Methods of treating autoimmune diseases by administering bispecific CD20xcd3 antibodies

Abstract

The present disclosure provides methods of treating an autoimmune disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a bispecific CD20xCD3 antibody comprising a first antigen-binding arm that specifically binds CD20 and a second antigen-binding arm that specifically binds CDS (e.g., odronextamab or a bioequivalent thereof). In some embodiments, the disclosed methods treat both an autoimmune disorder (e.g., aHUS) and a B-cell cancer (e.g., lymphoma).

Description

Docket No. 179227.05202METHODS OF TREATING AUTOIMMUNE DISEASES BY ADMINISTERING BISPECIFIC CD20xCD3 ANTIBODIESFIELD

[0001] The present disclosure relates to methods of treating an autoimmune disease by administering to the subject a therapeutically effective amount of a bispecific antibody (e.g., odronextamab) that binds to CD20 and CD3.SEQUENCE LISTING

[0002] The sequence listing of the present application is submitted electronically in XML format with a file name of “SeqList11987,” a creation date of December 17, 2025, and a size of 15,466 bytes. The submitted sequence listing is part of the specification and is hereby incorporated by reference in its entirety.BACKGROUND

[0003] Autoimmune diseases include a myriad of heterogenous conditions in which a subject’s immune system attacks the subject’s healthy cells, tissues, and / or organs. B cells contribute to autoimmune disease pathogenesis in multiple ways, including by producing autoantibodies, serving as antigen-presenting cells, and producing cytokines. Current strategies for treating autoimmune diseases include use of corticosteroids, immunosuppressive agents, and B cell-targeting agents. Such strategies often have limited potency and / or persistence, are not suitable for chronic use, or both. Thus, effective therapies for subjects with autoimmune diseases are needed.

[0004] B-cell cancers are a group of heterogeneous cancers of the white blood cells known as B-lymphocytes and include leukemias (located in the blood) and lymphomas (located in the lymph nodes). B-cell lymphomas include, but are not limited to, non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL). Lymphomas are divided into indolent (slow- growing) or aggressive lymphomas. A common indolent lymphoma is follicular lymphoma, while the most common aggressive lymphoma is diffuse large B-cell lymphoma. B-cell leukemias include, but are not limited to, acute lymphoblastic leukemia, hairy cell leukemia, and B-cell chronic lymphocytic leukemia.

[0005] Most B-cell cancers express CD20. Methods for treating cancer by targeting CD20 are known in the art. For example, the chimeric anti-CD20 monoclonal antibody rituximab has been used or suggested for use in treating cancers such as NHL, chronic lymphocyticDocket No. 179227.05202leukemia (CLL), and small lymphocytic lymphoma (SLL), as monotherapy or more typically in combination with chemotherapy. Although anti-CD20 tumor-targeting strategies have shown great promise in clinical settings, not all patients respond to anti-CD20 therapy, and some patients have been shown to develop resistance to or exhibit incomplete responses to anti-CD20 therapy (e.g., partial depletion of peripheral B-cells), for reasons that are not well understood (but which typically do not include loss of CD20 expression). Some patients relapse with a more aggressive phenotype or chemotherapy-resistant disease. Many patients with aggressive lymphomas have poor prognosis and less than 50% chance of relapse-free survival. The prognosis for patients who relapse or are refractory to therapy remains dismal with median survival after salvage therapy of 2 to 8 months. In addition, high-dose chemotherapy leads to severe adverse side effects. Thus, there is a high unmet need for therapies that are effective in preventing relapse and have less side effects for patients with B-cell cancers.

[0006] Activation of T cells naturally occurs through their T cell receptors (TCR) in complex with CD3 subunits (CD3y£-CD3b£-CD3^) by ligation to cognate peptides displayed on major-histocompatibility complex (MHC) molecules on antigen-presenting cells (APC). Antibodies against CD3 have been shown to cluster CD3 on T cells, thereby causing T cell activation in a manner similar to the engagement of the TCR by peptide-loaded MHC molecules. Bispecific monoclonal antibodies designed to target both CD20 and CD3 bridge CD20-expressing cells with cytotoxic T cells, resulting in CD20-directed polyclonal T cell killing.SUMMARY

[0007] In one aspect, the disclosed technology relates to a method of treating an autoimmune disease in a subject in need thereof, including administering to the subject one or more doses of a therapeutically effective amount of a bispecific CD20xCD3 antibody including a first antigen-binding arm that specifically binds CD20 and a second antigen-binding arm that specifically binds CD3. In some embodiments, the autoimmune disease is alopecia areata, autoimmune hepatitis, autoimmune pancreatitis, autoimmune thrombocytopenic purpura, autoimmune urticaria, celiac disease, Crohn's disease, diabetes type I, eosinophilic enterogastritis, eosinophilic fasciitis, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hemolytic anemia, inflammatory bowel disease, inflammatory myopathies, multiple sclerosis, myasthenia gravis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatic fever, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erthyematosus, ulcerative colitis, vasculitis, vitiligo, or Wegener's granulomatosis.

[0008] In some embodiments, the autoimmune disease is a C5-associated disease orDocket No. 179227.05202disorder. In some embodiments, the C5-associated disease or disorder is acute respiratory distress syndrome, adult respiratory distress syndrome, age-related macular degeneration, allergy, Alport’s syndrome, Alzheimer’s disease, asthma, atherosclerosis, atypical hemolytic uremic syndrome (aHUS), complement activation caused by balloon angioplasty, bronchoconstriction, bullous pemphigoid, a burn, C3 glomerulopathy, capillary leak syndrome, a chemical injury, chronic obstructive pulmonary disease, Crohn's disease, diabetes, diabetic macular edema, diabetic nephropathy, diabetic retinopathy, dyspnea, emphysema, epilepsy, fibrogenic dust diseases, frostbite, geographic atrophy, glomerulopathy, Goodpasture's Syndrome, Guillain-Barre Syndrome, a hemodialysis complication, hemolytic anemia, hemoptysis, hereditary angioedema, hyperacute allograft rejection, hypersensitivity pneumonitis, an immune complex disorder, immune complex-associated inflammation, an inflammatory disorder, inherited CD59 deficiency, an injury due to inert dusts and / or minerals, interleukin-2 induced toxicity during IL-2 therapy, lupus nephritis, membranoproliferative glomerulonephritis, membranoproliferative nephritis, mesenteric artery reperfusion after aortic reconstruction, mesenteric artery reperfusion after infectious disease, mesenteric artery reperfusion after sepsis, multiple sclerosis, myasthenia gravis, myocardial infarction, neuromyelitis optica, neuromyelitis optica, obesity, ocular angiogenesis, an organic dust disease, a parasitic disease, Parkinson's disease, paroxysmal nocturnal hemoglobinuria, pneumonia, a post-ischemic reperfusion condition, post-pump syndrome in cardiopulmonary bypass or renal bypass, progressive kidney failure, a proteinuric kidney disease, psoriasis, a pulmonary embolism, a pulmonary infarct, pulmonary fibrosis, pulmonary vasculitis, renal ischemia, a renal ischemia-reperfusion injury, a renal transplant, rheumatoid arthritis, schizophrenia, a smoke injury, stroke, systemic lupus erythematosus, systemic lupus erythematosus nephritis, a thermal injury, a traumatic brain injury, uveitis, vasculitis, or xenograft rejection. In some embodiments, the C5-associated disease or disorder is aHUS.

[0009] In some embodiments, the subject is being treated for the autoimmune disease. In some embodiments, the subject is being treated with a C5 inhibitor. In some embodiments, the subject has a comorbidity.

[0010] In some embodiments, the subject has a cancer selected from the group consisting of anal cancer, angiosarcoma, basal cell carcinoma, bladder cancer, bone cancer, brain cancer, breast cancer, a B cell cancer, cervical cancer, cholangiocarcinoma, chondrosarcoma, colon cancer, colorectal cancer, cutaneous squamous cell carcinoma, endometrial cancer, esophageal cancer, glioblastoma multiforme, head & neck squamous cell cancer, hepatocellular carcinoma, kidney cancer, leukemia, liver cancer, lung cancer,Docket No. 179227.05202lymphoma, melanoma, Merkel cell carcinoma, myeloma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, salivary gland cancer, skin cancer, soft tissue sarcoma, stomach cancer, testicular cancer, and uterine cancer.

[0011] In some embodiments, the subject has a B-cell cancer. In some embodiments, the subject has acute lymphoblastic leukemia, Burkitt lymphoma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin lymphoma, lymphoblastic lymphoma, mantle cell lymphoma, marginal zone lymphoma (MZL), non-Hodgkin lymphoma, primary mediastinal B-cell lymphoma, small lymphocytic lymphoma, or Waldenstrom macroglobulinemia. In some embodiments, the subject has MZL.

[0012] In some embodiments, the subject has elevated levels of an autoantibody. In some embodiments, the autoantibody inhibits C5 activity. In some embodiments, the autoantibody inhibits factor H activity. In some embodiments, the autoantibody specifically binds factor H. In some embodiments, the autoantibody binds SCR domain 19 of factor H. In some embodiments, the subject has elevated levels of total IgM class antibodies.

