Antitumor Activity of MEDI3726 (ADCT-401), a Pyrrolobenzodiazepine Antibody-Drug Conjugate Targeting PSMA, in Preclinical Models of Prostate Cancer
| Autor: | He Liu, Neil H. Bander, Sae Kim, Ronald Herbst, Kevin Schifferli, Francois D'Hooge, Song Cho, Philip Howard, Ryan Fleming, Eva Corey, Francesca Zammarchi, Lauren Adams, Nazzareno Dimasi, Carin E. G. Havenith, Kapil Vashisht, Karma Dacosta, Wanda King, Simon Chivers, Sandamali Dissanayake, Ravinder Tammali, David A. Tice, Steve Coats, Martin Korade, Francois Bertelli, Patrick Van Berkel, Halla W. Reinert, Simon Corbett, Mary Jane Hinrichs, David G. Williams, Peter Tyrer, Charles E. Britten, Patrick Strout, John A. Hartley, Noel R. Monks |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Glutamate Carboxypeptidase II Male Cancer Research Antibody-drug conjugate Immunoconjugates Drug Evaluation Preclinical Pyrrolobenzodiazepine Gene Expression Cross Reactions urologic and male genital diseases 03 medical and health sciences chemistry.chemical_compound Prostate cancer Mice 0302 clinical medicine Glutamate carboxypeptidase Antineoplastic Agents Immunological Prostate Cell Line Tumor LNCaP Glutamate carboxypeptidase II medicine Biomarkers Tumor Animals Humans Cancer Prostatic Neoplasms medicine.disease Immunohistochemistry Xenograft Model Antitumor Assays Disease Models Animal Macaca fascicularis 030104 developmental biology medicine.anatomical_structure Oncology chemistry 030220 oncology & carcinogenesis Antigens Surface Cancer research |
| Zdroj: | Molecular cancer therapeutics. 17(10) |
| ISSN: | 1538-8514 |
| Popis: | 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). Mol Cancer Ther; 17(10); 2176–86. ©2018 AACR. |
| Databáze: | OpenAIRE |
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