Methods of treating prostate cancer with anti-prostate specific membrane antigen antibodies

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 - 54 . (canceled) 
     
     
         55 . A method of treating a cancer associated with vascular endothelial cells expressing prostate specific membrane antigen (PSMA) in a subject, the method comprising administering to the subject an effective amount of an anti-PSMA antibody, or antigen binding fragment thereof, which comprises the amino acid sequence shown as SEQ ID NO:22, the amino acid sequence shown as SEQ ID NO:50, the light chain variable region amino acid sequence of the antibody produced by the NS0 cell line having ATCC Accession Number PTA-3709, or the light chain variable region amino acid sequence of the antibody produced by the NS0 cell line having ATCC Accession Number PTA-4174, wherein the antibody, or antigen binding fragment thereof, binds to the vascular endothelial cells such that the cancer is treated. 
     
     
         56 . A method of treating a cancer associated with vascular endothelial cells expressing prostate specific membrane antigen (PSMA) in a subject, the method comprising administering to the subject an effective amount of an anti-PSMA antibody, or antigen binding fragment thereof, which comprises the amino acid sequence shown as SEQ ID NO:21, the amino acid sequence shown as SEQ ID NO:49, the heavy chain variable region amino acid sequence of the antibody produced by the NS0 cell line having ATCC Accession Number PTA-3709 or the heavy chain variable region amino acid sequence of the antibody produced by the NS0 cell line having ATCC Accession Number PTA-4174, wherein the antibody, or antigen binding fragment thereof, binds to the vascular endothelial cells such that the cancer is treated. 
     
     
         57 . A method of treating a cancer associated with vascular endothelial cells expressing prostate specific membrane antigen (PSMA) in a subject, the method comprising administering to the subject an effective amount of an anti-PSMA antibody, or antigen binding fragment thereof, which comprises the amino acid sequence encoded by the nucleotide sequence shown as nucleic acid residues 261-581 of SEQ ID NO:25, the nucleotide sequence shown as SEQ ID NO:52, the light chain variable region nucleotide sequence of the antibody produced by the NSO cell line having ATCC Accession Number PTA-3709, or the light chain variable region nucleotide sequence of the antibody produced by the NS0 cell line having ATCC Accession Number PTA-4174, wherein the antibody, or antigen binding fragment thereof, binds to the vascular endothelial cells such that the cancer is treated. 
     
     
         58 . A method of treating a cancer associated with vascular endothelial cells expressing prostate specific membrane antigen (PSMA) in a subject, the method comprising administering to the subject an effective amount of an anti-PSMA antibody, or antigen binding fragment thereof, which comprises the amino acid sequence encoded by the nucleotide sequence shown as nucleic acid residues 261-605 of SEQ ID NO:23, the nucleotide sequence shown as SEQ ID NO:51, the heavy chain variable region nucleotide sequence of the antibody produced by the NS0 cell line having ATCC Accession Number PTA-3709, or the heavy chain variable region nucleotide sequence of the antibody produced by the NS0 cell line having ATCC Accession Number PTA-4174, wherein the antibody, or antigen binding fragment thereof, binds to the vascular endothelial cells such that the cancer is treated. 
     
     
         59 . A method of treating a cancer associated with vascular endothelial cells expressing prostate specific membrane antigen (PSMA) in a subject, the method comprising administering to the subject an effective amount of an anti-PSMA antibody, or antigen binding fragment thereof, which comprises:
 a light chain variable region comprising the amino acid sequence shown as SEQ ID NO:22, the amino acid sequence shown as SEQ ID NO:50, the light chain variable region amino acid sequence of the antibody produced by the NS0 cell line having ATCC Accession Number PTA-3709, or the light chain variable region amino acid sequence of the antibody produced by the NS0 cell line having ATCC Accession Number PTA-4174; and   a heavy chain variable region comprising the amino acid sequence shown as SEQ ID NO:21, the amino acid sequence shown as SEQ ID NO:49, the heavy chain variable region amino acid sequence of the antibody produced by the NS0 cell line having ATCC Accession Number PTA-3709, or the heavy chain variable region amino acid sequence of the antibody produced by the NS0 cell line having ATCC Accession Number PTA-4174,   wherein the antibody, or antigen binding fragment thereof, binds to the vascular endothelial cells such that the cancer is treated.   
     
     
         60 . The method of  claim 59 , wherein the antibody, or antigen binding fragment thereof, comprises: a light chain variable region comprising the amino acid sequence shown as SEQ ID NO:22, or the light chain variable region amino acid sequence of the antibody produced by the NS0 cell line having ATCC Accession Number PTA-3709; and a heavy chain variable region comprising the amino acid sequence shown as SEQ ID NO:21, or the heavy chain variable region amino acid sequence of the antibody produced by the NS0 cell line having ATCC Accession Number PTA-3709. 
     
     
         61 . The method of  claim 60 , wherein the antibody, or antigen binding fragment thereof, comprises two heavy chains and two light chains. 
     
     
         62 . The method of  claim 60 , wherein the antibody, or antigen binding fragment thereof, is linked to a cytotoxic moiety. 
     
     
         63 . The method of  claim 60 , wherein the antibody, or antigen binding fragment thereof, is coupled to a cytotoxic moiety. 
     
     
         64 . The method of  claim 60 , wherein the antibody comprises a heavy chain constant region of human isotype IgG1. 
     
     
         65 . The method of  claim 60 , wherein the antigen binding fragment is selected from the group consisting of Fab, F(ab′) 2 , Fv, and single chain Fv fragments. 
     
     
         66 . The method of  claim 60 , further comprising administering one or more cytotoxic agents. 
     
     
         67 . The method of  claim 60 , further comprising administering one or more immunomodulatory agents. 
     
     
         68 . The method of  claim 60 , further comprising administering one or more additional therapeutic modalities. 
     
     
         69 . The method of  claim 55 , wherein the antibody, or antigen binding fragment thereof comprises: a light chain variable region comprising the amino acid sequence shown as SEQ ID NO:50, or the light chain variable region amino acid sequence of the antibody produced by the NS0 cell line having ATCC Accession Number PTA-4174; and a heavy chain variable region comprising the amino acid sequence shown as SEQ ID NO:49, or the heavy chain variable region amino acid sequence of the antibody produced by the NS0 cell line having ATCC Accession Number PTA-4174. 
     
     
         70 . The method of  claim 69 , wherein the antibody, or antigen binding fragment thereof, comprises two heavy chains and two light chains. 
     
     
         71 . The method of  claim 69 , wherein the antibody, or antigen binding fragment thereof, is linked to a cytotoxic moiety. 
     
     
         72 . The method of  claim 69 , wherein the antibody, or antigen binding fragment thereof, is coupled to a cytotoxic moiety. 
     
     
         73 . The method of  claim 69 , wherein the antibody comprises a heavy chain constant region of human isotype IgG1. 
     
     
         74 . The method of  claim 69 , wherein the antigen binding fragment is selected from the group consisting of Fab, F(ab′) 2 , Fv, and single chain Fv fragments. 
     
     
         75 . The method of  claim 69 , further comprising administering one or more cytotoxic agents. 
     
     
         76 . The method of  claim 69 , further comprising administering one or more immunomodulatory agents. 
     
     
         77 . The method of  claim 69 , further comprising administering one or more additional therapeutic modalities.