Antagonist anti-cd40 monoclonal antibodies and methods for their use

Abstract

Compositions and methods of therapy for treating diseases mediated by stimulation of CD40 signaling on CD40-expressing cells are provided. The methods comprise administering a therapeutically effective amount of an antagonist anti-CD40 antibody or antigen-binding fragment thereof to a patient in need thereof. The antagonist anti-CD40 antibody or antigen-binding fragment thereof is free of significant agonist activity, but exhibits antagonist activity when the antibody binds a CD40 antigen on a human CD40-expressing cell. Antagonist activity of the anti-CD40 antibody or antigen-binding fragment thereof beneficially inhibits proliferation and/or differentiation of human CD40-expressing cells, such as B cells.

That which is claimed is: 
     
         1 . A method for inhibiting growth or differentiation of a normal human B cell, or for inhibiting proliferation of a normal human B cell wherein said proliferation is augmented by the interaction of a CD40 ligand with a CD40 antigen expressed on the surface of said B cell, comprising contacting said B cell with an effective amount of a human anti-CD40 monoclonal antibody selected from the group consisting of:
 a) the monoclonal antibody CHIR-5.9 or CHIR-12.12;   b) the monoclonal antibody produced by the hybridoma cell line 5.9 deposited with the ATCC as Patent Deposit No. PTA-5542 or by the hybridoma cell line 12.12 deposited with the ATCC as Patent Deposit No. PTA-5543;   c) a monoclonal antibody comprising a light chain variable domain containing residues 44-54, 70-76, and 109-117 of SEQ ID NO:2, and a heavy chain variable domain containing residues 50-54, 69-84, and 114-121 of SEQ ID NO:4;   d) a monoclonal antibody comprising a light chain variable domain containing residues 46-52, 70-72, and 111-116 of SEQ ID NO:2, and a heavy chain variable domain containing residues 45-51, 72-74, and 115-120 of SEQ ID NO:4;   e) a monoclonal antibody comprising a light chain variable domain comprising residues 21-132 of SEQ ID NO:2;   f) a monoclonal antibody comprising a heavy chain variable domain comprising residues 20-139 of SEQ ID NO:4;   g) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of:
 (i) residues 21-239 of SEQ ID NO:2; 
 (ii) SEQ ID NO:2; 
 (iii) residues 20-469 of SEQ ID NO:4; 
 (iv) SEQ ID NO:4; 
 (v) residues 20-469 of SEQ ID NO:5; 
 (vi) SEQ ID NO:5; 
 (vii) residues 21-132 of SEQ ID NO:2 and residues 20-139 of SEQ ID NO:4; 
 (viii) residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:4; 
 (ix) residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:5; 
 (x) SEQ ID NO:2 and SEQ ID NO:4; and 
 (xi) SEQ ID NO:2 and SEQ ID NO:5; 
   h) a monoclonal antibody comprising a light chain variable domain containing residues 44-54, 70-76, and 109-117 of SEQ ID NO:6, and a heavy chain variable domain containing residues 50-54, 69-84, and 114-121 of SEQ ID NO:7;   i) a monoclonal antibody comprising a light chain variable domain containing residues 46-52, 70-72, and 111-116 of SEQ ID NO:6, and a heavy chain variable domain containing residues 45-51, 72-74, and 115-120 of SEQ ID NO:7;   j) a monoclonal antibody comprising a light chain variable domain comprising residues 21-132 of SEQ ID NO:6;   k) a monoclonal antibody comprising a heavy chain variable domain comprising residues 20-144 of SEQ ID NO:7;   l) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of:
 (i) residues 21-239 of SEQ ID NO:6; 
 (ii) SEQ ID NO:6; 
 (iii) residues 20-474 of SEQ ID NO:7; 
 (iv) SEQ ID NO:7; 
 (v) residues 20-474 of SEQ ID NO:8; 
 (vi) SEQ ID NO:8; 
 (vii) residues 21-132 of SEQ ID NO:6 and residues 20-144 of SEQ ID NO:7; 
 (viii) residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:7; 
 (ix) residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:8; 
 (x) SEQ ID NO:6 and SEQ ID NO:7; and 
 (xi) SEQ ID NO:6 and SEQ ID NO:8; 
   m) a monoclonal antibody having an amino acid sequence encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of the sequence shown in SEQ ID NO:1, the sequence shown in SEQ ID NO:3, and both the sequence shown in SEQ ID NO:1 and SEQ ID NO:3;   n) a monoclonal antibody that binds to an epitope capable of binding the monoclonal antibody produced by the hybridoma cell line 5.9 or 12.12;   o) a monoclonal antibody that binds to an epitope comprising residues 82-87 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   p) a monoclonal antibody that binds to an epitope comprising residues 82-89 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   q) a monoclonal antibody that competes with the monoclonal antibody CHIR-5.9 or CHIR-12.12 in a competitive binding assay;   r) a monoclonal antibody comprising the complementarity determining regions (CDRs) of the monoclonal antibody CHIR-12.12 or CHIR-5.9;   s) the monoclonal antibody of preceding item a) or a monoclonal antibody of any one of preceding items c)-r), wherein said antibody is recombinantly produced;   t) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of any one of preceding items a)-s), wherein said fragment retains the capability of specifically binding to said human CD40 antigen; and   u) a conjugated form of the monoclonal antibody of any one of preceding items a)-t);   said antibody or fragment thereof being free of significant agonist activity, and whereby when said antibody or fragment thereof binds to said CD40 antigen on said B cell, the growth or differentiation of said B cell is inhibited.   
     
