising QQWTSNPPT and the CDI^ of the heavy chain variable region of murine anti-CD20 MAb comprises CDRl comprising amino acids SYNMH, CDR2 comprising amino acids AIYPGNGDTSYNQKFKG and CDR3 comprising amino acids STYYGGDWYFDV. But the humanized anti-CD20 MAb or fr£^jnMt thereof may fiiriher contain in tie FRs of tile light and heavy chain variable regions of the antibody at least one amino acid fixim tiie coirespondit^ FRs of tiie murine MAb. The humanized MAbs may fiirther contain the light and heavy chain constant regioiK of a human antibody. Specifically, the humanized anti-CD20 MAb or fragment tiiereof contmns at least one amino acid residue 1, 5, 27, 30, 38, 48, 67, 68, 70, 95, U5 and 116 of tiie murine heavy chain variable region of Fig. 4A, designated as hA20VHl or hA20VH2 and of at least one amino acid residue 4, 21, 35, 38, 45, 46, 59, 99, 104 and 106 of the murine light chain variable region Fig. 4B, designated hA20Vk. One or more of the murine amino acid sequences can be maintained in the human FR regions of die light and heavy variable chains if necessary to maintain proper binding or to enhance binding to the CD20 antigea More preferably the humanized anti-CD20 MAb or fragment thereof of the present invention comprises the hA20Vk of Figure 4B and the hA2VHl of Figure 4A. Most preferably, the humanized anfi-CD20 MAb or fragment thereof of the present invention comprises the hA20Vlc of Figure 4B and the hA2VH2 of Figure 4A. This latter sequence contains more human amino acid sequences in the FRs of the VH2 chain than the VHl, and thus is more humanized. The prefeired chimeric anti-CD20 (cCD20) MAb or fiBgment thereof of the present invention comprises the CDRs of a murine anti-CD20 MAb and the FR regions of the light and heavy chain variable regions of die murine anti-CD 20 MAb, i.e., the Fvs of the parental murine MAb, and fee light and heavy chain constant regions of a human antibody, wherein the chimeric anti-CD20 IvlAb or fragment ffa^'eof retains substantially the B-cell, and B-cell lymphoma and leukemia cell targeting of the murine anti-CD20 MAb, wherein the CDRs of the light chain variable region of the chimaic anti-CD20 MAb comprise CDRl comprising amino acids RASSSVSYIH, RASSSLSFMH or RASSSVSYMH; CDR2 comprising amino acids ATSNLAS; and CDR3 comprising amino acids QQWTSNPPT, HQWSSNPLT or QQSFSNPPT; and the CDRs of the heavy chain variable r^on of the chimaic anti-CD20 MAb comprise CDRl comprising amino acids SYNMH; CDR2 con^rising amino acids AIYPGNGDTSYNQKFKG and CDRS comprising STYYGGDWYFDV, STYYGGDWYFNV, SHYGSNYVDYFDV or WYYSNSYWYFDV with the foUowii^ provisos, (a) w4ierein the CDR3 of the heavy chain variable region does not comprise STYYGGDWYFNV, when die CDRl of the hght chain variable rc^on comprises amino acids RASSSVSYIH, CDR2 of the U^t chain variable region conqirises ammo acids ATSNLAS, CDR3 of the Hght chain variable region comprises amino acids QQWTSNPPT, CDRl of the heavy chain variable region comprises amino acids SYNMH, and CDR2 of the light chain variable region comprises amino acids AIYPGNGDTSYNQKFKG; (b) wherein the CDR3 oi tne neavy chain, variable region does not comprise SHYGSNYVDYFDV, when Ifae CDRl of the light cham variable region comprises amino acids RASSSLSFMH, CDR2 of tlie light chain variable region comprises amino acids ATSNLAS, CDR3 of the l^t chain varmble region comprises amino acids HQWSSNPLT, CDRl of the heavy chain variable region comprises amino acids SYNMH, and CDR2 of the light chain variable region comprises amino acids AIYPGNGDTSYNQKJKG; and (c) wherein the CDR3 of ttie heavy chain variable region does not comprise WyySNSyWYFDV, when the CDRl of the light cham variable region comprises amino acids RASSSVS YMH, CDR2 of the light chain variable region comprises amino acids ATSNLAS, CDR3 of the light chain variable region comprises amino acids QQSFSNPPT, CDRl of the heavy chain variable region comprises amino acids SYNMH, and CDR2 of the light chain variable region comprises amino acids AIYPGNGDTSYNQKFKG. More preferably the chimeric anti-CD20 MAb or fiBgment thereof comprising the complementarity-detramining regions (CDRs) of a mmine anti-CD20 MAb and the ftamewoii: (FR) regions of flie light and heavy chain variable regions of the murine anti-CD20 MAb and the light and heavy chain constant regions of a human antibody, wherein the chimeric anti-CD20 MAb or fiagment thereof retains substantially the B-cell, and B-cell lymjA-oma and leukania cell targeting of the murine anti-CD20 MAb, wherdn the CDRs of &e li^t chain variable region of the chimeric antd-CD20 MAb comprises the CDRs shown m Figs. 4B and 4A, respectively, designated cA20Vk and cA20VH. Most preferably, the chim«ic anti-CD20 MAb or fiagment thereof con^nises the li^t and heavy chain variable regions of murine anti-CD20 MAb shown in Figs. 4B and 4A, respectively, designated cA20Vk and cA20 VH. The present invention also encompasses a huroaa anti-CD20 MAb or fiagment thereof comprising the light and heavy chain variable and constant regioia of a human antibody, wherein said human CD20 MAb retains substantially the B-cell, and B-cell lymphoma and leukemia, cell tai^etii^ and cell binding characteristics of a murine anti-CD20 MAb, wherem the CDRs of tiie h^ chain variable region of the human anti-CD20 MAb comprises tiie same CDRs as set forth above for the chimeric and humanized anti-CD20 mAbs and as ahnwn in Vim^ A A ^^^ /tr> The present invention is also intended to encompass antibody fusion proteins or fragments thereof comprising at least two anti-CD20 mAbs or fragments thereof, as described above. The antibody fusion protein or fragment thereof of the present invention is also intended to encompass an antibody fusion protein or fragment tiiereof comprising at least one first anti-CD20 MAb or fragment tiiereof as described above and at least one second MAb or fragment thereof, other than the antiCD20 MAb or fr^ment described above. More preferably this second MAb is a MAb reactive with CD4, CDS, CDS, CD14, CD15, CD19, CD21, CD22, CD23, CD25, CD33, CD37, CD38, CD40, CD40L, CD46, CD52, CD54, CD74. CD80, CD126, B7, MUCl, MUC2, MUC3, MUC4, la, HM1.24, HLA-DR, tenascin, VEGF, PIGF, an oncogene, oncogene product, or a combination thereof, and even an anti-CD20 MAb that is different than the anti-CD20 MAb described herein. The antibody fiision proteins of the present invention may be composed of one CD20 MAb and one or more of the second mAbs to provide specificity to different antigens, and are described in more det^ below. Tlie humanized, chimeric and human anti-CD20 antibody may possess enhanced afiEmily hmding with the epitope, as well as antitumor and anti-B-cell activity, as a result of CDR mutation and manipulation of the CDR and other sequences in the variable region to obtain a superior therapeutic agent for the treatment of B-cell disorders, including B-cell lymphomas and leukemias and autoimmune diseases. Modification to the binding specificity, affinity or avidity of an antibody is known and described in WO 98/44001, as affinity maturation, and this application summarizes methods of modification and is incorporated in its entirety by reference. It may also be desirable to modify the antibodies of fhe present invention to improve effector function, e.g., so as to enhance antigen-dependent cell-mediated cytotoxicity (ADCC) and/or complement dependent cytotoxicity (CDC) of the antagonist. One or more amino acid substitutions or the introduction of cysteine in the Fc region may be made, thereby improving internalization capability and/or increased complement-mediated cell kiUing and ADCC. See Caron et al, J. Ex. Med 176:1191-1195 (1991) and Shopes, BJ. Immunol. 148:2918-2022 (1992), incorporated herein by reference in then entirety. An antibody fiision protein may be prepared that has dual Fc regions witti both enhanced complement lysis and ADCC capabilities. The present invention is also directed to DMA sequences comprising a nucleic acid encoding a MAb or fragment thereof selected from the groi^ consisting (a) an anti-CD20 MAb or fragment thereof as described herein, (b) an antibody fusion protein or ferment fliaeof comprisii^ at least two of the anti-CD20 mAbs or fragments thereof, (c) an antibody fusion protein or fi^gment thereof comprising at least one first MAb or fragment thereof comprising the anti-CD20 MAb or fragment thereof as described herein and at least one second MAb or fragment thereof, other than the antiCD20 MAb or fi'^ment thereof, and (d) an antibody fijsion protein or fragment thereof comprising at least one first MAb or fragment thereof comprising the anti-CD20 MAb or fr^ment thereof and at least one second MAb or fi^^ment thereof, wherein the second MAb is a MAb reactive with CD4, CDS, CDS, CD14, CD15, CD19, CD2I, CD22. CD23, CD25, CD33. CD37, CD38, CD40, CD40L, CD46, CD52, CD54, CD74, CD80, CD126, B7, MUCl, MUC2, MUC3, MUC4, la, HMI.24, HLA-DR, tenascin, VEGF, PIGF, an oncogene, oncogene product, or a combination thereof. Also eaicomjKissed by the present invaition are esqiression vectors conqirising the DNA sequences. These vectors contain the light and heavy chain constant regions and the binge region of the human immunoglobulin, m tfie case of vectors for use m preparing the humanized, chimeric and human anti-CD20 mAbs or antibody fiision proteins hereof or fragments thereof These vectors additionally contain, where required, promoters that eiqiress ^ mAbs in &s selected host cell, immunoglobulin enhances and signal or leader sequences. Vectors that are particularly useful in tiie present invention are pdHL2 or GS, particulaily when used to eu^ress a chimeric, hunmiizfid or human antibodies, such as gigs, vjbexe the vector codes for the heavy and li^t chain constant regions and hinge region of IgGl. More preferably, the light and heavy chain constant regions and hinge region are from a human EU myeloma immunoglobulin, where optionally at least one of the amino add in the allotype positions is changed to that found in a different IgGl allotype, and wherein optionally amino acid 253 of ibe, heavy chain of EU based on the EU mmibw system may be replaced with alanine. See Edehnan et cd., Proc. Natl. Acad Sci USA 63: 7S-85 (1969), incoiporated herein m its entirety by reference. Host cells containing the DNA sequences encoding the auti-CD20 mAbs or fr^ments thereof or antibody fijsion proteins or fragments tiiereof of the present invention or host cells containing the vectors that contain tiiese DNA sequences are encompassed by the present invention. Particularly usefixl host cells are mammalian cells, more specifically lymjrfiocytic cells, such as myeloma cells, discussed in more detail below. Also encompassed by the present invention is the method of expressing the anti-CD20 MAb or fragment thereof or antibody fusion protein or fragment thereof comprisii^: (a) transfecting a mammalian cell with a DNA sequence of encoding the anti-CD20 mAbs or fragments thereof or antibody fusion proteins or fragments thereof, and (b) culturing the cell transfected with the DNA sequence that secretes the anti-CD20 or fragment thereof or antibody fusion protein or fragment thereof. Known techniques may be used that include a selection marker on the vector so tiiat host cells that oqiress the mAbs and the marker can be easily selected. The present invention particularly encompasses B-lymphoma cell and leukemia cell targeting diagnostic or flier^eutic conjugates comprising an antibody component comprising an anti-CD20 MAb or figment thereof or an antibody fiision protein or fragment thereof of the present invention that binds to the B-lymphoma or leukemia cell, that is bound to at least one di^nostic or at least one therqwutic agent. The diagnostic conjugate comprises the antibody component comprising an anti-CD20 MAb or fragment thereof or an antibody fusion protein or fragment thereof wiierein ttie di^nostic agent comprises at least one photoactive di^nostic agent, and more preferably wherein the label is a radioactive label widi an enei^ between 60 and 4,000 keV or a non-radioactive label. The radioactive label is preferably a gamma-, beta-, and posifron-emitting isotope and is selected from the group consisting of I, "'I, •"!, '^'I, ^^Y, '^Re, "'«Re,^Cu, "Cu, "V ^^Ga, '^Ga, "^Tc, "^c. '*F, "C, '^, '^O, '^Br and combinations thereof The diz^ostic conjugate of the i»esent invention also utilizes a diagnostic agent, such as a contrast agent, for example, such as mai^anese, u^on or gadolinium. Tlie tfaer^eutic conjugate of the present invention comprises an antibody component comprising an antibody fiision protein or fragment thereof, wherein each of said mAbs or fragments thereof are bound to at least one therapeutic agent. The therapeutic conjugate of preferably is selected from the group consisting of a radioactive label, an immunomodulator, a hormone, a photoactive therapeutic agem, a cytotoxic agent, whidi may be a drag or a toxin, and a combination thereof. The dn^s useful in the present invention are tfiose drugs that possess the irfiarmaceutical property selected from the group consisting of antimitotic, antikinase, alkylating, antimetabolite, antibiotic, alkaloid, antiai^ogenic, apoptotic agents and Mimbinations thereof More specifically, tliese drugs are selected from the group consisting of nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, triazenes, folic acid analogs, COX-2 inhibitors, pyrimidine analogs, purine analogs, antibiotics, enzymes, epipodophyllotoxins, platinum coordination con^>lexes, vinca alkaloids, substituted ureas, methyl hydrazine derivatives, adrenocortical suppressants, antagonists, endostattn, taxols, camptothecins, anthracyclines, taxanes, and their analogs, and a combination thereof The toxins encompassed by the present invention are selected fiwn the group consisting of licdn, abrin, alpha toxin, saporin, ribonuclease (RNase), e.g., onconase, DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtherin toxin, Pseudomonas exotoxin, and Pseudomonas endotoxin. Usefiil therapeutic conjugates of the present invKition are immunomc«iuiators selected fiom the group consistii^ of a cytokine, a stem cell growth fector, a lymphotoxin, a hematopoietic factor, a colony stimulating factor (CSF), an interferon (IFN). erythropoietin, tiirombopoietin and a combination thereof. Specifically usefiil are lymphotoxios such as tumor necrosis fector (TNF), hematopoietic factors, such as interleukin (IL), colony stimulating factor, such as granulocyte-colony stimulating fector (G-CSF) or granulocyte macrophage-colony stimulating fector (GM-CSF)), interferon, such as interferons-a, -P or -y, and stem cell growth factor, such as designated "SI factor". More specifically, immunomodulatoi, such as lL-1, IL-2; IL-3, IL-6, IL-10, IL-12, IL-18, IL-21 interfetoa-y, TNF-a or a combination thereof are useful in the present invention. Particularly useful tiierapeutic conjugates comprise one or more radioactive labels that have an energy between 60 and 700 keV. Such radioactive labels are selected fi«m the group consistmg of =^Ac, "Ga, ^,, '"in, "^I, '^'l, '^'Re, '*«Re, '"LU, ^-P, , *'*Cu. ^'Cu, ^^^Bi, ^"Bi, ^"At and combinations thereof Other useful thergqieutic conji^ates are photoactive therapeutic ^ent, such as a chromogen or dye. Other useful therapeutic conjugates comprise oligonucleotides, especially antisense oligonucleotides that preferably are directed against oncogenes and oncogene products of B-cell malignancies, such as bcl-2. The present invention particularly encompasses methods of treatu^ a B-celi lymphoma or leukemia cell disease or an autoimmune disease in a subject, such as a mammal, including humans, domestic or companion pets, such as dogs and cats, compiisii^ administering to the subject a therapeutically effective amount of an anti-CD20 MAb or a fragment thereof of the present invention, foimulated in a phannaceutically acceptable vehicle. This therapy utilizes a *'naked antibody" that does not have a therapeutic agent bound to it. The administration of tiie "naked anli-CD20 antibody" can be supplemented by administering to the subject concurrently or sequentially a dierapeutically effective amount of another "naked antibody" that binds to or is reactive with another antigen on the surface of the target cell or that has other functions, such as effector functions in the Fc pordon of the MAb, that is therapeutic and which is discussed herein. Preferred additional mAbs are at least one humanized, chimeric, human or murine (in the case of non-human animals) MAb selected from the group consisting of aMAb reactive with CD4, CDS, CD8, CD14, CD15, CD19, CD20, CD21, CD22, CD23, CD25, CD33, CD37, CD38. CD40, CD40L. CD46, CD52, CD54, CD74, CD80, CD126, B7, MUCl, la, HMl.24, and HLA-DR, tenascin, VEGF, PIGF, an oncogene, oncogene product, or a combination thereof, fonnulated m a phannaceutically acceptable vdiicle. Both the naked anti-CD20 therapy alone or in combination with other naked mAbs as discussed above can be fiirther supplemented with the administration, either concurrentiy or sequentially, of a therapeutically effective amount of at least one therapeutic agent, fonnulated in a phamiaceutically acceptable vehicle. As discussed herein tiie therapeutic agent may comprises a cytotoxic agent, a radioactive label, an immunomodulator, a hormone, an enzyme, an oligonucleotide, a photoactive therapeutic agent or a combination &ereof, formulated in a phannaceutically acceptable vehicle. In anotiier ther^ieutic method, bolh the naked anti-CD20 ther^y alone or m combination with oflier naked mAbs, as discussed