Antagonist anti-cd40 antibody pharmaceutical compositions

Abstract

Stable liquid pharmaceutical compositions comprising an antagonist anti-CD40 antibody as a therapeutically or prophylactically active component and methods useful in their preparation are provided. These compositions comprise the antagonist anti-CD40 antibody, a buffering agent to maintain the pH of the composition between about pH 5.0 and about pH 7.0, and an amount of arginine-HCl sufficient to render the liquid composition near isotonic. The stable liquid antagonist anti-CD40 antibody-containing pharmaceutical compositions of the invention find use in methods for treating proliferative diseases and diseases having an autoimmune and/or inflammatory component.

1 - 34 . (canceled) 
     
     
         35 . A method for treating a subject having a cancer or pre-malignant condition that is associated with CD40-expressing cells, said method comprising administering a pharmaceutically effective amount of a stable liquid pharmaceutical composition comprising:
 a) an antagonist anti-CD40 monoclonal antibody as a therapeutically or prophylactically active component, wherein said monoclonal antibody is capable of specifically binding to a human CD40 antigen expressed on the surface of a human B cell, said monoclonal antibody being free of significant agonist activity when bound to the CD40 antigen expressed on the surface of said B cell;   b) an amount of arginine in its acidic form (arginine-HCl) sufficient to render said composition near isotonic; and   c) a buffering agent to maintain the pH of said composition within a range from about pH 5.0 to about pH 7.0, wherein said buffering agent is a citrate/citric acid buffer.   
     
     
         36 . The method of  claim 35 , wherein said cancer is characterized by neoplastic B cell growth. 
     
     
         37 . The method of  claim 36 , wherein said cancer is selected from the group consisting of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, multiple myeloma, B cell lymphoma, high-grade B cell lymphoma, intermediate-grade B cell lymphoma, low-grade B cell lymphoma, B cell acute lympohoblastic leukemia, Hodgkin's disease, plasmacytoma, follicular lymphoma, follicular small cleaved lymphoma, follicular large cell lymphoma, follicular mixed small cleaved lymphoma, diffuse small cleaved cell lymphoma, diffuse small lymphocytic lymphoma, prolymphocytic leukemia, lymphoplasmacytic lymphoma, marginal zone lymphoma, mucosal associated lymphoid tissue lymphoma, monocytoid B cell lymphoma, splenic lymphoma, hairy cell leukemia, diffuse large cell lymphoma, mediastinal large B cell lymphoma, lymphomatoid granulomatosis, intravascular lymphomatosis, diffuse mixed cell lymphoma, diffuse large cell lymphoma, immunoblastic lymphoma, Burkitt's lymphoma, AIDS-related lymphoma, Waldenstrom's Macroglobulinemia, mantle cell lymphoma, and heavy chain disease. 
     
     
         38 . The method of  claim 35 , wherein said cancer is a non-B cell hematological malignancy. 
     
     
         39 . The method of  claim 38 , wherein said malignancy is selected from the group consisting of acute leukemias, myeloblastic leukemias, acute myelocytic leukemias, promyelocytic leukemia, myelomonocytic leukemia, monocytic leukemia, erythroleukemia, chronic myelocytic leukemia, and polycythemia vera. 
     
     
         40 . The method of  claim 35 , wherein said cancer is a solid tumor comprising neoplastic cells expressing CD40 antigen. 
     
     
         41 . The method of  claim 40 , wherein said solid tumor is selected from the group consisting of lung carcinoma, breast carcinoma, ovarian carcinoma, skin carcinoma, colon carcinoma, urinary bladder carcinoma, liver carcinoma, gastric carcinoma, prostate cancer, renal cell carcinoma, nasopharyngeal carcinoma, squamous cell carcinoma, thyroid papillary carcinoma, cervical carcinoma, and sarcomas. 
     
     
         42 . The method of  claim 35 , wherein said pre-malignant condition is monoclonal gammopathy of undetermined significance (MGUS). 
     
     
         43 . A method for treating a subject having an inflammatory disease or autoimmune disease that is associated with CD40-expressing cells, said method comprising administering a therapeutically effective amount of a stable liquid pharmaceutical composition comprising:
 a) an antagonist anti-CD40 monoclonal antibody as a therapeutically or prophylactically active component, wherein said monoclonal antibody is capable of specifically binding to a human CD40 antigen expressed on the surface of a human B cell, said monoclonal antibody being free of significant agonist activity when bound to the CD40 antigen expressed on the surface of said B cell;   b) an amount of arginine in its acidic form (arginine-HCl) sufficient to render said composition near isotonic; and   c) a buffering agent to maintain the pH of said composition within a range from about pH 5.0 to about pH 7.0, wherein said buffering agent is a citrate/citric acid buffer.   
     
     
         44 . The method of  claim 43 , 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. 
     
     
         45 - 62 . (canceled) 
     
     
         63 . The method of  claim 35 , wherein said composition has an osmolality of about 240 mmol/kg to about 360 mmol/kg. 
     
     
         64 . The method of  claim 35 , wherein the concentration of said buffering agent in said compositions is about 5 mM to about 100 mM, is about 5 mM to about 20 mM, or is about 10 mM. 
     
     
         65 . The method of  claim 35 , wherein said buffering agent in said composition is a sodium citrate/citric acid buffer. 
     
     
         66 . The method of  claim 35 , wherein said composition comprises arginine-HCl at a concentration of about 50 mM to about 200 mM, at a concentration of about 100 mM to about 175 mM, at a concentration of about 100 mM to about 175 mM, or at a concentration of about 150 mM. 
     
