Compositions and Methods for Diagnosing and Treating Cancer

Abstract

Isolated antibodies that specifically bind the human MET Receptor and inhibit MET signaling are described. Also described are methods of treating cancer, the methods comprising administering a therapeutically effective amount of the provided MET antibodies and combinations thereof.

1 - 135 . (canceled) 
     
     
         136 . An isolated polynucleotide encoding an antibody that specifically binds human MET, wherein the antibody is selected from the group consisting of:
 (a) an antibody comprising (i) a heavy chain CDR1 comprising GFSLSTSGMVVS (SEQ ID NO:3), a heavy chain CDR2 comprising FISWDDDKYYSTSLKT (SEQ ID NO:4), and a heavy chain CDR3 comprising EPGRYGGYYFDY (SEQ ID NO:5); and (ii) a light chain CDR1 comprising RASQTISHYLA (SEQ ID NO:8), a light chain CDR2 comprising AASILQS (SEQ ID NO:9), and a light chain CDR3 comprising QQYSGFPV (SEQ ID NO:10);   (b) an antibody-comprising (i) a heavy chain CDR1 comprising GGSISGYYWS (SEQ ID NO: 13), a heavy chain CDR2 comprising EIYYAGSTLYNPSLKG (SEQ ID NO:14), and a heavy chain CDR3 comprising HYGLDWFGDTGMDV (SEQ ID NO:15); and (ii) a light chain CDR1 comprising SGDNLGDKYVH (SEQ ID NO:18), a light chain CDR2 comprising DDNERPSG (SEQ ID NO:19), and a light chain CDR3 comprising SAYGSHSGT (SEQ ID NO:20); and   (c) an antibody comprising (i) a heavy chain CDR1 comprising GGSISGYYWS (SEQ ID NO:13), a heavy Chain CDR2 comprising EIYYAGSTLYNPSLKG (SEQ ID NO:14), and a heavy chain CDR3 comprising HYGLDWFGDTGMDV (SEQ ID NO:15); and (ii) a light chain. CDR1 comprising SGDNLGEQYVH (SEQ ID NO:23), a light chain CDR2 comprising DDSERPSG (SEQ ID NO:24), and a light chain CDR3 comprising QSYTFYPNSR (SEQ ID NO:25).   
     
     
         137 . The polynucleotide of  claim 136 , wherein the antibody comprises:
 (a) a heavy chain variable region having at least 95% identity to SEQ ID NO:2 and a light chain variable region having at least 95% identity to SEQ ID NO:7;   (b) a heavy chain variable region having at least 95% identity to SEQ ID NO:12 and a light chain variable region having at least 95% identity to SEQ ID NO:17; or   (c) a heavy chain variable region having at least 95% identity to SEQ ID NO:12 and a light chain variable region having at least 95% identity to SEQ ID NO:22.   
     
     
         138 . The isolated polynucleotide of  claim 136 , wherein the antibody comprises:
 (a) a polypeptide having the amino acid sequence of SEQ ID NO:2 and a polypeptide having the amino acid sequence of SEQ ID NO:7;   (b) a polypeptide having the amino acid sequence of SEQ ID NO:12 and a polypeptide having the amino acid sequence of SEQ ID NO:17; or   (c) a polypeptide having the amino acid sequence of SEQ ID NO:12 and a polypeptide having the amino acid sequence of SEQ ID NO:22.   
     
     
         139 . The polynucleotide of  claim 136 , wherein the antibody is a monovalent antibody. 
     
     
         140 . The polynucleotide of  claim 136 , wherein the antibody is an antigen-binding antibody fragment. 
     
     
         145 . The polynucleotide of  claim 140 , wherein the antibody fragment is monovalent. 
     
     
         146 . A vector comprising the polynucleotide of  claim 136 . 
     
     
         147 . An isolated cell comprising the polynucleotide of  claim 136 . 
     
     
         148 . An isolated cell comprising the vector of  claim 147 . 
     
