Targeted systemic therapy of prostate cancer with a monoclonal antibody to prostate-specific membrane antigen.
For the last 60 years, hormonal therapy has been the cornerstone of treatment of metastatic prostate cancer. Unfortunately, hormonal therapy is purely palliative and improved systemic therapies are necessary. Monoclonal antibodies (mAbs) have proven valuable in the treatment of several diseases including cancer. mAbs act by focusing an immune response on or by targeting delivery of highly cytotoxic agents to the cancer cells without targeting normal cells. Prostate-specific membrane antigen (PSMA) has been identified as an ideal antigenic target in prostate cancer. PSMA is the most well-established, highly restricted prostate cancer cell surface antigen. It is expressed at high density on the cell membrane of all prostate cancers, and after antibody binding, the PSMA-antibody complex is rapidly internalized along with any payload carried by the antibody. J591 is the first IgG mAb developed to target the extracellular domain of PSMA, and it has been deimmunized (humanized) to allow repeated dosing in patients. Three phase I studies are in progress, two using the beta-emitting radiometals yttrium 90 and lutetium 177, and a third using a cytotoxin (DM1) linked to J591. Imaging of patients after they have received radiolabeled J591 demonstrates excellent tumor targeting.
Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.
Neil H
NH
Bander
David M
DM
Nanus
Matthew I
MI
Milowsky
Lale
L
Kostakoglu
Shankar
S
Vallabahajosula
Stanley J
SJ
Goldsmith
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D000915:Antibody Affinity / Q000276:immunology; D000954:Antigens, Surface / Q000276:immunology; D017321:Clinical Trials, Phase I as Topic; D003603:Cytotoxins / Q000008:administration & dosage; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods; D004353:Drug Evaluation, Preclinical; D005110:Extracellular Space / Q000187:drug effects / Q000276:immunology; D005455:Fluorescent Antibody Technique; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D008187:Lutetium / Q000008:administration & dosage; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000276:immunology / Q000628:therapy*; D016719:Radioimmunodetection; D011868:Radioisotopes / Q000008:administration & dosage; D016896:Treatment Outcome; D015021:Yttrium Radioisotopes / Q000008:administration & dosage
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D003603:Cytotoxins; D007074:Immunoglobulin G; C478680:J591 monoclonal antibody; D011868:Radioisotopes; D015021:Yttrium Radioisotopes; D008187:Lutetium; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II