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.

1 . (canceled) 
     
     
         2 . An antibody drug conjugate comprising an anti-191P4D12 antibody or antigen binding fragment thereof, wherein:
 a) the anti-191P4D12 antibody or antigen binding fragment thereof binds an epitope within the V domain of 191P4D12, wherein the V domain comprises amino acids 1-150 of SEQ ID NO: 2, and wherein the antibody or antigen binding fragment thereof binds to at least A76 and S91 of SEQ ID NO: 2; or   b) the antibody or antigen binding fragment thereof binds to the extracellular domain of 191P4D12 with a KD of 1.6 × 10 -8  M or less as determined by surface plasmon resonance, and wherein the extracellular domain of 191P4D12 comprises amino acids 1-348 of SEQ ID NO: 2.   
     
     
         3 . The antibody drug conjugate of  claim 2 , wherein the antibody or antigen binding fragment thereof binds to the extracellular domain of 191P4D12 with a KD of 1.6 × 10 -8  or less as determined by surface plasmon resonance, wherein the extracellular domain of 191P4D12 comprises amino acids 1-348 of SEQ ID NO: 2, and wherein the antibody or antigen binding fragment thereof binds to at least A76 and S91 of SEQ ID NO: 2. 
     
     
         4 . The antibody drug conjugate of  claim 2 , wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least 80% homologous to the heavy chain variable region amino acid sequence set forth in SEQ ID NO:7 and a light chain variable region comprising an amino acid sequence at least 80% homologous to the light chain variable region amino acid sequence set forth in SEQ ID NO:8. 
     
     
         5 . The antibody drug conjugate of  claim 4 , wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, or 90% homologous to the heavy chain variable region amino acid sequence set forth in SEQ ID NO:7 and a light chain variable region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, or 90% homologous to the light chain variable region amino acid sequence set forth in SEQ ID NO:8. 
     
     
         6 . The antibody drug conjugate of  claim 2 , wherein:
 a) the antigen binding fragment is an Fab, F(ab′)2, Fv or scFv fragment;   b) the antibody is a fully human antibody; or   c) the antibody or antigen binding fragment thereof is recombinantly produced.   
     
     
         7 . The antibody drug conjugate of  claim 2 , wherein the antibody or antigen binding fragment thereof is conjugated to MMAE via a linker. 
     
     
         8 . The antibody drug conjugate of  claim 7 , wherein the linker comprises valine-citrulline. 
     
     
         9 . The antibody drug conjugate of  claim 7 , wherein the linker is an enzyme-cleavable linker, wherein the linker unit forms a bond with a sulfur atom of the antibody or antigen binding fragment thereof. 
     
     
         10 . The antibody drug conjugate of  claim 7 , wherein the linker unit has a formula of: -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; wherein the stretcher unit has the structure of Formula (1) below; the amino acid unit is valine citrulline; and the spacer unit is a PAB group having the structure of Formula (2) below;
                                             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.   
     
     
         11 . The antibody drug conjugate of  claim 2 , comprising:
 a) from 1 to 10 units of MMAE per said antibody or antigen binding fragment;   b) from 2 to 5 units of MMAE per said antibody or antigen binding fragment; or   c) from 3 to 5 units of MMAE per said antibody or antigen binding fragment.   
     
     
         12 . The antibody drug conjugate of  claim 2 , wherein the antibody drug conjugate has the following structure:
                       wherein L- represents the anti-191P4D12 antibody or antigen binding fragment, and p ranges from 1 to 10.   
     
     
         13 . The antibody drug conjugate of  claim 12 , wherein p is from 3 to 5. 
     
     
         14 . The antibody drug conjugate of  claim 12 , wherein p is 3.8. 
     
     
         15 . An anti-191P4D12 antibody or antigen binding fragment thereof, wherein:
 a) the anti-191P4D12 antibody or antigen binding fragment thereof binds an epitope within the V domain of 191P4D12, wherein the V domain comprises amino acids 1-150 of SEQ ID NO: 2, and wherein the antibody or antigen binding fragment thereof binds at least A76 and S91 of SEQ ID NO: 2; or   b) the anti-191P4D12 antibody or antigen binding fragment thereof binds to the extracellular domain of 191P4D12 with a KD of 1.6 × 10 -8  M or less as determined by surface plasmon resonance, and wherein the extracellular domain of 191P4D12 comprises amino acids 1-348 of SEQ ID NO: 2.   
     
     
         16 . The antibody or antigen binding fragment thereof of  claim 15 , wherein the anti-191P4D12 antibody or antigen binding fragment thereof binds to the extracellular domain of 191P4D12 with a KD of 1.6 nM or less as determined by surface plasmon resonance, wherein the extracellular domain of 191P4D12 comprises amino acids 1-348 of SEQ ID NO: 2, and wherein the antibody or antigen binding fragment thereof binds at least A76 and S91 of SEQ ID NO: 2. 
     
     
         17 . The antibody or antigen binding fragment thereof of  claim 15 , wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least 80% homologous to the heavy chain variable region amino acid sequence set forth in SEQ ID NO:7 and a light chain variable region comprising an amino acid sequence at least 80% homologous to the light chain variable region amino acid sequence set forth in SEQ ID NO:8. 
     
     
         18 . The antibody or antigen binding fragment thereof of  claim 17 , wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, or 90% homologous to the heavy chain variable region amino acid sequence set forth in SEQ ID NO:7 and a light chain variable region comprising an amino acid sequence at least 85%, 86%, 87%, 88%, 89%, or 90% homologous to the light chain variable region amino acid sequence set forth in SEQ ID NO:8. 
     
     
         19 . The antibody or antigen binding fragment thereof of  claim 15 , wherein:
 a) the antigen binding fragment is an Fab, F(ab′)2, Fv or scFv fragment;   b) the antibody is a fully human antibody; or   c) the antibody or antigen binding fragment is recombinantly produced.   
     
     
         20 . A pharmaceutical composition comprising a therapeutically effective amount of the antibody or antigen binding fragment thereof of  claim 15 , and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is for preventing or treating cancer in a human subject. 
     
     
         21 . The pharmaceutical composition of  claim 20 , wherein the cancer comprises tumor cells expressing 191P4D12. 
     
     
         22 . The pharmaceutical composition of  claim 20 , wherein the cancer is colon cancer, ovarian cancer, esophageal cancer, head and neck cancer, pancreatic cancer, lung cancer, bladder cancer, or breast cancer. 
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein the cancer is bladder cancer. 
     
     
         24 . The pharmaceutical composition of  claim 22 , wherein the cancer is breast cancer. 
     
     
         25 . The pharmaceutical composition of  claim 22 , wherein the cancer is esophageal cancer. 
     
     
         26 . The pharmaceutical composition of  claim 22 , wherein the cancer is head and neck cancer. 
     
     
         27 . The pharmaceutical composition of  claim 23 , wherein the bladder cancer is advanced bladder cancer. 
     
     
         28 . The pharmaceutical composition of  claim 23 , wherein the bladder cancer is metastatic bladder cancer.