Potent antitumor activity of an auristatin-conjugated, fully human monoclonal antibody to prostate-specific membrane antigen.
Prostate-specific membrane antigen (PSMA) is the prototypic cell-surface marker of prostate cancer and provides an attractive target for monoclonal antibody (mAb) targeted therapies. In this study, a novel antibody-drug conjugate (ADC) was generated by linking a fully human PSMA mAb to monomethylauristatin E (MMAE), a potent inhibitor of tubulin polymerization. The PSMA ADC was evaluated for antitumor activity in vitro and in a mouse xenograft model of androgen-independent human prostate cancer. The PSMA ADC eliminated PSMA-expressing cells with picomolar potency and >700-fold selectivity in culture. When used to treat mice with established human C4-2 tumors, the PSMA ADC significantly improved median survival 9-fold relative to vehicle or isotype-matched ADC (P = 0.0018) without toxicity. Treatment effects were also manifest as significant (P = 0.0068) reduction in serum levels of prostate-specific antigen (PSA). Importantly, 40% of treated animals had no detectable tumor or measurable PSA at day 500 and could be considered cured. The findings support development of PSMA antibody-auristatin conjugates for therapy of prostate cancer.
Ma
Dangshe
D
PSMA Development Co. LLC, Tarrytown, New York, USA. dma@progenics.com
Hopf
Christine E
CE
Malewicz
Andrew D
AD
Donovan
Gerald P
GP
Senter
Peter D
PD
Goeckeler
William F
WF
Maddon
Paul J
PJ
Olson
William C
WC
D016475:3T3 Cells; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology; D000954:Antigens, Surface / Q000276:immunology* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D043425:Glutamate Carboxypeptidase II / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D009842:Oligopeptides; C105791:soblidotin; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II