above, can be further supplemented wifii the administration, either concurrently or sequentially, of a ther^Kutically effective amount of at least one thenqjcutic conjugate, described haein and fonnulated in a phaimaceuticaliy acceptable vehicle. The antibodv component of die tiieraneutic conjugate comprises at least one humanized, chimeric, human or murine (for non-human subjects) MAb selected from the group consisting of a MAb reactive vath CD4, CDS, CDS, CDU, CD15, CD19, CD20, CD21, CD22. CD23, CD25, CD33, CD37, CD38, CD40, CD40L, CD46, CD52, CD54, CD74, CD80, CD126, B7, MUCl, MUC2, MUC3, MUC4, la, HM1.24, and HLA-DR, tenascJn, VEGF, PIGF, an oncogene, oncogene product, or a combination thereof, formulated in a pharmaceutically acceptable vehicle. As discussed herein the therapeutic agent may comprise a cytotoxic agent, a radioactive label, an immiinomodulator, a honnoue, a photoactive therapeutic agent or a combination thereof, formukted in a pharmaceutically acceptable vdiicle. As described herein the present invention particularly encompasses a method of treating a B-cell lymphoma or leukemia or an autoimmune disease in a subject comprising administering to a subject a therapeutically effective amount of an antibody fiision protein or fragment thereof comprising at least two anti-CD20 mAbs or fragments thereof of the present invention or comprising at least one anti-CD20 MAb or fragment thereof of the present invention and at least one additional MAb, preferably selected from the group consisting of mAbs reactive wife Cm, CDS, CD8, CDU, CD15, CD19, CD20, CD21, CD22, CD23, CD25, CD33, CD37, CD3S, CD40, CD40L, CD46, CD52, CD54, CD74, CD80, CD126. B7, MUCl, MUC2, MUC3, MUC4, la, HM1.24, and HLA-DR, tenascin, VEGF, PIGF^ an oncogene, oncogene product, or a combination thereof, foramlated in a pharmaceuticaily ay;eptable vehicle. This ther^utic method can further be si^plemented with the administration to the subject concuiiently or sequentially of a therapeutically effective amount of at least one therapeutic ^ait, fomiuUted in a pharmaceittically accqitable vehicle, wherein the therapeutic agent is preferably a cytotoxic agent, a radioactive label, an immunomodulator, a hormone, a photoactive therapeutic agent or a combination thereof, formulated in a pharmaceutically acceptable vehicle. Further, the antibody fiision proteins can be tKhninistered to a subject concunently or sequentially a therapeuticaUy effective amount of a thraapeutic conjugate comprising at least one MAb bound to at least one ther^eutic agent, wdierein said MAb component of the conji^ate ptefecabty comprises at least one humanized, chimeric, human or murine (for non-human subjects) MAb selected from ftie grot^ consisting of a MAb reactive with CD4, CDS, CDS, CD14. CD15- CDIO r-non rnoi --T^^-^ CD23, CD25, CD33, CD37, CD38, CD40, CD40L, CD46, CD52, CD54, CD74, CD80, CDI26, B7, MUCl, MUC2, MUC3, MUC4, Ja, HM1.24, and HLA-DR. tenascin, VEGF, PlGF, an oncogene, oncogene product, or a combination thereof, formulated in a pharmaceutically acceptable vehicle. The antibody fusion protein itself can be conjugated to a therapeutic agent and thus provides a vehicle to attach more than one therapeutic agent to an antibody component and these therapeutic agents can be a combination of different recited agents or combinations of the same agents, such as two different ther^eutic radioactive labels. Also encompassed by the present invention is a method of diagnosing a B-cell lymphoma or leukemia in a subject comprising administering to the subject, such as a mammal, including humans and domestic and companion pets, such as dogs, cats, rabbits, guinea pigs, a diagnostic conjugate comprising an anti-CD20 MAb or fragment thereof or an antibody fusion protein or fragment thereof of the present invention that binds to the lymphoma or leukemia cell, whereui the anti-CD20 MAb or fragment thereof or antibody fiision proteia or fragment thereof is bound to at least one diagnostic agent, foraiulated in a phannaceutically acceptable vehicle. The useful diagnostic agents are described herein. 2. Definitions In the description that follows, a number of terms are used and the following definitions are provided to faciUtate understanding of the present invention. An antibody, as described herein, refers to a full-length (i.e., naturally occurring or formed by normal immunoglobulin gene fragment recombinatorial processes) immunoglobulin molecule (e.g., an IgG antibody) or an immunologically active (i.e., specifically binding) portion of an immunogiobulin molecule, like an antibody fragment. An antibody fragment is a portion of an antibody such as F(ab')3, F(ab)2, Fab', Fab, Fv, scFv and the like. Regardless of structure, an antibody fragment binds with the same antigen that is recognized by flie intact antibody. For example, an anti-CD20 monoclonal antibody fragment binds with an epitope of CD20. The term "antibody fragment" also includes any synthetic or genetically engineered protein that acts like an antibody by binding to a specific antigen to form a complex. For example, antibody fragments include isolated fr^ments consisting of the variable regions, such as the "Fv" fragments consisting of the variable regions of the heavy and light chains, recombinant single chain polypeptide molecules in which light and heavy variable regions are connected by a peptide linker ("scFv proteins"), and minimal recognition units consisting of the amino acid residues that mimic the hypervariable region. A nalced antibody is generally an entire antibody which is not conjugated to a therapeutic agent. This is so because the Fc portion of the antibody moleciile provides effector fimctions, such as complement fixation and ADCC (antibody dependent cell cytotoxicity), which set mechanisms into action that may result hi cell lysis. Hciwever, it is possible that the Fc portion is not required for tiierapeutic function , witii other mechanisms, such as apoptosis, coming into play. Naked antibodies include both polyclonal and monoclonal antibodies, as well as certain recombinant antibodies, such as chimeric, humanized or human antibodies. A chimeric antibody is a recombinant protein thai contains the variable domains including the complementarity determining regions (CDRs) of an antibody derived from one species, preferably a rodent antibody, while the constant domains of the antibody molecule is derived from those of a human antibody. For veterinary applications, the constant domains of the chimeric antibody may be derived fix)m that of other species, such as a cat or dog, A humanized antibody is a recombinant protein in which the CDRs from an antibody from one spedes; e.g., a rodent antibody, is fransferred from the heavy and light variable chains of the rodent antibody into human heavy and light variable domains. The constant domains of the antibody molecule is derived from those of a human antibody. A hiunan antibody is an antibody obtained from trgjisgenic mice ttiat have been "engineered" to produce specific human antibodies in response to antigenic challenge. In this technique, elements of the hxunan heavy and light chain locus are introduced into strains of mice derived from embryonic stem cell lines that contain targeted disnqitions of the endogenous heavy chain and light chain loci. The dransgenic mice can synthesize human antibodies specific for human antigens, and the mice can be used to produce human antibody-secreting hybridomas. Methods for obtainir^ human antibodies from transgenic mice are described by Green et al., Nature Genet. 7:13 (1994), Lonberg et at, Nature 365:856 (1994), and Taylor et al. Int. Immun. 6:519 (1994). A fully human antibody also can be constructed by genetic or chromosomal transfeclion methods, as well as phage display technology, all of which are known in the art. See for example, McCafferty et al. Nature 348:552-553 (1990) for the production of human antibodies and fragments thereof in vitro, from immunoglobulin variable domain gene repertoires from uninmiuni2Ed donors. In this technique, antibody variable domain genes are cloned in-frame into either a major or minor coat protein gene of a filamentous bacteriophage, 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 the fimctional properties of the antibody also result in selection of the gene encoding the antibody exhibiting those properties. In this way, 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 and Chiswell, Current Opinion in Structural Biology 3-.5564-571 (1993). Human antibodies may also be generated by in vitro activated B cells. See U.S. Patent Nos. 5,567,610 and 5,229^275, which are incorporated in their entirety by reference. A therapeutic a^ent is a molecule or atom which is administered separately, concurrently or sequentially with an antibody moiety or conjugated to an antibody moiety, i.e., antibody or antibody fragment, or a subfragment, and is useful in the treatment of a disease. Examples of therapeutic agents include antibodies, antibody fragments, drugs, toxins, nucleases, hormones, immunomodulators, chelators, boron compounds, photoactive agents or dyes and radioisotopes. A diagnostic agent is a molecule or atom which is administered conjugated to an antibody moiety, i.e., antibody or antibody fragment or subfragment, and is useful in diagnosing a disease by locating the cells containing the antigen. Useful diagnostic agents include, but are not limited to, radioisotopes, dyes (such as with the biotin-streptavidm complex), contrast agents, fluorescent conqwimds or molecules and enhancing agents (e.g. paramagnetic ions) for magnetic resonance imaging (MRI). U.S. Patent No. 6,331,175 describes MRI technique and the preparation of antibodies conjugated to a MRI enhancing agent and is incorporated in its entirety by reference. Preferably, the diagnostic agents are selected from the group consisting of radioisotopes, enhancii^ ^ents for use in magnetic resonance imaging, and fluorescent compounds. In order to load an antibody con^)onent with radioactive metals or paramagnetic ions, it may be necessary to react it wilii a reagent having a long tail to which are attached a multiplicity of chelating groups for binding the ions. Such a tail can be a polymer such as a polylysine, polysaccharide, or other derivatized or derivatizable chain having pendant groups to which can be bound chelatii^ groups such as, e.g., ethylenediaroinetetraacetic acid (EDTA), dieliiylenetriaminepentaacetic acid (DTPA), porphyrins, polyamines, crown ethers, bis-thiosemicarbazones, polyoximes, and like groups known to be useful for this purpose. Chelates axe coupled to the peptide antigens using standard chemistries. The chelate is normally linked to tiie antibody by a group which enables formation of a bond to the molecule with minimal loss of immunore^tivity and minimal aggregation and/or internal cross-linking, other, more imusual, methods and reagents for conjugating chelates to antibodies are disclosed in U.S. Patent 4,824,659 to Hawthome, entitled "Antibody Conjugates", issued April 25,1989, flie disclosure of wWch is incoiporated herein in its entirety by reference. Particularly usefiU metal-chelate combinations include 2-faeozyl-DTPA and its monomethyl and cyclohexyl analogs, used with (^agnostic isotopes in the general energy range of 60 to 4,000 keV, such as '^^I, "'l, '^I, '^^I, ^^Cu, ^Cu, "F, ""In, "Ga, 'Go, ^^c, ^"Tc, '^C,'% 'O, '^T , for radio-imaging. The same chelates, when complexed with non-radioactive m^als, sudi as manganese, iron and gadolinium are useful for MRl, w^en used alor^ witii the antibodies of the invention. Macrocychc chelates such as NOTA, DOTA, and TETA are of use with a variety of metals and radiometals, most particularly with radionuclides of gallium, yttrium and copper, respectively. Such metal-chelate complexes can be made very stable by tailoring the ring size to the metal of interest. Other ring-type chelates such as macrocyclic polyethers, which arc of interest for stably binduig nuclides, such as ^^Ra for RAIT are encon^)assed by the invention. An immunoconjugate is a conjugate of an antibody component with a tiierapeutic or diagnostic agent. The diagnostic agent can comprise a radioactive or non-radioactive label, a contrast agent (such as for m^netic resonance imaging, computed tomography or ultrasound), and the radioactive label can be a gamma-, beta-, alpha-. Auger electron-, or positron-emitting isotope. An expression vector is a DNA molecules comprising a gene that is expressed in a host cell. Typic^ly, gene ejqpression is placed under the control of catain regulatory elements, including constitutive or inducible promoters, tissue-specific regulatory elements and enhancers. Such a gene is said to be "operably Imked to" the regulatory elements. A recombiaant host may be any prokaryotic or eukaiyotic cell that contains either a cloning vector or expression vector. This term also mcludes those prokaryotic or eukaryotic cells, as well as an transgenic animal, that have been genetically engineered to contain the cloned gene{s) in the chromosome or genome of the host cell or cells of the host cells. Suitable mammalian host cells include myeloma cells, such as SP2/0 cells, and NSO cells, as well as Chinese Hamster Ovary (CHO) cells, hybridoma cell lines and other mammalian host cell usefiil for e:q)ressing antibodies. Also particularly usefiil to express mAbs and other fiision proteins, is a human cell line, PER.C6 disclosed in WO 0063403 A2, which produces 2 to 200-fold more recombinant protein as compared to conventional mammalian cell lines, such as CHO, COS, Vero, Hela, BHK and SP2- cell lines. Special transgernc animals witii a modified immune system are particularly usefiil for making fully human antibodies. As used herein, the term antibody fiision protein is a recombinantiy produced antigen-binding molecule in which two or more of the same or different single-chain antibody or antibody fragment segments with the same or different specificities are linked. Valency of the fiision protein indicates how many binding arms or sites the fiision protein has to a single antigen or epitope; i.e., monovalent, bivalent, trivalent or mutiivalent. The multivalency of the antibody fiision protein means that it can take advantage of multiple interactions in bmding to an antigen, thus increasing the avidity of binding to the antigen. Specificity indicates how many antigens or epitopes an antibody fiision protein is able to bind; i.e., monospecific, bispecific, trispecific, multispecific. Using these defirutions, a natural antibody, e.g., an IgG, is bivalent because it has two binding arms but is monospecific because it binds to one epitope. Monospecific, multivalent fiision proteins have more than one binding site for an epitope but only binds with one epitope, for example a diabody with two binding site reactive with tiie same antigen. The fiision protein may comprise a single antibody component, a multivalent or multispecific combination of different antibody components or multiple copies of the same antibody component. Tlie fiision protein may additionally comprise an antibody or an antibody fragment and a therapeutic agent Examples of therapeutic agents suitable for such fiision proteins include immunomodulators ("antibody-immunomodulator fiision protein") and toxins ("antibody-toxin fusion protein"). One preferred toxin comprises a ribonuclease (RNase), preferably a recombinant RNase. A multispecific antibody is an antibody that can bind simultaneously to at least two targets that are of different shiicture, e.g., two different antigens, two different epitopes on the same antigen, or a hapten and/or an antigen or epitope. One specificity would be for a B-cell, T-cell, myeloid-, plasma-, and mast-cell antigen or epitope. Another specificity could be to a different antigen on the same cell type, such as CD20, CD19, CD21, CD23, CD46, CD80, HLA-DR, CD74, MUCl, and CD22 on B-cells. Multispecific, multivalent antibodies are constructs that have more than one binding site, and the binding sites are of different specificity. For example, a diabody, where one binding site reacts with one antigen and the otiier with the other antigen. A bispecific antibody is an antibody that can bind simultaneously to two targets wluch are of different structure. Bispecific antibodies (bsAb) and bispecific antibody fragments (bsFab) have at least one ann that specifically binds to, for example, a B-ceil, T-cell, myeloid-, plasma-, and mast-cell antigen or epitope and at least one other arm tiiat specifically binds to a targetable conjugate that bears a ther^eutic or diagnostic agent A variety of bispecific fusion proteins can be produced using molecular engineering. In one form, the bispecific fusion protein is monovalent, consisting of, for example, a scFv wath a single binding site for one antigen and a Fab fragment with a single binding site for a second antigen. In another form, the bi^ecific fusion protein is divalent, consisting of, for example, an IgG with a binding site for one antigen and two scFv with two binding sites for a second antigen. Caninized or felinized antibodies are recombinant proteins in wiiicb rodent (or another species) complementarity determining regions of a monoclonal antibody have been transferred from heavy and light variable chains of rodent (or another species) unmunoglobulin into a dog or cat, re^ctively, immunoglobulin variable domam. Domestic animals include large animals sijch as horses, cattle, sheep, goats, llanuis, alpacas, and pigs, as well as con^anion animals. In a preferred embodiment, the