[0013] In some embodiments, the bispecific antibody is administered to the subject in one or more doses of about 0.1 mg / kg to about 15 mg / kg of body weight of the subject. In some embodiments, the bispecific antibody is administered to the subject in one or more doses of about 1 mg to about 800 mg. In some embodiments, the bispecific antibody is administered to the subject once a day, once every two days, once every three days, once every five days, once every week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, each dose of the one or more doses of the bispecific antibody is administered 0.5 to 12 weeks after the immediately preceding dose. In some embodiments, at least one of the one or more doses of the bispecific antibody includes a dose having a greater amount of the bispecific antibody than the immediately preceding dose thereof. In some embodiments, at least one of the one or more doses of the bispecific antibody is administered in two or more split doses. In some embodiments, at least one of the two or more split doses includes the identical amount of the bispecific antibody. In some embodiments, at least one of the two or more split doses is administered at least about 0.5 days after the immediately preceding dose. In some embodiments, at least one of the two or more split doses is administered about 1 day after the immediately preceding dose. In some embodiments, the bispecific antibody is administered intravenously, subcutaneously, or intraperitoneally.

[0014] In some embodiments, the subject has received one or more prior anti-autoimmune disease therapy. In some embodiments, the subject is relapsed after and / or refractory to treatment with one or more anti-autoimmune disease therapy. In someDocket No. 179227.05202embodiments, administration of the bispecific antibody leads to stable reduction of anti-factor H autoantibodies.

[0015] In some embodiments, the administration of the bispecific antibody leads to discontinuation of a complement inhibition therapy. In some embodiments, the complement inhibition therapy includes an anti-C5 antibody. In some embodiments, the autoimmune disease is aHUS, and administration of the bispecific antibody leads to discontinuing the complement inhibition therapy; wherein no relapse of aHUS occurs for at least 4 months subsequent to discontinuation of the complement inhibition therapy.

[0016] In some embodiments, administration of the bispecific antibody leads to one or more of (a) reduction in hemolytic or microangiopathic anemia; (b) reduction of formation of abnormal blood clots; (c) reduction in the likelihood of stroke and / or heart attack, and (d) prevention or delay of permanent renal damage. In some embodiments, the autoimmune disease is aHUS, and administration of the bispecific antibody leads to reduction of one or more of abdominal pain, confusion, diarrhea, edema, fatigue, hemolysis, microangiopathic anemia, nausea / vomiting, systemic thrombotic microangiopathy, and platelet activation. In some embodiments, the subject has lymphoma and administration of the bispecific antibody leads to tumor regression, complete response, or partial response.

[0017] In some embodiments, the first antigen-binding arm of the bispecific antibody includes three heavy chain CDRs (A-HCDR1, A-HCDR2, and A-HCDR3) and three light chain CDRs (LCDR1, LCDR2, and LCDR3), and wherein A-HCDR1 comprises the amino acid sequence of SEQ ID NO: 4; A-HCDR2 comprises the amino acid sequence of SEQ ID NO: 5; A-HCDR3 comprises the amino acid sequence of SEQ ID NO: 6; LCDR1 comprises the amino acid sequence of SEQ ID NO: 7; LCDR2 comprises the amino acid sequence of SEQ ID NO: 8; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 9. In some embodiments, the first antigen-binding arm of the bispecific antibody includes a heavy chain variable region (A-HCVR) having the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 2.

[0018] In some embodiments, the second antigen-binding arm of the bispecific antibody includes three heavy chain CDRs (B-HCDR1, B-HCDR2, and B-HCDR3) and three light chain CDRs (LCDR1, LCDR2, and LCDR3), and wherein B-HCDR1 comprises the amino acid sequence of SEQ ID NO: 10; B-HCDR2 comprises the amino acid sequence of SEQ ID NO: 11; B-HCDR3 comprises the amino acid sequence of SEQ ID NO: 12; LCDR1 comprises the amino acid sequence of SEQ ID NO: 7; LCDR2 comprises the amino acid sequence of SEQ ID NO: 8; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 9. In someDocket No. 179227.05202embodiments, the second antigen-binding arm of the bispecific antibody includes a heavy chain variable region (B-HCVR) having the amino acid sequence of SEQ ID NO: 3 and a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 2.

[0019] In some embodiments, the bispecific antibody includes a first heavy chain including the HCVR of the first antigen-binding domain, a second heavy chain including the HCVR of the second antigen-binding domain, and a common light chain including the LCVR of the first and second antigen-binding domains, wherein the first heavy chain includes the amino acid sequence of SEQ ID NO: 13. In some embodiments, the bispecific antibody includes a first heavy chain including the HCVR of the first antigen-binding domain, a second heavy chain including the HCVR of the second antigen-binding domain, and a common light chain including the LCVR of the first and second antigen-binding domains, wherein the second heavy chain includes the amino acid sequence of SEQ ID NO: 15.

[0020] In some embodiments, the bispecific antibody includes a first heavy chain including the HCVR of the first antigen-binding domain, a second heavy chain including the HCVR of the second antigen-binding domain, and a common light chain including the LCVR of the first and second antigen-binding domains, wherein the light chain includes the amino acid sequence of SEQ ID NO: 14. In some embodiments, the bispecific antibody is odronextamab. In some embodiments, the bispecific antibody is odronextamab, mosunetuzumab, glofitamab, epcoritamab, plamotamab, EX103, or FBTA05.

[0021] In another aspect, the disclosed technology relates to a kit including a bispecific CD20xCD3 antibody including a first antigen-binding arm that specifically binds CD20 and a second antigen-binding arm that specifically binds CD3, in combination with written instructions for use of a therapeutically effective amount of the bispecific antibody for treating an autoimmune disease in a subject in need thereof.

[0022] In another aspect, the disclosed technology relates to a bispecific CD20xCD3 antibody including a first antigen-binding arm that specifically binds CD20 and a second antigen-binding arm that specifically binds CD3 for use in a method of treating an autoimmune disease in a subject in need thereof.

[0023] Other embodiments of the present disclosure will become apparent from the detailed description below.Docket No. 179227.05202BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figures 1A and 1B relate to Example 1 and are graphs showing the efficacy of odronextamab in treating marginal zone lymphoma (MZL) and lowering total IgM and specific IgM autoantibodies to complement factor H in a patient with MZL. Figure 1A shows a time course of the concentration in patient’s serum of total IgM. Figure 1B shows a time course of the concentration in patient’s serum of anti-factor H IgM. Ibrutinib therapy was administered for 14 months, and odronextamab therapy was started the following month thereafter. Total IgM normal range: 40-230 mg / dL. Anti-factor H IgM normal range: 0-10.3 AU / mL.DETAILED DESCRIPTION

[0025] It is to be understood that the present disclosure is not limited to the particular methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, and that the scope of the present disclosure will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, preferred methods and materials are now described. All publications mentioned herein are hereby incorporated by reference in their entirety unless otherwise stated.Methods of Treatment

[0026] The present disclosure includes methods for treating an autoimmune disease or disorder by administering to a subject in need thereof a bispecific CD20xCD3 antibody.

[0027] As used herein, an “autoimmune disease” refers to a disease, disorder or condition in which a subject’s immune system mistakenly attacks its own healthy cells, tissues, and organs. In some embodiments, the an autoimmune disease is alopecia areata, autoimmune hepatitis, autoimmune pancreatitis, autoimmune thrombocytopenic purpura, autoimmune urticaria, celiac disease, Crohn's disease, diabetes type I, eosinophilic enterogastritis, eosinophilic fasciitis, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hemolytic anemia, inflammatory bowel disease, inflammatory myopathies, multiple sclerosis, myasthenia gravis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatic fever, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erthyematosus, ulcerative colitis, vasculitis, vitiligo, or Wegener's granulomatosis.Docket No. 179227.05202

[0028] In some embodiments, the autoimmune disease is a C5-associated disease or disorder, such as acute respiratory distress syndrome; adult respiratory distress syndrome; age-related macular degeneration; allergy; Alport’s syndrome; Alzheimer’s disease; asthma; atherosclerosis; atypical hemolytic uremic syndrome (aHUS); complement activation caused by balloon angioplasty; bronchoconstriction; bullous pemphigoid; a burn; C3 glomerulopathy; capillary leak syndrome; a chemical injury; chronic obstructive pulmonary disease; Crohn's disease; diabetes; diabetic macular edema; diabetic nephropathy; diabetic retinopathy; dyspnea; emphysema; epilepsy; fibrogenic dust diseases; frostbite; geographic atrophy; glomerulopathy; Goodpasture's Syndrome; Guillain-Barre Syndrome; a hemodialysis complication; hemolytic anemia; hemoptysis; hereditary angioedema; hyperacute allograft rejection; hypersensitivity pneumonitis; an immune complex disorder; immune complex-associated inflammation; an inflammatory disorder; inherited CD59 deficiency; an injury due to inert dusts and / or minerals; interleukin-2 induced toxicity during IL-2 therapy; lupus nephritis; membranoproliferative glomerulonephritis; membranoproliferative nephritis; mesenteric artery reperfusion after aortic reconstruction; mesenteric artery reperfusion after infectious disease; mesenteric artery reperfusion after sepsis; multiple sclerosis; myasthenia gravis; myocardial infarction; neuromyelitis optica; neuromyelitis optica; obesity; ocular angiogenesis; an organic dust disease; a parasitic disease; Parkinson's disease; paroxysmal nocturnal hemoglobinuria; pneumonia; a post-ischemic reperfusion condition; post-pump syndrome in cardiopulmonary bypass or renal bypass; progressive kidney failure; a proteinuric kidney disease; psoriasis; a pulmonary embolism, a pulmonary infarct; pulmonary fibrosis; pulmonary vasculitis; renal ischemia; a renal ischemia-reperfusion injury; a renal transplant; rheumatoid arthritis; schizophrenia; a smoke injury; stroke; systemic lupus erythematosus; systemic lupus erythematosus nephritis; a thermal injury; a traumatic brain injury; uveitis; vasculitis; or xenograft rejection.

