ANTI-cMet ANTIBODY DRUG CONJUGATES AND METHODS FOR THEIR USE

Abstract

The present disclosure provides antibody drug conjugates that bind human cMET, their methods of making, and their uses to treat patients having cancer.

We claim: 
     
         1 .- 137 . (canceled) 
     
     
         138 . A method of treating a non-small cell lung cancer (“NSCLC”) that overexpresses cMet, comprising administering to a human subject having said NSCLC an anti-cMet antibody drug conjugate (“ADC”), wherein the conjugated drug is monomethyl auristatin E (“MMAE”), and the ADC has the following structure: 
       
         
           
           
               
               
           
         
         wherein Ab is an anti-human cMet antibody which is an IgG antibody comprising heavy chains each consisting of the amino acid sequence of SEQ ID NO:86 and light chains each consisting of the amino acid sequence of SEQ ID NO:87, n has a value of 2 or 4, and conjugation of each of the MMAE drugs to the Ab is via a thioether linkage formed with a sulfhydryl group of a cysteine residue, 
         and wherein the anti-cMet ADC is administered in an amount ranging from about 0.15 mg/kg to about 3.3 mg/kg once every two weeks (Q2W) or once every three weeks (Q3W). 
       
     
     
         139 . The method of  claim 138 , in which the ADC is administered as monotherapy. 
     
     
         140 . The method of  claim 139 , wherein the ADC is administered in an amount of about 1.9 mg/kg once every two weeks (Q2W). 
     
     
         141 . The method of  claim 139 , in which the NSCLC is a non-squamous NSCLC. 
     
     
         142 . The method of  claim 139 , in which the NSCLC is squamous NSCLC. 
     
     
         143 . The method of  claim 139 , in which a cMet overexpressing tumor of the NSCLC cancer carries cells having amplification of the MET gene. 
     
     
         144 . The method of  claim 139 , in which a cMet overexpressing tumor of the NSCLC cancer carries cells having a mutation of the MET gene. 
     
     
         145 . The method of  claim 139 , in which the cMet overexpressing tumor of the NSCLC cancer carries cells having a mutation of the EGFR gene. 
     
     
         146 . The method of  claim 138 , in which the ADC is administered adjunctive to an additional anticancer agent, wherein the additional anticancer agent is administered according to its FDA-approved dosing regimen. 
     
     
         147 . The method of  claim 146 , wherein the additional agent is a tyrosine kinase inhibitor (TKI). 
     
     
         148 . The method of  claim 147 , wherein the TKI is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). 
     
     
         149 . The method of  claim 148 , wherein the EGFR-TKI is erlotinib. 
     
     
         150 . The method of  claim 146 , wherein the ADC is administered in an amount of about 1.9 mg/kg once every two weeks (Q2W). 
     
     
         151 . The method of  claim 146 , wherein the ADC is administered in an amount of about 2.7 mg/kg once every three weeks (Q3W). 
     
     
         152 . The method of  claim 146 , in which the NSCLC is a non-squamous NSCLC. 
     
     
         153 . The method of  claim 146 , in which the NSCLC is squamous NSCLC. 
     
     
         154 . The method of  claim 146 , in which a cMet overexpressing tumor of the NSCLC cancer carries cells having amplification of the MET gene. 
     
     
         155 . The method of  claim 146 , in which a cMet overexpressing tumor of the NSCLC cancer carries cells having a mutation of the MET gene. 
     
     
         156 . The method of  claim 146 , in which the cMet overexpressing tumor of the NSCLC cancer carries cells having a mutation of the EGFR gene. 
     
     
         157 . A method of treating a gastric cancer that overexpresses cMet, comprising administering to a human subject having said gastric cancer an anti-cMet antibody drug conjugate (“ADC”), wherein the conjugated drug is monomethyl auristatin E (“MMAE”), and the ADC has the following structure: 
       
         
           
           
               
               
           
         
         wherein Ab is an anti-human cMet antibody which is an IgG antibody comprising heavy chains each consisting of the amino acid sequence of SEQ ID NO:86 and light chains each consisting of the amino acid sequence of SEQ ID NO:87, n has a value of 2 or 4, and conjugation of each of the MMAE drugs to the Ab is via a thioether linkage formed with a sulfhydryl group of a cysteine residue, 
         and wherein the anti-cMet ADC is administered in an amount ranging from about 0.15 mg/kg to about 3.3 mg/kg once every two weeks (Q2W) or once every three weeks (Q3W). 
       
     
     
         158 . The method of  claim 157 , in which a biopsy of the cMet overexpressing tumor tissue from the subject has an immunohistochemistry (IHC) score of 2+ and/or an H-score of greater than or equal to 150. 
     
     
         159 . The method of  claim 157 , in which the ADC is administered as monotherapy. 
     
     
         160 . The method of  claim 157 , in which the ADC is administered adjunctive to an additional anticancer agent, wherein the additional anticancer agent is administered according to its FDA-approved dosing regimen. 
     
     
         161 . A method of treating a gastroesophageal cancer that overexpresses cMet, comprising administering to a human subject having said gastroesophageal cancer an anti-cMet antibody drug conjugate (“ADC”), wherein the conjugated drug is monomethyl auristatin E (“MMAE”), and the ADC has the following structure: 
       
         
           
           
               
               
           
         
         wherein Ab is an anti-human cMet antibody which is an IgG antibody comprising heavy chains each consisting of the amino acid sequence of SEQ ID NO:86 and light chains each consisting of the amino acid sequence of SEQ ID NO:87, n has a value of 2 or 4, and conjugation of each of the MMAE drugs to the Ab is via a thioether linkage formed with a sulfhydryl group of a cysteine residue, 
         and wherein the anti-cMet ADC is administered in an amount ranging from about 0.15 mg/kg to about 3.3 mg/kg once every two weeks (Q2W) or once every three weeks (Q3W). 
       
     
     
         162 . The method of  claim 161 , in which a biopsy of the cMet overexpressing tumor tissue from the subject has an immunohistochemistry (IHC) score of 2+ and/or an H-score of greater than or equal to 150. 
     
     
         163 . The method of  claim 161 , in which the ADC is administered as monotherapy. 
     
     
         164 . The method of  claim 161 , in which the ADC is administered adjunctive to an additional anticancer agent, wherein the additional anticancer agent is administered according to its FDA-approved dosing regimen. 
     
     
         165 . A composition comprising an anti-cMet antibody drug conjugate (“ADC”), sucrose, polysorbate 80, and histidine, wherein the conjugated drug is monomethyl auristatin E (“MMAE”), and the ADC has the following structure: 
       
         
           
           
               
               
           
         
         wherein Ab is an anti-human cMet antibody which is an IgG antibody comprising heavy chains each consisting of the amino acid sequence of SEQ ID NO:86 and light chains each consisting of the amino acid sequence of SEQ ID NO:87, n has a value of 2 or 4, and conjugation of each of the MMAE drugs to the Ab is via a thioether linkage formed with a sulfhydryl group of a cysteine residue. 
       
     
     
         166 . The composition of  claim 165 , which is an aqueous composition buffered with histidine at pH 6.0, wherein the aqueous composition comprises about 7% (w/v) sucrose, 0.03% (w/v) polysorbate 80, and 10 mM histidine.