Antibody drug conjugates (ADC) that bind to 191P4D12 proteins

Abstract

Antibody drug conjugates (ADC's) that bind to 191P4D12 protein and variants thereof are described herein. 191P4D12 exhibits tissue specific expression in normal adult tissue, and is aberrantly expressed in the cancers listed in Table I. Consequently, the ADC's of the invention provide a therapeutic composition for the treatment of cancer.

The invention claimed is: 
     
       1. An antibody drug conjugate comprising an antibody or antigen binding fragment thereof conjugated to monomethyl auristatin E (MMAE), wherein the antibody or fragment comprises the heavy chain variable region consisting of an amino acid residue 20 to amino acid residue 136 of SEQ ID NO:7 and the light chain variable region consisting of an amino acid residue 23 to amino acid residue 130 of SEQ ID NO:8. 
     
     
       2. The antibody drug conjugate of  claim 1 , wherein the antibody comprises a the heavy chain consisting of an amino acid residue 20 to amino acid residue 466 of SEQ ID NO:7 and a the light chain consisting of the amino acid residue 23 to amino acid residue 236 of SEQ ID NO:8. 
     
     
       3. An antibody drug conjugate comprising an antibody or antigen binding fragment thereof conjugated to 1 to 10 units of monomethyl auristatin E (MMAE), wherein the antibody or fragment comprises the heavy chain variable region consisting of the amino acid sequence of the heavy chain variable region of an antibody produced by a hybridoma deposited under American Type Culture Collection (ATCC) Accession No. PTA-11267, and the light chain variable region consisting of the amino acid sequence of the light chain variable region of an antibody produced by a hybridoma deposited under ATCC Accession No. PTA-11267. 
     
     
       4. The antibody drug conjugate of  claim 3 , wherein the antibody comprises the heavy chain consisting of the amino acid sequence of the heavy chain of an antibody produced by a hybridoma deposited under ATCC. Accession No. PTA-11267, and the light chain consisting of the amino acid sequence of the light chain of an antibody produced by a hybridoma deposited under ATCC. Accession No. PTA-11267. 
     
     
       5. The antibody drug conjugate of  claim 1 , wherein the fragment is an Fab, F(ab′) 2 , Fv or scFv fragment. 
     
     
       6. The antibody drug conjugate of  claim 1 , wherein the antibody is a fully human antibody. 
     
     
       7. The antibody drug conjugate of  claim 1 , which wherein the antibody is recombinantly produced. 
     
     
       8. A pharmaceutical composition that comprises a therapuetically effective amount of the antibody drug conjugate of  claim 1  and a pharmaceutically acceptable excipient in a human unit dose form. 
     
     
       9. The pharmaceutical composition of  claim 8 , wherein the composition is for cancer treatment. 
     
     
       10. The pharmaceutical composition of  claim 9 , wherein the cancer is selected from the group consisting of pancreatic cancer, lung cancer, bladder cancer, and breast cancer. 
     
     
       11. The pharmaceutical composition of  claim 8 , wherein the composition is administered in combination with radiation or a chemotherapeutic agent. 
     
     
       12. The pharmaceutical composition of  claim 8  comprises the antibody drug conjugate of  claim 1  and  further comprising a therapeutically effective amount of chemotherapeutic agent in a human unit dose form. 
     
     
       13. A method of treating cancer in a subject, comprising administering to said subject an a therapeutically effective amount of the antibody drug conjugate of  claim 1 . 
     
     
       14. A method for treating cancer in a subject, comprising administering to said subject an a therapeutically effective amount of an the antibody drug conjugate of  claim 1  and radiation. 
     
     
       15. A method for treating cancer in a subject, comprising administering to said subject an a therapeutically effective amount of an the antibody drug conjugate of  claim 1  and a chemotherapeutic agent. 
     
     
       16. The antibody drug conjugate of claim 1, wherein the antibody drug conjugate has the following structure: 
       
         
           
           
               
               
           
         
         wherein L- represents the antibody or antigen binding fragment thereof and p ranges from about 1 to about 10. 
       
     
     
       17. The antibody drug conjugate of claim 16, wherein p ranges from about 2 to about 5. 
     
     
       18. The antibody drug conjugate of claim 1, wherein the antibody or antigen binding fragment thereof is conjugated to MMAE via an enzyme-cleavable linker unit. 
     