[0029] As used herein, the terms “treating”, “treat”, or the like, mean to alleviate or reduce the severity of at least one symptom or indication, or to eliminate the causation of symptoms either on a temporary or permanent basis, of an autoimmune disease or other disease or condition disclosed herein.

[0030] In some embodiments, effective treatment of a subject further includes treating or preventing a symptom or indication of a C5-associated disease or disorder, such as atypical hemolytic uremic syndrome (aHUS). Symptoms and indications of aHUS include, but are not limited to, one or more of: abdominal pain, confusion, diarrhea, edema, fatigue,Docket No. 179227.05202hemolysis, microangiopathic anemia, nausea / vomiting, systemic thrombotic microangiopathy (formation of blood clots in small blood vessels throughout the body), and platelet activation.

[0031] As used herein, the expression “a subject in need thereof’ means a human or non-human mammal that exhibits one or more symptoms or indications of an autoimmune disease or other disease or condition disclosed herein, and / or who has been diagnosed with an autoimmune disease or other disease or condition disclosed herein, and who needs treatment for the same. As used herein, the term “subject” is interchangeable with the term “patient.”

[0032] In some embodiments, “a subject in need thereof’ may be diagnosed with a primary or a metastatic tumor and / or with one or more symptoms or indications including, but not limited to, enlarged lymph node(s), swollen abdomen, chest pain / pressure, unexplained weight loss, fever, night sweats, persistent fatigue, loss of appetite, enlargement of spleen, itching.

[0033] In some embodiments, the expression includes a subject with a solid tumor. As used herein, the term “solid tumor” refers to an abnormal mass of tissue that usually does not contain cysts or liquid areas. Solid tumors may be benign (not cancer) or malignant (cancer). For the purposes of the present disclosure, the term “solid tumor” means malignant solid tumors. The term includes different types of solid tumors named for the cell types that form them, e.g. sarcomas, carcinomas and blastomas. In certain embodiments, the methods of the present disclosure are used for treating a subject with heme tumors. As used herein, the term “heme tumor” refers to cancers affecting blood cells (e.g., B cells or T cells) and includes leukemias, lymphomas and multiple myeloma. Examples of heme tumor include Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, and multiple myeloma.

[0034] In some embodiments, the cancer is anal cancer, angiosarcoma, basal cell carcinoma, bladder cancer, bone cancer, brain cancer, breast cancer, a B cell cancer, cervical cancer, cholangiocarcinoma, chondrosarcoma, colon cancer, colorectal cancer, cutaneous squamous cell carcinoma, endometrial cancer, esophageal cancer, glioblastoma multiforme, head & neck squamous cell cancer, hepatocellular carcinoma, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell carcinoma, myeloma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, salivary gland cancer, skin cancer, soft tissue sarcoma, stomach cancer, testicular cancer, uterine cancer.

[0035] In some embodiments, the expression “a subject in need thereof” includes subjects with primary or established B-cell tumors. In specific embodiments, the expressionDocket No. 179227.05202includes human subjects that have and need treatment for a B-cell malignancy, e.g., acute lymphoblastic leukemia, Burkitt lymphoma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, Hodgkin lymphoma, lymphoblastic lymphoma, lymphomatoid granulomatosis, lymphoplasmacytoid lymphoma, mantle cell lymphoma, marginal zone lymphoma, non-Hodgkin lymphoma, primary mediastinal B-cell lymphoma, small lymphocytic lymphoma, Waldenstrom macroglobulinemia. In a further embodiment, the expression includes persons with a pathologic subtype of a B-cell cancer. In other specific embodiments, the expression includes subjects with CD20+ tumors (e.g., a tumor with CD20 expression as determined by flow cytometry on = 20% of leukemic lymphoblasts). In certain embodiments, the expression “a subject in need thereof” includes patients with a B-cell cancer that is resistant to or refractory to or is inadequately controlled by prior therapy.

[0036] In some embodiments, the subject to be treated by the disclosed methods has received prior therapy comprising anti-autoimmune disease therapy. Non-limiting examples of prior anti-autoimmune disease therapy may include treatment with one or more of the following therapeutic agents: abatacept, azathioprine, belimumab, baricitinib, a C5 inhibitor (e.g., eculizumab), colchicine, cyclosporine, dapsone, hydroxychloroquine, an IL-1 inhibitor (e.g., anakinra, canakinumab, rilonacept), an IL-4 inhibitor (dupilumab), an IL-5 inhibitor (benralizumab, mepolizumab, reslizumab), an IL-6 inhibitor (e.g., sarilumab, tocilizumab), an IL-12 inhibitor (ustekinumab), an IL-17 inhibitor (secukinumab, ixekizumab, brodalumab) an IL-23 inhibitor (guselkumab), methotrexate, mycophenolate, omalizumab, rituximab, a steroid (e.g., dexamethasone, methylprednisolone, prednisone), sulfasalazine, a TNF inhibitor (e.g., adalimumab, certolizumab, golimumab, etanercept, infliximab), tofacitinib, upadacitinib, and vedolizumab.

[0037] In some embodiments, the methods of the present disclosure are used for treating a subject with a liquid tumor. As used herein, the term “liquid tumor” refers to cancerous cells present in body fluids or soft tissue, such as blood or bone marrow. The expression “liquid tumor” includes cancers arising from connective or supporting tissue (e.g., bone or muscle) (referred to as sarcomas), cancers arising from the body’s glandular cells and epithelial cells which line body tissues (referred to as carcinomas), and cancers of the lymphoid organs such as lymph nodes, spleen and thymus (referred to as lymphomas). Lymphoid cells occur in almost all tissues of the body and therefore, lymphomas may develop in a wide variety of organs. In some embodiments, the disclosed methods are used for treating a subject with a liquid tumor comprising a lymphoma or leukemia.Docket No. 179227.05202

[0038] In some embodiments, the methods of the present disclosure are used for treating a subject with a B-cell cancer. In some embodiments, the B-cell cancer is selected from Hodgkin's lymphoma, non-Hodgkin's lymphoma, follicular lymphoma, small lymphocytic lymphoma, lymphoplasmacytoid lymphoma, marginal zone lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, B-cell lymphomas, lymphomatoid granulomatosis, Burkitt's lymphoma, acute lymphoblastic leukemia, hairy cell leukemia, and B-cell chronic lymphocytic leukemia.

[0039] In certain embodiments, the disclosed methods include administering a therapeutically effective amount of a bispecific CD20xCD3 antibody (e.g., odronextamab or a bioequivalent thereof) in combination with an additional therapeutic agent or therapy. In some embodiments, the additional therapeutic agent or therapy may include one or more of radiation, surgery, a chemotherapeutic agent, a cancer vaccine, a PD-1 inhibitor or antagonist antibody, a PD-L1 inhibitor or antagonist antibody, a L G-3 inhibitor or antagonist antibody, a CTLA-4 inhibitor or antagonist antibody, a TIM3 inhibitor or antagonist antibody, a BTLA inhibitor or antagonist antibody, a TIGIT inhibitor or antagonist antibody, a CD47 inhibitor or antagonist antibody, a CD28 activator, a CD38 inhibitor or antagonist antibody, an anti-GITR antibody, an indoleamine-2,3-dioxygenase (IDO) inhibitor or antagonist antibody, a vascular endothelial growth factor (VEGF) antagonist, an angiopoietin-2 (Ang2) inhibitor or antagonist antibody, a transforming growth factor beta (TGF|3) inhibitor or antagonist antibody, an epidermal growth factor receptor (EGFR) inhibitor or antagonist antibody, an antibody to a tumor-specific antigen, Bacillus Calmette-Guerin vaccine, granulocyte-macrophage colony-stimulating factor, a cytotoxin, an interleukin 6 receptor (IL-6R) inhibitor, an interleukin 4 receptor (IL-4R) inhibitor or antagonist antibody, an IL-10 inhibitor or antagonist antibody, IL-2, IL-7, IL-12, IL-21, IL-15, an antibody-drug conjugate, an oncolytic virus, an anti-inflammatory drug, a dietary supplement, and combinations thereof.

[0040] In certain embodiments, administering the bispecific CD20xCD3 antibody to a subject with an autoimmune disorder leads to reduction or reduced incidence of one or more of: platelet activation, hemolysis (rupture or destruction of red blood cells), abdominal pain, confusion, difficulty swallowing, edema, fatigue, hemoglobinuria, hemolytic anemia, nausea / vomiting, diarrhea, microangiopathic anemia, shortness of breath, and heart palpitations.

