Site specific her2 antibody drug conjugates

Abstract

The present invention provides site specific HER2 antibody drug conjugates and methods for preparing and using the same.

1 - 23 . (canceled) 
     
     
         24 . A method of treating a HER2 expressing cancer in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a composition comprising an antibody drug conjugate of the formula:
   Ab-(L-D),   wherein:   (a) Ab is an antibody that binds to HER2 and comprises
 (1) a heavy chain variable region comprising three CDRs comprising SEQ ID NOs:2, 3 and 4; 
 (2) a heavy chain constant region of any of SEQ ID NOs:17, 5, 13, 21, 23, 25, 27, 29, 31, 33, 35, 37 or 39; 
 (3) a light chain variable region comprising three CDRs comprising SEQ ID NOs:8, 9 and 10; 
 (4) a light chain constant region of any of SEQ ID NOs:41, 11 or 43; and 
   (b) L-D is a linker-drug moiety, wherein L is a linker, and D is a drug, with the proviso that when the heavy chain constant region is SEQ ID NO:5 the light chain constant region is not SEQ ID NO:11.   
     
     
         25 . The method of  claim 24 , wherein the cancer is a solid tumor. 
     
     
         26 . (canceled) 
     
     
         27 . The method of  claim 24 , wherein the solid tumor is selected from the group consisting of breast cancer, ovarian cancer, lung cancer and gastric cancer. 
     
     
         28 . The method of  claim 27 , wherein the breast cancer is estrogen and progesterone receptor negative or triple negative breast cancer (TNBC). 
     
     
         29 . The method of  claim 27 , wherein the lung cancer is non-small cell cancer (NSLC). 
     
     
         30 . The method of  claim 24 , wherein the subject has been previously treated with trastuzumab and/or trastuzumab emtansine either of which alone or in combination with another therapeutic agent. 
     
     
         31 . The method of  claim 30 , wherein the therapeutic agent is a taxane. 
     
     
         32 . The method of  claim 30 , wherein the cancer is resistant to, refractory to and/or relapsed from treatment with trastuzumab and/or trastuzumab emtansine either of which alone or in combination with another therapeutic agent. 
     
     
         33 . The method of  claim 32 , wherein the therapeutic agent is a taxane. 
     
     
         34 . The method of  claim 24 , wherein the cancer expresses HER2 at a high level. 
     
     
         35 . The method of  claim 34 , wherein the cancer expresses HER2 at a 3+ level as determined by immunohistochemistry (IHC) and/or a fluorescence in situ hybridization (FISH) amplification ratio of ≥2.0. 
     
     
         36 . The method of  claim 24 , wherein the cancer expresses HER2 at a moderate level. 
     
     
         37 . The method of  claim 36 , wherein the cancer expresses HER2 at a 2+ level as determined by immunohistochemistry (IHC) and/or a fluorescence in situ hybridization (FISH) amplification ratio of <2.0 
     
     
         38 . The method of  claim 24 , wherein the cancer expresses HER2 at a low level. 
     
     
         39 . The method of  claim 38 , wherein the cancer expresses HER2 at a 1+ level as determined by immunohistochemistry (IHC) and/or a fluorescence in situ hybridization (FISH) amplification ratio of <2.0. 
     
     
         40 . The method of  claim 35 , wherein IHC is performed using a Dako Hercptest™ assay and FISH is performed using a Dako HER2 FISH Pharm Dx′ assay. 
     
     
         41 . The method of  claim 37 , wherein IHC is performed using a Dako Hercptest™ assay and FISH is performed using a Dako HER2 FISH Pharm Dx′ assay. 
     
     
         42 . The method of  claim 39 , wherein IHC is performed using a Dako Hercptest™ assay and FISH is performed using a Dako HER2 FISH Pharm Dx′ assay. 
     
     
         43 . The method of  claim 24 , wherein:
 (a) the antibody comprises a heavy chain comprising SEQ ID NO:18 and a light chain comprising SEQ ID NO:42; and   (b) L is a linker of vc and D is an auristatin of 2-methylalanyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1 S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         44 . The method of  claim 24 , wherein:
 (a) the antibody comprises a heavy chain comprising SEQ ID NO:14 and a light chain comprising SEQ ID NO:44; and   (b) L is a linker of AcLysvc and D is an auristatin of 2-methylalanyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1 S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide or a pharmaceutically acceptable salt or solvate thereof.