     
         67 . The method of  claim 35 , wherein said composition further comprises a surfactant or methionine, wherein said methionine is present in said composition in an amount sufficient to inhibit oxidation of at least one oxidizable amino acid residue in said anti-CD40 monoclonal antibody during storage of said composition. 
     
     
         68 . The method of  claim 35 , wherein said antagonist anti-CD40 monoclonal antibody in said composition 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 or   
     
     
         12 . 12;
 c) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of the sequence shown in SEQ ID NO:6, the sequence shown in SEQ ID NO:7, the sequence shown in SEQ ID NO:8, both the sequence shown in SEQ ID NO:6 and SEQ ID NO:7, and both the sequence shown in SEQ ID NO:6 and SEQ ID NO:8;   d) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of the sequence shown in SEQ ID NO:2, the sequence shown in SEQ ID NO:4, the sequence shown in SEQ ID NO:5, both the sequence shown in SEQ ID NO:2 and SEQ ID NO:4, and both the sequence shown in SEQ ID NO:2 and SEQ ID NO:5;   e) 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;   f) 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;   g) 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;   h) 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;   i) a monoclonal antibody that competes with the monoclonal antibody CHIR-5.9 or CHIR-12.12 in a competitive binding assay;   j) the monoclonal antibody of preceding item a) or a monoclonal antibody of any one of preceding items c)-i), wherein said antibody is recombinantly produced; and   k) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of any one of preceding items a)-j), wherein said fragment retains the capability of specifically binding to said human CD40 antigen.   
     
     
         69 . The method of  claim 68 , 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. 
     
     
         70 . The method of  claim 68 , wherein said antagonist anti-CD40 monoclonal antibody is present in said composition at a concentration of about 0.1 mg/ml to about 50.0 mg/ml, at a concentration of about 1.0 mg/ml to about 35.0 mg/ml, or at a concentration of about 10.0 mg/ml to about 35.0 mg/ml. 
     
     
         71 . The method of  claim 70 , wherein said composition comprises arginine-HCl at a concentration of about 50 mM to about 200 mM, and wherein said buffering agent is sodium citrate/citric acid buffer at a concentration of about 5 mM to about 20 mM. 
     
     
         72 . The method of  claim 71 , wherein the anti-CD40 monoclonal antibody is the monoclonal antibody CHIR-12.12 or CHIR-5.9, or an antigen-binding fragment thereof. 
     
     
         73 . The method of  claim 43 , wherein said composition has an osmolality of about 240 mmol/kg to about 360 mmol/kg. 
     
     
         74 . The method of  claim 43 , wherein the concentration of said buffering agent in said compositions is about 5 mM to about 100 mM, is about 5 mM to about 20 mM, or is about 10 mM. 
     
     
         75 . The method of  claim 43 , wherein said buffering agent in said composition is a sodium citrate/citric acid buffer. 
     
     
         76 . The method of  claim 43 , wherein said composition comprises arginine-HCl at a concentration of about 50 mM to about 200 mM, at a concentration of about 100 mM to about 175 mM, at a concentration of about 100 mM to about 175 mM, or at a concentration of about 150 mM. 
     
     
         77 . The method of  claim 43 , wherein said composition further comprises a surfactant or methionine, wherein said methionine is present in said composition in an amount sufficient to inhibit oxidation of at least one oxidizable amino acid residue in said anti-CD40 monoclonal antibody during storage of said composition. 
     
     
         78 . The method of  claim 43 , wherein said antagonist anti-CD40 monoclonal antibody in said composition 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 or 12.12;   c) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of the sequence shown in SEQ ID NO:6, the sequence shown in SEQ ID NO:7, the sequence shown in SEQ ID NO:8, both the sequence shown in SEQ ID NO:6 and SEQ ID NO:7, and both the sequence shown in SEQ ID NO:6 and SEQ ID NO:8;   d) a monoclonal antibody comprising an amino acid sequence selected from the group consisting of the sequence shown in SEQ ID NO:2, the sequence shown in SEQ ID NO:4, the sequence shown in SEQ ID NO:5, both the sequence shown in SEQ ID NO:2 and SEQ ID NO:4, and both the sequence shown in SEQ ID NO:2 and SEQ ID NO:5;   e) 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;   f) 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;   g) 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;   h) 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;   i) a monoclonal antibody that competes with the monoclonal antibody CHIR-5.9 or CHIR-12.12 in a competitive binding assay;   j) the monoclonal antibody of preceding item a) or a monoclonal antibody of any one of preceding items c)-i), wherein said antibody is recombinantly produced; and   k) a monoclonal antibody that is an antigen-binding fragment of a monoclonal antibody of any one of preceding items a)-j), wherein said fragment retains the capability of specifically binding to said human CD40 antigen.   
     
     
         79 . The method of  claim 78 , 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. 
     
     
         80 . The method of  claim 78 , wherein said antagonist anti-CD40 monoclonal antibody is present in said composition at a concentration of about 0.1 mg/ml to about 50.0 mg/ml, at a concentration of about 1.0 mg/ml to about 35.0 mg/ml, or at a concentration of about 10.0 mg/ml to about 35.0 mg/ml. 
     
     
         81 . The method of  claim 80 , wherein said composition comprises arginine-HCl at a concentration of about 50 mM to about 200 mM, and wherein said buffering agent is sodium citrate/citric acid buffer at a concentration of about 5 mM to about 20 mM. 
     
     
         82 . The method of  claim 81 , wherein the anti-CD40 monoclonal antibody is the monoclonal antibody CHIR-12.12 or CHIR-5.9, or an antigen-binding fragment thereof.