Anti-cd3 antibodies and methods of use

Abstract

The invention provides anti-cluster of differentiation 3 (CD3) antibodies and methods of using the same.

What is claimed is: 
     
         1 . An anti-cluster of differentiation 3 (CD3) antibody, wherein the anti-CD3 antibody comprises a binding domain comprising the following six hypervariable regions (HVRs):
 (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1;   (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2;   (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3;   (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4;   (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and   (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6.   
     
     
         2 . The anti-CD3 antibody of  claim 1 , wherein the binding domain comprises (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8; or (c) a VH domain as in (a) and a VL domain as in (b). 
     
     
         3 . The anti-CD3 antibody of  claim 2 , wherein the VH domain comprises the amino acid sequence of SEQ ID NO: 7. 
     
     
         4 . The anti-CD3 antibody of  claim 2 , wherein the VL domain comprises the amino acid sequence of SEQ ID NO: 8. 
     
     
         5 . An anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising (a) a VH domain comprising an amino acid sequence of SEQ ID NO: 7 and (b) a VL domain comprising an amino acid sequence of SEQ ID NO: 8. 
     
     
         6 . The anti-CD3 antibody of any one of  claims 1 - 5 , wherein the anti-CD3 antibody binds the human CD3ε polypeptide with a K D  of 0.5 nM or lower. 
     
     
         7 . The anti-CD3 antibody of  claim 6 , wherein the anti-CD3 antibody binds the human CD3ε polypeptide with a K D  of 0.3 nM or lower. 
     
     
         8 . The anti-CD3 antibody of  claim 7 , wherein the anti-CD3 antibody binds the human CD3ε polypeptide with a K D  of 0.1 nM or lower. 
     
     
         9 . The anti-CD3 antibody of any one of  claims 1 - 5 , wherein the anti-CD3 antibody comprises a substitution mutation in the Fc region that reduces effector function. 
     
     
         10 . The anti-CD3 antibody of  claim 9 , wherein the substitution mutation is an aglycosylation site mutation. 
     
     
         11 . The anti-CD3 antibody of  claim 10 , wherein the aglycosylation site mutation is at amino acid residue N297, L234, L235, and/or D265 (EU numbering). 
     
     
         12 . The anti-CD3 antibody of  claim 11 , wherein the aglycosylation site mutation is selected from the group consisting of N297G, N297A, L234A, L235A, and D265A. 
     
     
         13 . The anti-CD3 antibody of any one of  claims 1 - 12 , wherein the anti-CD3 antibody is monoclonal, human, humanized, or chimeric. 
     
     
         14 . The anti-CD3 antibody of any one of  claims 1 - 13 , wherein the anti-CD3 antibody is an antibody fragment that binds CD3. 
     
     
         15 . The anti-CD3 antibody of  claim 14 , wherein the antibody fragment is selected from the group consisting of Fab, Fab′-SH, Fv, scFv, and (Fab′) 2  fragments. 
     
     
         16 . The anti-CD3 antibody of any one of  claims 1 - 14 , wherein the anti-CD3 antibody is a full-length antibody. 
     
     
         17 . The anti-CD3 antibody of any one of  claims 1 - 16 , wherein the anti-CD3 antibody is an IgG antibody. 
     
     
         18 . The anti-CD3 antibody of any one of  claims 1 - 17 , wherein the anti-CD3 antibody is a monospecific antibody. 
     
     
         19 . The anti-CD3 antibody of any one of  claims 1 - 17 , wherein the anti-CD3 antibody is a multispecific antibody. 
     
     
         20 . The anti-CD3 antibody of  claim 19 , wherein the multispecific antibody is a bispecific antibody. 
     
     
         21 . The anti-CD3 antibody of  claim 20 , wherein the bispecific antibody comprises a second binding domain that binds to a second biological molecule, wherein the second biological molecule is a cell surface antigen on a target cell other than an immune effector cell. 
     
     
         22 . The anti-CD3 antibody of  claim 21 , wherein the cell surface antigen is expressed in low copy number on the target cell. 
     