domestic animal is a horse. Companion animals include animals kept as pets. ITiese are primarily dogs and cats, aWiough small rodents, such as guinea pigs, hamsters, rats, and ferrets, are also included, as are subhuman primates such as monkeys. In a preferred embodiment the companion animal is a dog or a cat 3. Preparation of Monoclonal Antibodies including Chimeric, Humanized and Human Antibodies Monoclonal antibodies (MAbs) are a homogeneous population of antibodies to a particular antigen and the antibody comprises only one type of antigen binding site and binds to only one epitope on an antigenic determinant. Rodent monoclonal antibodies to specific antigens may be obtained by methods known to those skilled in the art 5ee, for example, Kohler and Milstein, A'a/we 256: 495 (1975), andCoUgan et al (eds.), CURRENT PROTOCOLS IN IMMUNOLOGY, VOL. 1, pages 2.5.1-2.6.7 (John Wiley & Sons 1991) [hereinafter "Coligan"]. Briefly, monoclonal antibodies can be obtained by injecting mice with a composition comprising an antigen, verifying the presence of antibody production by removing a serum sample, removing the spleen to obtain B-lymphocytes, fusing the B-lymphocytes with myeloma cells to produce hybridomas, cloning the hybridomas, selecting positive clones w4uch produce antibodies to the antigen, culturing die clones that produce antibodies to the antigen, and isolating the antibodies from Uie hybridoma cultures. MAbs can be isolated and purified fi-om hybridoma cultures by a variety of well-established techniques. Such isolation techniques include affinity chromatography with Protein-A Sepharose, size-exclusion chromatography, and ion-exchange chromatography. See, for example, CoUgan at pages 2.7.1-2.7.12 and pages 2.9.1-2.9.3. Also, see Baines etal, "Purification of Immunoglobulin G (IgG)," in METHODS IN MOLECULAR BIOLOGY, VOL. 10, pages 79-104 (The Humana Press, Inc. 1992). After the initial raising of antibodies to the immunogen, the antibodies can be sequenced and subsequently prepared by recombinant techniques. Hmnani2a1ion and chimerization of murine antibodies and antibody fi^gments are well known to those skilled in the art. For example, humanized monoclonal antibodies are produced by transfenii^ mouse complementary determining regions frojn heavy and light variable chains of the mouse immunoglobulin into a human variable domain, and then, substituting human residues in the frantework regions of die murine counterparts. The use of antibody components derived fiom humanized monoclonal antibodies obviates potential problems associated witii the immunogenicity of murine constant regions. General techniques for cloning mmine imraxmoglobulin variable domains are described, for example, by the publication of Orlandi et al., Proc. Nat'l Acad. Sci. USA 86: 3833 (1989), which is incorporated by reference in its entirety. Techniques for constructii^ chimeric antibodies are well known to those of skill in the art. As an example, Leung et al. Hybridoma 75:469 (1994), describe how they produced an LL2 chimera by combining DNA sequences encoding the VK and VH domains of LL2 monoclonal antibody, an anti-CD22 antibody, with respective human K and IgGj constant region domains. This publication also provides the nucleotide sequences of the LL2 Ught and heavy chain variable regions, VK and VH, respectively. Techniques for producing humanized MAbs are described, for example, by Jones et al.. Nature 321: 522 (1986), Riechmann et al, Nature 332: 323 (1988), Verhoeyen et al.. Science 239:1534 (1988), Carter et al, Proc Nat'l Acad. Sci. USA 89: 4285 (1992), Sandhu, Crit. Rev. Biotech. 12:437 (1992), and Singer et al.. J. Immun. J50: 2844 (1993), each of which is hereby incorporated by reference. A chimeric antibody is a recombinant protein that contains the variable domains including the CDRs derived fi-om one species of animal, such as a rodent antibody, while the remainder of the antibody molecule; i.e., the constant domains, is derived fi-om a human antibody. Accordii^ly, a chimeric monoclonal antibody can also be humanized by replacmg the sequences of the murine FR in the variable domains of die chimeric MAb with one or more different human FR. Specifically, mouse CDRs are transferred from heavy and Ught variable chains of the mouse immunoglobulin into the corresponding variable domains of a human antibody. As simply transferring mouse CDRs into human FRs often results in a reduction or even loss of antibody afSnity, additional modification might be required in order to restore the original affinity of the murine antibody. This can be accomphshed by tiie replaiement of one or more some human residues in the FR regions with tiieir murine countaparts to obtain an antibody that pcBsesses good binding affinity to its epitope. See, for example. Tempest et al. Biotechnology 9:266 (1991) and VeAoeyen et al.. Science 239:1534 (1988). Furfiier, the affinity of humanized, chimeric and human MAbs to a specific epitope can be mcreased by mutaeraiesis of the CDRs, so that a IOWCT dose of antibody may be as effective as a higher dose of a lower afOnity MAb prior to mutagenesis. See for exan^le, WO0029584A1 Another method for producing the antibodies of the present invraition is by production in the milk of transgenic hvestock. See, e.g., Colman, A., Biochem. Soc. Symp., 63: 141-147,1998; U.S. Patent 5,827,690, both of which are incorporated in their entirety by reference. Two DNA constructs are prepared wiiich contain, respectively, DNA segments encoding paired immunoglobulin heavy and light chains. The DNA segments are cloned into expression vectors which contmn a promoter sequence that is preferentially expressed in mammaty epithelial cells. Examples include, but are not limited to, promoters ftom rabbit, cow and sheep casein genes, the cow a-lactoglobulin gene, the sheep p-lactoglobulin gene and the mouse ^ey acid protein gene. Preferably, the inserted fragment is flanked on its 3' side by cognate genomic sequences from a mammary-specific gene. TMs provides a polyadenylation site and transcript-stabilizing sequences. The expression cassettes are co-injected into the pronuclei of fertilized, mammalian eggs, viiiich are then implanted into the uterus of a recipient female and allowed to gestate. After birth, flie progeny are screened for the presence of both transgenes by Southern analysis. In order for the antibody to be present, both heavy and Ught chain genes must be expressed concurrently in the same cell. Milk from fransgenic females is analyzed for the presence and ftmctionality of the antibody or antibody fragment using standard immunological metiiods known in the art. The antibody can be purified from the milk using standard methods known in the art. A fidly human antibody of the present invention, i.e., human anti-CD20 MAbs or other human antibodies, such as anti-CD22, anti-CD19, anti-CD23, or anti-CD21 MAbs for combination tiierapy vnih humanized, chimeric or human anti-CD20 antibodies, can be obtained from a transgenic non-hunwa animal. See, e.g., Mendez etal. Nature Genetics, 15:146-156 (1997); U.S. Patent No. 5,633,425, which are incorporated in their entirety by reference. For example, a human antibody can be recovered from a transgenic mouse possessing human immunoglobulin loci. The mouse humoral immune system is humanized by inactivating die endogenous immunoglobulin genes and introducing human innnunoglobulin loci. The human immimoglobulin loci are exceedingly complex and comprise a large number of discrete segments which together occupy almost 0.2% of frie human genome. To ensure that transgenic mice are capable of producing adequate repertoires of antibodies, large portions of human heavy- and light-chain loci must be introduced into the mouse genome. This is accomplished in a stepwise process beginning with the formation of yeast artificial chromosomes (YACs) containing either human heavy-or light-chain immunoglobulin loci in germline configuration. Since each insert is approxunately 1 Mb in size, YAC constmction requires homologous recombination of overlapping fi^agments of the immunoglobulin loci. The two YACs, one containing the heavy-chain loci and one containing the light-chain loci, are introduced separately into mice via fusion of YAC-containing yeast spheroblasts witii mouse embryonic stem cells. Embryonic stem cell clones are then microinjected into mouse blastocysts. Resulting chimeric males are screened for their ability to transmit the YAC through their germline and are bred with mice deficient in murine antibody production. Breeding the two transgenic strains, one containing the human heavy-chain loci and the other containing the human light-chain loci, creates progeny wiiich prodxxce human antibodies in response to inmiunization. Further recent methods for producii^ bispecific mAbs include ei^jineered recombinant mAbs w^iich have additional cysteine residues so that they crosslink more strongly than the more common immunoglobulin isotypes. See, e.g., FitzGerald et al., Protein ]&ig. 10(10):1221-1225,1997. Anotherapproach is to engineer recombinant fiision proteins linking two or more different sii^le-chain antibody or antibody fragment segments with the needed dual specificities. See, e.g., Coloma et al., Nature Biotech. 15:159-163,1997. A variety ofbispecific fiision proteins canbe produced using molecular engineerir^. In one form, the bispecific fiision protein is monovalent, consisting of, for example, a scFv with a single binding site for one antigen and a Fab fragment with a single binding site for a second antigen. In another forai, the bispecific fiision protem is divalent, consisting of, for example, an IgG with two binding sites for one antigen and two scFv witii two binding sites for a second antigen. Bispecific fusion proteins linking two or more different single-chain antibodies or antibody fiagments are produced in similar manner. Recombinant methods can be used to produce a variety of fiision proteins. For example a fiision protein comprising a Fab fragment derived firam a humanized monocloiKil auti-CD20 antibody and a scFv derived from a murine anti-diDTPA can be produced. A flexible linker, such as GGGS connects the scFv to the constant region of the heavy chain of the aiiti-CD20 antibody. Ahematively, the scFv can be connected to the constant region of the light chain of another humanized antibody. j^propriate linker sequences necessary for the in-frame connection of the heavy chain Fd to the scFv are mtroduced into the VL and VK domains through PCR reactions. The DNA fragment encoding the scFv is then ligated into a staging vector containing a DNA sequence encoding the CHI domain. The resulting scFv-CHl construct is excised and Ugated into a vector containing a DNA sequence encoding the VH region of an anti-CD20 antibody. The resulting vector can be used to transfect an ^projaiate host cell, such as a mammalian cell for the expression of the bispecific fiision protein. 4. Production of Antibody Fragments Antibody fragments which recognize specific epitopes can be generated by known techniques. The antibody fragments are antigen binding portions of an antibody, such as F(ab')2, Fab', Fab, Fv, sFv and the like. Other antibody fi-agments include, but are not limited to: the F(ab) '2 fragments wdiich can be produced by pepsin digestion of the antibody molecule and the Fab' fragments, which can be generated by reducing disulfide bridges of the F(ab)'2 fragments. Alternatively, Fab' expression libraries can be constructed (Huse et al., 1989, Science, 246:1274-1281) to allow r^id and easy identification of monoclonal Fab' fragments with the desired specificity. The present invention encompasses antibodies and antibody fragments. A single chain Fv molecule (scFv) comprises a VL domain and a VH domain. The VL and VH domains associate to form a target binding site. These two domains are fiutiier covalently linked by a peptide linker (L). A scFv molecule is denoted as eidier VL-L-VH if the VL domain is the N-terminal part of the scFv molecule, or as VH-L-VL if the VH domain is the N-terminal part of the scFv molecule. Methods for making scFv molectiles and designing suitable peptide linkers are described m US Patent No. 4,704,692, US Patent No. 4,946,778, R. Raag and M. Whitlow, ""Single ChainFvs"FASEB Vol9:73-80(1995)andILE. BfrdandB.W. Walker,"Single Chain Antibody Variable Regions," TmTECU, Vol 9:132-137(1991). These references are incorporated herein by reference. An antibody fragment can be prepared by proteolytic hydrolysis of the full lengdi antibody or by expression in E. coli or another host of flie DNA coding for the fragment. An antibody fragment can be obtained by pepsin or papain digestion of fiiH length antibodies by conventional methods. For example, an antibody fragment can be produced by en2ymatic cleavage of antibodies with pepsin to provide a 5 S fragment denoted F(ab')2. This fragment caa be further cleaved using a thiol reducing agent, and optionally a blocking group for the sulfhydryl groiq>s resulting from cleavage of disulfide linkages, to produce 3.5S Fab' monovalent fiagments. Alternatively, an enzymatic cleavage using papain produces two monovalent Fab firagments and an Fc fragment directly. These methods are described, for example, by Goldenberg, U.S. PatentNos. 4,036.945 and 4,331,647 and refea^nces contained therem, which patents are incorporated herem in their entireties by refer^ce. Also, see Uisonoff etal,. Arch Biocliem. Biophys. 89: 230 (1960); Porter, Biocfiem. J. 73: 119 (1959), Edelman et al, in METHODS IN ENZYMOLOGY VOL. 1, page 422 (Academic Press 1967), and Coligan at pages 2.8.1-2.8.10 and 2.IO.-2.10.4. Another form of an antibody fragment is a peptide coding for a single complementarity-determining region (CDR). A CDR is a segment of the variable region of an antibody that is complementary in structure to the epitopw to which the antibody binds and is more variable than the rest of the variable region. Accordingly, a CDR is sometimes referred to as hypervariable region. A variable region comprises three CDRs. CDR peptides can be obtained by constructing genes encodii^ the CDR of an antibody of interest. Such genes are pre^)are4 for example, by using the polymenise chain reaction to synthesize the variable region from RNA of antibody-producir^ cells. See, for example, Larrick et al. Methods: A Companion to Methods in Ermmology 2:106 (1991); Courtenay-Luck, "Genetic Manipulation of Monoclonal Antibodies," in MONOCLONAL ANTIBODIES: PRODUCTION, ENOnsfEERlNG AND CLINICAL APPLICATION, Rittere/a/, (eds.), pages 166-179 (Cambridge University Press 1995); and Ward et al, "Genetic Manipulation and Expression of Antibodies," in MONOCLONAL ANTIBODIES: PRINCIPLES AND APPLICATIONS, Birch et al, (eds.), pages 137-185 (Wiley-Liss, Inc. 1995). Other methods of cleaving antibodies, such as separation of heavy chains to form monovalent light-heavy chain fragments, further cleavage of fragments, or other enzymatic, chemical or genetic techniques may also be used, so long as the fiagments bind to the antigen that is recognized by flie intact antibody. 5. Muldspeciiic and multivalent antibodies The anti-CD20 antibodies, as well as other antibodies with different specificities for use in combination therapy, described herein, can also be made as multispecific antibodies (comprising at least one binding site to a CD20 epitope or antigen and at least one binding site to another epitope on CD20 or another antigen) and multivalent antibodies {comprising multiple binding sites to the same epitope or antigen). Multivalent target binding proteins are described in US Serial No. 09/911,610 (Leung et al.), which is incorporated herein by reference in its entirety. The present invention provides a bispecific antibody or antibody fragment laving at least a binding region that specifically binds a targeted cell n^rker and at least one other binding region that specifically binds a targetable conjugate. The targetable conjugate comprises a carrier jwrtion which comprises or bears at least one epitope recognized by at least one binding region of the bispecific antibody or antibody fir^ment. A variety of recombinant methods can be used to produce bispecific antibodies and antibody firagments as described above. An anti-CD20 multivalent antibody is also contemplated in the present invention. This multivalent target binding protein is constructed by association of a first and a second polypeptide. The first polypeptide comprises a first single chmn Fv molecule covalently linked to a first immunoglobuUn-hke domain which preferably is an immimoglobulin light chain variable region domain. The second polypeptide comprises a second single chain Fv molecule covalently linked to a second immunoglobulin-Uke domain which preferably is an immunoglobulin heavy chain variable region domain. Each of the first and second single chain Fv molecules forms a target bindii^ site, and the first and second immunoglobulin-Iike domains associate to form a third target bindii^ site. A single chain Fv molecule with the VL-L-VH configuration, wherein L is a linker, may associate with Mother single chain Fv molecule with the VH-L-VL configuration to fonn a bivalent dimer. In this case, the VL domain of flie first scFv and the VH domain of the second scFv molecule associate to form one target binding site, while tiie VH domain of the first scFv and the VL domain of the second scFv associate to form the other target binding site. Another embodiment of the present invention is a CD20 bispecific, trivalent targeting protein comprising two heterologous polypeptide chains associated non-covalently to form three binding sites, two of which have affinity for one target and a third which has afOnity for a hapten that can be made and attached to a carrier for a diagnostic and/or fher^eutic agent. Preferably, the binding protein has two CD20 binding sites and one CD22 binding site. The bispecific, trivalent targeting agents have two different scFvs, one scFv contains two VH domains fi-om one antibody connected by a short linker to the VL domain of another antibody and die second scFv contains two VL domains from the first antibody connected by a short linker to the VH domain of tiie other antibody. The methods for generating multiv^ent, mnltispecific agents from VH and VL domains provide that individual chains synthesized fi-om a DNA plasmid in a host organism are composed entkely of VH domains (the VH-diain) or entirely of VL domains (the VL-chain) in such a way that any agent of multivalency and multispecificity can be produced by non-covalent association of one VH-chain with one VL-chain. For example, forming a trivalent, ttispecific agent, the Vn-chain will consist of the amino acid sequences of three Vndomains, each from an antibody of different specificity, joined by peptide linkers of variable ler^ths, and the VL-chmn will consist of complementary VL domains, joined by peptide linkers similar to those used for the Vifchain, Since the VH and VL domains of antibodies associate in an anti-parallel fashion, the preferred method in this invention has the VL domains in the VL-chain arranged in the reverse order of the VH domains in the Vn-chain. 