     
         2 . A method for inhibiting antibody production by B cells in a human patient, comprising administering to a human patient an effective amount of a human anti-CD40 monoclonal antibody or fragment thereof selected from the group consisting of:
 a) the monoclonal antibody CHIR-5.9 or CHIR-12.12;   b) the monoclonal antibody produced by the hybridoma cell line 5.9 deposited with the ATCC as Patent Deposit No. PTA-5542 or by the hybridoma cell line 12.12 deposited with the ATCC as Patent Deposit No. PTA-5543;   c) a monoclonal antibody comprising a light chain variable domain containing residues 44-54, 70-76, and 109-117 of SEQ ID NO:2, and a heavy chain variable domain containing residues 50-54, 69-84, and 114-121 of SEQ ID NO:4;   d) a monoclonal antibody comprising a light chain variable domain containing residues 46-52, 70-72, and 111-116 of SEQ ID NO:2, and a heavy chain variable domain containing residues 45-51, 72-74, and 115-120 of SEQ ID NO:4;   e) a monoclonal antibody comprising a light chain variable domain comprising residues 21-132 of SEQ ID NO:2;   f) a monoclonal antibody comprising a heavy chain variable domain comprising residues 20-139 of SEQ ID NO:4;   g) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of:
 (i) residues 21-239 of SEQ ID NO:2; 
 (ii) SEQ ID NO:2; 
 (iii) residues 20-469 of SEQ ID NO:4; 
 (iv) SEQ ID NO:4; 
 (v) residues 20-469 of SEQ ID NO:5; 
 (vi) SEQ ID NO:5; 
 (vii) residues 21-132 of SEQ ID NO:2 and residues 20-139 of SEQ ID NO:4; 
 (viii) residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:4; 
 (ix) residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:5; 
 (x) SEQ ID NO:2 and SEQ ID NO:4; and 
 (xi) SEQ ID NO:2 and SEQ ID NO:5; 
   h) a monoclonal antibody comprising a light chain variable domain containing residues 44-54, 70-76, and 109-117 of SEQ ID NO:6, and a heavy chain variable domain containing residues 50-54, 69-84, and 114-121 of SEQ ID NO:7;   i) a monoclonal antibody comprising a light chain variable domain containing residues 46-52, 70-72, and 111-116 of SEQ ID NO:6, and a heavy chain variable domain containing residues 45-51, 72-74, and 115-120 of SEQ ID NO:7;   j) a monoclonal antibody comprising a light chain variable domain comprising residues 21-132 of SEQ ID NO:6;   k) a monoclonal antibody comprising a heavy chain variable domain comprising residues 20-144 of SEQ ID NO:7;   l) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of:
 (i) residues 21-239 of SEQ ID NO:6; 
 (ii) SEQ ID NO:6; 
 (iii) residues 20-474 of SEQ ID NO:7; 
 (iv) SEQ ID NO:7; 
 (v) residues 20-474 of SEQ ID NO:8; 
 (vi) SEQ ID NO:8; 
 (vii) residues 21-132 of SEQ ID NO:6 and residues 20-144 of SEQ ID NO:7; 
 (viii) residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:7; 
 (ix) residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:8; 
 (x) SEQ ID NO:6 and SEQ ID NO:7; and 
 (xi) SEQ ID NO:6 and SEQ ID NO:8; 
   m) a monoclonal antibody having an amino acid sequence encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of the sequence shown in SEQ ID NO:1, the sequence shown in SEQ ID NO:3, and both the sequence shown in SEQ ID NO:1 and SEQ ID NO:3;   n) a monoclonal antibody that binds to an epitope capable of binding the monoclonal antibody produced by the hybridoma cell line 5.9 or 12.12;   o) a monoclonal antibody that binds to an epitope comprising residues 82-87 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   p) a monoclonal antibody that binds to an epitope comprising residues 82-89 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   q) a monoclonal antibody that competes with the monoclonal antibody CHIR-5.9 or CHIR-12.12 in a competitive binding assay;   r) a monoclonal antibody comprising the complementarity determining regions (CDRs) of the monoclonal antibody CHIR-12.12 or CHIR-5.9;   s) the monoclonal antibody of preceding item a) or a monoclonal antibody of any one of preceding items c)-r), wherein said antibody is recombinantly produced;   t) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of any one of preceding items a)-s), wherein said fragment retains the capability of specifically binding to said human CD40 antigen; and   u) a conjugated form of the monoclonal antibody of any one of preceding items a)-t);   said antibody or fragment thereof being free of significant agonist activity, and whereby when said antibody or fragment thereof binds to said CD40 antigen on said B cell, the growth or differentiation of said B cell is inhibited.   
     