     
         23 . The anti-CD3 antibody of  claim 22 , wherein the cell surface antigen is expressed at less than 35,000 copies per target cell. 
     
     
         24 . The anti-CD3 antibody of  claim 22  or  23 , wherein the cell surface antigen is expressed at about 100 copies per target cell to about 30,000 copies per target cell. 
     
     
         25 . The anti-CD3 antibody of any one of  claims 21 - 24 , wherein the cell surface antigen is a tumor antigen. 
     
     
         26 . The anti-CD3 antibody of  claim 25 , wherein the tumor antigen is Ly6G6D (lymphocyte antigen 6 complex, locus G61). 
     
     
         27 . The anti-CD3 antibody of  claim 26 , wherein Ly6G6D is expressed at about 20,000 copies per target cell to about 30,000 copies per target cell. 
     
     
         28 . An anti-CD3 antibody, wherein the anti-CD3 antibody is a bispecific antibody that binds to CD3 located on an immune effector cell and a cell surface antigen that is expressed in low copy number on a target cell other than the immune effector cell, wherein the bispecific antibody comprises an anti-CD3 arm comprising a first binding domain comprising the following six HVRs:
 (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1;   (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2;   (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3;   (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4;   (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and   (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6; and   
       an anti-cell surface antigen arm comprising a second binding domain. 
     
     
         29 . The anti-CD3 antibody of  claim 28 , wherein the cell surface antigen is a tumor antigen. 
     
     
         30 . The anti-CD3 antibody of  claim 29 , wherein the tumor antigen is Ly6G6D. 
     
     
         31 . The anti-CD3 antibody of any one of  claims 1 - 30 , wherein the anti-CD3 antibody comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH1 1 ) domain, a first CH2 (CH2 1 ) domain, a first CH3 (CH3 1 ) domain, a second CH1 (CH1 2 ) domain, second CH2 (CH2 2 ) domain, and a second CH3 (CH3 2 ) domain. 
     
     
         32 . The anti-CD3 antibody of  claim 31 , wherein at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain. 
     
     
         33 . The anti-CD3 antibody of  claim 32 , wherein the CH3 1  and CH3 2  domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH3, domain is positionable in the cavity or protuberance, respectively, in the CH3 2  domain. 
     
     
         34 . The anti-CD3 antibody of  claim 33 , wherein the CH3 1  and CH3 2  domains meet at an interface between said protuberance and cavity. 
     
     
         35 . The anti-CD3 antibody of any one of  claims 31 - 34 , wherein the CH2 1  and CH2 2  domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH2, domain is positionable in the cavity or protuberance, respectively, in the CH2 2  domain. 
     
     
         36 . The anti-CD3 antibody of  claim 35 , wherein the CH2 1  and CH2 2  domains meet at an interface between said protuberance and cavity. 
     
     
         37 . An isolated nucleic acid encoding the anti-CD3 antibody of any one of  claims 1 - 36 . 
     
     
         38 . A vector comprising the isolated nucleic acid of  claim 37 . 
     
     
         39 . A host cell comprising the vector of  claim 38 . 
     
     
         40 . The host cell of  claim 39 , wherein the host cell is a mammalian cell. 
     
     
         41 . The host cell of  claim 40 , wherein the mammalian cell is a Chinese hamster ovary (CHO) cell. 
     
     
         42 . The host cell of  claim 39 , wherein the host cell is a prokaryotic cell. 
     
     
         43 . The host cell of  claim 42 , wherein the prokaryotic cell is  E. coli.    
     
     
         44 . A method of producing the anti-CD3 antibody of any one of  claims 1 - 36 , the method comprising culturing the host cell of  claim 39  in a culture medium. 
     
     
         45 . The method of  claim 44 , wherein the method further comprises recovering the anti-CD3 antibody from the host cell or the culture medium. 
     
     
         46 . An immunoconjugate comprising the anti-CD3 antibody of any one of  claims 1 - 36  and a cytotoxic agent. 
     