6. Diabodies, Triabodies and Tetrabodies The anti-CD20 antibodies of the present invention can also be used to prepare fiinctional bispecific single-chain antibodies (bscAb), also called diabodies, and can be produced in mammahan cells using recombinant methods. See, e.g.. Mack et aL, Proc. Natl. Acad Set, 92; 7021-7025,1995, incorporatEd. For example, bscAb are produced by joining two sir^le-chain Fv fiagments via a glycine-serine linker using recombinant me&ods. Tlie V light-chain (VL) and V heavy-chan (VH) domains of two antibodies of interest are isolated using standard PCR mefliods. The VL and VH cDNA's obtained firom each hybridoma are then joined to form a single-chain fi-agment in a two-step fiasion PCR. The first PCR step introduces the (Gly4-Seri)3 linker, and the second step joins the VL and VH amplicons. Each single chain molecule is then cloned into a bacterial expression vector. Following amplification, one of the sii^le-chain molecules is excised and sub-cloned into the other vector, containing the second single-chain molecule of interest The resulting bscAb fragment is subcloned into an eukaryotic expression vector. Functional protein expression can be obtained by transfecting the vector into Chinese hamster ovary cells. Bispecific fi^ion proteins are prqiared in a similar manna:. Bispecific single-cham antibodies and bispecific fiision proteins are included within the scope of the present invention. For example, a humanized, chimeric or human anti-CD20 monoclonal antibody can be used to produce antigen specific diabodies, triabodies, and tetrabodies. The monospecific diabodies, triabodies, and tetrabodies bind selectively to targeted antigens and as the number of binding sites on the molecule mcreases, the affinity for the target cell increases and a longer residence time is observed at the desired location. For diabodies, the two chains coa^iiising the VH polypeptide of flie humanized CD20 MAb connected to the VK polypeptide of the humanized CD20 MAb by a five amino acid residue linker are utilized. Each chain forms one half of the humanized CD20 diabody. In the case of triabodies, the three chains comprising VH polypeptide of the humanized CD20 MAb connected to the VR polypeptide of the humanized CD20 MAb by no linker are utilized. Each chain forms one third of flie hCD20 triabody. The ultimate use of the bispecific diabodies described herein is for pre-targeting CD20 positive tumors for subsequent specific delivery of diagnostic or therapeutic agents. These diabodies bmd selectively to targeted antigens allowing for increased afSnity and a longer residence time at the desired location. Moreover, non-antigen bound diabodies are cleared from the body quickly and exposure of normal tissues is mmimized. Bispecific antibody point mutations for enhancing the rate of clearance can be found in US Provisional Application No. 60/361,037 to Qu et al. (Atty DocketNo. 18733/1037), which is incorporated herein by reference in its entirety. Bispecific diabodies for affinity enhancement are disclosed in US Application Nos. 10/270,071 (Rossi etal), 10/270,073 (Rossi etai:) and 10/328,190 (Rossi et al), which are incorporated herein by reference in their entirely. Tlie diagnostic and ther^wutic agents can include isotopes, drugs, toxins, cytokines, hormones, growth f^itors, conjugates, radionuclides, and metals. For example. gadolinium meta! is used for magnetic resonance imaging (MRI). Examples of radionuclides are ^^^Ac, '«F. ^«Ga, ^'Oa, '^Y, 'Y, "V '^'l, '^^I, '^I,'"»Tc, ^^'"Tc, '«^e. '^'Re, '"Lu, «Cu, **Cu, "Cu, ^'^Bi, ='^Bi, ^^P, "C, 'H 'O, '^Br, and ^'^At. Other radionuclides are also available as diagnostic and therapeutic agents, especially those in the energy range of 60 to 4,000 keV. More recently, a tetravalent tandem diabody (termed tandab) with dual specificity has also been reported (Cochlovius et alj. Cancer Research (2000) 60: 4336-4341). The bispecific tandab is a dimer of two identical polypeptides, each containing four variable domains of two different antibodies (VHI, VLI, Vm, V^) linked in an orientation to facilitate the formation of two potential binding sites for each of the two different specificities upon self-association. 7. Conjugated multivalent and muUispecific anti-CD20 antibodies In another embodiment of the instant invention is a conjugated multivalent auti-CD20 antibody. Additional amino acid residues may be added to either the N- or C-terminus of the first or the second polypeptide. The additional amino acid residues may comprise a peptide tag, a signal peptide, a cytokine, an enzyme (for example, a pro-drug activating enzyme), a hormone, a peptide toxin, such as pseudomonas extoxin, a peptide drug, a cytotoxic protein or other fimctionai proteins. As used herein, a flmctional protein is a protein which has a biological function. In one embodiment, drugs, toxins, radioactive compounds, enzymes, hormones, cytotoxic proteins, chelates, cytokines and other fimctionai agents may be conjugated to the multivalent target binding protein, preferably through covalent attachments to tiie side chains of the amino acid residues of the multivalent target bmding protein, for example amme, carboxyl, phenyl, thiol or hydroxyl groups, Various conventional linkers may be used for this piapose, for example, diisocyanates, diisolhiocyanates, bis(hydroxysuccinimide) esters, carbodiimides, maleimide-hydroxysuccinimide esters, glutaraldehyde and the like. Conjugation of agents to the multivalent protein preferably does not significautiy affect the protein's binding specificity or affinity to its target. As used herein, a functional agent is an agent vrfiich has a biological function, A preferred fimctionai agent is a cytotoxic agent. In still otho- embodim^its, bispecific antibody-directed delivery of therapeutics or prodrug polymers to in vivo targets c^ be combined with bispecific antibody delivery of radionuclides, such that combination chemotherapy and radioimmunotherapy is achieved. Each therapy can be conjugated to the targetable conjugate and administered simultaneously, or the nuclide can be given as part of a first targetable conjugate and the drug given in a later step as part of a second targetable conjugate. In another embodiment, cytotoxic agents may be conjugated to a polymeric carrier, and the polymeric carrier may subsequently be conjugated to the multivalent target binding protein. For this method, see Ryser et al., Proc. Natl. Acad Sci- USA, 75:3867-3870,1978, US Patent No. 4,699,784 and US Patent No. 4,046,722, which are incorporated herein by reference. Conjugation preferably does not significantly affect the binding specificity or affinity of the nnUtivalent binding protein. 8. Humanized, Chimeric and Human Antibodies Us£ for Treatment and Diagnosis Humanized, chimeric and human monoclonal antibodies, i.e., anti-CD20 MAbs and other MAbs described herein, in accordance with this invention are suitable for use in therapeutic methods and diagnostic methods. ,,^;cordingly, the {wesent invention contemplates the administration of the humanized, chimeric and human antibodies of the present invention alone as a naked antibody or administered as a multimodal ther^y, temporally according to a dosing regimen, but not coiyugated to, a thea^apeutic agent The ef&cacy of die naked anii-CD20 MAbs can be enhanced by sv^jplementing naked antibodies with one or more other naked antibodies, i.e., MAbs to specific antigens, such as CD4, CDS, CDS, CD14, CD15, CD19, CD2I, CD22, C023, CD25, CD33, CD37, CD38, CD40, CD40L, CD46, CD52, CD54, CD74, CD80, CD126, B7. MUCl, la, HMl .24, or HLA-DR, tenascm, VEGF, PIGF, an oncogene, an oncogene product, or a combination thereofwith one or more immimocoiyugates of anti-CD20, or antibodies to theses recited antigens, conjugated with therapeutic agents, mcluding drags, toxins, immunomodulators, bonnones, ther^wutic radionuchdes, etc., with one or more therapeutic agents, including drugs, toxins, immunomodulators, hormones, flierapeutic radionuclides, etc., administered concurrency or sequentially or according to a prescribed dosii^ regimen, imth fee MAbs. Prpfiwv^ U-/-**ii antinme ™,.i,.-i- *i equivalent to human CD19, CD20, CD21, CD22, CD23, CD46, CD52, CD74, CD80, and CDS antigens. Preferred T-cell antigens include those equivalent to human CD4, CDS and CD25 (the IL-2 receptor) antigens. An equivalent to HLA-DR antigen can be used in treatment of both B-cell and T-cell disorders. Particularly preferred B-cell antigens are those equivalent to human CDI9, CD22, CD21, CD23, CD74, CD80, and HLA-DR antigens. Particularly preferred T-cell antigens are tiiose equivalent to human CD4, CDS and CD25 antigens. CD46 is an antigen on the surface of cancer cells that block complement-dependent lysis (CDC). Further, the present invention conten^lates the administration of ai immunoconjugate for diagnostic and therapeutic uses in B cell lynq^homas and other disease oi disorders. An immunoconjugate, as described herein, is a molecule comprising an antibody component and a thaapeutic or diagnostic agent, including a peptide wWch may bear the diagnostic or tiierapeutic agent An immunoconjugate retains the immunoreactivity of the antibody component, i.e., the antibody moiety has about die same or slightly reduced abilily to bind the cognate antigen ai^er conjugation as before conjugatioiL A wide variety of diagnostic and ther^Mutic agents can be advantageously conjugated to the antibodies of tiie invention. The therapeutic agents recited here are those agents that also are usefiil for administration separately with the naked antibody as described above. Ther^utic ^ents mclude, for example, chemotherapeutic drugs sucAx as vinca alkaloids, anthiacycUnes, epidophyllotoxin, taxanes, antimetabolites, alkylating agents, antikinase agents, antibiotics, Cox-2 inhibitors, antimitotics, antiangiogenlc and apoptotoic agents, particularly doxorubicin, metiiotrexate, taxol, CPT-11, camptothecans, and others &om tiiese and other classes of anticaicrar j^ente , and the like. Olher useful cancer chemotherapeutic drugs for die preparation of immimoconjugates and antibody fusion proteins include nitrogen mustards, alkyl sulfonates, nitiosoureas, triazenes, foUc acid analogs, COX-2 inhibitors, pyrimidine analogs, purine analogs, platinum coordination complexes, hormones, and the like. Suitable chemotherapeutic ^ents are described in REMINGTON'S PHARMACEUTICAL SCIENCES, 19tii Ed. (Mack Pubhshing Co. 1995), and iii GOODMAN AND GILMANS THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 7th Ed. (MacMiUan Publishmg Co. 1985), as well as revised editions of these publications. Other suitable chemotherapeutic agents, such as experimental drugs, are known to those of skill m the art. Additionally, a chelator such as DTP A, DOTA, TETA, or NOTA oi a suitable peptide, to which a detectable label, such as a fluorescent molecule, or cytotoxic agent, such as a heavy metal or radionuclide, can be conjugated. For example, a therapeutically useful immimoconjugate can be obtained by conjugating a photoactive agent or dye to an antibody composite. Fluorescent compositions, such as fluorochrome, and other chromogens, or dyes, such as porphyrins sensitive to visible light, have been used to detect and to treat lesions by directing the suitable Ught to the lesion. In therapy, this has been termed photoradiation, phototherapy, or photodynamic therapy (Jori et al. (eds.), PHOTODYNAMIC THERAPY OF TUMORS AND OTHER DISEASES (Libreria Progetto 1985); van den Bergh, Chem. Britain 22:430 (1986)). Moreover, monoclonal antibodies have been coupled with photoactivated dyes for achieving photothenqjy. Mew et al, J. Immunol. 130:1473 (1983); idem., Cancer Res. 45:43H0 (1985); Osetoffetal, Proc. Natl. Acad Sci. USA 83:S744 (1986); idem.. Photochem. Photobiol 46:%3 (1987); Hasan etal. Prog. Clin. Biol Res. 288:471 (1989); Tatsuta et al. Lasers Surg. Med 9:422 (1989); Pelegrin et a!., Cancer tf7:2529 (1991). However, these earlier studies did not include use of endoscopic therapy applications, especially with the use of antibody fragments or subfragments. Thus, the present invention contemplates the therapeutic use of immunoconjugates comprising photoactive agents or dyes. Also contemplated by the present invention are the use of radioactive and non¬radioactive agents as diagnostic agents. A suitable non-radioactive diagnostic agent is a contrast agent suitable for magnetic resonance imaging, computed tomography or ultrasoimd. Magnetic imaging agents include, for example, non-radioactive metals, such as manganese, iron and gadolinium, complexed with metal-chelate combinations that include 2-beiizyl-DTPA and its monomethyl and cyclohexyl analogs, when used along with the antibodies of the invention. See U.S. Serial No. 09/921,290 filed on October 10, 2001, wiiich is incorporated in its entirety by reference. Furthermore, a radiolabeled antibody or immunoconjugate may comprise a y-emittir^ radioisotope or a positron-emitter useful for diagnostic imaging. Suitable radioisotopes, particularly in lie energy range of 60 to 4,O0OkeV, include '^'l, ^"l, 124j^ 86y^ 62^^ 64^^ liy 67Q^ «Q^^ 99^^^ 94n.^^^ ISj^ U,-,^ l^^ ISQ^ 75^^^ ^j ^^ like. See for example, U.S. Patent Application entitled "Labeling Targeting Agents with Gallium-68"- Inventors G.L.Griffiths and W.J. McBride, (U.S. Provisional Application No. 60/342,104), vMch discloses positron emitters, such as '^F, ^^Ga, ^'"Tc. and (he like, for imaging purposes and which is incorporated in its entirety by reference. Particularly useful therapeutic radionuclides include, but are not limited to, ^^P, ^^P, "'Sc, ^Cu, ^^Cu, "Ga, ^"Y, '"Ag, '"in, '% "'l, '«Pr, ^"Sm, '^'Xb, '^Dy, '^0, '^V "^, ""Re, ''Re, ^'^Pb. =^^Bi, ^'^Bi, ^"At, ^Ra and ^^Ac. Particularly usefiil diagnostic/detection radionuclides include, but are not limited to, '% ^^Fe, ^^Cu, "Cu. "Cu, ^'Ga, '"Ga, ^. «^Zr, ^""Tc, ^Tc, ^Tc, "^hi, '^I, '^^, U5j^ i3»I, ^^-^^^Gd, '^P, ^Y, ""^Re, and '=Lu. A toxin, such as Pseudomonas exotoxin, may also be complexed to or form the therapeutic agent portion of an antibody fiision protein of an anti-CD20 antibody of the present invention. Other toxins suitably employed in the preparation of such conjugates or Other fusion proteins, include ricin, abrin, ribonuclease ^INase), DNase I, Siaplrylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtherin toxin, Pseudomonas exotoxin, and Pseudomonas endotoxin. See, for example, Pastan et al. Cell 47:641 (1986), and Goldenbei^, CA - A Cancer Journal for Clinicians 44:43 (1994). Additional toxins suitable for use in the present invention are Imown to those of skill in the art and are disclosed m U.S. Patent 6,077,499, which is incorporated in its entirety by reference. An immunomodulator, such as a cytokine may also be conjugated to, or form the therapeutic agent portion of an antibody fijsion protein or be administered with the humanized anti-CD20 antibodies of the present invention. Suitable cytokines for the present invention mclude, but are not limited to, interferons and interleukins, as described below. An ohgonucleotide, such the antisense molecules inhibiting bcl-2 expression that are described in U.S. 5,734,033 (Reed) which is incorporated by reference in its entirety, may also be conjugated to, or form AM therapeutic agent portion of an antibody fusion protein or be administered with the humanized anti-CD20 antibodies of the present invention. 