Human CTLA-4 antibodies and their uses

Abstract

The present invention provides novel human sequence antibodies against human CTLA-4 and methods of treating human diseases, infections and other conditions using these antibodies.

1 . A method for treating a patient having a disorder that can be treated by augmenting a T-cell mediated immune response, which method comprises administering a therapeutically effective dose of a human sequence antibody, or antigen binding portion thereof, that specifically binds to human CTLA-4.  
     
     
         2 . The method of  claim 1  wherein T-cell subpopulations marked by CD antigens CD4, CD8, CD25 or CD69 remain stable during and subsequent to administration of the CTLA-4 antibody.  
     
     
         3 . The method of  claim 1 , wherein the human sequence CTLA-4 antibody blocks binding of human CTLA-4 to human B7.  
     
     
         4 . The method of  claim 1 , wherein the disorder is cancer.  
     
     
         5 . The method of  claim 4 , which method further comprises administering a tumor specific antigen vaccine in conjunction with the human sequence CTLA-4 antibody.  
     
     
         6 . The method of  claim 5 , wherein the tumor specific vaccine is a whole tumor cell vaccine.  
     
     
         7 . The method of  claim 6 , wherein tumor cells of the whole tumor cell vaccine are modified to express GM-CSF.  
     
     
         8 . The method of  claim 6 , wherein tumor cells of the whole tumor cell vaccine are modified to express IL-2.  
     
     
         9 . The method of  claim 5 , wherein the vaccine comprises a tumor specific antigen selected from the group consisting of telomerase and heat shock protein (HSP).  
     
     
         10 . The method of  claim 5 , wherein the cancer is melanoma.  
     
     
         11 . The method of  claim 10 , wherein the vaccine comprises gp 100.  
     
     
         12 . The method of  claim 10 , wherein the vaccine comprises MAGE.  
     
     
         13 . The method of  claim 10 , wherein the vaccine comprises Trp-2.  
     
     
         14 . The method of  claim 5 , wherein the patient has prostate cancer.  
     
     
         15 . The method of  claim 14 , wherein the vaccine comprises TRAMP.  
     
     
         16 . The method of  claim 5 , wherein the patient has epithelial cancer.  
     
     
         17 . The method of  claim 5 , wherein the vaccine is a tumor antigen-loaded dendritic cell vaccine.  
     
     
         18 . The method of  claim 4 , wherein the cancer is prostate cancer.  
     
     
         19 . The method of  claim 4 , wherein the cancer is melanoma.  
     
     
         20 . The method of  claim 4 , wherein the cancer is epithelial cancer.  
     
     
         21 . The method of  claim 1 , wherein the antibody comprises: 
 (a) a heavy chain variable amino acid sequence having the amino acid sequence set forth in SEQ ID NO:19; and    (b) a light chain variable amino acid sequence having the amino acid sequence set forth in SEQ ID NO:9.    
     
     
         22 . The method of  claim 1 , wherein the antibody comprises: 
 (a) a heavy chain variable amino acid sequence having the amino acid sequence set forth in SEQ ID NO:17; and    (b) a light chain variable amino acid sequence having the amino acid sequence set forth in SEQ ID NO:7.    
     
     
         23 . The method of  claim 1 , wherein the antibody comprises: 
 (a) a heavy chain variable amino acid sequence having the amino acid sequence set forth in SEQ ID NO:23; and    (b) a light chain variable amino acid sequence having the amino acid sequence set forth in SEQ ID NO:13.    
     
     
         24 . The method of  claim 1 , wherein the antibody comprises: 
 (a) a heavy chain variable region having CDR sequences set forth in SEQ ID NOS:27, 32 and 37; and    (b) a light chain variable region having CDR sequences set forth in SEQ ID NOS:24, 29 and 35.    
     
     
         25 . The method of  claim 1 , wherein the antibody comprises: 
 (a) a heavy chain variable region having CDR sequences set forth in SEQ ID NOS:27, 33 and 37; and    (b) a light chain variable region having CDR sequences set forth in SEQ ID NOS:25, 30 and 35.    
     
     
         26 . The method of  claim 1 , wherein the antibody comprises: 
 (a) a heavy chain variable region having CDR sequences set forth in SEQ ID NOS:28, 34 and 38; and    (b) a light chain variable region having CDR sequences set forth in SEQ ID NOS:26, 31 and 36.    
     
