QLS2401: A novel PSMA/STEAP1/CD3 tri-specific T-cell engager for the treatment of mCRPC

Prostate cancer (PCa) is one of the most common malignancies in men worldwide. Approximately 10%-20% of PCa patients develop castration-resistant PCa (CRPC) within 5 years and subsequently progress to metastatic CRPC (mCRPC). Current approved therapies for mCRPC patients offer limited survival benefits with unsatisfied long-term remission, underscoring an urgent need for novel therapeutic options. Both STEAP1 (Six Transmembrane Epithelial Antigens of the Prostate 1) and PSMA (Prostate-Specific Membrane Antigen) are frequently co-expressed at high levels in mCRPC, presenting dual targeting opportunity to enhance efficacy. Here, we report the generation and preclinical development of QLS2401, a novel PSMA/STEAP1/CD3 tri-specific TCE engineered to have optimized CD3 affinity and tumor associated antigen (TAA)-binding valency to enhance T cell-mediated cytotoxicity and mitigate the resistance resulting from single antigen-loss. QLS2401 causes potent target-dependent and T cell-mediated cytotoxicity against prostate cancer cell lines and induces tumor regression in prostate cancer xenograft models, demonstrating superior or comparable efficacy to the xaluritamig analog. The avidity-driven activity of QLS2401 enables selectivity for tumor cells with higher STEAP1- and PSMA- expression than normal cells. QLS2401 was well-tolerated in a toxicity study in cynomolgus monkeys, with an HNSTD (Highest Non-Severely Toxic Dose) significantly higher than that of the xaluritamig analog. In conclusion, preclinical studies have demonstrated that QLS2401 exhibits an expanded therapeutic window, superior efficacy and improved tolerability compared to the xaluritamig analog.