     
         149 . An isolated polynucleotide comprising at least one polynucleotide sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:11, SEQ ID NO:16, and SEQ NO:21. 
     
     
         150 . The polynucleotide of  claim 149  comprising SEQ ID NO:1 and SEQ ID NO:6. 
     
     
         151 . The polynucleotide of  claim 149  comprising SEQ ID NO:11 and SEQ ID NO:16. 
     
     
         152 . The polynucleotide of  claim 149  comprising SEQ ID NO:11 and SEQ ID NO:21. 
     
     
         153 . An isolated polynucleotide comprising a polynucleotide sequence which hybridizes to a polynucleotide sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:6, SEQ ID NO:11, SEQ ID NO:16, and SEQ ID NO:21, or its complement. 
     
     
         154 . The polynucleotide of  claim 153 , wherein the hybridization is under stringent hybridization conditions. 
     
     
         155 . An isolated polynucleotide encoding a first arm of a bispecific antibody, wherein the first arm of the bispecific antibody specifically binds human MET and is selected from the group consisting of:
 (a) an antibody comprising (i) a heavy chain CDR1 comprising GFSLSTSGMVVS (SEQ ID NO:3), a heavy chain CDR2 comprising FISWDDDKYYSTSLKT (SEQ ID NO:4), and a heavy chain CDR3 comprising EPGRYGGYYFDY (SEQ ID NO:5); and (ii) a light chain CDR1 comprising RASQTISHYLA (SEQ ID NO:8), a light chain CDR2 comprising AASILQS (SEQ ID NO:9), and a light chain CDR3 comprising, QQYSGFPV (SEQ ID NO:10);   (b) an antibody comprising (i) a heavy chain CDR1 comprising GGSISGYYWS (SEQ ID NO:13), a heavy chain CDR2 comprising EIYYAGSTLYNPSLKG (SEQ ID NO:14), and a heavy chain CDR3 comprising HYGLDWFGDTGMDV (SEQ ID NO:15); and (ii) a light chain CDR1 comprising SGDNLGDKYVH (SEQ ID NO:18), a light chain CDR2 comprising DDNERPSG (SEQ ID NO:19), and a light chain CDR3 comprising SAYGSHSGT (SEQ ID NO:20); and   (c) an antibody comprising (i) a heavy chain CDR1 comprising GGSISGYYWS (SEQ ID NO:13), a heavy chain CDR2 comprising EIYYAGSTLYNPSLKG (SEQ ID NO:14), and a heavy chain CDR3 comprising HYGLDWFGDTGMDV: (SEQ ID NO:15); and (ii) a light chain CDR1 comprising SGDNLGEQYVH (SEQ ID NO:23), a light chain CDR2 comprising DDSERPSG (SEQ ID NO:24), and a light chain CDR3 comprising QSYTFYPNSR (SEQ ID NO 25).   
     
     
         156 . The polynucleotide of  claim 155 , Wherein the first arm of the bispecific antibody comprises:
 (a) a heavy chain variable region having at least 95% identity to SEQ ID NO:2 and a light chain variable region having at least 95% identity to SEQ ID NO:7;   (b) a heavy chain variable region having at least 95% identity to SEQ ID NO:12 and a light chain variable region having at least 95% identity to SEQ ID NO:17; or   (c) a heavy chain variable region having at least 95% identity to SEQ ID NO:12 and a light chain variable region having at least 95% identity to SEQ ID NO:22.   
     
     
         157 . The isolated polynucleotide of  claim 155 , wherein the first arm of the bispecific antibody comprises:
 (a) a polypeptide having the amino acid sequence of SEQ ID NO:2 and a polypeptide having the amino acid sequence of SEQ ID NO:7;   (b) a polypeptide having the amino acid sequence of SEQ ID NO:12 and a polypeptide having the amino acid sequence of SEQ ID NO: 17; or   (c) a polypeptide having the amino acid sequence of SEQ ID NO:12 and a polypeptide having the amino acid sequence of SEQ ID NO:22.