SCR-M030, an innovative and potential first-in-class trispecific T cell engager targeting PSMA and STEAP1 for mCRPC

Metastatic castration-resistant prostate cancer (mCRPC) represents a highly aggressive and incurable disease, with limited therapeutic options and a dismal prognosis. Among the most promising molecular targets, prostate-specific membrane antigen (PSMA) and six-transmembrane epithelial antigen of the prostate 1 (STEAP1) are both markedly overexpressed in mCRPC, and their expression levels correlate positively with tumor aggressiveness and resistance to androgen-deprivation therapy. Notably, PSMA exhibits significant inter- and intratumoral heterogeneity, a factor that may underlie the heterogeneous clinical responses observed with PSMA-directed agents. In contrast, STEAP1 demonstrates a more uniform distribution across malignant cells, and its expression pattern partially complements that of PSMA in a subset of patients. Leveraging the complementary expression of STEAP1 and PSMA, we generated a first-in-class trispecific T-cell engager (TCE), SCR-M030, that concomitantly binds STEAP1 with high affinity, PSMA with moderate affinity, and CD3 with deliberately attenuated affinity. This avidity-optimized architecture drives preferential docking to double-positive tumor cells, conferring a marked binding advantage over single-target engagement. Functionally, SCR-M030 outperformed PSMA-CD3 and STEAP1-CD3 bispecific controls in vitro, eliciting superior lysis of medium-to-low antigen-expressing tumor cells while releasing minimal cytokines in target-negative conditions, forecasting a reduced risk of CRS. In PBMC-reconstituted prostate cancer xenograft mouse models, SCR-M030 demonstrated specific, dose-dependent antitumor activity. Notably, in the 22RV1 model, SCR-M030 exhibited more potent tumor suppression than the AMG509 analog. Finally, rat pharmacokinetic profiling revealed a long plasma half-life and full compatibility with both intravenous and subcutaneous dosing routes, supporting flexible clinical administration. In conclusion, the novel trispecific TCE SCR-M030 is a strategically designed therapy that demonstrates potent efficacy against challenging low-expression tumors by simultaneously targeting PSMA and STEAP1 with differential affinity. Its robust in vivo performance, favorable pharmacokinetics, and superiority over a relevant comparator underscore its strong potential as a next-generation therapeutic for prostate cancer.