Compositions and methods for the diagnosis and treatment of tumor

Abstract

The invention is directed to antibody drug conjugate compositions of matter useful for the diagnosis and treatment of tumors in mammals and to methods of using those compositions of matter for the same.

1 - 23 . (canceled) 
     
     
         24 . A method of therapeutically treating a mammal having a cancerous tumor comprising cells that express a protein comprising the amino acid sequence of SEQ ID NO:2, said method comprising administering to said mammal a therapeutically effective amount of an antibody drug conjugate comprising an antibody covalently attached by a linker to one or more toxin drug moieties, the compound having the formula:
     Ab -( L - D ) p      
       or a pharmaceutically acceptable salt or solvate thereof, wherein:
 Ab is an antibody that comprises three light chain hypervariable regions (HVR-L1, HVR-L2 and HVR-L3) and three heavy chain hypervariable regions (HVR-H1, HVR-H2 and HVR-H3) wherein 
 (a) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 119; 
 (b) HVR-L2 comprises the amino acid sequence of SEQ ID NO:121; 
 (c) HVR-L3 comprises the amino acid sequence of SEQ ID NO:122; 
 (d) HVR-H1 comprises the amino acid sequence of SEQ ID NO:123; 
 (e) HVR-H2 comprises the amino acid sequence of SEQ ID NO: 125; and 
 (f) HVR-H3 comprises the amino acid sequence of SEQ ID NO:183; 
 L is a linker; 
 D is a toxin drug moiety; and 
 p is 1 to about 20. 
 
     
     
         25 - 78 . (canceled) 
     
     
         79 . The method of  claim 24 , wherein Ab is a humanized 3A5. 
     
     
         80 . The method of  claim 24  wherein the antibody comprises the V H  sequence of SEQ ID NO:208 and the V L  sequence of SEQ ID NO:211. 
     
     
         81 . The method of  claim 24  or  80 , wherein D is a maytansinoid. 
     
     
         82 . The method of  claim 24  or  80 , wherein the maytansinoid is DM1. 
     
     
         83 . The method of  claim 24  or  80 , wherein D is an auristatin. 
     
     
         84 . The method of  claim 24  or  80 , wherein the auristatin is MMAE or MMAF. 
     
     
         85 . The method of  claim 24  or  80 , wherein L is MC-val-cit-PAB or MC. 
     
     
         86 . The method of  claim 24  or  80 , wherein L is SMCC, SPP, or BMPEO. 
     
     
         87 . The method of  claim 24  or  80 , wherein the antibody drug conjugate is selected from the formula: Ab-MC-val-cit-PAB-MMAE, Ab-MC-val-cit-PAB-MMAF, Ab-MC-MMAE, Ab-MC-MMAF, Ab-SPP-DM1, and Ab-SMCC-DM1. 
     
     
         88 . The method of  claim 80 , wherein the antibody drug conjugate is Ab-MC-val-cit-PAB-MMAE. 
     
     
         89 . The method of  claim 24 ,  80  or  88 , wherein the antibody is attached to the linker through a cysteine thiol of the antibody. 
     
     
         90 . The method of  claim 24 ,  80  or  88 , wherein the cancer is selected from the group consisting of prostate cancer, cancer of the urinary tract, pancreatic cancer, lung cancer, breast cancer, colon cancer and ovarian cancer. 
     
     
         91 . The method of  claim 24 ,  80  or  88 , wherein the patient is administered a chemotherapeutic agent, in combination with the antibody-drug conjugate compound, where the chemotherapeutic agent is selected from letrozole, oxaliplatin, doxetaxel, 5-FU, leucovorin, lapatinib, and gemcitabine.