9. Preparation of Immunoconjugates Any of the antibodies or antibody fiision proteins of the present invention can be conjugated with one or more therapeutic or diagnostic agents. Generally, one therapeutic or diagnostic agent is attached to each antibody or antibody fragment but more than one therapeutic agent or diagnostic agent can be attached to the same antibody or antibody fragment. The antibody fiision proteins of the present invention comprise two or more antibodies or fragments thereof and each of the antibodies that composes this fiision protein can contain a therapeutic agent or diagnostic agent. Additionally, one or more of the antibodies of the antibody fiision protein can have more than one therapeutic of diagnostic agent attached. Further, the therapeutic agents do not need to be the same but can be different ther^ieiitic agents. For example, one can attach a drug and a radioisotope to the same fiision protein. Particularly, an IgG can be radiolabeled with '^'l and attached to a drug. The ^^^I can be incorporated into the tyrosine of the IgG and the drug attached to the epsilon amino group of the IgG lysines. Both therapeutic and diagnostic agents also can be attached to reduced SH groups and to the carbohydrate side chains. Radionuclides suitable for treating a disease tissue substantially decay by beta-particle emission and include, but are not limited to: ^^P, ^^P, '^Sc, ^^e, ^Cu, '^'Cu, "Se, ^'As, «^Sr, «>Y. ^o, "'^Rh, '"Pd, "'Ag, ^"l, '^'l, "^Pr, ^«Pr, '^^ ^"Sm, '^'Tb, '^o, "'^Er, '"Lu, ""^Re, '««Re, '**Re, '^% '^Au, '^Au, ^"Pb, ^'^Pb and ^'^Bi. Maximum decay energies of usefiil beta-particle-emitting nuclides are preferably 20-5,000 keV, more preferably 100-4,000 keV, and most preferably 500-2,500 keV. Also preferred are radionuclides that substantially decay witii Auger-emitting particles. For exan^le, =^«Co, ^'Oa, "'^^Br, ^"^c, '"^"Rh, "«Pt, "^In, ^^^Sb, '^% '"HO, '^^'"Os and '^Ir. Decay energies of usefiil Auger-particle-emitting nuclides are preferably Radionuclides usefiil as diagnostic agents utilizing gamma-ray detection include, but are not limited to: ^'Cr, "Co, ^"Co, '^Fe, "Cu, ^'Oa, "Se, "RU, ^^C, "V "'"'In, '^I, 1251, "'I, '^^, '"Hg, and ^"'TI. Decay energies of usefiil gamma-ray emitting radionuclides are preferably 20-2000 keV, more preferably 60-600 keV, and most preferably 100-300 keV. Radionuclides useM for positron emission tomography include, but are not limited to: '¥, ^'Mn, """Mn, "Fe, "Co, "Cu, ^*Cu, ^^Ga, ^^As, "Br. '^Br, ^^-Rb, *^Sr, *^Y, *V 94mTc, "V ^^\ and '^L Total decay energies of useful positron-emitting radionuclides are preferably Bispecific antibodies of the present invention are usefiil in pretargeting methods and provide a preferred way to deliver two therapeutic agents or two diagnostic agents to a subject. U.S. Serial Nos. 09/382,186 and 09/337,756 discloses a method of pretargeting using a bispecific antibody, in which the bispecific antibody is labeled with ^^I and deUvered to a subject, followed by a divalent peptide labeled with '^"'Tc, and are incoipor^ed herein by reference in their entirety. Pretai^eting methods are also described in US Serial Nos. 09/823,746 (Hansen et a/.) and 10/150,654 (Goldenberg et al.), and US Provisional Application filed January 31, 2003, entitled "Methods and Compositions for Administration of Therapeutic and Diagnostic Agents, Atty Docket No. 018733/1103 (McBride et al), wiiich are all also incorporated herein by reference in their entirety. The delivery results in excellent tumor/normal tissue ratios for '^I and ^'^c, thus showing the utihty of two diagnostic radioisotopes. Any combination of known tiierapeutic agoits or diagnostic agents can be used to label the antibodies and antibody fiision proteins. The binding specificity of the antibody component of the MAb conjugate, the efficacy of the ther^eutic agent or diagnostic agent and the effector activity of the Fc portion of tiie antibody can be detemiined by standard testing of the conjugates. Tlie invention is directed to a method for pretargeting a cell in a patiaits suffering fiiam a B-cell lymphoma or leukemia or an autoimmune disease comprising: (i) administering an antibody fusion protein or fiagment thereof tiiat is multispecific having at least one arm that specifically binds the cell and at least one other arm diat specifically binds a targetable conjugate; (ii) optionally, administering to the patient a clearii^ composition, and allowing the composition to clear non-antigen bound antibody f\Jsioa protein or fiagment thereof fiom circulation; and (iii) admimstering to the patient a ta^etable conjugate comprising a earner portion which comprises or bears at least one epitope recognizable by at least one other arm of the antibody fiision protein or fragment thereof, and is conjugated at least one first therapeutic or diagnostic ^ent. The antibody fiision protein of die present invention should be multispecific antibody. In a preferred embodiment the antibody is a bispecific antibody, and can be a diabody. The first therapeutic agent is selected fiom the group consisting of a radioactive label, an immunomodulator, a hormone, a photoactive therapeutic agent, a cytotoxic agent, an oligonucleotide and a combination thereof and wherein the first diagnostic agent is at least one of a radioactive label, a photoactive diagnostic agent or a non-radioactive label. The antibody fusion protein or fragment thereof also may be conjugated to a second ther^Kutic, such as at least one radioactive label, an immunomodulator, a hormone, a phobDactive therapeutic agent, a cytotoxic agent, an oligonucleotide and a combination thereof or may be conjugated ttie second diagnostic agent, such as at least one of a radioactive label, a photoactive diagnostic agent or a non-radioactive label. In one embodiment, the first and second therapeutic j^ent or di^nostic ^ent are the same. A therapeutic or diagnostic agent can be attached at die hinge region of a reduced antibody component via disulfide bond formation. As an alternative, such peptides can be attached to the antibody component using a heterobifimctional cross-linker, such as A'^succinyl 3-(2-pyridyldithio)propionate (SPDP). Yu et al.. Int. J. Cancer 56: 244 (1994). General techniques for such conjugation are well-known in die art. See, for example, Wong, CHEMISTRY OF PROTEIN CONJUGATION AND CROSS-LINKING (CRC Press 1991); Upeslacis et al., "Modification of Antibodies by Chemical Mefliods," in MONOCLONAL ANTIBODIES: PRINCIPLES AND APPLICATIONS, Birch et al (eds.). pages 187-230 (Wiley-Liss, Inc. 1995); Price, "Production and Characterization of Synthetic Peptide-Derived Antibodies," in MONOCLONAL ANTIBODIES: PRODUCTION, ENGINEERING AND CLINICAL APPLICATION, Ritter et al (eds.), pages 60-84 (Cambridge University Press 1995). Alternatively, the therapeutic or diagnostic ^ent can be conjugated via a carbohydrate moiety in the Fc region of the antibody. The carbohydrate group can be used to increase the loading of the same peptide that is bound to a thiol group, or tiie carbohydrate moiety can be used to bind a difierent peptide. Methods for conjugating peptides to antibody components via an antibody carbohydrate moiety are well-known to those of skill in the art. See, for exan^jle, Shihera/., M J. Cancer 41: 832 (1988); Shihef a/.. Int. J. Cancer 46: 1101 (1990); and Shih et al, U.S. Patent No. 5,057,313, all of which are incorporated in theij entirety by reference. The general method involves reacting an antibody component having an oxidized carbohydrate portion with a cairier polymer that has at least one free amine fimction and that is loaded with a plurality of peptide. This reaction results in an initial Schiff base (imine) linkage, which can be stabilized by reduction to a secondary amine to form the final conjugate. The Fc region is absent if the antibody used as the antibody component of the immimoconjugate is an antibody fragment. However, it is possible to introduce a carbohydrate moiety into the light chain variable region of a fiiU length antibody or antibody fragment. See, for example, Leung ef a/.,.//mmw/io/. 75^:5919(1995); Hansen et al, U.S. Patent No. 5,443,953 (1995), Leimg et al. U.S. patent No. 6,254,868, all of wliich are incorporated in their entirety by reference. The engineered carbohydrate moiety is used to attach the therapeutic or diagnostic agent. 10. Pharmaceutically Acceptable Excipients The humanized, chimeric and human anti-CD20 mAbs to be deUvered to a subject can consist of the MAb alone, immunoconjugate, fusion protein, or can comprise one.or more phannaceutically suitable excipients, one or more additional ingredients, or some combination of these. The unmunoconjugate or naked antibody of the present invention can be formulated according to known methods to prepare pharmaceutically useful compositions, whereby the immunoconjugate or naked antibody are combined in a mixture witii a pharmaceutically suitable excipient. Sterile phosphate-buffered saline is one example of a phannaceutically suitable excipient. Other suitable excipients are well-known to (hose in the art. See, for example, Ansel et al, PHARMACEUTICAL DOSAGE FORMS AND DRUG DELIVERY SYSTEMS, 5tii Edition (Lea & Febiger 1990). and Gennaro (ed.), REMINGTON'S PHARMACEUTICAL SCIENCES, IStti Edition (Mack Publishing Company 1990), and revised editions thereof The immunoconjugate or naked antibody of the present invration can be formulated for intravenous administiation via, for exMnple, bolus injection or continuous jnfiision. Preferably, the antibody of the present mvention is infused over a period of less than about 4 hours, and more preferably, over a period of less than about 3 hours. For example, the first 25-50 mg could be infused within 30 minutes, preferably even IS mia, and the remainder infused over the next 2-3 hrs. Fonnulations for injection can be presented in muX dosage form, e.g., in ampules or in multi-dose containers, wOh an added preservative. "Hie compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspendmg, stabilizing and/or dispersing agents. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Additional pharmaceutical methods may be employed to control the dumtion of action of the therapeutic or diagnostic conjugate or naked antibody. Control release preparations can be prepared throu^ the use of polymers to complex or adsorb the immunoconjugate or naked antibody. For example, biocompatible polymers include matrices of poly(etiiylene-co-viGyl acetate) and matrices of a polyanhydiide copolymer of a stearic acid dimer and sebacic acid. Sherwood et ai, Bio/Technology 10:1446(1992). Tlie rate of release of an immunoconjugate or antibody from such a matrix depends itpon the molecular weight of the immunoconjugate or antibody, the amount of immunoconjugate, antibody within flie matrix, and the size of dispersed particles. Saltzinaiietal.,Biophys. J. 55: 163 (1989); Sherwood e^(i/.,swprfl!. Other soUd dosage forais are described in Ansel et ai, PHARMACEUTICAL DOSAGE FORMS AND DRUG DELIVERY SYSTEMS, 5th Edition (Lea & Febiger 1990), and Genuaro (ed.), REMINGTON'S PHARMACEUTICAL SCIENCES, 18th Edition (Mack Publishing Con^any 1990), and revised editions thereof. The immunoconjugate, antibody fiision proteins, or naked antibody may also be administered to a mammal subcutaneously or even by other parenteral routes. Moreover, the adraiiustration may be by continuous infusion or by single or multiple boluses. Preferably, the antibody of the present invention us infused over a period of less fiian about 4 hours, and more preferably, over a period of less fiian about 3 hours. This is preferably performed by infusing slowly at first For example, a dose of 25 to 50 mg is infijsed within 15-30 minutes and the remainder of the dose is infiised over a period of up to 2-3 hrs. In general, the dosage of an administered immunoconiueate. fusion protein or naked antibody for humans will vary depending upon such factors as the patient's age, weight, height, sex, general medical condition and previous medical history. Typically, it is desirable to provide the recipient with a dosage of immunoconjugate, antibody fusion protein or naked antibody that is in the range of from about 1 mg/kg to 20 mg/kg as a single intravenous infusion, although a lower or higher dosage also may be administered as circumstances dictate. Therefore, 1-20 mg/kg for a 70 kg patient, for example, is a dose of 70-1,400 mg, or 41 -824 mg/m^ for a 1.7-m patient. This dosage may be repeated as needed, for example, once per week for 4-10 weeks, preferably once per week for 8 weeks, and more preferably, once per week for 4 weeks. It may also be given less frequently, such as every other week for several months. More specifically, an antibody of the present invention, such as naked anti-CD20, may be administered as one dosage every 2 or 3 weeks, repeated for a total of at least 3 dosages. Also preferred, the antibodies ofthe present invention may be administered once per week for 4-8 weeks. In other words, if the dosage is lowered to approximately 200-300 mg/m^ (which is 340 mg per dosage for a 1.7-m patient, or 4.9 mg/kg for a 70 kg patient), it may be administered once weekly for 4 to 8 weeks. Alternatively, the dosE^e schedule may be decreased, namely every 2 or 3 weeks for 2-3 months; for example, if the dosage is 300-500 mg/m^ (i.e., 510-850 mg for a 1.7-m patient, or 7.3-12 mg/kg for a 70 kg patient). The dosmg schedule can optionally be repeated at other intervals and dosage may be given dirough various parenteral routes, with appropriate adjustment of the dose and schedule. For purposes of ther^y, die immunoconjugate, fusion protein, or naked antibody is administered to a mammal in a tiier^ieutically effective amount. A suitable subject for the present invention are usually a human, although a non-human animal subject is also contemplated. An antibody preparation is said to be administered in a "therapeutically effective amount" if the amount administered is physiologically significanl. An agent is physiologically significant if its presence results m a detectable change in the physiology of a recipient mammal. In particular, an antibody preparation of tiie present invention is physiologically significant if its presence invokes an antitumor response or mitigates the signs and symptoms of an autoimmune disease state. A physiologically significant effect could also be the evocation of a humoral and/or cellular immune response in the recipient mammal. 11. Methods of Treatment The present mventioti contemplates the use of naked anti-CD20 antibodies of the present invention as the primary composition for treatment of B cell disorders and other diseases. In particiUar, the compositions described herein are particularly useful for treatment of various autoimmune as well as indolent forms of B-cell lymphomas, aggressive forms of B-cell lymphomas, chronic lymphatic leukemias, acute lymphatic leukemias, and WaldenstrSm's macroglohulinemia. For example, the humanized anti-CD20 antibody components and immunoconjugates can be used to treat both indolent and aggressive forms of non-Hodgkin's lymphoma. Tlie compositions for treatment contain at least one humanized, chimeric or human monoclonal anti-CD20 antibody alone or in combination with other antibodies, such as other humanized, chimeric, or human antibodies, therapeutic agents or immunomodulators. In particular, combination ftiraapy with a fully human antibody is also contemplated and is produced by the methods as set forth above. Naked or conjugated antibodies to the same or different epitope or antigen may be also be combined with one or more of the antibodies of the present invention. For example, a humanized, chimeric or human naked anti-CD20 antibody may be combined with another naked humanized, naked chimeric or naked human anti-CD20, a humanized, chimeric or human naked anti-CD20 antibody may be combined with an anti-CD20 immunoconjugate, a naked anti-CD20 antibody may be combined with an anti-CD22 radioconjugate or an aati-CD22 naked antibody may be combined with a humanized, chimeric or human anti-CD20 antibody conjugated to an isotope, or one or more chemother^reutic agents, cytokines, toxins or a combination tiiereof. A fusion protein of a humanized, chimeric or human CD20 antibody and a toxin or immunomodulatot, or a fusion protein of at least two different B-cell antibodies (e.g., a CD20 and a CD22 MAb) may also be used in this invention. Many different antibody combinations, targeting at least two different antigens associated with B-cell disorders, as Usted already above, may be constructed, either as naked antibodies or as partly naked and partly conjugated with a ther^eutic agent or immunomodulator, or merely in combination with another ther^)eulic agents, sudi as a cytotoidc drug or with radiation. As used herein, the term "immunomodulator" includes cytokines, stem eel! growlh factors, lymphotoxins, such as tumor necrosis factor (TNF), and hematopoietic factors, such as interleukins {e.g., interleukin-1 (IL-1), IL-2, IL-3, IL-6, IL-10, IL-12, IL-21 and IL-18), colony stimulating factors (e.g., granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage-colony stimulating factor ' (GM-CSF)), interferons (e.g., interferons-a, -p and -y), the stem cell growtfi factor designated "SI factor," erythropoietin and thrombopoietin. Examples of suitable immunomodulator moieties include IL-2, IL-6, IL-IO, IL-12, IL-18, IL-21, interferon-y, TNF-a, and the like. Alternatively, subjects can receive naked anti-CD20 antibodies and a separately administered cj^okine, wliich can be administered before, concurrently or after administration of the naked anti-CD20 antibodies. As discussed supra, the anti-CD20 antibody may also be conjugated to the immunomodulator. The immunomodulator may also be conjugated to a hybrid antibody consisting of one or more antibodies binding to different antigens. Multimodal therapies of the present invention further include immunotherapy with naked anti-CD20 antibodies supplemented with administration of anti-CD22, anti-CD19, anti-CD21, anti-CD74, anti-CD80, anti-CD23. anti-CD46 or HLA-DR (including the invariant chain) antibodies in the form of naked antibodies, fusion proteins, or as immunoconjugates. The naked anti-CD20 antibodies or fragments thereof may also be supplanented with naked antibodies j^ajnst a MUCl antigaitiiat is expressed on certain B-cells. These antibodies include polyclonal, monoclonail, chimeric, human or humanized antibodies that reco^iize at least one epitope on these antigenic determinants. Anti-CD 19 and anti-CD22 antibodies are known to those of skill in the art. See, for example, Ghetie er a/., CancerRes. ^5:2610 (1988); Hekman etal, Cancer Immunol Immunother. 