     
         47 . A composition comprising the anti-CD3 antibody of any one of  claims 1 - 36 . 
     
     
         48 . The composition of  claim 47 , further comprising a pharmaceutically acceptable carrier, excipient, or diluent. 
     
     
         49 . The composition of  claim 48 , wherein the composition is a pharmaceutical composition. 
     
     
         50 . The composition of any one of  claims 47 - 49 , wherein the composition further comprises a PD-1 axis binding antagonist or an additional therapeutic agent. 
     
     
         51 . The anti-CD3 antibody of any one of  claims 1 - 36  for use as a medicament. 
     
     
         52 . The anti-CD3 antibody of any one of  claims 1 - 36  for use in treating or delaying progression of a cell proliferative disorder or an autoimmune disorder in a subject in need thereof. 
     
     
         53 . The anti-CD3 antibody of any one of  claims 1 - 36  for use in enhancing immune function in a subject having a cell proliferative disorder or an autoimmune disorder. 
     
     
         54 . The anti-CD3 antibody of  claim 52  or  53 , wherein the cell proliferative disorder is a cancer. 
     
     
         55 . The anti-CD3 antibody of  claim 54 , wherein the cancer is selected from the group consisting of esophageal cancer, stomach cancer, small intestine cancer, large intestine cancer, colorectal cancer, breast cancer, non-small cell lung cancer, non-Hodgkin's lymphoma (NHL), B cell lymphoma, B cell leukemia, multiple myeloma, renal cancer, prostate cancer, liver cancer, head and neck cancer, melanoma, ovarian cancer, mesothelioma, glioblastoma, germinal-center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphoid leukemia (CLL), marginal zone lymphoma (MZL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), Waldenstrom macroglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt's lymphoma (BL), B-cell prolymphocytic leukemia, Splenic marginal zone lymphoma, Hairy cell leukemia, Splenic lymphoma/leukemia, unclassifiable, Splenic diffuse red pulp small B-cell lymphoma, Hairy cell leukemia variant, WaldenstrOm macroglobulinemia, Heavy chain diseases, a Heavy chain disease, γ Heavy chain disease, μ Heavy chain disease, Plasma cell myeloma, Solitary plasmacytoma of bone, Extraosseous plasmacytoma, Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), Nodal marginal zone lymphoma, Pediatric nodal marginal zone lymphoma, Pediatric follicular lymphoma, Primary cutaneous follicle centre lymphoma, T-cell/histiocyte rich large B-cell lymphoma, Primary DLBCL of the CNS, Primary cutaneous DLBCL, leg type, EBV-positive DLBCL of the elderly, DLBCL associated with chronic inflammation, Lymphomatoid granulomatosis, Primary mediastinal (thymic) large B-cell lymphoma, Intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, Plasmablastic lymphoma, Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease, Primary effusion lymphoma: B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, and B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. 
     
     
         56 . The anti-CD3 antibody of  claim 55 , wherein the cancer is esophageal cancer. 
     
     
         57 . The anti-CD3 antibody of  claim 54 , wherein the cancer is an adenocarcinoma. 
     
     
         58 . The anti-CD3 antibody of  claim 57 , wherein the adenocarcinoma is metastatic adenocarcinoma. 
     
     
         59 . The anti-CD3 antibody of  claim 57  or  58 , wherein the adenocarcinoma is a colorectal adenocarcinoma, a gastric adenocarcinoma, or a pancreatic adenocarcinoma. 
     
     
         60 . The anti-CD3 antibody of  claim 52  or  53 , wherein the autoimmune disorder is selected from the group consisting of rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus (SLE), Wegener's disease, inflammatory bowel disease, idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), autoimmune thrombocytopenia, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, myasthenia gravis, vasculitis, diabetes mellitus, Reynaud's syndrome, Sjorgen's syndrome, glomerulonephritis, Neuromyelitis Optica (NMO) and IgG neuropathy. 
     
     
         61 . Use of the anti-CD3 antibody of any one of  claims 1 - 36  in the manufacture of a medicament for treating or delaying progression of a cell proliferative disorder or an autoimmune disorder. 
     
