Bispecific antibody with dual-payload ADC for metastatic castration-resistant prostate cancer

Treatment of metastatic castration-resistant prostate cancer (mCRPC) remains a significant clinical challenge. While monospecific ADCs have shown promise, target heterogeneity often leads to treatment resistance and relapse. To address this, we developed a bispecific ADC (BsADC) targeting both Prostate-Specific Membrane Antigen (PSMA) and Six-Transmembrane Epithelial Antigen of the Prostate 1 (STEAP1). The BsADC is armed with two distinct payloads with different mechanism of action: designed to enhance antitumor efficacy through dual antigen targeting and synergistic payload mechanisms. A humanized bispecific antibody against PSMA and STEAP1 was generated. The antibody was site-specifically conjugated with tubulin inhibitor and a topoisomerase 1 inhibitor. The PSMA/STEAP1 BsADC demonstrated optimal affinity, simultaneous binding to both targets, with no observable cross-reactivity to unrelated antigens. Unlike monospecific ADC, the BsADC was efficacious against cell lines expressing either or both antigens. The combination of MMAE and TOP1i payloads induced synergistic cell killing. In vivo, the dual-targeted, dual-payload BsADC achieved robust and durable tumor regressions in both homogeneous (PSMA+STEAP1+) and critically, in heterogeneous xenograft models. We have successfully developed a novel BsADC that co-targets PSMA and STEAP1 and delivers two mechanistically distinct warheads. This approach mitigates the issue of antigen escape and leverages synergistic payload activity, resulting in superior efficacy against heterogeneous prostate tumors. Our compelling preclinical data warrant further clinical development, and this BsADC represents a promising therapeutic candidate for patients with mCRPC, including those resistant to current ADC therapies.