     
       19. The antibody drug conjugate of claim 18, wherein the enzyme-cleavable linker unit comprises a Val-Cit linker. 
     
     
       20. The antibody drug conjugate of claim 18, wherein the linker unit forms a bond with a sulfur atom of the antibody or antigen binding fragment thereof. 
     
     
       21. The antibody drug conjugate of claim 1, wherein the antibody or antigen binding fragment thereof is conjugated to MMAE via a linker unit that has the formula: -A a -W w -Y y -; wherein -A- is a stretcher unit, a is 0 or 1; -W- is an amino acid unit, w is an integer ranging from 0 to 12; and -Y- is a spacer unit, y is 0, 1, or 2. 
     
     
       22. The antibody drug conjugate of claim 21, wherein the stretcher unit has the structure of Formula I below; wherein the amino acid unit is Val-Cit; and wherein the spacer unit is a p-aminobenzyl alcohol (PAB) group having the structure of Formula II below; 
       
         
           
           
               
               
           
         
        
       
     
     
       23. The antibody drug conjugate of claim 22, wherein the stretcher unit forms a bond with a sulfur atom of the antibody or antigen binding fragment thereof; and wherein the spacer unit is linked to MMAE via a carbamate group. 
     
     
       24. The method of claim 13, wherein the subject is a human subject. 
     
     
       25. The method of claim 24, wherein the cancer is colon cancer, pancreatic cancer, ovarian cancer, breast cancer, lung cancer, bladder cancer, esophageal cancer, head cancer, or neck cancer. 
     
     
       26. The method of claim 25, wherein the cancer is bladder cancer. 
     
     
       27. The method of claim 26, wherein the bladder cancer is advanced bladder cancer. 
     
     
       28. The method of claim 26, wherein the bladder cancer is metastatic bladder cancer. 
     
     
       29. The method of claim 25, wherein the cancer is colon cancer. 
     
     
       30. The method of claim 25, wherein the cancer is pancreatic cancer. 
     
     
       31. The method of claim 25, wherein the cancer is ovarian cancer. 
     
     
       32. The method of claim 25, wherein the cancer is breast cancer. 
     
     
       33. The method of claim 25, wherein the cancer is lung cancer. 
     
     
       34. The method of claim 25, wherein the cancer is esophageal cancer. 
     
     
       35. The method of claim 25, wherein the cancer is head cancer. 
     
     
       36. The method of claim 25, wherein the cancer is neck cancer. 
     
     
       37. The method of claim 24, wherein the cancer has tumor cells expressing 191P4D12. 
     
     
       38. The method of claim 37, wherein the cancer is bladder cancer. 
     
     
       39. The method of claim 24, comprising administering to the human subject about 0.5 to about 10 milligrams of the antibody drug conjugate per kilogram of the subject's body weight. 
     
     
       40. The method of claim 24, comprising administering to the human subject about 0.5 to about 2 milligrams of the antibody drug conjugate per kilogram of the subject's body weight. 
     
     
       41. The method of claim 13, further comprising administering a therapeutically effective amount of a second therapeutic antibody. 
     
     
       42. The antibody drug conjugate of claim 16, wherein the antibody is a fully human monoclonal antibody, wherein the antibody is an IgG1, and wherein p ranges from about 2 to about 5. 
     
     
       43. A pharmaceutical composition that comprises a therapeutically effective amount of the antibody drug conjugate of claim 1 and a pharmaceutically acceptable excipient. 
     
     
       44. A pharmaceutical composition that comprises a therapeutically effective amount of the antibody drug conjugate of claim 42 and a pharmaceutically acceptable excipient. 
     
     
       45. The pharmaceutical composition of claim 44, wherein p ranges from about 3 to about 4. 
     
     
       46. The pharmaceutical composition of claim 44, wherein p is about 3.8. 
     
     
       47. A method of treating cancer in a human subject, comprising administering to said subject a therapeutically effective amount of the antibody drug conjugate of claim 42. 
     
     
       48. The method of claim 47, wherein the cancer is bladder cancer. 
     
     
       49. The method of claim 48, wherein the bladder cancer is advanced bladder cancer. 
     
     
       50. The method of claim 48, wherein the bladder cancer is metastatic bladder cancer. 
     
     
       51. The method of claim 48, comprising administering to the human subject about 0.5 to about 10 milligrams of the antibody drug conjugate per kilogram of the subject's body weight. 
     