32:364(1991); Longo,Curr. Opin. Oncol. 5:353 (1996) and U.S. Patent Nos. 5,798,554 and 6,187,287, incorporated in their entirety by reference. In another form of multimodal therapy, subjects receive naked anti-CD20 antibo(Kes, and/or immunoconjugates, in conjunction with standard cancer chemotherapy. For example, "CVB" (1.5 g/m^ cyclophosphamide, 200-400 mgW etopoade, and 150-200 mg/m^ carmustine) is a i^,inien used to treat imnrHodgkin's lymphoma. VaUiet al, Eur. J. Haematol. 51: \%i\99y). Other suitable combination chemodierapeutic regimens are well-known to those of skill in the art. See, for example, Freedman et al, "Non-Hodgkin's Lymphomas," in CANCER MEDICINE, VOLUME 2, 3rd Edition, Holland et al (eds.), p^es 2028-2068 (Lea & Febiger 1993). As an illustration, first generation chemotherapeutic regimens for freatment of intermediate-grade non-Hodgkin's lymphoma (NHL) include C-MOPP (cyclophosphamide, vincristine, procarbazine and prednisone) and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). A useful second generation chemotherapeutic regimen is m-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexameHiasone and leucovorin), while a suitable third generation regimen is MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin and leucovorin). Additional usefiU dmgs include phenyl butyrate and brostatin-1. In a preferred multimodal therapy, both chemotherapeutic drugs and cytokines are co-administered with an antibody, immunoconjugate or fiision protein according to the present invention. The cytokines, chemotherapeutic drugs and antibody or immunoconjugate can be administered in any order, or together. In a preferred embodiment, NHL or tie autoimmune disease is treated witii 4 weekly iniiisions of the humanized anti-CD20 antibody at a does of 200-400 mg/m^ weekly for 4 consecutive weeks (iv over 2-6 hours), repeated as needed over the next months/yrs. Preferably, the humanized anti-CD-20 antibody is administered at a dose of 200-300 mg/m^ once every other week or every third week, for 4 to 8 injections. Also preferred, NHL is treated with 4 weekly infusions as above, or injections less frequently as above, but combined with epratuzumAb (anti-CD22 humanized antibody) on the same days, at a dose of 360 mg/m^, givea as iv infusion over 1 hour, either before, during or after the anti-CD20 monoclonal antibody iniiision. Or, tiie antibodies used in combmation therapy may also be infused in alternative sequences, such that they are alternated on different weeks, resulting in each being given every other week for a total injection sequence for each of 4 to 8 or more doses. These dosage schedules can then be repeated at different mtervals, such as every 3-6 months, depending on the patient's clinical status and response to each ther^y regunen. Still preferred, NHL is tteated with 4 weekly infusions, or less frequent infiisions, of the anti-CD20 antibody as above, combiiKd with one or more injections of CD22 MAb radiolabeled with a therapeutic isotope such as ytlrium-90 (at a total dose of Y-90 between 5 and 35 mCi/meter-square as one or more injections over a period of weeks or months). US Serial No. 09/590,284 (Goldenberg et al.) discloses immunotherapy of autoimmune disorders using an anti-CD22 antibody, wiiich is incorporated herein by reference in its entirety. In addition, a therapeutic composition of the present invention can contain a mixture or hybrid molecules of monoclonal naked anti-CD2D antibodies directed to different, non-blocking CD20 epitopes. Accordingly, the present invention contemplates therapeutic compositions comprising a mixture of monoclonal anti-CD20 antibodies that bind at least two CD20 epitopes. Additionally, the tiierapeutic composition described herein may contain a mixture of anti-CD20 antibodies with varying CDR sequences. Although naked anti-CD20 antibodies are the primary therapeutic compositions for treatment of B cell lymphoma and autoimmune diseases, the efficacy of such antibody ther^y can be enhanced by supplementing tiie naked antibodies, with supplemental agents, such as immimomodulators, like interferons, including IFNf, IFNb and IFNy, interleukms mcludmg IL-I, IL-2, IL-6, IL-12, IL-15, IL-18, IL-21, and cytokmes including G-CSF and GM-CSF. Accordingly, tiie CD20 antibodies can be combined not only with antibodies and cytokines, either as mixtures (given separately or in some predetermined dosing regiment) or as conjugates or fusion proteins to the anti-CD20 antibody, but also can be given as a combination with drugs. For example, the anti-CD20 antibody may be combined with CHOP as a 4-dmg chemotherapy regimen. Additionally, a naked anti-CD20 antibody may be combmed witii a naked anti-CD22 antibodies and CHOP or fiudarabine as a drug combination for NHL ther^y. Immunotherapy of B-cell malignancies using an anti-CD22 antibody is described in US Patent No. 6,183,744 (Goldenberg et ah) and US Serial No. 09/307,816 (Goldenberg et al.), which are incorporated herein by reference in then- entirety. The supplemental therapeutic compositions can be administered before, concurrentiy or after administiation of the anti-CD20 antibodies. As discussed siqjra, the antibodies of the present invention can be used for treating B cell lymphoma and leukemia, and other B cell diseases or disorders. For example, anti-CD20 antibodies can be used to treat B-cell related autoimmune diseases, including Class in autoimmune diseases such as immime-mediated thrombocytopenias, such as acute idiopathic thrombocytopenic purpura and chronic idiopathic thrombocytopenic purpura, dermatomyositis, Sjogren's syndrome, multiple sclerosis, Sydenham's chorea, myasthenia gravis, systemic lupus erytfaanatosus. lupus nephritis, rheumatic fever, rheumatoid arthritis, polyglandular syndromes, bullous pemphigoid, diabetes mellitus, Henoch-Schonlein purpura, post-streptococcal nephritis, eiythema nodosum, Takayasu's arteritis, Addison's disease, rheumatoid ardiritis, sarcoidosis, ulcerative colitis, erythema multiforme, IgA nephropathy, polyarteritis nodosa, ankylosing spondylitis, Goodpasture's syndrome, thromboangitis ubiterans,, primary biliary cirrhosis, Hashimoto's thyroiditisj thyrotoxicosis, scleroderma, chronic active hepatitis, polymyositis/dermatomyositis, polychondritis, pamphigus vulgaris, Wegener's granulomatosis, membranous nephropathy, amyotrophic lateral sclerosis, tabes dorsalis, giant cell mteritis/polymyalgia, pernicious anemia, rapidly jwogressive glomerulonephritis and fibrosing alveolitis. Anti-CD20 antibodies may also induce apoptosis in cells expressing the CD20 antigen. Evidence of this induction is supported in the literature. For example, it was demonstmted that apoptosis could be induced using lymphoid cells that have Fc-receptors reactive with the IgGl-Fc of CD20 MAbs that crQssUnked. See Shan etal. Cancer Immunol. Immunother. 48(12):673-683 (2000). Finther, it was reported that aggregates of a chimeric CD20 MAb, i.e., homopolymers, induced apoptosis. See Ghetie et al. Blood 97(5): 1392-1398 (2000) and Ghetie ei d., Free. Natl Acad Sci USA 94(14): 7509-7514 (1997). Antibodies specific to the CD20 surface antigen of B cells can be injected into a mammahan subject, which then bind to the CD20 cell surface antigen of botii norm^ and imiligi»nt B cells. A mammalian subject includes humans and domestic animals, including pets, such as dogs and cats. The anti-CD20 mAbs of the present invention, i.e., humanized, chimeric, human, caninized and felinized, and even murine anti-CD20 mAbs, can be used to treat the non-human mammalian subjects w^ien there is a ^lecies crossreactivity for the CD20 antigen. See Examples 10 and 11, below. The murine mAbs, which are immunogenic in humans, are usually less immunogenic in non-human mammalian subjects. The anti-CD20 antibody bound to the CD20 surface antigen leads to flie destruction and depletion of neoplastic B cells. Because both nonnal and malignant B cells eiqsress the CD20 antigen, the anti-CD20 antibody will result in B cell deatiL However, only normal B cells will repopulate and the mahgnant B cells will be eradicated or significautiy reduced. Additionally, chemical agents or radioactive labels having the potential to destroy tiie tumor can be conjugated to the anti-CD20 antibody such that the agent is specifically targeted to the neoplastic B cells. 12. Expression Vectors The DNA sequence encoding a humanized, chimeric or human anti-CD20 MAb can be recombinantly engineered into a variety of known host vectors that provide for replication of the nucleic acid. These vectors can be designed, using known methods, to contain the elements necessary for directing transcription, translation, or both, of the nucleic acid in a cell to vAdch it is delivered. Known methodology can be used to generate expression constructs the have a protein-coding sequence operably linked with appropriate transcriptional/translational control signals. These methods include in vitro recombinant DNA techniques and synthetic techniques. For example, see Sambrook et al, 1989, MOLECULAR CLONING: A LABORATORY MANUAL, Cold Spring Harbor Laboratory (New York); Ausubel et al, 1997, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John WUey & Sons (New York). Also provided for in this invention is the delivery of a polynucleotide not associated with a vector. Vectors suitable for use in the instant invention can be viral or non-viral. Particular examples of viral vectors include adenovirus, AAV, herpes simplex virus, lentivirus, and retrovirus vectors. An example of a non-viral vector is a plasmid. In a preferred embodiment, the vector is a plasmid. An expression vector, as described herein, is a polynucleotide comprising a gene that is expressed in a host cell. Typically, gene expression is placed under the control of certain regulatory elements, including constitutive or inducible promoters, tissue-specific regulatory elements, and enhancers. Such a gene is said to be "operably linked to" the regulatory elements. Preferably, ttie e:q)ression vector of the instant invention comprises the DNA seqtience encoding a humanized, chimeric or human anti-CD20 MAb, which includes both the heavy and the li^t chain variable and constant regions. However, two e:q)ression vectors may be used, with one comprising the heavy chain variable and constant regions and the other comprising the li^t chain variable and constant regions. Still preferred, the expression vector finther comprises a promoter. Because any strong promoter can be used, a DNA sequence encoding a secretion signal peptide, a genomic sequence encoding a human IgGl heavy chain constant region, an Ig enhancer element and at least one DNA sequence encoding a selection marker. Also contemplated herein is a method for expressing a humanized anti-CD20 MAb, comprising (i) linearizing at least one expression vector conaprising a DNA sequence encoding a humanized, chimeric, or human anti-CD20 MAb, (ii) transfecting mammalian cells with at least one of sajd linearized vector, (iii) selecting transfected cells which express a marker gene, and (iv) identifying Ae cells secreting the humanized anti-CD20 MAb from flie transfected ceils. 13. Methods of Making Anti-CD20 Antibodies In general, the VK (variable light chain) and VH (variable heavy chain) sequences for an anti-CD20 MAb can be obtained by a variety of molecular cloning procedures, such as RT-PCR, 5'-RACE, and cDNA Ubraiy screening. Specifically, tiie V genes of an anti-CD20 MAb can be cloned by PCR amplification from a cell that expresses a miirine or chimeric anti-CD20 MAb, sequenced. To confirm iheh authenticity, the cloned VL and VH genes can be e:q)ressed in cell culture as a chimeric Ab as described by Orlandi et al.,(Proc. Natl. Acad Sci., USA, 86:3833 (1989)) which is incorporated by reference. Based on the V gene sequences, a humanized anti-CD20 MAb can then be designed and coiKtructed as desaibed by Leung et al. (Mol. Immunol, 32: 1413 (1995)), which is incorporated by reference. cDNA can be prepared from any known hybridoma Ime or transfected cell line producing a murine or chimeric anti-CD20 MAb by genraal molecular cloning techniques (Sambrook et al.. Molecular Cloning, A laboratory manual, 2"*" Ed (1989)). The VK sequeiKe for the MAb may be amplified usmg the primers VKIBACK and VKIFOR (Orlandi et al, 19^9) or the extended primer set described by Leung et al. [BioTechniques, 15: 286 (1993)), wiiich is incorporated by reference, while VH sequences can be an^)lified using the primer pair VHlBACKATilFOR (Oriandi et al., 1989 above), or the primers annealmg to the constant region of murine IgG described by Leung et al. (Hybridoma, 13:469 (1994)), which is mcorporated by reference. The PCR reaction mixtures containing 10 ^1 of tiie first strand cDNA product, 10 nl of lOX PCR buffer [500 mM KCl, 100 mM Tris-HCl (pH 8.3), 15 mM UgCh, and 0.01% (w/v) gelatin] (Peridn Ehner Cetus, Norwalk, CTX 250 \M of each dNTP, 200 nM of the primers, and 5 units of Taq DNA polymerase (Peridn Ehner Cetus) can be subjected to 30 cycles of PCR. Each PCR cycle preferably consists of denaturation at 94°C for 1 min, annealing at 50 °C for 1.5 min, and polymerization at 72 C for 1.5 min. Amplified VK and VH ftagments can be pixrified on 2% agarose (BioRad, Richmond, CA). Similarly, the humanized V genes can be constructed by a combination of long oligonucleotide template syntheses and PCR amplification as described by Leung et al. (MoL Immunol., 32: I4I3 (1995)). See Example 3 for a method for the synthesis of an oligo A and an oligo B on an automated RNA/DNA synthesizer (Apphed Biosystans, foster City, CA) for use in constructing hiananized V genes. PCR prodiBts for VK can be subclcmed into a staging vector, such as a pBR327-based staging vector, VKpBR, that contains an Ig promoter, a signal peptide sequence and convenient restriction sites to facilitate in-frame Ugation of the VK PCR products. PCR products for VH can be subcloned into a similar staging vector, such as the pBluescript-based VHpBS. Individual clones containing the respective PCR products may be sequenced by, for example, the method of Sanger et al (Proc. Natl Acad Sci., USA, 74: 5463 (1977)), wtidi is incorporated by refo-ence. The DNA sequences described herein are to be taken as includii^ all alleles, mutants and variants thereof, whether occurring naturally or induced. The expression cassettes containing the VK and VH, together wifli the promoter and signal peptide sequences can be excised from VKpBR and VHpBS, respectively, by double restriction digestion as HindlH-BainHI fragments. The VK and VH expression cassettes can tiien be ligated into appropriate expression vectors, such as pKh and pGlg, respectively (Leung et al., Hybridoma, 13:469 (1994)). The eq)ression vectors can be co-tiansfected into an appropriate cell, e.g., myeloma Sp2/0-Agl4 (ATCC^ VA), colonies selected for hygromycin resistance, and si^matant fluids monitored for production of a chimeric or humanized anti-CD20 MAb by, for example, an ELISA assay, as described below. Alternately, the VK and VH egression cassettes can be assembled in the modified stagh^ vectors, VKpBR2 and VI^BS2, excised as Xbal/BamHI and Xhol/BamHl fragments, respectively, and subcloned into a single expression vector, such as pdHL2, as described by Gilles et al. (J. Immunol Methods 125:191 (1989) and also shown in Losman et al., Cancer, 80:2660 (1997)) for tiie expression in Sp2/0-Agl4 cells. Another vector tiiat is usefiil in the present mveijtion is the GS vector, as described m Barnes et al, Cytotechnology 32:109-123 (2000), which is preferably ejqpressed in the NSO cell line and CHO cells. Otiier ^jpropriate mammalian expression systems are described in Werner et al, Arzneini.