[0041] In some embodiments, administering the bispecific CD20xCD3 antibody to a subject with an autoimmune disorder leads to reduction or reduced incidence of deep vein thrombosis and / or reduction or reduced incidence of systemic thrombotic microangiopathyDocket No. 179227.05202(formation of blood clots in small blood vessels throughout the body). In some embodiments, administering the bispecific CD20xCD3 antibody to a subject with an autoimmune disorder leads to reduction or reduced incidence of: likelihood of pulmonary embolism, stroke, and / or heart attack. In some embodiments, administering the bispecific CD20xCD3 antibody to a subject with an autoimmune disorder leads to prevention or delay of one of more of kidney failure, end-stage renal disease, and permanent renal damage.

[0042] The present disclosure also includes methods for treating both autoimmune disease and lymphoma by administering to a subject in need thereof a bispecific CD20xCD3 antibody disclosed herein. In some embodiments, the disclosed methods eliminate the need for treatment with a C5 inhibitor. For instance, concurrent treatment with a C5 inhibitor may be discontinued. In some embodiments, the disclosed methods lead to superior control of C5 activity as compared to that achieved with anti-C5 antibody therapy. In some embodiments, the disclosed methods lead to stable reduction of blood concentration of sC5b-9 to within a normal range for at least 4 months (e.g., at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, or longer) subsequent to discontinuation of C5 inhibitor therapy. In some embodiments, the disclosed methods lead to a decrease in total IgM levels relative to total IgM levels prior to administration of the bispecific CD20xCD3 antibody. For instance, total IgM levels may be reduced by 10%, 20%, 30%, 40%, 50%, or more. In some embodiments, the disclosed methods lead to a decrease in autoantibody (e.g., anti-factor H IgM) levels relative to autoantibody (e.g., anti-factor H IgM) levels prior to administration of the bispecific CD20xCD3 antibody. For instance, such autoantibody levels may be reduced by 10%, 20%, 30%, 40%, 50%, or more. In some embodiments, the disclosed methods lead to complete clearance of autoantibodies (e.g., anti-factor H IgM autoantibodies). For instance, complete clearance may be achieved within 6 months of start of treatment - e.g., within 6 months, within 5 months, within 4 months, within 3 months, or within 2 months.Bispecific CD20xCD3 Antibodies

[0043] The disclosed methods comprise administering a therapeutically effective amount of a bispecific antibody that specifically binds CD3 and CD20. Such antibodies may be referred to herein as, e.g., “CD20xCD3,” or “anti-CD20 x anti-CD3”, or “anti-CD20 / anti-CD3,” or “CD20 / CD30,” bispecific antibodies, or other similar terminology.

[0044] As used herein, the expression “bispecific antibody” refers to an immunoglobulin protein comprising at least a first antigen-binding domain and a second antigenbinding domain, which includes a bispecific antibody or antigen-binding fragment thereof. In theDocket No. 179227.05202context of the present disclosure, the first antigen-binding domain specifically binds a first antigen (e.g., CD20), and the second antigen-binding domain specifically binds a second, distinct antigen (e.g., CD3). Each antigen-binding domain of a bispecific antibody comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), each comprising three CDRs. In the context of a bispecific antibody, the CDRs of the first antigen-binding domain may be designated with the prefix “A” and the CDRs of the second antigen-binding domain may be designated with the prefix “B.” Thus, the CDRs of the first antigen-binding domain may be referred to herein as A-HCDR1, A-HCDR2, and A-HCDR3; and the CDRs of the second antigen-binding domain may be referred to herein as B-HCDR1, B-HCDR2, and B-HCDR3.

[0045] The first antigen-binding domain and the second antigen-binding domain are each connected to a separate multimerizing domain. As used herein, a “multimerizing domain” is any macromolecule, protein, polypeptide, peptide, or amino acid that has the ability to associate with a second multimerizing domain of the same or similar structure or constitution. In the context of the present disclosure, the multimerizing component is an Fc portion of an immunoglobulin (comprising a CH2-CH3 domain), e.g., an Fc domain of an IgG selected from the isotypes lgG1, lgG2, lgG3, and lgG4, as well as any allotype within each isotype group.

[0046] Bispecific antibodies of the present disclosure typically comprise two multimerizing domains, e.g., two Fc domains that are each individually part of a separate antibody heavy chain. The first and second multimerizing domains may be of the same IgG isotype, e.g., lgG1 / lgG1, lgG2 / lgG2, lgG4 / lgG4. Alternatively, the first and second multimerizing domains may be of different IgG isotypes such as, e.g., lgG1 / lgG2, lgG1 / lgG4, lgG2 / lgG4, etc.

[0047] Any bispecific antibody format or technology may be used to make the bispecific antigen-binding molecules of the present disclosure. For example, an antibody or fragment thereof having a first antigen-binding specificity can be functionally linked (e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody or antibody fragment having a second antigenbinding specificity to produce a bispecific antigen-binding molecule. Specific exemplary bispecific formats that can be used in the context of the present disclosure include, without limitation: scFv-based or diabody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-lg, Quadroma, knobs-into-holes, common light chain (e.g., common light chain with knobs-into-holes, etc.), CrossMab, CrossFab, (SEED)body, leucine zipper, Duobody, lgG1 / lgG2, dual-acting Fab (DAF)-lgG, and Mab2bispecific formats (see, e.g., Klein et al. 2012, mAbs 4:6, 1-11, and references cited therein, for a review of the foregoing formats).Docket No. 179227.05202

[0048] In the context of bispecific antibodies of the present disclosure, Fc domains may comprise one or more amino acid changes (e.g., insertions, deletions, or substitutions) as compared to the wild-type, naturally occurring version of the Fc domain. For example, the present disclosure includes bispecific antigen-binding molecules comprising one or more modifications in the Fc domain that results in a modified Fc domain having a modified binding interaction (e.g., enhanced or diminished) between Fc and FcRn. In one embodiment, the bispecific antigen-binding molecule comprises a modification in a CH2 or a CH3 region, wherein the modification increases the affinity of the Fc domain to FcRn in an acidic environment (e.g., in an endosome where pH ranges from about 5.5 to about 6.0). Non-limiting examples of such Fc modifications are disclosed in US20150266966, incorporated herein in its entirety.

[0049] The present disclosure also includes bispecific antibodies comprising a first Ig CH3 domain and a second Ig CH3 domain, wherein the first and second Ig CH3 domains differ from one another by at least one amino acid, and wherein at least one amino acid difference reduces binding of the bispecific CD20xCD3 antibody to Protein A as compared to a bispecific antibody lacking the amino acid difference. In one embodiment, the first Ig CH3 domain binds Protein A, and the second Ig CH3 domain contains a mutation that reduces or abolishes Protein A binding such as an H95R modification (by IMGT exon numbering; H435R by EU numbering). The second CH3 may further comprise a Y96F modification (by IMGT; Y436F by EU). Further modifications that may be found within the second CH3 include: D16E, L18M, N44S, K52N, V57M, and V821 (by IMGT; D356E, L358M, N384S, K392N, V397M, and V4221 by EU) in the case of lgG1 antibodies; N44S, K52N, and V821 (IMGT; N384S, K392N, and V4221 by EU) in the case of lgG2 antibodies; and Q15R, N44S, K52N, V57M, R69K, E79Q, and V821 (by IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q, and V4221 by EU) in the case of lgG4 antibodies.

[0050] In certain embodiments, the Fc domain may be chimeric, combining Fc sequences derived from more than one immunoglobulin isotype. For example, a chimeric Fc domain can comprise part or all of a CH2 sequence derived from a human lgG1, human lgG2 or human lgG4 CH2 region, and part or all of a CH3 sequence derived from a human lgG1, human lgG2 or human lgG4. A chimeric Fc domain can also contain a chimeric hinge region. For example, a chimeric hinge may comprise an “upper hinge” sequence, derived from a human lgG1, a human lgG2 or a human lgG4 hinge region, combined with a “lower hinge” sequence, derived from a human lgG1, a human lgG2 or a human lgG4 hinge region. A particular example of a chimeric Fc domain that can be included in any of the antigen-binding molecules set forth herein comprises, from N- to C-terminus: [lgG4 CHl]-[lgG4 upper hinge]-[lgG2 lower hinge]-Docket No. 179227.05202[lgG4 Cn2]-[lgG4 CH3], Another example of a chimeric Fc domain that can be included in any of the antigen-binding molecules set forth herein comprises, from N- to C-terminus: [lgG1 Cm]-[lgG1 upper hinge]-[lgG2 lower hinge]-[lgG4 CH2]-[lgG1 CH3], These and other examples of chimeric Fc domains that can be included in any of the antigen-binding molecules of the present disclosure are described in US20140243504, which is herein incorporated in its entirety. Chimeric Fc domains having these general structural arrangements, and variants thereof, can have altered Fc receptor binding, which in turn affects Fc effector function.