     
         3 . A method for treating a human subject for an inflammatory disease or autoimmune disease, comprising administering to said subject an effective amount of an antagonist anti-CD40 monoclonal antibody that specifically binds Domain 2 of human CD40 antigen, wherein said antibody is free of significant agonist activity when bound to human CD40 antigen. 
     
     
         4 . The method of  claim 3 , wherein said monoclonal antibody is a human antibody. 
     
     
         5 . The method of  claim 4 , wherein said human monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-5.9 or CHIR-12.12;   b) the monoclonal antibody produced by the hybridoma cell line 5.9 deposited with the ATCC as Patent Deposit No. PTA-5542 or by the hybridoma cell line 12.12 deposited with the ATCC as Patent Deposit No. PTA-5543;   c) a monoclonal antibody comprising a light chain variable domain containing residues 44-54, 70-76, and 109-117 of SEQ ID NO:2, and a heavy chain variable domain containing residues 50-54, 69-84, and 114-121 of SEQ ID NO:4;   d) a monoclonal antibody comprising a light chain variable domain containing residues 46-52, 70-72, and 111-116 of SEQ ID NO:2, and a heavy chain variable domain containing residues 45-51, 72-74, and 115-120 of SEQ ID NO:4;   e) a monoclonal antibody comprising a light chain variable domain comprising residues 21-132 of SEQ ID NO:2;   f) a monoclonal antibody comprising a heavy chain variable domain comprising residues 20-139 of SEQ ID NO:4;   g) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of:
 (i) residues 21-239 of SEQ ID NO:2; 
 (ii) SEQ ID NO:2; 
 (iii) residues 20-469 of SEQ ID NO:4; 
 (iv) SEQ ID NO:4; 
 (v) residues 20-469 of SEQ ID NO:5; 
 (vi) SEQ ID NO:5; 
 (vii) residues 21-132 of SEQ ID NO:2 and residues 20-139 of SEQ ID NO:4; 
 (viii) residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:4; 
 (ix) residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:5; 
 (x) SEQ ID NO:2 and SEQ ID NO:4; and 
 (xi) SEQ ID NO:2 and SEQ ID NO:5; 
   h) a monoclonal antibody comprising a light chain variable domain containing residues 44-54, 70-76, and 109-117 of SEQ ID NO:6, and a heavy chain variable domain containing residues 50-54, 69-84, and 114-121 of SEQ ID NO:7;   i) a monoclonal antibody comprising a light chain variable domain containing residues 46-52, 70-72, and 111-116 of SEQ ID NO:6, and a heavy chain variable domain containing residues 45-51, 72-74, and 115-120 of SEQ ID NO:7;   j) a monoclonal antibody comprising a light chain variable domain comprising residues 21-132 of SEQ ID NO:6;   k) a monoclonal antibody comprising a heavy chain variable domain comprising residues 20-144 of SEQ ID NO:7;   l) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of:
 (i) residues 21-239 of SEQ ID NO:6; 
 (ii) SEQ ID NO:6; 
 (iii) residues 20-474 of SEQ ID NO:7; 
 (iv) SEQ ID NO:7; 
 (v) residues 20-474 of SEQ ID NO:8; 
 (vi) SEQ ID NO:8; 
 (vii) residues 21-132 of SEQ ID NO:6 and residues 20-144 of SEQ ID NO:7; 
 (viii) residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:7; 
 (ix) residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:8; 
 (x) SEQ ID NO:6 and SEQ ID NO:7; and 
 (xi) SEQ ID NO:6 and SEQ ID NO:8; 