     
         27 . The method of  claim 1 , wherein the antibody comprises: 
 (a) a heavy chain variable region of a human V H  3-30.3 gene; and    (b) a light chain variable region of a human V K  A-27 gene.    
     
     
         28 . The method of  claim 27 , wherein the antibody is capable of binding human CTLA-4 with a binding affinity of about 10 8  M −1  or greater.  
     
     
         29 . The method of  claim 27 , wherein the antibody is capable of binding human CTLA-4 with a binding affinity of about 10 9  M −1  or greater.  
     
     
         30 . The method of  claim 27 , wherein the antibody inhibits binding of the human CTLA-4 to human B7.  
     
     
         31 . The method of  claim 5 , wherein the antibody comprises: 
 (a) a heavy chain variable amino acid sequence having the amino acid sequence set forth in SEQ ID NO:19; and    (b) a light chain variable amino acid sequence having the amino acid sequence set forth in SEQ ID NO:9.    
     
     
         32 . The method of  claim 5 , wherein the antibody comprises: 
 (a) a heavy chain variable amino acid sequence having the amino acid sequence set forth in SEQ ID NO:17; and    (b) a light chain variable amino acid sequence having the amino acid sequence set forth in SEQ ID NO:7.    
     
     
         33 . The method of  claim 5 , wherein the antibody comprises: 
 (a) a heavy chain variable amino acid sequence having the amino acid sequence set forth in SEQ ID NO:23; and    (b) a light chain variable amino acid sequence having the amino acid sequence set forth in SEQ ID NO:13.    
     
     
         34 . The method of  claim 5 , wherein the antibody comprises: 
 (a) a heavy chain variable region having CDR sequences set forth in SEQ ID NOS:27, 32 and 37; and    (b) a light chain variable region having CDR sequences set forth in SEQ ID NOS:24, 29 and 35.    
     
     
         35 . The method of  claim 5 , wherein the antibody comprises: 
 (a) a heavy chain variable region having CDR sequences set forth in SEQ ID NOS:27, 33 and 37; and    (b) a light chain variable region having CDR sequences set forth in SEQ ID NOS:25, 30 and 35.    
     
     
         36 . The method of  claim 5 , wherein the antibody comprises: 
 (a) a heavy chain variable region having CDR sequences set forth in SEQ ID NOS:28, 34 and 38; and    (b) a light chain variable region having CDR sequences set forth in SEQ ID NOS:26, 31 and 36.    
     
     
         37 . The method of  claim 5 , wherein the antibody comprises: 
 (a) a heavy chain variable region of a human V H  3-30.3 gene; and    (b) a light chain variable region of a human V K  A-27 gene.    
     
     
         38 . The method of  claim 37 , wherein the antibody is capable of binding human CTLA-4 with a binding affinity of about 10 8  M −1  or greater.  
     
     
         39 . The method of  claim 37 , wherein the antibody is capable of binding human CTLA-4 with a binding affinity of about 109 M-1 or greater.  
     
     
         40 . The method of  claim 37 , wherein the antibody inhibits binding of the human CTLA-4 to human B7.  
     
     
         41 . The method of  claim 5 , wherein the antibody comprises: 
 (a) a heavy chain variable region of a human V H  3-33 gene; and    (b) a light chain variable region of a human V K  L-15 gene.    
     
     
         42 . The method of  claim 41 , wherein the antibody is capable of binding human CTLA-4 with a binding affinity of about 10 8  M −1  or greater.  
     
     
         43 . The method of  claim 41 , wherein the antibody is capable of binding human CTLA-4 with a binding affinity of about 10 9  M −1  or greater.  
     
     
         44 . The method of  claim 41 , wherein the antibody inhibits binding of the human CTLA-4 to human B7.  
     
     
         45 . A method for treating a patient having a disorder that can be treated by augmenting a T-cell mediated immune response, which method comprises administering a therapeutically effective dose of a human sequence CTLA-4 antibody 10D1, or antigen binding portion thereof.  
     
     
         46 . The method of  claim 45 , wherein the disorder is cancer.  
     
     
         47 . The method of  claim 46 , which further comprises administering a tumor specific antigen vaccine in conjunction with the 10D1 antibody.  
     
