The anti-STEAP1/PSMA ADC, DXC008: Assessment of anti-tumor efficacy, pharmacokinetic, and toxicity properties.

Abstract

e17161 Background: Six-transmembrane epithelial antigen of prostate-1 (STEAP1) is highly expressed in multiple tumor types, including prostate cancer, Ewing’s sarcoma, gastric cancer, and ovarian cancer, making it a compelling therapeutic target. DXC008 is a novel dual-target antibody-drug conjugate (ADC) designed to target both STEAP1 and prostate-specific membrane antigen (PSMA), and utilizes a topoisomerase I inhibitor payload that disrupts DNA synthesis and effectively inhibits tumor cell proliferation. This study evaluated the preclinical efficacy, pharmacokinetics, and safety of DXC008. Methods: The pharmacological properties of DXC008 were evaluated in STEAP1/PSMA-positive cell lines, cell-derived xenograft (CDX) models, and rhesus monkeys. Key assessments included antitumor efficacy, pharmacokinetics, and preclinical safety, with toxicity evaluated in a two-month repeated-dose study. Results: DXC008 exhibited high affinity for both STEAP1 and PSMA, with efficient internalization into tumor cells. In vitro and in vivo studies demonstrated dose-dependent antitumor activity, with DXC008 outperforming single-target ADCs. Pharmacokinetic analysis showed DXC008 to have favorable characteristics, including high stability, prolonged half-life, and high systemic exposure. In toxicity studies, DXC008 was well-tolerated, with the highest non-severely toxic dose (HNSTD) of 40 mg/kg in rhesus monkeys. A phase I clinical trial to evaluate the safety, tolerability, pharmacokinetic characteristics and efficacy of DXC008 at 2.8 mg/kg-28 mg/kg every 2 weeks in patients with advanced solid tumors is on-going. Conclusions: DXC008 exhibits a promising preclinical profile, including potent dual-target antitumor activity, favorable pharmacokinetics, and a well-tolerated safety profile. These findings demonstrate the potential of DXC008 to become a best-in-class (BIC) STEAP1/PSMA-targeting ADC, and to offer a favorable benefit-risk ratio for clinical development.