[0051] According to certain exemplary embodiments of the present disclosure, the bispecific CD20xCD3 antibody comprises heavy chain variable regions (A-HCVR and B-HCVR), light chain variable region (LCVR), and / or complementarity determining regions (CDRs) comprising any of the amino acid sequences of the bispecific CD20xCD3 antibodies as set forth in US Patent Publication No. 20150266966. In certain exemplary embodiments, the bispecific CD20xCD3 antibody that can be used in the context of the methods of the present disclosure comprises: (a) a first antigen-binding arm that binds to CD20 comprising the heavy chain complementarity determining regions (A-HCDR1, A-HCDR2, and A-HCDR3) of a heavy chain variable region (A-HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and the light chain complementarity determining regions (LCDRs) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; and (b) a second antigen-binding arm that binds to CD3 comprising the heavy chain CDRs (B-HCDR1, B-HCDR2, and B-HCDR3) of a HCVR (B-HCVR) comprising the amino acid sequence of SEQ ID NO: 3 and the light chain CDRs of a LCVR comprising the amino acid sequence of SEQ ID NO: 2. According to certain embodiments, the A-HCDR1 comprises the amino acid sequence of SEQ ID NO: 4; the A-HCDR2 comprises the amino acid sequence of SEQ ID NO: 5; the A-HCDR3 comprises the amino acid sequence of SEQ ID NO: 6; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 7; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 8; the LCDR3 comprises the amino acid sequence of SEQ ID NO: 9; the B-HCDR1 comprises the amino acid sequence of SEQ ID NO: 10; the B-HCDR2 comprises the amino acid sequence of SEQ ID NO: 11; and the B-HCDR3 comprises the amino acid sequence of SEQ ID NO: 12. In yet other embodiments, the bispecific CD20xCD3 antibody comprises: (a) a first antigen-binding arm comprising a HCVR (A-HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a LCVR comprising the amino acid sequence of SEQ ID NO: 2; and (b) a second antigen-binding arm comprising a HCVR (B-HCVR) comprising the amino acid sequence of SEQ ID NO: 3 and a LCVR comprising the amino acid sequence of SEQ ID NO: 2.Docket No. 179227.05202

[0052] In one embodiment, the bispecific CD20xCD3 antibody comprises a first heavy chain comprising the HCVR of the first antigen-binding domain, a second heavy chain comprising the HCVR of the second antigen-binding domain, and a common light chain comprising the LCVR of the first and second antigen-binding domains, wherein the first heavy chain comprises the amino acid sequence of SEQ ID NO: 13. In one embodiment, the bispecific CD20xCD3 antibody comprises a first heavy chain comprising the HCVR of the first antigenbinding domain, a second heavy chain comprising the HCVR of the second antigen-binding domain, and a common light chain comprising the LCVR of the first and second antigen-binding domains, wherein the second heavy chain comprises the amino acid sequence of SEQ ID NO: 15. In one embodiment, the bispecific CD20xCD3 antibody comprises a first heavy chain comprising the HCVR of the first antigen-binding domain, a second heavy chain comprising the HCVR of the second antigen-binding domain, and a common light chain comprising the LCVR of the first and second antigen-binding domains, wherein the light chain comprises the amino acid sequence of SEQ ID NO: 14. In one embodiment, the bispecific CD20xCD3 antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 13, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 15, and a common light chain comprising the amino acid sequence of SEQ ID NO: 14.

[0053] Other bispecific CD20xCD3 antibodies that can be used in the context of the methods of the present disclosure include mosunetuzumab, glofitamab, epcoritamab, plamotamab, EX103, FBTA05, or e.g., any of the antibodies as set forth in US20140088295 and US20150166661. In some embodiments, the bispecific CD20xCD3 antibody is REGN1979 (also known as odronextamab), as set forth in W02020047389.Pharmaceutical Compositions and Administration

[0054] The present disclosure provides therapeutic pharmaceutical compositions comprising a bispecific CD20xCD3 antibody as disclosed herein. Such pharmaceutical compositions may be formulated with suitable pharmaceutically acceptable carriers, excipients, buffers, and other agents that provide suitable transfer, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTIN™), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixturesDocket No. 179227.05202containing carbowax. See Powell et al., "Compendium of excipients for parenteral formulations" PDA, J Pharm Sci Technol 52:238-311 (1998).

[0055] Various delivery systems are known and can be used to administer the pharmaceutical composition of the present disclosure, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the mutant viruses, receptor-mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol. Chem. 262: 4429-4432). Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents.

[0056] A pharmaceutical composition of the present disclosure can be delivered subcutaneously or intravenously with a standard needle and syringe. In addition, with respect to subcutaneous delivery, a pen delivery device readily has applications in delivering a pharmaceutical composition of the present disclosure. Such a pen delivery device can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical composition within the cartridge has been administered, and the cartridge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device comes prefilled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

[0057] In certain situations, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump may be used. In another embodiment, polymeric materials can be used; see, e.g., Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Fla. In yet another embodiment, a controlled release system can be placed in proximity of the composition's target, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled release systems are discussed in the review by Langer, 1990, Science 249:1527-1533.

[0058] The injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc. These injectableDocket No. 179227.05202preparations may be prepared by known methods. For example, the injectable preparations may be prepared, eg., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections. As the aqueous medium for injections, there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As the oily medium, there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared is preferably filled in an appropriate ampoule.

[0059] Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.Administration Regimens

[0060] The present disclosure includes methods comprising administering to a subject a bispecific CD20xCD3 antibody at a dosing frequency of about four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or less frequently so long as a therapeutic response is achieved. The dose of the bispecific CD20xCD3 antibody may vary depending upon the age and the size of a subject to be administered, target disease, conditions, route of administration, and the like.

[0061] In certain embodiments, each dose of the bispecific CD20xCD3 antibody is administered in more than 1 fractions, e.g., in 2-5 fractions (“split dosing”) within the given dosing period. The bispecific CD20xCD3 antibody may be administered in split doses to reduce or eliminate the cytokine “spikes” induced in response to administration of the antibody. Cytokine spikes refer to the clinical symptoms of the cytokine release syndrome (“cytokine storm”) and infusion related reactions, seen in patients administered anti-CD20 antibodies. In certain embodiments, the methods of the present disclosure comprise administering one or more doses of the bispecific CD20xCD3 antibody to a subject in need thereof, wherein a dose of the bispecific CD20xCD3 antibody is administered as split doses, or in more than 1 fractions, e.g., as 2 fractions, as 3 fractions, as 4 fractions or as 5 fractions within the given dosing period.Docket No. 179227.05202In certain embodiments, a dose of the bispecific CD20xCD3 antibody is split into 2 or more fractions, wherein each fraction comprises an amount of the antibody equal to the other fractions. For example, a dose of bispecific CD20xCD3 antibody comprising 1000 micrograms may be administered once a week, wherein the dose is administered in 2 fractions within the week, each fraction comprising 500 micrograms. In certain embodiments, a dose of the bispecific CD20xCD3 antibody is administered split into 2 or more fractions, wherein the fractions comprise unequal amounts of the antibody, e.g., more than or less than the first fraction. For example, a dose of bispecific CD20xCD3 antibody comprising 1000 micrograms may be administered once a week, wherein the dose is administered in 2 fractions within the week, wherein the first fraction comprises 700 micrograms and the second fraction comprises 300 micrograms. As another example, a dose of bispecific CD20xCD3 antibody comprising 1000 micrograms may be administered once in 2 weeks, wherein the dose is administered in 3 fractions within the 2-week period, wherein the first fraction comprises 400 micrograms, the second fraction comprises 300 micrograms and the third fraction comprises 300 micrograms.

[0062] In certain embodiments, the present disclosure provides a dosing regimen for administering an anti-CD3 x anti-CD20 bispecific antibody to a subject to treat an autoimmune disease or disorder, comprising: (a) administering an initial dose of 0.7 mg of the bispecific antibody to the subject, wherein the initial dose is split into a first dose fraction comprising 0.2 mg of the bispecific antibody and a second dose fraction comprising 0.5 mg of the bispecific antibody, wherein the first dose fraction is administered to the subject followed by the second dose fraction over two days during week 1 of the dosing regimen; (b) administering a first intermediate dose of 4 mg of the bispecific antibody to the subject, wherein the first intermediate dose is split into two equal fractions (a first fraction and a second fraction), each comprising 2 mg of the bispecific antibody, wherein the two fractions of the first intermediate dose are administered over two days during week 2 of the dosing regimen; (c) administering a second intermediate dose of 20 mg of the bispecific antibody to the subject, wherein the second intermediate dose is split into two equal fractions (a first fraction and a second fraction), each comprising 10 mg of the bispecific antibody, wherein the two fractions of the second intermediate dose are administered over two days during week 3 of the dosing regimen; (d) administering a full dose of the bispecific antibody to the subject weekly during from week 4 of the dosing regimen. In certain embodiments, the methods comprise administering a maintenance dose of the bispecific antibody to the subject in subsequent weeks (e.g., week 14 or after) of the dosing regimen. In certain embodiments, the full dose of the bispecific antibody is administered once in 2 weeks, once in 4 weeks or once in eight weeks.Docket No. 179227.05202

[0063] In certain embodiments, multiple doses of a bispecific CD20xCD3 antibody may be administered to a subject over a defined time course. The methods according to this aspect of the present disclosure comprise sequentially administering to a subject one or more doses of a bispecific CD20xCD3 antibody in combination with one or more doses of an additional therapeutic agent, as disclosed herein.Dosage

[0064] The amount of bispecific CD20xCD3 antibody administered to a subject according to the methods of the present disclosure is, generally, a therapeutically effective amount. As used herein, the phrase “therapeutically effective amount” means an amount of bispecific CD20xCD3 antibody that results in one or more of reduction in anemia (e.g., hemolytic or microangiopathic anemia); reduction of the incidence of formation of abnormal blood clots (e.g., systemic thrombotic microangiopathy, deep vein thrombosis, or a pulmonary embolism); reduction in the likelihood of stroke and / or heart attack; prevention or delay of kidney failure, end-stage renal disease, and / or permanent renal damage; and alleviation or reduction of the severity of any autoimmune disease symptom disclosed herein.