     
         62 . Use of the anti-CD3 antibody of any one of  claims 1 - 36  in the manufacture of a medicament for enhancing immune function in a subject having a cell proliferative disorder or an autoimmune disorder. 
     
     
         63 . The use of  claim 61  or  62 , wherein the cell proliferative disorder is a cancer. 
     
     
         64 . The use of  claim 63 , wherein the cancer is selected from the group consisting of esophageal cancer, stomach cancer, small intestine cancer, large intestine cancer, colorectal cancer, breast cancer, non-small cell lung cancer, non-Hodgkin's lymphoma (NHL), B cell lymphoma, B cell leukemia, multiple myeloma, renal cancer, prostate cancer, liver cancer, head and neck cancer, melanoma, ovarian cancer, mesothelioma, glioblastoma, germinal-center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphoid leukemia (CLL), marginal zone lymphoma (MZL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), Waldenstrom macroglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt's lymphoma (BL), B-cell prolymphocytic leukemia, Splenic marginal zone lymphoma, Hairy cell leukemia, Splenic lymphoma/leukemia, unclassifiable, Splenic diffuse red pulp small B-cell lymphoma, Hairy cell leukemia variant, WaldenstrOm macroglobulinemia, Heavy chain diseases, a Heavy chain disease, γ Heavy chain disease, μ Heavy chain disease, Plasma cell myeloma, Solitary plasmacytoma of bone, Extraosseous plasmacytoma, Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), Nodal marginal zone lymphoma, Pediatric nodal marginal zone lymphoma, Pediatric follicular lymphoma, Primary cutaneous follicle centre lymphoma, T-cell/histiocyte rich large B-cell lymphoma, Primary DLBCL of the CNS, Primary cutaneous DLBCL, leg type, EBV-positive DLBCL of the elderly, DLBCL associated with chronic inflammation, Lymphomatoid granulomatosis, Primary mediastinal (thymic) large B-cell lymphoma, Intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, Plasmablastic lymphoma, Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease, Primary effusion lymphoma: B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, and B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. 
     
     
         65 . The use of  claim 64 , wherein the cancer is esophageal cancer. 
     
     
         66 . The use of  claim 63 , wherein the cancer is an adenocarcinoma. 
     
     
         67 . The use of  claim 66 , wherein the adenocarcinoma is metastatic adenocarcinoma. 
     
     
         68 . The use of  claim 66  or  67 , wherein the adenocarcinoma is a colorectal adenocarcinoma, a gastric adenocarcinoma, or a pancreatic adenocarcinoma. 
     
     
         69 . The use of  claim 61  or  62 , wherein the autoimmune disorder is selected from the group consisting of rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus (SLE), Wegener's disease, inflammatory bowel disease, idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), autoimmune thrombocytopenia, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, myasthenia gravis, vasculitis, diabetes mellitus, Reynaud's syndrome, Sjorgen's syndrome, glomerulonephritis, Neuromyelitis Optica (NMO) and IgG neuropathy. 
     
     
         70 . A method of treating or delaying the progression of a cell proliferative disorder or an autoimmune disorder in a subject in need thereof, the method comprising administering to the subject the anti-CD3 antibody of any one of  claims 1 - 36 . 
     
     
         71 . A method of enhancing immune function in a subject having a cell proliferative disorder or an autoimmune disorder, the method comprising administering to the subject an effective amount of the anti-CD3 antibody of any one of  claims 1 - 36 . 
     
     
         72 . The method of  claim 70  or  71 , wherein the cell proliferative disorder is a cancer. 
     
