Antitumor Activity of MEDI3726 (ADCT-401), a Pyrrolobenzodiazepine Antibody–Drug Conjugate Targeting PSMA, in Preclinical Models of Prostate Cancer

Song Cho, Francesca Zammarchi, David G. Williams, Carin E.G. Havenith, Noel R. Monks, Peter Tyrer, Francois D'Hooge, Ryan Fleming, Kapil Vashisht, Nazzareno Dimasi, Francois Bertelli, Simon Corbett, Lauren Adams, Halla Weihe Reinert, Sandamali Dissanayake, Charles E. Britten, Wanda King, Karma Dacosta, Ravinder Tammali, Kevin SchifferliPatrick Strout, Martin Korade, III, Mary Jane Masson Hinrichs, Simon Chivers, Eva Corey, He Liu, Sae Kim, Neil H. Bander, Philip W. Howard, John A Hartley, Steve Coats, David A. Tice, Ronald Herbst, Patrick H van Berkel

Research output: Contribution to journalArticlepeer-review

Abstract

Prostate-specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase that is highly expressed in nearly all prostate cancers with the highest expression in metastatic castration-resistant prostate cancer (mCRPC). The prevalence of increased surface expression and constitutive internalization of PSMA make it an attractive target for an antibody–drug conjugate (ADC) approach to treating patients with mCRPC. MEDI3726 (previously known as ADCT-401) is an ADC consisting of an engineered version of the anti-PSMA antibody J591 site specifically conjugated to the pyrrolobenzodiazepine (PBD) dimer tesirine. MEDI3726 specifically binds the extracellular domain of PSMA and, once internalized, releases the PBD dimer to crosslink DNA and trigger cell death. In vitro, MEDI3726 demonstrated potent and specific cytotoxicity in a panel of PSMA-positive prostate cancer cell lines, consistent with internalization and DNA interstrand crosslinking. In vivo, MEDI3726 showed robust antitumor activity against the LNCaP and the castration-resistant CWR22Rv1 prostate cancer cell line xenografts. MEDI3726 also demonstrated durable antitumor activity in the PSMA-positive human prostate cancer patient–derived xenograft (PDX) LuCaP models. This activity correlated with increased phosphorylated Histone H2AX in tumor xenografts treated with MEDI3726. MEDI3726 is being evaluated in a phase I clinical trial as a treatment for patients with metastatic castrate-resistant prostate cancer (NCT02991911).
Original languageEnglish
Pages (from-to)2176-2186
Number of pages11
JournalMolecular Cancer Therapeutics
Volume17
Issue number10
DOIs
Publication statusPublished - 1 Oct 2018

Keywords

  • Pharmacology
  • ADC
  • Targeted therapies
  • PBD

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