[0065] In the disclosed methods, a therapeutically effective amount of the bispecific CD20xCD3 antibody can be from about 0.02 mg to about 1200 mg, such as about 0.1 mg to about 1000 mg, about 0.5 mg to about 900 mg, about 1 mg to about 800 mg, about 0.02 mg, about 0.05 mg, about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 520 mg, about 540 mg, about 560 mg, about 580 mg, about 660 mg, about 680 mg, about 700 mg, about 720 mg, about 740 mg, about 760 mg, about 780 mg, about 800 mg, 820 mg, about 840 mg, about 860 mg, about 880 mg, about 860 mg, about 880 mg, about 900 mg, about 920 mg, about 940 mg, about 960 mg, about 980 mg, about 1000 mg, about 1020 mg, about 1040 mg, about 1060 mg, about 1080 mg, about 1100 mg, about 1120 mg, about 1140 mg, about 1160 mg, about 1180 mg, or about 1200 mg.

[0066] The amount of bispecific CD20xCD3 antibody contained within the individual doses may be expressed in terms of milligrams of antibody per kilogram of subject body weight ( / .e., mg / kg). In certain embodiments, the bispecific CD20xCD3 antibody used in the methods ofDocket No. 179227.05202the present disclosure may be administered to a subject at a dose of about 0.0001 to about 100 mg / kg of subject body weight, such as about 0.001 mg / kg to about 15 mg / kg, about 0.003 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.2 mg / kg to about 3 mg / kg, about 0.005 mg / kg, about 0.01 mg / kg, about 0.15 mg / kg, about 0.2 mg / kg, about 0.25 mg / kg, about 0.3 mg / kg, about 0.35 mg / kg, about 0.4 mg / kg, about 0.45 mg / kg, about 0.5 mg / kg, about 0.55 mg / kg, about 0.6 mg / kg, about 0.65 mg / kg, about 0.7 mg / kg, about 0.75 mg / kg, about 0.8 mg / kg, about 0.85 mg / kg, about 0.9 mg / kg, about 0.95 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, or about 15 mg / kg.EXAMPLES

[0067] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions of the present disclosure and are not intended to limit the scope of what the inventors regard as their invention. Likewise, the disclosure is not limited to any particular preferred embodiments described herein. Indeed, modifications and variations of the embodiments may be apparent to those skilled in the art upon reading this specification and can be made without departing from its spirit and scope. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Centigrade, room temperature is about 25°C, and pressure is at or near atmospheric.Example 1 : MZL with aHUS treated with odronextamab

[0068] Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) often linked to complement hyperactivation, caused by mutations of genes encoding for complement inhibitors (loss-of-function mutations) or complement activators (gain-of-function mutations) or by autoantibodies mainly against the complement inhibitor factor H. This is a case report of a woman with a refractory gastric marginal zone lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT) that experienced aHUS due to the production of anti-factor H autoantibodies of the IgM class without any genetic complement related abnormalities. Despite standard MALT lymphoma therapies (Helicobacter pylori eradication, rituximab, ibrutinib) and aHUS control by C5 inhibition with eculizumab, the lymphoma continued toDocket No. 179227.05202progress, until initiation of odronextamab, a humanized bispecific antibody that binds to CD3 on T cells and CD20 on B cells. Odronextamab therapy quickly (within weeks) led to a complete response of lymphoma and to a significant decrease in IgM anti-factor H autoantibodies. During the follow-up, complement activity markers remained in the normal range, thus, after 3 months, eculizumab was safely discontinued. During the subsequent 10 months of odronextamab therapy, no relapse of both lymphoma and aHUS has been observed. In this individual, a bispecific antibody to T and B cells was an effective treatment for both lymphoproliferation and autoimmunity.

[0069] Atypical hemolytic uremic syndrome is a thrombotic microangiopathy often related to complement dysregulation due either to gene defects (gain-of-function mutation of activators or loss-of-function of inhibitors) or to autoantibodies against factor H (FH) usually of the IgG class (Dragon-Drurey, 2010) and, less commonly, of the IgM class (Cugno, 2021). Most of the cases associated with IgG anti-FH result from a genetic predisposition in a homozygous deletion in genes of complement FH related antigens (CFHR3-CFHR1) (Zipfel, 2010). Conversely, autoantibodies of the IgM class are not associated with any genetic background, and they have been described with a frequency 6-fold higher in the setting of hematopoietic stem cell transplant-associated TMA (TA-TMA) (Cugno, 2021).

[0070] Extranodal MALT MZL is a non-Hodgkin lymphoma, originating in mucosal lymphoid tissues. When it involves gastric mucosa, it may be related to chronic Helicobacter Pylori (HP) infection (Violeta, 2018). In the setting of lymphoproliferative diseases, there may be a production of autoantibodies against specific human proteins, which may induce different organ dysfunctions and complications that sometimes overcome the severity of the primary disease (Craig, 2010; Cugno, 2008). Described herein is a case of MALT lymphoma complicated by IgM anti-FH autoantibodies followed by complement-mediated aHUS.

[0071] Case Description: A 39-year-old woman, without previous relevant medical history, presented with abdominal bloating and dyspepsia. Gastroscopy revealed a MALT MZL. She had a minimal bone marrow disease infiltration with a monoclonal IgM antibody and a normal blood count. MALT-lnternational Prognostic Index score was 1 / 3 at diagnosis. Moreover, she tested positive for HP, thus she underwent eradication treatment with bismuth subcitrate potassium, metronidazole and tetracycline.

[0072] Despite successful HP eradication, the patient experienced disease progression confirmed by a gastric echo-endoscopy that showed ulcers (up to 2 cm), gastric wall thickening, and perigastric and celiac tripod adenopathies. The patient received first-line rituximab monotherapy for 8 doses of 375 mg / sqm (4 weekly followed by 4 monthly). DespiteDocket No. 179227.05202endoscopic and histologic persistence of lymphoma, given the optimal clinical control, watchful waiting was chosen.

[0073] At the age of 45 years, the patient experienced arthralgia and steroid-refractory thrombocytopenia. Disease localizations were unchanged, except for an increase in monoclonal IgM (3 g / L). Second-line therapy with rituximab (4 weekly) and bendamustine was started, with complete recovery of platelet count and undetectable IgM levels, but without significant changes in disease localizations.

[0074] At the age of 53 years, the patient experienced fatigue, fever, and generalized edema. Laboratory tests showed Coombs-test negative hemolytic anemia (Hb: 6.7 g / dL; LDH: 762 U / mL; undetectable haptoglobin; schistocytes: 1%), thrombocytopenia (25,000 / mm3), and acute kidney injury (serum creatinine [sCr]: 3.9 mg / dL) with proteinuria (500 mg / dL). ADAMTS13 activity was in the normal range (82%) and C3 was consumed (0.39 g / L [normal range 0.90-1.80 g / L]). Given the lack of diarrhea, a diagnosis of aHUS was made.

[0075] A complete disease re-staging was performed: fluorodeoxyglucose18-positron emission tomography (PET) was negative and bone marrow infiltration was stable, but monoclonal IgM levels significantly increased up to 11 g / L. Third-line therapy with ibrutinib was started, but, on day 4, a worsening of renal function and a concomitant spike in the monoclonal IgM levels (14.8 g / L) led to treatment interruption and initiation of a specific treatment for aHUS with the C5 inhibitor eculizumab (900 mg i.v. once weekly for 4 weeks followed by 1200 mg i.v. every 2 weeks). After the initial 4 doses of C5 inhibitor, we observed a prompt improvement of all laboratory parameters of aHUS including a complete recovery of kidney function. Ibrutinib was then reintroduced and well tolerated. Laboratory investigations documented a high titer of IgM anti-FH with no IgG or IgA anti-FH and no genetic abnormality in complement regulatory genes. The complement activation marker sC5b-9 was as high as 1882 ng / mL (normal range 150-400 ng / mL) before eculizumab initiation, and it decreased to a nadir of 213 ng / mL during C5 inhibition. IgM anti-FH autoantibodies were characterized for their interaction with different factor H domains by a competition assay with known anti-FH monoclonal antibodies that recognize specific domains related to short consensus repeats (SCRs) epitopes. The binding of the patient’s autoantibodies to FH was found to be inhibited by monoclonal antibody L20 mapping at SCR19, the active site of FH for its binding to endothelial cells.

