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 - 78 . (canceled) 
     
     
         79 . A pharmaceutical formulation comprising an antibody drug conjugate, and a pharmaceutically acceptable diluent, carrier or excipient, wherein the antibody drug conjugate comprises an antibody covalently attached by a linker to one or more toxin drug moieties, the conjugate 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. 
 
 
     
     
         80 . The pharmaceutical formulation of  claim 79  further comprising a therapeutically effective amount of a chemotherapeutic agent selected from letrozole, oxaliplatin, doxetaxel, 5-FU, leucovorin, lapatinib, and gemcitabine. 
     
     
         81 . An article of manufacture comprising
 an antibody-drug conjugate comprising an antibody covalently attached by a linker to one or more toxin drug moieties, the conjugate 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; 
 a container; and 
 a package insert or label indicating that the compound can be used to treat cancer characterized by the overexpression of a TAT10772 polypeptide. 
 
     
     
         82 . The article of manufacture of  claim 81  wherein the cancer is prostate cancer, cancer of the urinary tract, pancreatic cancer, lung cancer, breast cancer, colon cancer or ovarian cancer. 
     
     
         83 . The article of manufacture of  claim 81 , wherein the antibody further comprises a V H  acceptor human consensus framework sequence of any one of SEQ ID NOS:184-193. 
     
     
         84 . The article of manufacture of  claim 81 , wherein the antibody further comprises a V L  acceptor human consensus framework sequence of any one of SEQ ID NOS:194-197. 
     
     
         85 . The article of manufacture of  claim 81 , wherein the antibody comprises a V H  acceptor human consensus framework sequence of any one of SEQ ID NOS:184-193 and a V L  acceptor human consensus framework sequence of any one of SEQ ID NOS:194-197. 
     
     
         86 . The article of manufacture of  claim 81 , wherein the antibody is an antibody fragment. 
     
     
         87 . The article of manufacture of  claim 81 , wherein the antibody is a chimeric or a humanized antibody. 
     
     
         88 . The article of manufacture of  claim 81 , wherein the antibody comprises the V H  sequence shown as SEQ ID NO:208. 
     
     
         89 . The article of manufacture of  claim 81 , wherein the antibody comprises the V L  sequence shown as SEQ ID NO:211. 
     
     
         90 . The article of manufacture of  claim 81 , wherein the antibody comprises the V H  sequence shown as SEQ ID NO:208 and the V L  sequence shown as SEQ ID NO:211. 
     
     
         91 . The article of manufacture of  claim 81 , wherein D is an auristatin. 
     
     
         92 . The article of manufacture of  claim 91 , wherein the auristatin is MMAE or MMAF. 
     
     
         93 . The article of manufacture of  claim 81 , wherein L is MC-val-cit-PAB or MC. 
     
     
         94 . The article of manufacture of  claim 81 , wherein L is SMCC, SPP, or BMPEO. 
     
     
         95 . The article of manufacture of  claim 81 , 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. 
     
     
         96 . The article of manufacture of  claim 81 , wherein the antibody drug conjugate has the formula Ab-MC-val-cit-PAB-MMAE. 
     
     
         97 . The article of manufacture of  claim 81 , wherein the antibody is attached to the linker through a non-native cysteine amino acid residue.