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

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. , MEDI3726 demonstrated potent and specific cytotoxicity in a panel of PSMA-positive prostate cancer cell lines, consistent with internalization and DNA interstrand crosslinking., 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). .

Systematic Review of Patient-Derived Xenograft Models for Preclinical Studies of Anti-Cancer Drugs in Solid Tumors

“…The majority of articles were categorized into this traditional method (54%, 53/98). An article representative of this method was published by Cho et al in 2018 [92]. In the study, the efficacy of anti-prostate-specific membrane antigen (PSMA) antibody drug conjugate (ADC) was assessed using prostate cancer models.…”

Design and characterization of homogenous antibody-drug conjugates with a drug-to-antibody ratio of one prepared using an engineered antibody and a dual-maleimide pyrrolobenzodiazepine dimer

“…18 Generation of the dual-maleimide PBD dimer SG3710 ( Figure S2 and supplementary appendix) was carried out in seven steps. The overall synthesis yield for the dual-maleimide PBD dimer SG3710 was 6.35%, a significant improvement over the 30-step route used to generate SG3249 that, despite being scalable to produce clinical-grade material, [22][23][24] had an overall yield of 0.54%. 18 Semi-preparative HPLC purification followed by lyophilization yielded SG3710 with a purity higher than 95%.…”

“…The SG3199 warhead was subsequently linked to a maleimidocaproyl-polyethylene glycol (PEG 8 ) linker via a self-immolative valine-alanine dipeptide at the N10 position to generate the SG3249 payload, which was used to prepare ADCs. [19][20][21][22][23][24] Drawing upon the success of SG3249 as an ADC payload, we hypothesized that functionalization of the symmetrical N10 nitrogen with an additional cathepsin-B cleavable valine-alanine dipeptide and PEG 8 -maleimide linker would result in a symmetrical dual-maleimide PBD dimer, SG3710 (Figure 1), which could be used to re-bridge two adjacent cysteines, such as the ones at the immunoglobulin G1 (IgG1) hinge. The symmetrical nature of the SG3710 payload offers several key structural features that not only expand the applicability of PBD dimers, but also offer enhancement of the biochemical properties of previous versions of PBD dimers, such as SG3249, which is composed of a single chemical linker (Figure 1).…”

Characterization of Disulfide Bond Rebridged Fab–Drug Conjugates Prepared Using a Dual Maleimide Pyrrolobenzodiazepine Cytotoxic Payload

“…The dual‐maleimide PBD SG3710 was synthesized using starting material from tesirine (SG3249, Figure a), a PBD payload used in several ADCs in clinical development . SG3710 contains two maleimide‐(polyethylene glycol) 8 ‐valine‐alanine‐ para ‐aminobenzoic acid linkers at each of the two symmetrical N10 positions of the PBD (Figure b).…”