   m) a monoclonal antibody having an amino acid sequence encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of the sequence shown in SEQ ID NO:1, the sequence shown in SEQ ID NO:3, and both the sequence shown in SEQ ID NO:1 and SEQ ID NO:3;   n) a monoclonal antibody that binds to an epitope capable of binding the monoclonal antibody produced by the hybridoma cell line 5.9 or 12.12;   o) a monoclonal antibody that binds to an epitope comprising residues 82-87 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   p) a monoclonal antibody that binds to an epitope comprising residues 82-89 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   q) a monoclonal antibody that competes with the monoclonal antibody CHIR-5.9 or CHIR-12.12 in a competitive binding assay;   r) a monoclonal antibody comprising the complementarity determining regions (CDRs) of the monoclonal antibody CHIR-12.12 or CHIR-5.9;   s) the monoclonal antibody of preceding item a) or a monoclonal antibody of any one of preceding items c)-r), wherein said antibody is recombinantly produced;   t) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of any one of preceding items a)-s), wherein said fragment retains the capability of specifically binding to said human CD40 antigen; and   u) a conjugated form of the monoclonal antibody of any one of preceding items a)-t).   
     
     
         6 . The method of  claim 5 , wherein said monoclonal antibody binds to said human CD40 antigen with an affinity (K D ) of at least about 10 −6  M to about 10 −12  M. 
     
     
         7 . The method of  claim 5 , wherein said fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
         8 . The method of  claim 5 , wherein said monoclonal antibody is recombinantly produced in a Chinese Hamster Ovary (CHO) cell line. 
     
     
         9 . The method of  claim 3 , wherein said inflammatory disease or autoimmune disease is selected from the group consisting of systemic lupus erythematosus (SLE), discoid lupus, lupus nephritis, sarcoidosis, juvenile arthritis, rheumatoid arthritis, psoriatic arthritis, Reiter's syndrome, ankylosing spondylitis, gouty arthritis, rejection of an organ or tissue transplant, graft versus host disease, multiple sclerosis, hyper IgE syndrome, polyarteritis nodosa, primary biliary cirrhosis, inflammatory bowel disease, Crohn's disease, celiac's disease (gluten-sensitive enteropathy), autoimmune hepatitis, pernicious anemia, autoimmune hemolytic anemia, psoriasis, scleroderma, myasthenia gravis, autoimmune thrombocytopenic purpura, autoimmune thyroiditis, Grave's disease, Hashimoto's thyroiditis, immune complex disease, chronic fatigue immune dysfunction syndrome (CFIDS), polymyositis and dermatomyositis, cryoglobulinemia, thrombolysis, cardiomyopathy, pemphigus vulgaris, pulmonary interstitial fibrosis, sarcoidosis, Type I and Type II diabetes mellitus, type 1, 2, 3, and 4 delayed-type hypersensitivity, allergy or allergic disorders, asthma, Churg-Strauss syndrome (allergic granulomatosis), atopic dermatitis, allergic and irritant contact dermatitis, urtecaria, IgE-mediated allergy, atherosclerosis, vasculitis, idiopathic inflammatory myopathies, hemolytic disease, Alzheimer's disease, and chronic inflammatory demyelinating polyneuropathy. 
     
