title: In vitro and in vivo responses of advanced prostate tumors to PSMA ADC, an auristatin-conjugated antibody to prostate-specific membrane antigen.
abstract: Prostate-specific membrane antigen (PSMA) is a membrane protein that is overexpressed manifold in prostate cancer and provides an attractive target for therapy. PSMA ADC is an antibody-drug conjugate (ADC) that consists of a fully human anti-PSMA monoclonal antibody conjugated to monomethylauristatin E through a valine-citrulline linker. In this study, the antitumor activity of PSMA ADC was evaluated against a panel of prostate cancer cell lines in vitro and in a novel in vivo model of taxane-refractory human prostate cancer. In vitro cell killing was efficient for cells with abundant PSMA expression (>10(5) molecules/cell; IC(50) ≤ 0.022 nmol/L) and 1,000-fold less efficient for cells with undetectable PSMA (IC(50) > 30 nmol/L). Intermediate potency (IC(50) = 0.80 nmol/L) was observed for cells with approximately 10(4) molecules of PSMA per cell, indicating a threshold PSMA level for selective cell killing. Similar in vitro activity was observed against androgen-dependent and -independent cells that had abundant PSMA expression. In vitro activity of PSMA ADC was also dependent on internalization and proper N-glycosylation/folding of PSMA. In contrast, less potent and nonselective cytotoxic activity was observed for a control ADC, free monomethylauristatin E, and other microtubule inhibitors. PSMA ADC showed high in vivo activity in treating xenograft tumors that had progressed following an initial course of docetaxel therapy, including tumors that were large (>700 mm(3)) before treatment with PSMA ADC. This study defines determinants of antitumor activity of a novel ADC. The findings here support the clinical evaluation of this agent in advanced prostate cancer.
authors.affiliation: Department of Cancer Biology, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
authors.forename: Xinning
authors.initials: X
authors.lastname: Wang
authors.forename: Dangshe
authors.initials: D
authors.lastname: Ma
authors.forename: William C
authors.initials: WC
authors.lastname: Olson
authors.forename: Warren D W
authors.initials: WD
authors.lastname: Heston
mesh_terms: D062365:Aminobenzoates / Q000737:chemistry; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000954:Antigens, Surface / Q000276:immunology / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008819:Mice, Nude; D050505:Mutant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009367:Neoplasm Staging; D009842:Oligopeptides / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D062365:Aminobenzoates; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D050505:Mutant Proteins; D009842:Oligopeptides; C569421:PSMA ADC; C543533:auristatin; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II