[0076] Effects of specific monoclonal antibodies (mAbs), targeted to known epitopes of FH, on the binding of patients’ autoantibodies to immobilized FH were assessed. The binding of serum anti-FH autoantibodies to immobilized FH was expressed as mean optical density (OD) of three experiments with SD. In the present patient, the binding was inhibited only by theDocket No. 179227.05202mAb L20 that interacts with the SCR domain 19 (the active site of FH for its binding to endothelial cells), whereas mAbs 0X23 (interacting with SCR1-4), 0X24 (interacting with SCR5), and C18 (interacting with SCR20) did not modify the binding of serum anti-FH autoantibodies to immobilized FH. The positive control was a patient with previously documented autoantibodies to FH that interact with domain 19. The negative control was normal pooled serum.

[0077] Within 6 months, renal function fully recovered with a nadir of sCr of 0.95 mg / dL and a urinary protein-to-urinary creatinine ratio of 0.14 mg / mg (normal <0.2 mg / mg). Eculizumab was continued, and the interval between doses was tailored according to global complement functional test 7 with a maintenance schedule of 1200 mg every 4 weeks, and aHUS remained in stable remission.

[0078] After 6 months on ibrutinib, disease assessment (clinical, endoscopic, serological, imaging and bone marrow) did not show any significant improvement. The treatment was continued until the patient was considered as a candidate for a subsequent therapeutic line.

[0079] The patient was then evaluated for the MZL cohort of the phase II ELM-2 study (NCT03888105) with the bispecific humanized antibody odronextamab, which binds to CD3 on T cells and CD20 on B cells, and was deemed eligible. At screening, PET showed a clear disease progression at the level of the gastric wall, peri-gastric lymph nodes, right lung apex and splenomegaly. The patient was admitted and started cycle 1 of intravenous odronextamab with the optimized step-up dosing regimen (0.2 mg on day 1; 0.5 mg on day 2; 2 mg on day 8; 9 mg on day 15 and 10 mg on day 16) with inpatient monitoring. Grade 1 cytokinerelease syndrome (CRS), observed at week 3, was successfully controlled with antipyretics and dexamethasone. When the nominal dose was reached (80 mg) no further CRS events were observed. The patient continued odronextamab as outpatient without any adverse event. At first restaging (week 12), a complete response (CR) was detected by PET, endoscopic gastric biopsy and bone marrow biopsy. Notably, total serum IgM rapidly decreased from 1864 mg / dL to 229 mg / dL (Figure 1A) and correspondingly IgM anti-FH were completely cleared (Figure 1B). After initiation of the bispecific antibody, three additional administrations of eculizumab were given (16, 42, and 67 days). Following the documented stable reduction of anti-FH autoantibodies, eculizumab was discontinued. The patient was then carefully monitored for aHUS relapse by home urine dip-stick for hemoglobinuria (twice weekly) and regular blood test at odronextamab administration. During the 8 months subsequent to eculizumab discontinuation, no sign of relapse was detected, and sC5b-9 stably remained in the normalDocket No. 179227.05202range. At the last follow-up (month 10) the patient continued to receive odronextamab (160 mg every two weeks) and remained in PET complete remission of lymphoma.

[0080] The study was approved by the ethics committee Milano Area 2 (No.623_2019bis) and carried out in conformity with the 2013 revision of the Declaration of Helsinki. The subject gave her written consent to participate in the study.

[0081] Discussion: The successful treatment with odronextamab not only induced a complete remission of the lymphoma but it also dramatically reduced anti-FH autoantibodies, leading to safely discontinuing C5 inhibition therapy and maintaining normal complement activity markers.

[0082] In adults, about 50% of patients with aHUS have a detectable complement abnormality among which the production of anti-FH autoantibodies of the IgG class is a well-known cause (Dragon-Durey, 2010; Zipfel, 2010). It has been shown that specific IgM can lead to FH loss-of-function, thus inducing aHUS (Cugno, 2021). This condition is more commonly encountered in TA-TMA, and the anti-FH autoantibodies of the IgM class, unlike anti-FH IgG, are not associated with FH-related gene deletions (Cugno, 2021). This case report shows that IgM anti-FH can be produced in the context of a lymphoproliferative disease. The absence of abnormalities in complement related genes and the interaction of the autoantibody with the reactive site of FH indicate that the autoantibody played a specific role in causing block of complement inhibition and the consequent complement hyperactivation and aHUS, regardless of whether the autoantibody originated from the MZL clone or from an autoreactive one. The rapid and complete response of aHUS to complement inhibition therapy further indicates the role of complement activation due to IgM anti-FH in the pathogenesis of this TMA. Additional issues of potential interest are: 1) the patient underwent eculizumab maintenance treatment tailored on global complement activity (targeted to <30%) as is usually done in patients on longterm eculizumab treatment (Cugno, 2022), allowing the safe increase of the interval between doses, and 2) the possibility of safely discontinuing C5 inhibition therapy once the risk of relapse has been controlled (Ardissino, 2014; Ardissino, 2024) as in this case by the successful treatment with odronextamab that zeroed the level of IgM anti-FH. Preliminary results of the phase II ELM-2 study reported encouraging findings with odronextamab in heavily pretreated relapsed or refractory MZL: CR rate of 79% and a 36-months progression-free survival rate of 69% (Kim, 2024). This report shows that bispecific CD20xCD3 antibodies are an additional therapeutic option in refractory autoimmune diseases.Docket No. 179227.05202

[0083] References1. Dragon-Durey et al., Semin Thromb Hemost. 2010 Sep;36(6):633-40.2. Cugno et al., J Am Soc Nephrol. 2021 May 3;32(5): 1227-1235.3. Zipfel et al., Pediatr Nephrol. 20100ct;25(10):2009-19.4. Violeta et al., J Med Life. 2018 Jul-Sep;11(3):187-193.5. Craig et al., Blood. 2010 Jan 21 ;115(3):581-91.6. Cugno et al., Autoimmun Rev. 2008 Dec;8(2): 156-9.7. Cugno et al., J Nephrol. 2022 May;35(4):1205-1211.8. A Study to Assess the Anti-Tumor Activity and Safety of Odronextamab in Adult Patients With B-cell Non-Hodgkin Lymphoma Who Have Been Previously Treated With Other Cancer Therapies (ELM-2). 2019-11-13 to 2029-12-21. Identifier: NCT03888105. clinicaltrials.gov / study / NCT038881059. Ardissino et al., Am J Kidney Dis. 2014 Oct;64(4):633-7.10. Ardissino etal., J Nephrol. 2024 May;37(4):1017-1026.11. Kim et al., Blood. 2024;144(Supplement 1):862-862.

[0084] The present disclosure is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

Claims

Docket No. 179227.05202We claim:

1. A method of treating an autoimmune disease in a subject in need thereof, comprising administering to the subject one or more doses of a therapeutically effective amount of a bispecific CD20xCD3 antibody comprising a first antigen-binding arm that specifically binds CD20 and a second antigen-binding arm that specifically binds CD3.

2. The method of claim 1 , wherein the autoimmune disease is alopecia areata, autoimmune hepatitis, autoimmune pancreatitis, autoimmune thrombocytopenic purpura, autoimmune urticaria, celiac disease, Crohn's disease, diabetes type I, eosinophilic enterogastritis, eosinophilic fasciitis, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hemolytic anemia, inflammatory bowel disease, inflammatory myopathies, multiple sclerosis, myasthenia gravis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatic fever, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erthyematosus, ulcerative colitis, vasculitis, vitiligo, or Wegener's granulomatosis.

3. The method of claim 1 , wherein the autoimmune disease is a C5-associated disease or disorder.

4. The method of claim 3, wherein the C5-associated disease or disorder is acute respiratory distress syndrome, adult respiratory distress syndrome, age-related macular degeneration, allergy, Alport’s syndrome, Alzheimer’s disease, asthma, atherosclerosis, atypical hemolytic uremic syndrome (aHUS), complement activation caused by balloon angioplasty, bronchoconstriction, bullous pemphigoid, a burn, C3 glomerulopathy, capillary leak syndrome, a chemical injury, chronic obstructive pulmonary disease, Crohn's disease, diabetes, diabetic macular edema, diabetic nephropathy, diabetic retinopathy, dyspnea, emphysema, epilepsy, fibrogenic dust diseases, frostbite, geographic atrophy, glomerulopathy, Goodpasture's Syndrome, Guillain-Barre Syndrome, a hemodialysis complication, hemolytic anemia, hemoptysis, hereditary angioedema, hyperacute allograft rejection, hypersensitivity pneumonitis, an immune complex disorder, immune complex-associated inflammation, an inflammatory disorder, inherited CD59 deficiency, an injury due to inert dusts and / or minerals, interleukin-2 induced toxicity during IL-2 therapy, lupus nephritis, membranoproliferative glomerulonephritis, membranoproliferative nephritis, mesenteric artery reperfusion after aortic reconstruction, mesenteric artery reperfusion after infectious disease, mesenteric artery reperfusion after sepsis, multiple sclerosis, myasthenia gravis, myocardial infarction,Docket No. 179227.05202neuromyelitis optica, neuromyelitis optica, obesity, ocular angiogenesis, an organic dust disease, a parasitic disease, Parkinson's disease, paroxysmal nocturnal hemoglobinuria, pneumonia, a post-ischemic reperfusion condition, post-pump syndrome in cardiopulmonary bypass or renal bypass, progressive kidney failure, a proteinuric kidney disease, psoriasis, a pulmonary embolism, a pulmonary infarct, pulmonary fibrosis, pulmonary vasculitis, renal ischemia, a renal ischemia-reperfusion injury, a renal transplant, rheumatoid arthritis, schizophrenia, a smoke injury, stroke, systemic lupus erythematosus, systemic lupus erythematosus nephritis, a thermal injury, a traumatic brain injury, uveitis, vasculitis, or xenograft rejection.

