TY - JOUR
T1 - Antitumor Activity of MEDI3726 (ADCT-401), a Pyrrolobenzodiazepine Antibody–Drug Conjugate Targeting PSMA, in Preclinical Models of Prostate Cancer
AU - Cho, Song
AU - Zammarchi, Francesca
AU - Williams, David G.
AU - Havenith, Carin E.G.
AU - Monks, Noel R.
AU - Tyrer, Peter
AU - D'Hooge, Francois
AU - Fleming, Ryan
AU - Vashisht, Kapil
AU - Dimasi, Nazzareno
AU - Bertelli, Francois
AU - Corbett, Simon
AU - Adams, Lauren
AU - Weihe Reinert, Halla
AU - Dissanayake, Sandamali
AU - Britten, Charles E.
AU - King, Wanda
AU - Dacosta, Karma
AU - Tammali, Ravinder
AU - Schifferli, Kevin
AU - Strout, Patrick
AU - Korade, III, Martin
AU - Hinrichs, Mary Jane Masson
AU - Chivers, Simon
AU - Corey, Eva
AU - Liu, He
AU - Kim, Sae
AU - Bander, Neil H.
AU - Howard, Philip W.
AU - Hartley, John A
AU - Coats, Steve
AU - Tice, David A.
AU - Herbst, Ronald
AU - van Berkel, Patrick H
PY - 2018/10/1
Y1 - 2018/10/1
N2 - 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).
AB - 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).
KW - Pharmacology
KW - ADC
KW - Targeted therapies
KW - PBD
UR - http://dx.doi.org/10.1158/1535-7163.mct-17-0982
U2 - 10.1158/1535-7163.mct-17-0982
DO - 10.1158/1535-7163.mct-17-0982
M3 - Article
SN - 1535-7163
VL - 17
SP - 2176
EP - 2186
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 10
ER -
