Antibody drug conjugates

Abstract

The present invention relates to anti-FGFR2 antibodies, antibody fragments, antibody drug conjugates, and their uses for the treatment of cancer.

1 . An antibody drug conjugate of the formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein 
         Ab is an antibody or antigen binding fragment thereof that specifically binds to human FGFR2; and 
         n is an integer from 1 to 10. 
       
     
     
         2 - 7 . (canceled) 
     
     
         8 . The antibody drug conjugate of  claim 1 , wherein said antibody or antigen binding fragment thereof comprises a heavy chain variable region that comprises: (a) a VH CDR1 of SEQ ID NO: 101, (b) a VH CDR2 of SEQ ID NO: 102, (c) a VH CDR3 of SEQ ID NO: 103; and a light chain variable region that comprises: (d) a VL CDR1 of SEQ ID NO: 111, (e) a VL CDR2 of SEQ ID NO: 112, (f) a VL CDR3 of SEQ ID NO: 113, wherein the CDR is defined in accordance with the Kabat definition. 
     
     
         9 . The antibody drug conjugate of  claim 1 , wherein said antibody or antigen binding fragment thereof comprises a heavy chain variable region that comprises: (a) a VH CDR1 of SEQ ID NO: 201, (b) a VH CDR2 of SEQ ID NO: 202, (c) a VH CDR3 of SEQ ID NO: 203; and a light chain variable region that comprises: (d) a VL CDR1 of SEQ ID NO: 211, (e) a VL CDR2 of SEQ ID NO: 212, (f) a VL CDR3 of SEQ ID NO: 213, wherein the CDR is defined in accordance with the Kabat definition. 
     
     
         10 . The antibody drug conjugate of  claim 1 , wherein said antibody or antigen binding fragment thereof comprises a heavy chain variable region that comprises: (a) a VH CDR1 of SEQ ID NO: 221, (b) a VH CDR2 of SEQ ID NO: 222, (c) a VH CDR3 of SEQ ID NO: 223; and a light chain variable region that comprises: (d) a VL CDR1 of SEQ ID NO: 231, (e) a VL CDR2 of SEQ ID NO: 232, (f) a VL CDR3 of SEQ ID NO: 233, wherein the CDR is defined in accordance with the Kabat definition. 
     
     
         11 . The antibody drug conjugate of  claim 1 , wherein said antibody or antigen binding fragment thereof comprises a heavy chain variable region that comprises: (a) a VH CDR1 of SEQ ID NO: 1, (b) a VH CDR2 of SEQ ID NO: 2, (c) a VH CDR3 of SEQ ID NO: 3; and a light chain variable region that comprises: (d) a VL CDR1 of SEQ ID NO: 11, (e) a VL CDR2 of SEQ ID NO: 12, (f) a VL CDR3 of SEQ ID NO: 13, wherein the CDR is defined in accordance with the Kabat definition. 
     
     
         12 . The antibody drug conjugate of  claim 1 , wherein said antibody or antigen binding fragment thereof comprises a heavy chain variable region that comprises: (a) a VH CDR1 of SEQ ID NO: 181, (b) a VH CDR2 of SEQ ID NO: 182, (c) a VH CDR3 of SEQ ID NO: 183; and a light chain variable region that comprises: (d) a VL CDR1 of SEQ ID NO: 191, (e) a VL CDR2 of SEQ ID NO: 192, (f) a VL CDR3 of SEQ ID NO: 193, wherein the CDR is defined in accordance with the Kabat definition. 
     
     
         13 - 30 . (canceled) 
     
     
         31 . A method of treating an FGFR2 positive cancer in a patient in need thereof, comprising administering to said patient the antibody drug conjugate of  claim 1 . 
     
     
         32 . The method of  claim 31 , wherein said cancer is selected from the group consisting of gastric cancer, breast cancer, alveolar rhabdomyosarcoma, liver cancer, adrenal cancer, lung cancer, colon cancer and endometrial cancer. 
     
     
         33 . The method of  claim 31  further comprising administering to said patient a tyrosine kinase inhibitor, an IAP inhibitor, a Bcl2 inhibitor, an MCL1 inhibitor, or another FGFR2 inhibitor. 
     
     
         34 . The method of  claim 33 , wherein said another FGFR2 inhibitor is 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea. 
     
     
         35 - 41 . (canceled) 
     
     
         42 . A nucleic acid that encodes the antibody or antigen binding fragment of  claim 1 . 
     
     
         43 . A vector comprising the nucleic acid of  claim 42 . 
     
     
         44 . A host cell comprising the vector according to  claim 43 . 
     
     
         45 . A process for producing an antibody or antigen binding fragment comprising cultivating the host cell of  claim 44  and recovering the antibody from the culture. 
     
     
         46 . A process for producing an anti-FGFR2 antibody drug conjugate comprising:
 (a) chemically linking SMCC to a drug moiety DM-1;   (b) conjugating said linker-drug to the antibody recovered from the cell culture of  claim 45 ; and   (c) purifying the antibody drug conjugate.   
     
     
         47 . The antibody drug conjugate made according to  claim 46  having an average DAR, measured with a UV spectrophotometer, about 3.5. 
     
     
         48 . (canceled) 
     
     
         49 . (canceled)