     
       52. The method of claim 48, comprising administering to the human subject about 0.5 to about 2 milligrams of the antibody drug conjugate per kilogram of the subject's body weight. 
     
     
       53. The antibody drug conjugate of claim 2, wherein the antibody is recombinantly produced. 
     
     
       54. The antibody drug conjugate of claim 2, wherein the antibody drug conjugate has the following structure: 
       
         
           
           
               
               
           
         
         wherein L- represents the antibody and p ranges from about 1 to about 10. 
       
     
     
       55. The antibody drug conjugate of claim 54, wherein p ranges from about 2 to about 5. 
     
     
       56. The antibody drug conjugate of claim 2, wherein the antibody is conjugated to MMAE via an enzyme-cleavable linker unit. 
     
     
       57. The antibody drug conjugate of claim 56, wherein the enzyme-cleavable linker unit comprises a Val-Cit linker. 
     
     
       58. The antibody drug conjugate of claim 56, wherein the linker unit forms a bond with a sulfur atom of the antibody. 
     
     
       59. The antibody drug conjugate of claim 2, wherein the antibody is conjugated to MMAE via a linker unit that has the formula: -A a -W w -Y y -; wherein -A- is a stretcher unit, a is 0 or 1; -W- is an amino acid unit, w is an integer ranging from 0 to 12; and -Y- is a spacer unit, y is 0, 1, or 2. 
     
     
       60. The antibody drug conjugate of claim 59, wherein the stretcher unit has the structure of Formula I below; wherein the amino acid unit is Val-Cit; and wherein the spacer unit is a PAB group having the structure of Formula II below; 
       
         
           
           
               
               
           
         
        
       
     
     
       61. The antibody drug conjugate of claim 60, wherein the stretcher unit forms a bond with a sulfur atom of the antibody or antigen binding fragment thereof; and wherein the spacer unit is linked to MMAE via a carbamate group. 
     
     
       62. A pharmaceutical composition that comprises a therapeutically effective amount of the antibody drug conjugate of claim 2 and a pharmaceutically acceptable excipient. 
     
     
       63. The pharmaceutical composition of claim 62 further comprising a therapeutically effective amount of chemotherapeutic agent. 
     
     
       64. A pharmaceutical composition that comprises a therapeutically effective amount of the antibody drug conjugate of claim 55 and a pharmaceutically acceptable excipient. 
     
     
       65. The pharmaceutical composition of claim 64, wherein p ranges from about 3 to about 4. 
     
     
       66. The pharmaceutical composition of claim 64, wherein p is about 3.8. 
     
     
       67. A method of treating cancer in a subject, comprising administering to said subject a therapeutically effective amount of the antibody drug conjugate of claim 2. 
     
     
       68. A method for treating cancer in a subject, comprising administering to said subject a therapeutically effective amount of the antibody drug conjugate of claim 2 and radiation. 
     
     
       69. A method for treating cancer in a subject, comprising administering to said subject a therapeutically effective amount of the antibody drug conjugate of claim 2 and a chemotherapeutic agent. 
     
     
       70. The method of claim 67, wherein the subject is a human subject. 
     
     
       71. The method of claim 70, wherein the cancer is colon cancer, pancreatic cancer, ovarian cancer, breast cancer, lung cancer, bladder cancer, esophageal cancer, head cancer, or neck cancer. 
     
     
       72. The method of claim 70, comprising administering to the human subject about 0.5 to about 10 milligrams of the antibody drug conjugate per kilogram of the subject's body weight. 
     
     
       73. The method of claim 71, comprising administering to the human subject about 0.5 to about 2 milligrams of the antibody drug conjugate per kilogram of the subject's body weight. 
     
     
       74. The method of claim 67, further comprising administering a therapeutically effective amount of a second therapeutic antibody. 
     
     
       75. A method of treating cancer in a human subject, comprising administering to said subject a therapeutically effective amount of the antibody drug conjugate of claim 55. 
     
     
       76. The method of claim 75, wherein the cancer is bladder cancer. 
     
     
       77. The method of claim 76, wherein the bladder cancer is advanced bladder cancer. 
     
     
       78. The method of claim 76, wherein the bladder cancer is metastatic bladder cancer. 
     
     
       79. The method of claim 76, comprising administering to the human subject about 0.5 to about 10 milligrams of the antibody drug conjugate per kilogram of the subject's body weight. 
     