     
         10 . A method for treating a human subject for transplant rejection, comprising administering to said subject an effective amount of an antagonist anti-CD40 monoclonal antibody that specifically binds Domain 2 of human CD40 antigen, wherein said antibody is free of significant agonist activity when bound to human CD40 antigen. 
     
     
         11 . The method of  claim 10 , wherein said monoclonal antibody is a human antibody. 
     
     
         12 . The method of  claim 11 , wherein said human monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-5.9 or CHIR-12.12;   b) the monoclonal antibody produced by the hybridoma cell line 5.9 deposited with the ATCC as Patent Deposit No. PTA-5542 or by the hybridoma cell line 12.12 deposited with the ATCC as Patent Deposit No. PTA-5543;   c) a monoclonal antibody comprising a light chain variable domain containing residues 44-54, 70-76, and 109-117 of SEQ ID NO:2, and a heavy chain variable domain containing residues 50-54, 69-84, and 114-121 of SEQ ID NO:4;   d) a monoclonal antibody comprising a light chain variable domain containing residues 46-52, 70-72, and 111-116 of SEQ ID NO:2, and a heavy chain variable domain containing residues 45-51, 72-74, and 115-120 of SEQ ID NO:4;   e) a monoclonal antibody comprising a light chain variable domain comprising residues 21-132 of SEQ ID NO:2;   f) a monoclonal antibody comprising a heavy chain variable domain comprising residues 20-139 of SEQ ID NO:4;   g) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of:
 (i) residues 21-239 of SEQ ID NO:2; 
 (ii) SEQ ID NO:2; 
 (iii) residues 20-469 of SEQ ID NO:4; 
 (iv) SEQ ID NO:4; 
 (v) residues 20-469 of SEQ ID NO:5; 
 (vi) SEQ ID NO:5; 
 (vii) residues 21-132 of SEQ ID NO:2 and residues 20-139 of SEQ ID NO:4; 
 (viii) residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:4; 
 (ix) residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:5; 
 (x) SEQ ID NO:2 and SEQ ID NO:4; and 
 (xi) SEQ ID NO:2 and SEQ ID NO:5; 
   h) a monoclonal antibody comprising a light chain variable domain containing residues 44-54, 70-76, and 109-117 of SEQ ID NO:6, and a heavy chain variable domain containing residues 50-54, 69-84, and 114-121 of SEQ ID NO:7;   i) a monoclonal antibody comprising a light chain variable domain containing residues 46-52, 70-72, and 111-116 of SEQ ID NO:6, and a heavy chain variable domain containing residues 45-51, 72-74, and 115-120 of SEQ ID NO:7;   j) a monoclonal antibody comprising a light chain variable domain comprising residues 21-132 of SEQ ID NO:6;   k) a monoclonal antibody comprising a heavy chain variable domain comprising residues 20-144 of SEQ ID NO:7;   l) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of:
 (i) residues 21-239 of SEQ ID NO:6; 
 (ii) SEQ ID NO:6; 
 (iii) residues 20-474 of SEQ ID NO:7; 
 (iv) SEQ ID NO:7; 
 (v) residues 20-474 of SEQ ID NO:8; 
 (vi) SEQ ID NO:8; 
 (vii) residues 21-132 of SEQ ID NO:6 and residues 20-144 of SEQ ID NO:7; 
 (viii) residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:7; 
 (ix) residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:8; 
 (x) SEQ ID NO:6 and SEQ ID NO:7; and 
 (xi) SEQ ID NO:6 and SEQ ID NO:8; 
   m) a monoclonal antibody having an amino acid sequence encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of the sequence shown in SEQ ID NO:1, the sequence shown in SEQ ID NO:3, and both the sequence shown in SEQ ID NO:1 and SEQ ID NO:3;   n) a monoclonal antibody that binds to an epitope capable of binding the monoclonal antibody produced by the hybridoma cell line 5.9 or 12.12;   o) a monoclonal antibody that binds to an epitope comprising residues 82-87 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   p) a monoclonal antibody that binds to an epitope comprising residues 82-89 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   q) a monoclonal antibody that competes with the monoclonal antibody CHIR-5.9 or CHIR-12.12 in a competitive binding assay;   r) a monoclonal antibody comprising the complementarity determining regions (CDRs) of the monoclonal antibody CHIR-12.12 or CHIR-5.9;   s) the monoclonal antibody of preceding item a) or a monoclonal antibody of any one of preceding items c)-r), wherein said antibody is recombinantly produced;   t) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of any one of preceding items a)-s), wherein said fragment retains the capability of specifically binding to said human CD40 antigen; and   u) a conjugated form of the monoclonal antibody of any one of preceding items a)-t).   
     
