Modified Antibodies to Prostate-Specific Membrane Antigen and Uses Thereof

Abstract

Modified antibodies, or antigen-binding fragments thereof, to the extracellular domain of human prostate specific membrane antigen (PSMA) are provided. The modified anti-PSMA antibodies, or antigen-binding fragments thereof, have been rendered less immunogenic compared to their unmodified counterparts to a given species, e.g., a human. Pharmaceutical compositions including the aforesaid antibodies, nucleic acids, recombinant expression vectors and host cells for making such antibodies and fragments are also disclosed. Methods of using the antibodies of the invention to detect human PSMA, or to ablate or kill a PSMA-expressing cell, e.g., a PSMA-expressing cancer or prostatic cell, either in vitro or in vivo, are also provided.

1 - 63 . (canceled) 
     
     
         64 . A method of treating prostate cancer in a subject comprising administering to the subject two or more doses of an antibody or antigen binding fragment thereof which binds to the extracellular domain of prostate specific membrane antigen (PSMA) and which is coupled to lutetium ( 177 Lu), wherein each dose is about 40 to 65% of the maximum tolerated dose (MTD) of the antibody molecule coupled to lutetium ( 177 Lu), to thereby treat the prostate cancer. 
     
     
         65 . The method of  claim 64 , wherein the prostate cancer is metastatic. 
     
     
         66 . The method of  claim 64 , wherein the prostate cancer is recurrent. 
     
     
         67 . The method of  claim 64 , wherein each dose is about 40 to 50% of the maximum tolerated dose (MTD) of the antibody molecule coupled to lutetium ( 177 Lu). 
     
     
         68 . The method of  claim 64 , further comprising determining if an additional dose or doses of the antibody molecule coupled to lutetium ( 177 Lu) will be administered to the subject and, if appropriate, administering one or more additional doses of the antibody molecule coupled to lutetium ( 177 Lu). 
     
     
         69 . The method of  claim 68 , wherein the one or more of the additional doses is administered at a dose which is about 40 to 60% of the MTD. 
     
     
         70 . The method of  claim 68 , wherein the one or more of the additional doses is administered at a dose which is less than 40% of the MTD. 
     
     
         71 . The method of  claim 64 , wherein the subject is administered up to five doses of the antibody molecule and each of the doses is about 40 to 60% of the MTD of the antibody molecule coupled to lutetium ( 177 Lu). 
     
     
         72 . The method of  claim 64 , wherein the subject is administered three or more doses of the antibody molecule and wherein each of the doses is about 40 to 65% the maximum tolerated doses (MTD) of the antibody molecule coupled to lutetium ( 177 Lu). 
     
     
         73 . The method of  claim 72 , wherein each of the doses is about 40 to 50% of the maximum tolerated dose (MTD) of the antibody molecule coupled to lutetium ( 177 Lu). 
     
     
         74 . The method of  claim 64 , further comprising evaluating the subject after one or more of the doses for hematologic toxicity. 
     
     
         75 . The method of  claim 64 , further comprising evaluating the subject after one or more of the doses for non-hematologic toxicity. 
     
     
         76 . The method of  claim 74 , further comprising determining whether to administer to the subject one or more therapeutic modalities which enhance blood cell counts in combination with a subsequent dose or doses based upon the evaluation of hematologic toxicity and, if appropriate, administering one or more therapeutic modalities which enhance blood cell count in combination with a subsequent dose or doses. 
     
     
         77 . A method of treating prostate cancer in a subject comprising administering to the subject two or more doses of an antibody or antigen binding fragment thereof which binds to the extracellular domain of prostate specific membrane antigen (PSMA) and which is coupled to lutetium ( 177 Lu), wherein each dose is administered at less than 60 mCi/m 2 , to thereby treat the prostate cancer. 
     
     
         78 . The method of  claim 77 , wherein each dose is administered at less than 45 mCi/m 2 . 
     
     
         79 . The method of  claim 77 , wherein at least one dose, preferably at least two doses, are administered at about 30 mCi/m 2  or less. 
     
     
         80 . The method of  claim 77 , wherein each dose is between about 15 to 45 mCi/m 2 . 
     
     
         81 . The method of  claim 77 , wherein each dose is about 30 mCi/m 2 . 
     
     
         82 . A method of treating pain experienced by a subject having or diagnosed with prostate cancer comprising administering two or more doses of an antibody or antigen binding fragment thereof which binds to the extracellular domain of prostate specific membrane antigen (PSMA) and which is coupled to lutetium ( 177 Lu), wherein each dose is about 40 to 65% of the maximum tolerated dose (MTD) of the antibody molecule coupled to lutetium ( 177 Lu), to thereby treat the pain. 
     
     
         83 . A method for treating metastatic lesions associated with prostate cancer in a subject, comprising administering to the subject two or more doses of an antibody or antigen binding fragment thereof which binds to the extracellular domain of prostate specific membrane antigen (PSMA) and which is coupled to lutetium ( 177 Lu), wherein each dose is about 40 to 65% of the maximum tolerated dose (MTD) of the antibody molecule coupled to lutetium ( 177 Lu), to thereby treat the metastatic lesion.