     
         48 . The method of  claim 47 , which further comprises administering the 10D1 antibody in conjunction with a whole tumor cell vaccine.  
     
     
         49 . The method of  claim 48 , wherein the whole tumor cell vaccine is modified to express GM-CSF.  
     
     
         50 . The method of  claim 48 , wherein the whole tumor cell vaccine is modified to express IL-2.  
     
     
         51 . The method of  claim 47 , wherein the vaccine comprises a tumor specific antigen selected from the group consisting of telomerase and heat shock protein (HSP).  
     
     
         52 . The method of  claim 47 , wherein the cancer is melanoma.  
     
     
         53 . The method of  claim 52 , wherein the vaccine comprises gp 100.  
     
     
         54 . The method of  claim 52 , wherein the vaccine comprises MAGE.  
     
     
         55 . The method of  claim 52 , wherein the vaccine comprises Trp-2.  
     
     
         56 . The method of  claim 47 , wherein the patient has prostate cancer.  
     
     
         57 . The method of  claim 56 , wherein the vaccine comprises TRAMP.  
     
     
         58 . The method of  claim 47 , wherein the patient has epithelial cancer.  
     
     
         59 . The method of  claim 47 , wherein the vaccine is a tumor antigen-loaded dendritic cell vaccine.  
     
     
         60 . The method of  claim 46 , wherein the cancer is prostate cancer.  
     
     
         61 . The method of  claim 46 , wherein the cancer is melanoma.  
     
     
         62 . The method of  claim 46 , wherein the cancer is epithelial cancer.  
     
     
         63 . The method of  claim 1 , wherein the disorder is an infectious disease.  
     
     
         64 . The method of  claim 63 , which further comprises administering a vaccine, which includes an antigen from a pathogen.  
     
     
         65 . The method of  claim 64 , wherein the antigen is from a pathogenic virus selected from the group consisting of: hepatitis A, hepatitis B, hepatitis C, herpes virus, adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.  
     
     
         66 . The method of  claim 65 , wherein the antigen is hepatitis B surface antigen.  
     
     
         67 . The method of  claim 64 , wherein the antigen is from a pathogenic bacteria selected from the group consisting of:  chlamydia , rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci,  klebsiella, proteus, serratia, pseudomonas, legionella , diphtheria,  salmonella , bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lymes disease bacteria.  
     
     
         68 . The method of  claim 64 , wherein the antigen is from a pathogenic fungi selected from the group consisting of:  Candida, Cryptococcus neoformans, Aspergillus , Genus  Mucorales, Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis  and  Histoplasma capsulatum.    
     
     
         69 . The method of  claim 64 , wherein the antigen is from a pathogenic parasite selected from the group consisting of:  Entamoeba histolytica, Balantidium coli, Naegleria fowleri, Acanthamoeba, Giardia lambia, Cryptosporidium, Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi , and  Nippostrongylus brasiliensis.    
     
     
         70 . A method for treating a patient having an infectious disease that can be treated by augmenting a T-cell mediated immune response, which method comprises administering a therapeutically effective dose a human CTLA-4 10D1 antibody.  
     
     
         71 . The method of  claim 70 , which further comprises administering a vaccine, which includes an antigen from a pathogen.  
     
     
         72 . The method of  claim 70 , wherein the antigen is from a pathogenic virus selected from the group consisting of: hepatitis A, hepatitis B, hepatitis C, herpes virus, adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.  
     
     
         73 . The method of  claim 72 , wherein the antigen is hepatitis B surface antigen.  
     
     
         74 . The method of  claim 71 , wherein the antigen is from a pathogenic bacteria selected from the group consisting of:  chlamydia , rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci,  klebsiella, proteus, serratia, pseudomonas, legionella , diphtheria,  salmonella , bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lymes disease bacteria.  
     
     
         75 . The method of  claim 71 , wherein the antigen is from a pathogenic fungi selected from the group consisting of:  Candida, Cryptococcus neoformans, Aspergillus , Genus  Mucorales, Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis  and  Histoplasma capsulatum.    
     
     
         76 . The method of  claim 71 , wherein the antigen is from a pathogenic parasite selected from the group consisting of:  Entamoeba histolytica, Balantidium coli, Naegleria fowleri, Acanthamoeba, Giardia lambia, Cryptosporidium, Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi , and  Nippostrongylus brasiliensis.