     
         13 . The method of  claim 12 , wherein said monoclonal antibody binds to said human CD40 antigen with an affinity (K D ) of at least about 10 −6  M to about 10 −12  M. 
     
     
         14 . The method of  claim 12 , wherein said fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
         15 . The method of  claim 12 , wherein said monoclonal antibody is recombinantly produced in a Chinese Hamster Ovary (CHO) cell line. 
     
     
         16 . The method of  claim 10 , wherein said treatment further comprises administering an immunosuppressive agent in a pharmaceutically acceptable excipient. 
     
     
         17 . The method of  claim 16 , wherein the immunosuppressive agent is selected from the group consisting of cyclosporine, FK506, rapamycin, corticosteroids, CTLA4-Ig, and anti-B Lymphocyte Stimulator antibody. 
     
     
         18 . A method for treating a human subject for rheumatoid arthritis, comprising administering to said subject an effective amount of an antagonist anti-CD40 monoclonal antibody that specifically binds Domain 2 of human CD40 antigen, wherein said antibody is free of significant agonist activity when bound to human CD40 antigen. 
     
     
         19 . The method of  claim 18 , wherein said monoclonal antibody is a human antibody. 
     
     
         20 . The method of  claim 19 , wherein said human monoclonal antibody is selected from the group consisting of:
 a) the monoclonal antibody CHIR-5.9 or CHIR-12.12;   b) the monoclonal antibody produced by the hybridoma cell line 5.9 deposited with the ATCC as Patent Deposit No. PTA-5542 or by the hybridoma cell line 12.12 deposited with the ATCC as Patent Deposit No. PTA-5543;   c) a monoclonal antibody comprising a light chain variable domain containing residues 44-54, 70-76, and 109-117 of SEQ ID NO:2, and a heavy chain variable domain containing residues 50-54, 69-84, and 114-121 of SEQ ID NO:4;   d) a monoclonal antibody comprising a light chain variable domain containing residues 46-52, 70-72, and 111-116 of SEQ ID NO:2, and a heavy chain variable domain containing residues 45-51, 72-74, and 115-120 of SEQ ID NO:4;   e) a monoclonal antibody comprising a light chain variable domain comprising residues 21-132 of SEQ ID NO:2;   f) a monoclonal antibody comprising a heavy chain variable domain comprising residues 20-139 of SEQ ID NO:4;   g) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of:
 (i) residues 21-239 of SEQ ID NO:2; 
 (ii) SEQ ID NO:2; 
 (iii) residues 20-469 of SEQ ID NO:4; 
 (iv) SEQ ID NO:4; 
 (v) residues 20-469 of SEQ ID NO:5; 
 (vi) SEQ ID NO:5; 
 (vii) residues 21-132 of SEQ ID NO:2 and residues 20-139 of SEQ ID NO:4; 
 (viii) residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:4; 
 (ix) residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:5; 
 (x) SEQ ID NO:2 and SEQ ID NO:4; and 
 (xi) SEQ ID NO:2 and SEQ ID NO:5; 
   h) a monoclonal antibody comprising a light chain variable domain containing residues 44-54, 70-76, and 109-117 of SEQ ID NO:6, and a heavy chain variable domain containing residues 50-54, 69-84, and 114-121 of SEQ ID NO:7;   i) a monoclonal antibody comprising a light chain variable domain containing residues 46-52, 70-72, and 111-116 of SEQ ID NO:6, and a heavy chain variable domain containing residues 45-51, 72-74, and 115-120 of SEQ ID NO:7;   j) a monoclonal antibody comprising a light chain variable domain comprising residues 21-132 of SEQ ID NO:6;   k) a monoclonal antibody comprising a heavy chain variable domain comprising residues 20-144 of SEQ ID NO:7;   l) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of:
 (i) residues 21-239 of SEQ ID NO:6; 
 (ii) SEQ ID NO:6; 
 (iii) residues 20-474 of SEQ ID NO:7; 
 (iv) SEQ ID NO:7; 
 (v) residues 20-474 of SEQ ID NO:8; 
 (vi) SEQ ID NO:8; 
 (vii) residues 21-132 of SEQ ID NO:6 and residues 20-144 of SEQ ID NO:7; 
 (viii) residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:7; 
 (ix) residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:8; 
 (x) SEQ ID NO:6 and SEQ ID NO:7; and 
 (xi) SEQ ID NO:6 and SEQ ID NO:8; 
   m) a monoclonal antibody having an amino acid sequence encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of the sequence shown in SEQ ID NO:1, the sequence shown in SEQ ID NO:3, and both the sequence shown in SEQ ID NO:1 and SEQ ID NO:3;   n) a monoclonal antibody that binds to an epitope capable of binding the monoclonal antibody produced by the hybridoma cell line 5.9 or 12.12;   o) a monoclonal antibody that binds to an epitope comprising residues 82-87 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   p) a monoclonal antibody that binds to an epitope comprising residues 82-89 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   q) a monoclonal antibody that competes with the monoclonal antibody CHIR-5.9 or CHIR-12.12 in a competitive binding assay;   r) a monoclonal antibody comprising the complementarity determining regions (CDRs) of the monoclonal antibody CHIR-12.12 or CHIR-5.9;   s) the monoclonal antibody of preceding item a) or a monoclonal antibody of any one of preceding items c)-r), wherein said antibody is recombinantly produced;   t) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of any one of preceding items a)-s), wherein said fragment retains the capability of specifically binding to said human CD40 antigen; and   u) a conjugated form of the monoclonal antibody of any one of preceding items a)-t).   
     