     
       80. The method of claim 76, comprising administering to the human subject about 0.5 to about 2 milligrams of the antibody drug conjugate per kilogram of the subject's body weight. 
     
     
       81. The antibody drug conjugate of claim 3, wherein the fragment is an Fab, F(ab′) 2 , Fv or scFv fragment. 
     
     
       82. The antibody drug conjugate of claim 3, wherein the antibody is a fully human antibody. 
     
     
       83. The antibody drug conjugate of claim 3, wherein the antibody drug conjugate has the following structure: 
       
         
           
           
               
               
           
         
         wherein L- represents the antibody or antigen binding fragment thereof and p ranges from about 2 to about 6. 
       
     
     
       84. A pharmaceutical composition that comprises a therapeutically effective amount of the antibody drug conjugate of claim 3 and a pharmaceutically acceptable excipient. 
     
     
       85. A method of treating cancer in a human subject, comprising administering to said subject a therapeutically effective amount of the antibody drug conjugate of claim 3. 
     
     
       86. A method for treating cancer in a human subject, comprising administering to said subject a therapeutically effective amount of the antibody drug conjugate of claim 3 and radiation. 
     
     
       87. A method for treating cancer in a human subject, comprising administering to said subject a therapeutically effective amount of the antibody drug conjugate of claim 3 and a chemotherapeutic agent. 
     
     
       88. The method of claim 85, wherein the cancer is colon cancer, pancreatic cancer, ovarian cancer, breast cancer, lung cancer, bladder cancer, esophageal cancer, head cancer, or neck cancer. 
     
     
       89. The method of claim 85, wherein the cancer is bladder cancer. 
     
     
       90. The method of claim 89, wherein the bladder cancer is advanced bladder cancer. 
     
     
       91. The method of claim 89, wherein the bladder cancer is metastatic bladder cancer. 
     
     
       92. A method of treating cancer in a human subject, comprising administering to said subject a therapeutically effective amount of the antibody drug conjugate of claim 83. 
     
     
       93. The method of claim 92, wherein the cancer is bladder cancer. 
     
     
       94. The method of claim 93, wherein the bladder cancer is advanced bladder cancer. 
     
     
       95. The method of claim 93, wherein the bladder cancer is metastatic bladder cancer. 
     
     
       96. The method of claim 93, comprising administering to the human subject about 0.5 to about 10 milligrams of the antibody drug conjugate per kilogram the subject's body weight. 
     
     
       97. The method of claim 93, comprising administering to the human subject about 0.5 to about 2 milligrams of the antibody drug conjugate per kilogram the subject's body weight. 
     
     
       98. The antibody drug conjugate of claim 4, wherein the antibody drug conjugate has the following structure: 
       
         
           
           
               
               
           
         
         wherein L- represents the antibody and p ranges from about 2 to about 6. 
       
     
     
       99. A pharmaceutical composition that comprises a therapeutically effective amount of the antibody drug conjugate of claim 4 and a pharmaceutically acceptable excipient. 
     
     
       100. A method of treating cancer in a human subject, comprising administering to said subject a therapeutically effective amount of the antibody drug conjugate of claim 4. 
     
     
       101. The method of claim 100, wherein the cancer is colon cancer, pancreatic cancer, ovarian cancer, breast cancer, lung cancer, bladder cancer, esophageal cancer, head cancer, or neck cancer. 
     
     
       102. The method of claim 100, wherein the cancer is bladder cancer. 
     
     
       103. The method of claim 102, wherein the bladder cancer is advanced bladder cancer. 
     
     
       104. The method of claim 102, wherein the bladder cancer is metastatic bladder cancer. 
     
     
       105. A method of treating cancer in a human subject, comprising administering to said subject a therapeutically effective amount of the antibody drug conjugate of claim 98. 
     
     
       106. The method of claim 105, wherein the cancer is bladder cancer. 
     
     
       107. The method of claim 106, wherein the bladder cancer is advanced bladder cancer. 
     
     
       108. The method of claim 106, wherein the bladder cancer is metastatic bladder cancer. 
     
     
       109. The method of claim 106, comprising administering to the human subject about 0.5 to about 10 milligrams of the antibody drug conjugate per kilogram of the subject's body weight. 
     
     
       110. The method of claim 106, comprising administering to the human subject about 0.5 to about 2 milligrams of the antibody drug conjugate per kilogram of the subject's body weight.