-Forsch7Drug Res. 48(11), Nr. 8, S70-880 (1998). Co-transfection and assay for antibody secreting clones by ELISA, can be carried out as follows. About 10 pg of VKpKh (light chmn expression vector) and 20 pg of VHpGlg (heavy chain expression vector) can be used for the transfection of 5 X 10* SP2/0 myeloma cells by electroporation (BioRad, Richmond, CA) according to Co et al., J. Immunol, 14S: 1149 (1992) vvbidi is incorporated by reference. Following transfection, cells may be grown in 96-weIl microtiter plates in complete HSFM medium (Life Technologies, Inc., Grand Island, NY) at 37'C, 5%C02- The selection process can be initiated after two days by the addition of hygromycui selection medium (Calbiochem, San Diego, CA) at a final concentration of 500 units/ml of hygromycin. Colonies typically ema^e 2-3 weeks post-electroporation. The cultures can then be expmided for finther analysis. Transfectoma clones that are positive for the secretion of chimeric or humanized heavy chain can be identified by ELISA assay. Briefly, supernatant samples (~100 pi) fitim transfectoma cultures are added in tripUcate to ELISA microtiter plates precoated with goat anti-human (GAH)-IgG, F(ab'}i fiBgment-specific antibody (Jackson ImmunoResearch, West Grove, PA). Plates are incubated for 1 h at room tempCTature. Unboraid proteins are removed by washing three times with w^sh buffer (PBS containing 0.05% polysorbate 20). Horseradish poioxidase (HRP) conjugated GAH-IgG, Fc fr^ment-specific antibodies (Jackson ImmunoReseardi) are added to the wells, (100 pi of antibody stock diluted x 10*, supplemented witii the unconjugated antibody to a fin?tl concentration of 1.0 pg/ml). Following an incubation of 1 h, the plates are washed, typically three times. A reaction solution, [100 pi, containii^ 167 pg of orthophenylene-diamine (OPD) (Sigma, St. Louis, MO), 0.025% hydiogea peroxide in PBS], is added to the wells. Color is allowed to develop in the dark for 30 minutes. The reaction is stopped by the addition of 50 pi of 4 N HCl solution mto each well before measuring absorbance at 490 nm in an automated ELISA reader (Bio-Tek instruments, Winooski, VT). Bound chimeric antibodies are than determined relative to an irrelevant chimeric antibody standard (obtainable ftom Scotgen, Ltd., Edinburg, Scodand). Antibodies can be isolated from cell culture media as follows. Transfectoma (ailtures are adapted to serum-fi:ee medium. For production of chimeric antibody, cells are grown as a 500 ml culture in roller bottles using HSFM. Cultures are centrifiiged and the supernatant filtered Uirough a 0.2 ^i membrane. The filtered medium is passed throng a protein A column (1x3 cm) at a flow rate of 1 ml/min. The resin is then washed with about 10 column volumes of PBS and protein A-bound antibody is eluted from the column with 0.1 M glycine buffer (pH 3.5) containing 10 mM EDTA. Fractions of 1.0 ml are collected in tubes containing 10 ^1 of 3 M Tris (pH 8.6), and protein concentrations detamined from Ha absorbance at 280/260 nm. Peak fractions are pooled, dialyzed against PBS, and the antibody concentrated, for example, with the Centricon 30 (Amicon, Beverly, MA). The antibody concentiation is determined by ELISA, as before, and its concentration adjusted to about 1 mg/ml i^ing PBS. Sodium azide, 0.01% (w/v), is convenientiy added to the sample as preserrative. The followii^ are the nucleotide sequences of the primars used to prepare the anti-CD20 antibodies: hA20VKA 5'-CATCTCTGAG CGCATCTGTT GGAGATAGGG TCACTATGAC TTGTAGGGCC AGCTCAAGTG TAAGTTACAT CCACTGGTTC CAGCAGAAAC CAGGGAAAGC ACCTAAACCC TGGATTTATG-3' hA20VKB S'-GGTGTCCCTG TCCGATTCTC TGGCAGCGGA TCTGGGACAG ATTACACTTT CACCATCAGC TCTCTTCAAC CAGAAGACAT TGCAACATAT TATTGTCAGC AGTGGACTAG TAACCCACCC ACGTTCGGTG-3' hA20VKA-Backward 5'-CAGCTGACCC AGTCTCCATC ATCTCTGAGC GCATCTGTrG-3' hA20VKA-Fonvard 5'-AGGTTCGAAG TGGCATAAAT CCAGGGTTTA GGTGCT-3' liA301^KB Backward 5'-CACTTCGAAC CTGGCTTCTG GTGTCCCTGT CCGATTCTC-3' bA20J^KB Forward S'-ACGTTAGATC TCCAGCTTGG TCCCTCCACC GAACGTGGGT GGGTTA-3' hA20VIIA 5'-CTGAAGTCAA GAAACCTGGG TCATCGGTGA AGGTCTCCTG CAAGGCTTCT GGCTAC ACCT TTACTAGIT A C AATATGC AC TGGGTCAAGC AGGCACCTGG ACAGGGTCTG GAATGGATFG G-3' IJA20VHB S'-ATCAGAAGTT CAAGGGTAAA GCCACACTGA CTGCCGACGA ATCCACCAAT ACAGCCTACA TGGAGCTGAG CAGCCTGAGG TCTGAGGACA CGGCATTTTA TTACTGTGCA AGATCGACTT ACTACGGCGG TGACTGGTAC TTCGATGTCT G-3' hAlOVHA Backward 5'-CAGCTGCAGC AATCAGGGGC TGAAGTCAAG AAACCTGGG-3' hA20iaU Forward 5 '-TTCCGGGATA AATAGCTCCA ATCCATTCCA GACCCTG-3' hA20VHB Backward 5'-ATCCCGGAAA TGGTGATACT TCCTACAATC AGAAGTTCAA GGGTAAAGCCA-3' U20VHB Forward 5'-GGAGACGGTG ACCGTGGTGC CTTGGCCCCA GACATCGAAG TACCAG- 3' hA20VH2A 5'-CTGAAGTCAA GAAACCTGGG TCATCAGTGA AGGTCTCCTG CAAGGCTTCT GGCTACACCT TTAGTAGTTA CAATATGCAC TGGGTCAGAC AGGCACCTGG ACAGGGTCTG GAATGGATGG G-3' liA20VH2B S'-ATCAGAAGTT CAAGGGTAGA GCCACAATAA CTGCCGACGA ATCCACCAAT ACAGCCTACA TGGAGCTGAG CAGCCTGAGG TCTGAGGACA CGGCATTTTA TTTITGTGCA AGATCGACTT ACTACGGCGG TGACTGGTAC TTCGATGTCT G-3' hA20VH2A Forward 5'-TTCCGGGATA AATAGCTCCC ATCCATTCCA GACCCTG-3' hA20VH2B Backward 5'-ATCCCGGAAA TGGTGATACT TCCTACAATC AGAAGTTCAA GGGTAGAGCC A-3' The invention is fiirther described by reference to the following examples, vMch are provided for illustration only. The invention is not limited to the examples but rather includes all variations that are evident fixjm the teachings provided hereiiL EXAMPLES Example 1. Construction of a humanized anti-CD20 antibody The VH and VK genes of A20, an anti-CD20 antibody, was obtained by RT-PCR using the primer pairs VHIBACK/ VHIFOR and VKIBACK/ VKIFOR, respectively Orlandi«o/.,(Proc.A'a//.^ca.Sc/..USA, 86: 3833(1989)). Multiple independent clones were sequenced to eliminate possible errors resultii^ from the PCR reaction. The cloned murine VH and VK sequences as the final PCR product were designated A20Vk (Figure lA) and A20VH (Figure IB), respectively. A chimeric A20 (cA20) antibody was constructed and expressed in Sp2/0 cell. The Vk and VH of sequences of cA20 are shown in Figure 2. The cA20 antibody bound to Raji cell and competed with radiolabeled A20 purified fixim the hybridoma cell culture supernatant (Figure 3). This result confirmed the authenticity of the cloned V genes. A sii^le light chain and two heavy chain variable region sequences encoding the humanized anti-hCD20 (hA20) antibody were designed and constructed. Human REI framework sequences were used for VK (Figure 1 A), and a combination of EU and NEWM frameworic sequences were used for VH (Figure IB). There are a number of amino acid changes in each chain outside of the CDR regions when compared to the starting human antibody frameworks. The heavy chain of hA20, 1IA20VH1, contains nine changes, while hA20VH2 contains three changes from the human EU frameworks (Figure 4A). hA20VH2 is preferred because it contains more amino acids from the human antibody framework region than hA20VHl ■ The light chain of hA20, hA20VK, contains seven amino acid changes from the REI fiBmework (Figure 4B). Example 2. Method of hA20 antibody construction Each variable chziin was constructed in two parts, a 5'- and 3'-half, designated as "A" and "B" respectively. Each half was produced by PCR amplification of a single strand synthetic oligonucleotide template with two short flanking primers, using Taq polymerase. The ampHfied fragments were first cloned into die pCR4 TA cloning vector from Invitrogen (Carlsbad, CA) and subjected to DNA sequencing. The templates and primer pairs are listed as follows: Template Primers VKA VkA-BackwardATcA-Forward VKB VkB-BackwanWkB-Forward VHl A VHA-B ackward/VH 1 A-Forward VHIB VHlB-BackwardA'HB-Forward VH2A VHA-BackwardATH2A-Forwaid VH2B VICB-BackwardAHB-Forward Light chain For constructing the fiill-length DNA of the humanized VK sequence, ol^o hA20VKA (120 mer) and hA20VKB (130 mer) were synthesized on an automated RNA/DNA syndiesizer (Applied Biosystems). liA20VKA and B represent the nt 26-145 and 166-195, respectively, of the hA20 VK. (See Fig. 5A) Oligo hA20VKA and B were cleaved from die siq>port and deprotected by treatment with concentrated ammonium hydroxide. After samples were vacuum-tried and resuspended in 100 ^1 of water, incomplete oligomers (less than 100-mer) were removed by centrifi^ation through a ChormaSpin-lOO column (Clontech, Palo Alto, CA). All flanking primers were prepared similarly, except ChromaSpui-30 columns were used to remove synthesis by-products. 1 (J of ChromaSpin column purified hA20VKA was PCR amplified in a reaction volume of 100 ^I containing 10 fd of 1 OX PCR buffer [500 mM KCl, 100 mM Tris-HCl (pH 8.3), 15 mM UgClj, and 0.01% (w/v) gelatin] (Perkin Ehner Cetus, Norwalk, CT), 250 pM of each dKTP, 200 nM of VkA-Backward and VicA-Forward, and 5 units of Taq DNA polymerase (Perkin Ehner Cetus). This reaction mixture was subjected to 30 cycles of PCR reaction consisting of denaturation at 94'^C for 1 min, annealing at 50 C for 1.5 min, and polymerization at 72 °C for 1.5 min. hA20VKB vfas PCR-ampIified by tiie primer pair VkB-Backward and VkB-Fonvard under similar condition. The amplified VKA and VKA fragments were purified on 2% agarose (BioRad, Richmond, CA). Unique restriction sites were designed at the ends of each fiagment to facilitate joining through DNA ligation. The amplified VKA fi-agment contained a PvuII restriction site, CAGCTG, at its 5'-end and a BstBI restriction site, TTCGAA, at the 3'-ead. The ampUfied VKB fragment contained a Bsffll restriction site at its 5'-end and a BglH restriction site, AGATCT, at the 3'-end. Assembly of the fiill-lei^th VK chain was accomplished by restriction enjyme digestion of each fr^menf with the appropriate 5'- and 3'-enzymes and Ugarion into the VKpBR2 vector previously digested with PvuII and BcU (BcU digested end is compatible with that of BgUI). The resulting ligated product contains the A firagment ligated to the PvnII site, the B fragment ligated to the BcU site, and the A and B fr^ments joined togettier at the BstBI site (Figure 5A). VK^BR2 is a modified staging vector of VKpBR (Leung et al., Hybridoma, 13:469 (1994)), mto which a Xbal restriction site was introduced at 14 bases upstream of the translation initiation codon. Upon confirmation of a correct open reading frame by DNA sequencing, the intact chain was removed fixim VKpBR2 as a Xbal to BamHI fragment and ligated into tiie pdHL2 e)q)ression vector. The vector containing only VK sequence was designated as hA20VKpdHL2. pdHL2 contains the expression cassettes for both human IgGl CI, C2, C3, and hinge regions (Fig. 7A) and flie human kappa chain Ck (Fig. 7B) under the control of IgH enhancer and MTi promoter, as well as a mouse dhfr gene, controlled by a weak SV40 promoter, as a marker for selection of transfectants and co-amplification of the trans-genes (Gillies et al., J. Immunol Methods 125:191 (1989); Losman et al.. Cancer 80:2660 (1997)). By retracing the VK and VH segments of pdHL2, different chimeric or humanized Abs can be expressed. Heavy chain For the construction of hA20VH 1, oligo VH1A (121 mer) and VH1B (151 mer), representing the nt 23-143 and 179-329, respectively, (See Fig. SB) were synthesized as described above. Similarly, for liA20VH2, oligo VH2A and VH2B were prepared. These oligos were PCR-amplified by their respective primer paifs as listed in Example 2. The same construction method as done for VK was carried out for both types of VH, with the following modifications: the 5'-end restriction site of the A Segments was PstI (CTGCAG) and the 3'-end restriction site of B fragments was BstEn (GGTCACC). These fragments were joined together vpon ligation into the VHpBS2 vector at a common Neil site (CCCGG), resulting in fiill-length VH sequences (Figure 5B and 5C) and confirmed by DNA sequencing. VHpBS2 is a modified staging vector of VHpBS (Leung et al., Hybridoma, 13:469 (1994)), into which a Xhol restriction site was intioduced at 16 bases upstream of the translation initiation codon. The assembled VH genes were subcloned as XhoI-BamHI restriction fragments into the expression vector containing the VK sequence, hA20VKpdHL2. Since the heavy chain region of pdHL2 lacks a BamHI restriction site, this ligation required use of the HNB linker to provide a bridge between the BamHI site of the variable chain and the HindlH site present in flie pdHL2 vector. The resixlting expression vectors were designated as hA20-lpdHL2 and liA20-2pdHL2. HNB linker 5'-AGCTTGCGGCCGC-3' 3'-ACGCCGGCGCTAG-5' Example 3. Transfection and Expression of liA20 Antibodies Approximately 30 jig of flie expression vectors for hA20 were lineari2ed by digestion witii Sail and transfected into Sp2/0-Agl4 cells by electioporation (450V and 25 pp). The transfected cells were plated into 96-well plates for 2 days and then selected for drug-resistance by adding MTX into the medium at a final concentration of 0.025 nM. MTX-resistant colonies emerged in fhe wells 2-3 weeks. Superpatants from colonies surviving selection were screened for human Ab secretion by ELISA assay. Briefly, 100 pi si^iematants were added into the wells of a microtiter plate ptecoated with GAH-IgG, F(ab')2 fir^ment-specific Ab and incubated for 1 h at room temperature. Unbound proteins were removed by washing three times with wash buflfer (PBS containing 0.05% polysoihate 20). HRP-conjugated GAH-IgG, Fc fiagment- / specific Ab was added to tlie wells. Following an incubation of 1 h, the plate was washed. The bound HRP-conjugated Ab was revealed by readii^ A490nm after the addition of a substrate solution containing 4 mM OPD and 0.04% H2O2. Positive cell clones were expanded and liA20-l and hA20-2 were purified fiiDni cell culture supernatant by affinity chromatography on a Protem A column. Example 4. Binding Activity of Anti-CD20 Antibodies A competition cell-bindit^ assay was carried out to assess the immimoreactivity of hA20 relative to the parent cA20 and the anti-CD20 Ab c2B8. A constant amount of '^^I-labeled murine A20 or c2B8 (100,000 cpm, ~10 jiCi/ng) was incubated with Raji cell in the presence of varjdng concentrations (0.2-700 nM) of hA20-l, '2, murine A20, cA20, or c2B8 at 4°C for 1-2 h. Unbound Abs were removed by washing the cells in PBS. The radioactivity associated with cells was determined after washing. As shown in Figure 6, both humanized A20 mAbs, hA20-l and liA20-2, exhibited comparable bmding activities as A20, the murine anti-CD20 MAb, cA20, and c2B8, a chimeric anti-CD20 MAb, when competing with binding of '^'r-A20 or *"l-c2B8 to Raji cells. By direct binding of radiolabeled Mabs to Raji cells and Scatahard plot aniaysis, die dissociation constants were measured to be 2.9 and 4.2 nm for cA20 and hA2D, respectively, in comparison to 3.9 nM for C2B8. In vitro crosslinldng experiments, using a goat anti- human IgG, Fc fiagment specific antibody to complex with tiie antibodies showed similar killing of Raji NHL cells between cA20 and liA20, as well as C2B8. Example 5. Treatment of a Patient with Relapsed Intermediate-Grade Non-Hodgkin's Lymphoma A patient with intemiediate gr^ non-Hodgkin's lymphoma has failed prior aggressive chemother^y, consisting of CHOP x 6, which led to a complete remission for four months, another course of CHOP x 6, resulting in progression, D-MOPP x 2, resulting in stable disease for three months, and CVB with peripheral stem cell transplantation, which led to a partial remission for five montiis. The patient presents with recurrent lymphoma in a neck lymph node, measurable by computerized tomography and palpation. The patient is mflised within 3 hrs with 450 mg of humanized CD20 monoclonal antibody A20 on days 0, 14, 28, and 42 with no serious adverse effects noted either during or immediately after the infusions. Eight weeks later, palpation of the neck node enlargement shows a measurable decrease of about 50%. Follow-up measurements made at twenty weeks post therapy show no evidence of the disease in the neck, and nowhere else, as confirmed by computed tomography studies of the body. Since new disease is not detected elsewhere, the patient is considered to be in complete remission. Follow-up studies every 10-12 weeks confirms a complete remission for at least ten months post therapy. Example 6. Treatment of a patieat with chronic idiopathic thrombocytopenia purpura A 45-year-old female with chronic idiopathic thrombocytopenia purpura has been treated with prednisone, gamma globulins, and high dose dexamethasone, but the disease progresses. She undergoes splenectomy, wWch fails to stabilize the disease. Her platelet count falls to less than 30,000/microhter, and hemorrhagic events increase in frequency. The patient is then treated with the humanized CD20 A20 MAb, 500 mg intravenously on the first week, followed by a dose of 250 mg given once every other week for a total of 4 injections. Ten weeks after the last dose of A20 a marked increase in platelet number is observed, to 150,000/microUter, and the hemorriiagic events disappear. Five months after die last antibody infiision the disease is in remission. Example 7. Treatment of a patient with progressive rheumatoid arthritis A 70 year old female, with severe progressive rheumatoid arthritis of the finger joints, wrists, and elbows, has failed ther^y with methotrexate, and obtains only minor reUef viien placed on Enbrel dier^y. The patient is then treated with A20 humaruzed CD20 MAb, 300 rag intravenously e^h week, for a period of four weeks. After 3 months, a 40% improvement in measures of disease activity is observed, which is maintained for 5 months. The patient is again tteated with A20, at the same dose and firequency. The patient continues to improve, and 6 months after the second A20 MAb therapy, a 60% improvement is observed. No human anti-A20 antibodies are observed at any time during, or after tiie A20 flierapy. Although normal B-cells are depleted &om the blood, no infectious complications, or other drug-related severe toxicity is observed. Example 8. Treatment of a patient with myasthenia gravis A 65 year old male has failed all conventional therapy for myasthenia gravis, and is admitted to a neurological intensive therapy unit The patient was stabilized by plasma exchange, and given intravenous immunoglobulin to reduce the titer of antiacetylcholine receptor antibody. The patient remained bedridden, and was then treated witti A20 humanized CD20 MAb, 400 mg intravenously once every other week, for a period of ten weeks. One week after tiie last dose of A20, no blood B-celts were detectable, and a significant drop in the titer of the anti-acetylcholine antibody was observed. Four months after the last A20 MAb dose the patient was mobile, and was released from the hospital. Example 9. Treatment of a Dog with Aggressive Non-Hodgldn's B-cell Lymphoma in Lymph Nodes and Bone Marrow A 65-pound, 7-year old male Golden Retriever is diagnosed with difiRise large cell aggressive lymphoma. The dog is placed on combination