     
         21 . The method of  claim 20 , wherein said monoclonal antibody binds to said human CD40 antigen with an affinity (K D ) of at least about 10 −6  M to about 10 −12  M. 
     
     
         22 . The method of  claim 20 , wherein said fragment is selected from the group consisting of a Fab fragment, an F(ab′) 2  fragment, an Fv fragment, and a single-chain Fv fragment. 
     
     
         23 . The method of  claim 20 , wherein said monoclonal antibody is recombinantly produced in a Chinese Hamster Ovary (CHO) cell line. 
     
     
         24 . The method of  claim 18 , wherein said treatment further comprises administering an immunosuppressive agent in a pharmaceutically acceptable excipient. 
     
     
         25 . The method of  claim 24 , wherein the immunosuppressive agent is selected from the group consisting of cyclosporine, FK506, rapamycin, corticosteroids, CTLA4-Ig, an anti-CD20 antibody, and anti-B Lymphocyte Stimulator antibody. 
     
     
         26 . The method of  claim 5 , further comprising combination therapy with at least one other therapy for said inflammatory disease or autoimmune disease, wherein said at least one other therapy is administered to said human subject prior to, during, or subsequent to administration of said antagonist anti-CD40 monoclonal antibody. 
     
     
         27 . The method of  claim 26 , wherein said at least one other therapy is selected from the group consisting of: surgery, organ perfusion, radiation therapy, steroid therapy, non-steroidal therapy, antibiotic therapy, antifungal therapy, hormone therapy, cytokine therapy, therapy with dermatological agents, immunosuppressive therapy, and other anti-inflammatory monoclonal antibody therapy. 
     