     
         73 . The method of  claim 72 , wherein the cancer is selected from the group consisting of esophageal cancer, stomach cancer, small intestine cancer, large intestine cancer, colorectal cancer, breast cancer, non-small cell lung cancer, non-Hodgkin's lymphoma (NHL), B cell lymphoma, B cell leukemia, multiple myeloma, renal cancer, prostate cancer, liver cancer, head and neck cancer, melanoma, ovarian cancer, mesothelioma, glioblastoma, germinal-center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphoid leukemia (CLL), marginal zone lymphoma (MZL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), Waldenstrom macroglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt's lymphoma (BL), B-cell prolymphocytic leukemia, Splenic marginal zone lymphoma, Hairy cell leukemia, Splenic lymphoma/leukemia, unclassifiable, Splenic diffuse red pulp small B-cell lymphoma, Hairy cell leukemia variant, WaldenstrOm macroglobulinemia, Heavy chain diseases, a Heavy chain disease, γ Heavy chain disease, μ Heavy chain disease, Plasma cell myeloma, Solitary plasmacytoma of bone, Extraosseous plasmacytoma, Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), Nodal marginal zone lymphoma, Pediatric nodal marginal zone lymphoma, Pediatric follicular lymphoma, Primary cutaneous follicle centre lymphoma, T-cell/histiocyte rich large B-cell lymphoma, Primary DLBCL of the CNS, Primary cutaneous DLBCL, leg type, EBV-positive DLBCL of the elderly, DLBCL associated with chronic inflammation, Lymphomatoid granulomatosis, Primary mediastinal (thymic) large B-cell lymphoma, Intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, Plasmablastic lymphoma, Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease, Primary effusion lymphoma: B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, and B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. 
     
     
         74 . The method of  claim 73 , wherein the cancer is esophageal cancer. 
     
     
         75 . The method of  claim 72 , wherein the cancer is an adenocarcinoma. 
     
     
         76 . The method of  claim 75 , wherein the adenocarcinoma is metastatic adenocarcinoma. 
     
     
         77 . The method of  claim 75  or  76 , wherein the adenocarcinoma is a colorectal adenocarcinoma, a gastric adenocarcinoma, or a pancreatic adenocarcinoma. 
     
     
         78 . The method of  claim 70  or  71 , wherein the autoimmune disorder is selected from the group consisting of rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus (SLE), Wegener's disease, inflammatory bowel disease, idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), autoimmune thrombocytopenia, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, myasthenia gravis, vasculitis, diabetes mellitus, Reynaud's syndrome, Sjorgen's syndrome, glomerulonephritis, Neuromyelitis Optica (NMO) and IgG neuropathy. 
     
     
         79 . The method of any one of  claims 70 - 78 , wherein the anti-CD3 antibody binds to (a) a CD3 molecule located on an immune effector cell and (b) a second biological molecule located on a target cell other than the immune effector cell. 
     
     
         80 . The method of  claim 79 , wherein the anti-CD3 antibody activates the immune effector cell following binding to (a) and (b). 
     
     
         81 . The method of  claim 80 , wherein the activated immune effector cell is capable of exerting a cytotoxic effect and/or an apoptotic effect on the target cell. 
     
     
         82 . The method of any one of  claims 70 - 81 , wherein the anti-CD3 antibody is administered to the subject in a dosage of about 0.01 mg/kg to about 10 mg/kg. 
     
     
         83 . The method of  claim 82 , wherein the anti-CD3 antibody is administered to the subject in a dosage of about 0.1 mg/kg to about 10 mg/kg. 
     
     
         84 . The method of  claim 83 , wherein the anti-CD3 antibody is administered to the subject in a dosage of about 1 mg/kg. 
     
     
         85 . The method of any one of  claims 70 - 84 , further comprising administering to the subject a PD-1 axis binding antagonist and/or an additional therapeutic agent. 
     
     
         86 . The method of  claim 85 , wherein the PD-1 axis binding antagonist or additional therapeutic agent is administered prior to or subsequent to the administration of the anti-CD3 antibody. 
     
     
         87 . The method of  claim 85 , wherein the PD-1 axis binding antagonist additional therapeutic agent is administered concurrently with the anti-CD3 antibody. 
     
     
         88 . The method of any one of  claims 85 - 87 , wherein the PD-1 axis binding antagonist is selected from the group consisting of a PD-1 binding antagonist, a PD-L1 binding antagonist, and a PD-L2 binding antagonist. 
     