5. The method of claim 4, wherein the C5-associated disease or disorder is aHUS.

6. The method of any one of claims 1-5, wherein the subject is being treated for the autoimmune disease.

7. The method of claim 6, wherein the subject is being treated with a C5 inhibitor.

8. The method of any one of claims 1-7, wherein the subject has a comorbidity.

9. The method of any one of claims 1-8, wherein the subject has a cancer selected from the group consisting of anal cancer, angiosarcoma, basal cell carcinoma, bladder cancer, bone cancer, brain cancer, breast cancer, a B cell cancer, cervical cancer, cholangiocarcinoma, chondrosarcoma, colon cancer, colorectal cancer, cutaneous squamous cell carcinoma, endometrial cancer, esophageal cancer, glioblastoma multiforme, head & neck squamous cell cancer, hepatocellular carcinoma, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell carcinoma, myeloma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, salivary gland cancer, skin cancer, soft tissue sarcoma, stomach cancer, testicular cancer, and uterine cancer.

10. The method of claim 9, wherein the subject has a B-cell cancer.

11. The method of claim 10, wherein the subject has acute lymphoblastic leukemia, Burkitt lymphoma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin lymphoma, lymphoblastic lymphoma, mantle cell lymphoma, marginal zone lymphoma (MZL), non-Hodgkin lymphoma, primary mediastinal B-cell lymphoma, small lymphocytic lymphoma, or Waldenstrom macroglobulinemia.Docket No. 179227.0520212. The method of claim 11 , wherein the subject has MZL.

13. The method of any one of claims 1-12, wherein the subject has elevated levels of an autoantibody.

14. The method of claim 13, wherein the autoantibody inhibits C5 activity.

15. The method of claim 13, wherein the autoantibody inhibits factor H activity.

16. The method of claim 13, wherein the autoantibody specifically binds factor H.

17. The method of claim 16, wherein the autoantibody binds SCR domain 19 of factor H.

18. The method of any one of claims 1-17, wherein the subject has elevated levels of total IgM class antibodies.

19. The method of any one of claims 1-18, wherein the bispecific antibody is administered to the subject in one or more doses of about 0.1 mg / kg to about 15 mg / kg of body weight of the subject.

20. The method of any one of claims 1-18, wherein the bispecific antibody is administered to the subject in one or more doses of about 1 mg to about 800 mg.

21. The method of any one of claims 1-20, wherein the bispecific antibody is administered to the subject once a day, once every two days, once every three days, once every five days, once every week, once every two weeks, once every three weeks, or once every four weeks.

22. The method of any one of claims 1-21, wherein each dose of the one or more doses of the bispecific antibody is administered 0.5 to 12 weeks after the immediately preceding dose.

23. The method of any one of claims 1-22, wherein at least one of the one or more doses of the bispecific antibody comprises a dose having a greater amount of the bispecific antibody than the immediately preceding dose thereof.

24. The method of any one of claims 1-20, wherein at least one of the one or more doses of the bispecific antibody is administered in two or more split doses.

25. The method of claim 24, wherein at least one of the two or more split doses comprises the identical amount of the bispecific antibody.Docket No. 179227.0520226. The method of claim 24, wherein at least one of the two or more split doses is administered at least about 0.5 days after the immediately preceding dose.

27. The method of claim 26, wherein at least one of the two or more split doses is administered about 1 day after the immediately preceding dose.

28. The method of any one of claims 1-27, wherein the bispecific antibody is administered intravenously, subcutaneously, or intraperitoneally.

29. The method of any one of claims 1-28, wherein the subject has received one or more prior anti-autoimmune disease therapy.

30. The method of any one of claims 1-28, wherein the subject is relapsed after and / or refractory to treatment with one or more anti-autoimmune disease therapy.

31. The method of any one of claims 1-30, wherein administration of the bispecific antibody leads to stable reduction of anti-factor H autoantibodies.

32. The method of any one of claims 1-31 , wherein the administration of the bispecific antibody leads to discontinuation of a complement inhibition therapy.

33. The method of claim 32, wherein the complement inhibition therapy comprises an antics antibody.

34. The method of claim 32 or 33, wherein the autoimmune disease is aHUS, and administration of the bispecific antibody leads to discontinuing the complement inhibition therapy; wherein no relapse of aHUS occurs for at least 4 months subsequent to discontinuation of the complement inhibition therapy.

35. The method of any one of claims 1-34, wherein administration of the bispecific antibody leads to one or more of (a) reduction in hemolytic or microangiopathic anemia; (b) reduction of formation of abnormal blood clots; (c) reduction in the likelihood of stroke and / or heart attack, and (d) prevention or delay of permanent renal damage.

36. The method of any one of claims 1-34, wherein the autoimmune disease is aHUS, and administration of the bispecific antibody leads to reduction of one or more of abdominal pain, confusion, diarrhea, edema, fatigue, hemolysis, microangiopathic anemia, nausea / vomiting, systemic thrombotic microangiopathy, and platelet activation.Docket No. 179227.0520237. The method of any one of claims 1-34, wherein the subject has lymphoma and administration of the bispecific antibody leads to tumor regression, complete response, or partial response.

38. The method of any one of claims 1-37, wherein the first antigen-binding arm of the bispecific antibody comprises three heavy chain CDRs (A-HCDR1, A-HCDR2, and A-HCDR3) and three light chain CDRs (LCDR1 , LCDR2, and LCDR3), and wherein A-HCDR1 comprises the amino acid sequence of SEQ ID NO: 4; A-HCDR2 comprises the amino acid sequence of SEQ ID NO: 5; A-HCDR3 comprises the amino acid sequence of SEQ ID NO: 6; LCDR1 comprises the amino acid sequence of SEQ ID NO: 7; LCDR2 comprises the amino acid sequence of SEQ ID NO: 8; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 9.

39. The method of any one of claims 1-38, wherein the first antigen-binding arm of the bispecific antibody comprises a heavy chain variable region (A-HCVR) having the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 2.

40. The method of any one of claims 1-39, wherein the second antigen-binding arm of the bispecific antibody comprises three heavy chain CDRs (B-HCDR1, B-HCDR2, and B-HCDR3) and three light chain CDRs (LCDR1 , LCDR2, and LCDR3), and wherein B-HCDR1 comprises the amino acid sequence of SEQ ID NO: 10; B-HCDR2 comprises the amino acid sequence of SEQ ID NO: 11 ; B-HCDR3 comprises the amino acid sequence of SEQ ID NO: 12; LCDR1 comprises the amino acid sequence of SEQ ID NO: 7; LCDR2 comprises the amino acid sequence of SEQ ID NO: 8; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 9.

41. The method of any one of claims 1-40, wherein the second antigen-binding arm of the bispecific antibody comprises a heavy chain variable region (B-HCVR) having the amino acid sequence of SEQ ID NO: 3 and a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 2.

42. The method of any one of claims 1-41 , wherein the bispecific antibody comprises a first heavy chain comprising the HCVR of the first antigen-binding domain, a second heavy chain comprising the HCVR of the second antigen-binding domain, and a common light chain comprising the LCVR of the first and second antigen-binding domains, wherein the first heavy chain comprises the amino acid sequence of SEQ ID NO: 13.Docket No. 179227.0520243. The method of any one of claims 1-42, wherein the bispecific antibody comprises a first heavy chain comprising the HCVR of the first antigen-binding domain, a second heavy chain comprising the HCVR of the second antigen-binding domain, and a common light chain comprising the LCVR of the first and second antigen-binding domains, wherein the second heavy chain comprises the amino acid sequence of SEQ ID NO: 15.

44. The method of any one of claims 1-43, wherein the bispecific antibody comprises a first heavy chain comprising the HCVR of the first antigen-binding domain, a second heavy chain comprising the HCVR of the second antigen-binding domain, and a common light chain comprising the LCVR of the first and second antigen-binding domains, wherein the light chain comprises the amino acid sequence of SEQ ID NO: 14.

45. The method of any one of claims 1-44, wherein the bispecific antibody is odronextamab.

46. The method of any one of claims 1-37, wherein the bispecific antibody is odronextamab, mosunetuzumab, glofitamab, epcoritamab, plamotamab, EX103, or FBTA05.

47. A kit comprising a bispecific CD20xCD3 antibody comprising a first antigen-binding arm that specifically binds CD20 and a second antigen-binding arm that specifically binds CD3, in combination with written instructions for use of a therapeutically effective amount of the bispecific antibody for treating an autoimmune disease in a subject in need thereof.

48. A bispecific CD20xCD3 antibody comprising a first antigen-binding arm that specifically binds CD20 and a second antigen-binding arm that specifically binds CD3 for use in a method of treating an autoimmune disease in a subject in need thereof.

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