     
         28 . A method for inhibiting a CD40 ligand-mediated CD40 signaling pathway in a normal human CD40-expressing cell, said method comprising contacting said cell with an effective amount of a human anti-CD40 monoclonal antibody selected from the group consisting of:
 a) the monoclonal antibody CHIR-5.9 or CHIR-12.12;   b) the monoclonal antibody produced by the hybridoma cell line 5.9 deposited with the ATCC as Patent Deposit No. PTA-5542 or by the hybridoma cell line 12.12 deposited with the ATCC as Patent Deposit No. PTA-5543;   c) a monoclonal antibody comprising a light chain variable domain containing residues 44-54, 70-76, and 109-117 of SEQ ID NO:2, and a heavy chain variable domain containing residues 50-54, 69-84, and 114-121 of SEQ ID NO:4;   d) a monoclonal antibody comprising a light chain variable domain containing residues 46-52, 70-72, and 111-116 of SEQ ID NO:2, and a heavy chain variable domain containing residues 45-51, 72-74, and 115-120 of SEQ ID NO:4;   e) a monoclonal antibody comprising a light chain variable domain comprising residues 21-132 of SEQ ID NO:2;   f) a monoclonal antibody comprising a heavy chain variable domain comprising residues 20-139 of SEQ ID NO:4;   g) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of:
 (i) residues 21-239 of SEQ ID NO:2; 
 (ii) SEQ ID NO:2; 
 (iii) residues 20-469 of SEQ ID NO:4; 
 (iv) SEQ ID NO:4; 
 (v) residues 20-469 of SEQ ID NO:5; 
 (vi) SEQ ID NO:5; 
 (vii) residues 21-132 of SEQ ID NO:2 and residues 20-139 of SEQ ID NO:4; 
 (viii) residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:4; 
 (ix) residues 21-239 of SEQ ID NO:2 and residues 20-469 of SEQ ID NO:5; 
 (x) SEQ ID NO:2 and SEQ ID NO:4; and 
 (xi) SEQ ID NO:2 and SEQ ID NO:5; 
   h) a monoclonal antibody comprising a light chain variable domain containing residues 44-54, 70-76, and 109-117 of SEQ ID NO:6, and a heavy chain variable domain containing residues 50-54, 69-84, and 114-121 of SEQ ID NO:7;   i) a monoclonal antibody comprising a light chain variable domain containing residues 46-52, 70-72, and 111-116 of SEQ ID NO:6, and a heavy chain variable domain containing residues 45-51, 72-74, and 115-120 of SEQ ID NO:7;   j) a monoclonal antibody comprising a light chain variable domain comprising residues 21-132 of SEQ ID NO:6;   k) a monoclonal antibody comprising a heavy chain variable domain comprising residues 20-144 of SEQ ID NO:7;   l) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of:
 (i) residues 21-239 of SEQ ID NO:6; 
 (ii) SEQ ID NO:6; 
 (iii) residues 20-474 of SEQ ID NO:7; 
 (iv) SEQ ID NO:7; 
 (v) residues 20-474 of SEQ ID NO:8; 
 (vi) SEQ ID NO:8; 
 (vii) residues 21-132 of SEQ ID NO:6 and residues 20-144 of SEQ ID NO:7; 
 (viii) residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:7; 
 (ix) residues 21-239 of SEQ ID NO:6 and residues 20-474 of SEQ ID NO:8; 
 (x) SEQ ID NO:6 and SEQ ID NO:7; and 
 (xi) SEQ ID NO:6 and SEQ ID NO:8; 
   m) a monoclonal antibody having an amino acid sequence encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of the sequence shown in SEQ ID NO:1, the sequence shown in SEQ ID NO:3, and both the sequence shown in SEQ ID NO:1 and SEQ ID NO:3;   n) a monoclonal antibody that binds to an epitope capable of binding the monoclonal antibody produced by the hybridoma cell line 5.9 or 12.12;   o) a monoclonal antibody that binds to an epitope comprising residues 82-87 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   p) a monoclonal antibody that binds to an epitope comprising residues 82-89 of the human CD40 sequence shown in SEQ ID NO:10 or SEQ ID NO:12;   q) a monoclonal antibody that competes with the monoclonal antibody CHIR-5.9 or CHIR-12.12 in a competitive binding assay;   r) a monoclonal antibody comprising the complementarity determining regions (CDRs) of the monoclonal antibody CHIR-12.12 or CHIR-5.9;   s) the monoclonal antibody of preceding item a) or a monoclonal antibody of any one of preceding items c)-r), wherein said antibody is recombinantly produced;   t) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of any one of preceding items a)-s), wherein said fragment retains the capability of specifically binding to said human CD40 antigen; and   u) a conjugated form of the monoclonal antibody of any one of preceding items a)-t).   
     
     
         29 . The method of  claim 28 , wherein said normal human CD40-expressing cell is a normal human B cell and said CD40 signaling pathway is B cell survival.