     
         89 . The method of  claim 88 , wherein the PD-1 axis binding antagonist is a PD-1 binding antagonist. 
     
     
         90 . The method of  claim 89 , wherein the PD-1 binding antagonist is selected from the group consisting of MDX 1106 (nivolumab), MK-3475 (pembrolizumab), CT-011 (pidilizumab), MEDI-0680 (AMP-514), PDR001, REGN2810, and BGB-108. 
     
     
         91 . The method of  claim 88 , wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist. 
     
     
         92 . The method of  claim 91 , wherein the PD-L1 binding antagonist is selected from the group consisting of MPDL3280A (atezolizumab), YW243.55.S70, MDX-1105, MEDI4736 (durvalumab), and MSB0010718C (avelumab). 
     
     
         93 . The method of  claim 88 , wherein the PD-1 axis binding antagonist is a PD-L2 binding antagonist. 
     
     
         94 . The method of  claim 93 , wherein the PD-L2 binding antagonist is an antibody or an immunoadhesin. 
     
     
         95 . A method of treating or delaying the progression of a cell proliferative disorder or an autoimmune disorder in a subject in need thereof, the method comprising administering to the subject an anti-CD3 antibody and a PD-1 axis binding antagonist, wherein the anti-CD3 antibody comprises an anti-CD3 arm and an anti-Ly6G6D arm. 
     
     
         96 . A method of enhancing immune function in a subject having a cell proliferative disorder or an autoimmune disorder, the method comprising administering to the subject an anti-CD3 antibody and a PD-1 axis binding antagonist, wherein the anti-CD3 antibody comprises an anti-CD3 arm and an anti-Ly6G6D arm. 
     
     
         97 . The method of  claim 95  or  96 , wherein:
 (a) the anti-CD3 arm comprises a first binding domain comprising:
 (i) a VH domain comprising an amino acid sequence of SEQ ID NO: 7, and 
 (ii) a VL domain comprising an amino acid sequence of SEQ ID NO: 8; and 
 
 (b) the PD-1 axis binding antagonist is an anti-PD-L1 antibody. 
 
     
     
         98 . The method of any one of  claims 95 - 97 , wherein the cell proliferative disorder is a cancer. 
     
     
         99 . The method of  claim 98 , wherein the cancer is esophageal cancer. 
     
     
         100 . The method of  claim 98 , wherein the cancer is an adenocarcinoma. 
     
     
         101 . The method of  claim 100 , wherein the adenocarcinoma is metastatic adenocarcinoma. 
     
     
         102 . The method of  claim 100  or  101 , wherein the adenocarcinoma is a colorectal adenocarcinoma, a gastric adenocarcinoma, or a pancreatic adenocarcinoma. 
     
     
         103 . The method of any one of  claims 70 - 102 , further comprising administering to the subject a glucocorticoid. 
     
     
         104 . The method of  claim 103 , wherein the glucocorticoid is dexamethasone. 
     
     
         105 . The method of any one of  claims 70 - 104 , further comprising administering to the subject rituximab. 
     
     
         106 . The method of any one of  claims 70 - 104 , further comprising administering to the subject obinutuzumab. 
     
     
         107 . The method of any one of  claims 70 - 106 , further comprising administering to the subject an antibody-drug conjugate (ADC). 
     
     
         108 . The method of any one of  claims 70 - 107 , wherein the anti-CD3 antibody is administered subcutaneously, intravenously, intramuscularly, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. 
     
     
         109 . The method of  claim 108 , wherein the anti-CD3 antibody is administered subcutaneously. 
     
     
         110 . The method of  claim 108 , wherein the anti-CD3 antibody is administered intravenously. 
     
     
         111 . The method of any one of  claims 70 - 110 , wherein the subject is human. 
     
     
         112 . A kit comprising:
 (a) the composition of any one of  claims 47 - 50 ; and   (b) a package insert comprising instructions for administering the composition to a subject to treat or delay progression of a cell proliferative disorder or an autoimmune disorder.