chemotiier^y with vincristine, cyclophosphamide, prednisolone, and doxorubicin, with good response. However, the dog subsequently is characterized as having progressive lymphadenopathy, and seven months after this is found to have extensive lymphoma infiltration of bone marrow, extensive iymphoadenopathy of neck, chest, abdomen, pelvis, and hqiatosplenomegaly. The dog is given therapy with 1F5 chimeric monoclonal antibody. The dog is infiised intravenously with 120 mg of 1F5 antibody, and the treatment is repeated weekly for 4 weeks following this initial treatment. Four months after the final dose of 1F5, a computerized tomography scan of the patiait shows no evidence of lymphoma, and all signs and symptoms of the disease were not evident. Example 10. Treatment of a Dog with Relapsed Intermediate-Grade Non-Hodgkin's Lymphoma A 78-poimd, 9-year old, German Shepherd dog with intemiediate grade non-Hodgldn's lymphoma receives chemotiierapy, which initially leads to a complete remission for five months, followed by another course of chemotherapy which results in stable disease for six months. The dog then presents with recurrent lymphoma in the chest and in a neck lymph node, both measurable by computerized tomography and palpation, respectively. The patient is infused with a ^Y-labeled immunoconjugate of L243 (HLA-DR) monoclonal antibody weekly for two weeks, at a radiation dose of 8 mCi m 50 mg of antibody protein, in combination wifli the A20 humanized CD20 antibody at a dose of 100 mg per each weekly infusion. Three weeks later, palpation of the neck node enlargement shows a measurable decrease, while a repeat computerized tomography scan of the chest shows a marked reduction in tumor. Follow-up measurements made at ten weeks post therapy show evidence of the disease in the neck or the chest being reduced by a about 60 percent Since new disease is not detected elsewhere, the patient is considered to be in partial remission. Follow-up studies every 10-12 weeks confirms a partial remission for at least 7 months post tiierapy. Example 11. Treatment of a Cat with Relapsed Lymphoma A 10-pound, 12-year-old, domestic short hair presents with enlargement of a single submandibular lymph node. After excision, there is recurrence of the lesion at 6 months. The lesion is again excised, but then reappears 6 months later. The cat is then given weekly treatments for 4 weeks with an '^^I-labeled Jmmunoconjugate of anti-CD20 B1 monoclonal antibody, at a radiation dose of 15 mCi in 45 mg antibody protein. The treatment is repeated 3 monttis later. When examined 3 months after the last treatment, a marked decrease can be palpated. No recinrence of the disease is observed for over one year. Example 12. Evalulation of chimeric and humanized anti-CD20 Mabs in human NHL cells in culture or xenografted in SCID mice The properties of a chimeric (cA20) and humanized (hA20) CD20 antibody was assessed in NHL cell Unes. The results demonsfrate that cA20 and hA20 behave similarly to Rituximab, stainiag more than 99% of Raji, Ramos, RL, Daudi and Su-DHL-6 cells and reacting with approximately 5% of lymphocjiBS (expected % B-ceUs). In all B-cell lines, specific growth inhibition was seen with the Mabs. hut the level 0 f inhibition varied between (he cell lines, with Su-DHL being (he most sensitive, hi the absence of cross-linking, murine anti-CD20, cA20, hA20 and rituximab all yielded between 77 and 90% inhibition, ^ith cross-linking, inhibition of proUferataion ranged from 94-98%. Rituximab, cA20, and hA20 were also similar in their ability to induce ^wptosis in Raji cells in the presence of a cross-linking second monoclonal antibody. Also, SCID mice were injected intravenously with 2.5X10^ Raji cells on day 0. Injections of murine, chimeric and humanized anti-CD20 antibodies, and the cA20 F(ab')2 fragment were initiated on day-1 with 100 SgAnjection of intact antibody, or 67 Sg/injection F(ab')2 fragment, five times per week for two weeks, the twice weekiy for three weeks. In one study, control mice died of disseminated disease with a median survivial time of 15 days post tumor innoculation, but median survival was extended to 38 days for cA20,22.5 days for hA20, and 21 days for miwine anti-CD20 treated mice (all statistically significant by log-rank analysis (p Example 13. Competitive cell surface binding assay. Ag-binding specificity and afFmity studies of humanized anti-CD20 Abs (cA20, hA20, and clF5), purified by affinity chromatography on a Protein A column) were evaluated by a cell surfece competitive binding assay with murine 2B8 and rituxunab (IDEC Pharmaceuticals Corp., San Diego, CA) (J'igure 8). Briefly, a constant amount (100,000 cpm, -10 iCiAg) of '"l-Iabeled (A) m2B8 or (B) rituxunab was incubated wifli Raji cells in the presence of vaiying concentrations (0.2-700 nM) of competmg Abs (cA20, hA20, ni2B8, clF5, or rituxunab) at 4°C for 1-2 h. Unbound Abs were removed by waslni^ the cells with PBS. Radioactivity associated with the cells was detemiined after ^^sh^ng. Figure 8 (A) is a comparison of flie bindmg activities of cA20 (square), hA20-l (triangle) and hA20-l (circle) with that of in2B8 (diamond); Figure 8 (B) Compares the binding activities of cA20 (square), clF5 (triangle) and rituximab (diamond). In another study, the binding activities of hA20 with other anti-CD20 Abs, rituximab and murine Bl were compared by a cell surfece competitive binding assay (Figure 9). Briefly, a constant amount (100,000 cpm, -10 iCi/ig) of '^^Mabeled rituximab was incubated witii Raji cells in tiie presence of varying concentrations (0.2-700 nM) of competiug Abs, hA20 (triangle), mBl (Downward triangle) or rituximab (square) at 4°C for 1-2 h. Unbound Abs were removed by washing the cells with PBS. Radioactivity associated with the cells was determined aiiter washing. The ICso values for these three Abs were calculated to be 6.8, 34, and 5, respectively, Example 14. Cytotoxic effect of crosslinked hA20 and other CD20 Abs on cultured lymphoma cells. Raj i ceils were treated with various CD20 Abs in the presence of a crosslinker (an anti-human IgG, Fc ftagment specific antibody) to complex the CD20 antibodies (Figure 10). A final concentration of 5 ig/ml of hA20, cA20, rituximab, or a positive control Ab, hLLl, was incubated with Raji cells, with 20 ig/ml of tiie crosslinker (red), without the crosslinker (orange), or with an anti-mouse IgG, Fc fiagment specific andbody (blue) for 48 h. Total cell and viable cell populations were measured by (A) trypan blue staining and cell counting or (B) MTT assay (B). The data show a similar effect of liA20 and rituximab on Raji NHL cell survival, and that the cytotoxic effect is dependent on the specific crosslinking of the antibodies. Example 15. In vivo therapy with hA20 and hLL2. Raji cells wer administered i.v. to 60 SCID mice, at 2.5 x 10* cells/100 jiymouse (Figure 12). MAbs were administered i.p. on days 1 to 11, followed by MAb injections twice per week, for approximately 3 weeks. The body weight of the animals was measured weekly until tiie study was terminated. The animals were examined daily for paralysis of the hind legs. When paralysis occured, the animals were sacrificed and necropsied for visual inspection of disseminated tumor nodules (specifically in liu^, kidneys, and ovaries). Control mice treated with a control humanized IgGl Ab, hMN-14 (an anti-CEA antibody), died of dissenainated disease manifested with CNS paralysis. The median survival time was 13 days post tumor i.v. inoculation. Median survival in the group treated with hA20 was extended to about 25 days. This value represents median survival increase of approximately 2 fold for hA20. Although the group treated with hLL2 alone showed the same median survival time compared to the control mice, treatment with combination of hA20 and hLL2 increased the median survival time of the mice to approxinmtely 30 days. We claim: 1. A chimeric, humanized or human monoclonal antibody that binds to CD20. the antibody having a light chain variable region CDR1 comprising a sequence RASSSVSYIH (SEQ ID NO:1); CDR2 comprising a sequence ATSNLAS (SEQ ID N0:4); and CDR3 comprising a sequence QQWTSNPPT (SEQ ID N0:5); and the antibody having a heavy chain variable region CDR1 comprising a sequence SYNMH (SEQ ID N0:8}; CDR2 comprising a sequence AIVPGNGDTSYNQKFKG (SEQ ID N0:9): and CDR3 comprising a sequence STYYGGDWYFDV {SEQ ID NO: 10} or a sequence WYYSNSYWYFDV (SEQ ID NO. 13)- 2. The antibody according to claim 1, wherein the antibody is a chimeric monoclonal antibody. 3. The antibody according to claim 1, wherein the antibody is a human or humanized monoclonal antibody. 4. The antibody according to claim 1, wherein CDR3 comprises a seqijence STYYGGDWYFDV {SEQ ID NO:10). 5. The 'antibody according to ciaim 1, \wlierein CDR3 comprises a sequence WYYSNSYWYFDV (SEQ ID NO: 13), 6. The antibody fusion protein, comprising at least two monoclonal antibodies, wherein at least one of Oie antibodies is an antibody according to claim 1, 7. The antibody fusion protein according to claim 6, comprising at least one monoclonal antibody that targets an antigen other than CD20. 8. The antibody fusion protein according to claim 6, comprising at least one monoclonal antibody that targets CD22, 9. An isolated DNA sequence comprising a nucleic acid encoding a monoclonal antibody as claimed in claim 1. 10. An isolated DNA sequence comprising a nucieic acid encoding an antibody fusior* protein as claimed in claim 6. 11. An expression vector comprising the DNA sequence of claim 9. 12. An expression vector comprising the DNA sequence of claim 10. 13. A micro-bial host eel) comprising the DNA sequence of claim 9. 14. A micro-bial host cell comprising the DNA sequence of claim 10. 15. A pdHL2 expression vector comprising the DNA sequence of claim 9, 16. ApdHL2expression vector comprising the DNA sequence of claim 10 17. A method for expression of a chimeric, humanized or human monoclonal antibody that binds to CD20, ^e antibody having a light chain variable region CDRI comprising a sequence RASSSVSYIH (SEQ ID NO:1); CDR2 comprising a sequence ATSNLAS (SEQ ID NO:4); and CDR3 comprising a sequence QQWTSNPPT (SEQ ID N0:5); and the antibody having a heavy chain variable region CDRI comprising a sequence SYNMH (SEQ ID N0;8); CDR2 comprising a sequence AIYPGNGDTSYNQKFKG (SEQ ID N0:9); and CDR3 comprising a sequence STYYGGDWYFDV (SEQ ID NO: 10) or a sequence WYYSNSYWYFDV (SEQ ID NO: 13), comprising: (a) transfecting a mammalian cell with a DNA sequence as claimed in claim 9; and (b) culturing the cell in a culture medium so that it secretes the antibody or antigen-binding fragment thereof; and (c) recovering the secreted antibody or antigen-binding fragment thereof from the culture medium after removal of the cells,. 18. A method for expression of a fusion protein comprising at least one chimeric, humanized or human monoclonal antibody that binds to CD20, the antibody having a light chain variable region CDRI comprising a sequence RASSSVSYIH {SEQ ID N0:1); CDR2 comprising a sequence ATSNLAS (SEQ ID N0:4); and CDR3 comprising a sequence QQWTSNPPT (SEQ ID N0:5); and the antibody having a heavy chain variable region CDRI comprising a sequence SYNMH (SEQ ID N0;8); CDR2 comprising a sequence AIYPGNGDTSYNQKFKG (SEQ ID N0:9); and CDR3 comprising a sequence STYYGGDWYFDV (SEQ ID NO:10) or a sequence WYYSNSYWYFDV (SEQ ID NO: 13), comprising: (a) transfecting a mammalian cell with a DNA sequence as claimed in claim 10; and De Penning & De Penning Page 11 (b) culturing the cell in a culture medium so that it secretes the antibody or antigen-binding fragment thereof; and (c) recovering the secreted antibody or antigen-binding fragment thereof from the cuKure medium after removal of the cells. 19, A therapeutic composition comprising an antitiody as claimed in claim 1 in combination with a pharmaceutically acceptable carrier. 20, The "fhefapeutic composition according to claim 19, wherein the pharmaceutically acceptable carrier is suitable for parenteral administration of the antibody. 21, The 'therapeutic composition according to claim 20, wherein the pharmaceutically acceptable carrier is suitable for intravenous administration of the antibody. 22, The therapeutic composition according to claim 20, wherein the phamnaceutically acceptable earner is suitable for subcutaneous administration of the antibody, 23, The. therapeutic composition according to claim 20, comprising a dose of about 1-20 mg/kg of the antibody. 24, The therapeutic composition accoreJing to claim 20, wherein the dose is about 1 mg/kg. 25, A humanized antibody or antigen-binding antibody fragment thereof that binds CD20 comprising hA20Vk {residues 20-125 of SEQ iO NO: 46) and hA20VH1 (SEQ (D NO: 41}. 26, A humanized antibody or antigen-binding antibody fragment thereof that binds CD20 comprising hA20Vk (residues 20-125 of SEQ ID NO: 46) and hA20VH2 (SEQ ID NO: 42), 27, The humanized antibody and antigen-binding fragments of claim 25, wherein the antigen-binding fragments are selected from the group consisting of F(ab')2, Fab', Fab, Fv and sFv. 28, The humanized antibody and antigen-binding fragments of claim 26, wherein the antigen-binding fragments are selected from the group consisting of F(ab')2, Fab', Fab, Fv and sFv, 29, An isolated DNA sequence comprising a nucleic acid encoding hA20Vk (residues 20-125 of SEQ ID NO: 46) and hA20VH1 (SEQ ID NO: 41). 30, An expression vector comprising the DNA sequence of claim 29. 31. An isolated micro-blal host cell comprising the DNA sequence of calin^ 29. 32. A method for expression of an antibody or antigen-binding fragment thereof comprising hA20Vk {residues 20-125 of SEQ ID NO: 46) and hA20VH1 (SEQ ID NO: 41), comprising: (a) transfecting a mammalian cell with a DNA sequence comprising a nucleic acid that encodes hA20Vk (residues 20-125 of SEQ ID NO: 46) and hA20VH1 (SEQ ID NO: 41); and (b) culturing the cell in a culture medium so that it secretes the antibody or antigen-binding fragment thereof; and (c) recovering the secreted antibody or antigen-binding fragment thereof from the culture medium after removal of the cells. 33. An isolated DNA sequence comprising a nucleic acid encoding hA20Vk {residues 20-125 of SEQ ID NO: 46) and hA20VH2 (SEQ ID NO; 42). 34. An expression vector comprising the DNA sequence of claim 33. 35. An isolated host cell comprising the DNA sequence of claim 33. 36. A method for expression of an antibody or antigen-binding fragment thereof comprising hA20Vk (residues 20-125 of SEQ ID NO: 46) and hA20VH2 (SEQ ID NO: 42). comprising: (a) transfecting a mammalian cell with a DNA sequence comprising a nucleic acid that encodes hA20Vk (residues 20-125 of SEQ ID NO: 46) and hA20VH2 (SEQ ID NO: 42); and (b) culturing the cell in a culture medium so that it secretes the antibody or antigen-binding fragment thereof; and (c) recovering the secreted antibody or antigen-binding fragment thereof from the culture medium after removal of the cells. 37. A therapeutic composition comprising an antibody or an antigen-binding fragment thereof as claimed in claim 25 in combination with a pharmaceutically acceptable carrier. 38. A therapeutic composition comprising an antibody or an antigen-binding fragment thereof as claimed in claim 26 in combination with a pharmaceutically acceptable carrier 39. The therapeutic composition according to claim 37 or 38, wherein the pharmaceutically acceptable carrier is suitable for parenteral administration of the antibody. 40. The "fherapeutic composition according to claim 37 or 38, wherein the pharmaceutically acceptable carrier is suitable for intravenous administration of the antibody. 41. The therapeutic composition according to claim 37 or 38, wherein the pharmaceutically acceptable carrier is suitable for subcutaneous administration of the antibody. 42. The .'therapeutic composition according to claim 37 or 38, comprising a dose of about 1-20 mg/kg of the antibody. 43. The Uierapeutic composition according to claim 37 or 38, wherein ttie dose is about 1 mg/kg. 44. An immunoconjugate comprising an antibody according to any of claims 1, 25 or 26 which is conjugated to a therapeutic agent or immunomodulator. 45. The immunoconjugate according to claim 46, wherein the antibody is conjugated to a therapeutic radionuclide. 46. The immunoconjugate according to claim 46. wherein the therapeutic agent is conjugated loan immunomodulator. 47. The Immunoconjugate according to claim 46, wherein the therapeutic agent is conjugated to a cytotoxic drug. |
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2017-chenp-2004 assignment.pdf
2017-chenp-2004 correspondence-others.pdf
2017-chenp-2004 correspondence-po.pdf
2017-chenp-2004 description (complete).pdf
2017-chenp-2004 pct search report.pdf
| Patent Number | 223247 | ||||||||||||
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| Indian Patent Application Number | 2017/CHENP/2004 | ||||||||||||
| PG Journal Number | 47/2008 | ||||||||||||
| Publication Date | 21-Nov-2008 | ||||||||||||
| Grant Date | 09-Sep-2008 | ||||||||||||
| Date of Filing | 09-Sep-2004 | ||||||||||||
| Name of Patentee | IMMUNOMEDICS, INC | ||||||||||||
| Applicant Address | 300 AMERICAN ROAD, MORRIS PLAINS, NJ 07950, | ||||||||||||
Inventors:
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| PCT International Classification Number | C07K16/28 | ||||||||||||
| PCT International Application Number | PCT/GB03/00665 | ||||||||||||
| PCT International Filing date | 2003-02-14 | ||||||||||||
PCT Conventions:
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