The affinity-optimized bispecific T cell engager W308051 selectively kills PSMA-expressing tumor cells with limited cytokine secretion

Metastatic castration‐resistant prostate cancer (mCRPC) remains a therapeutic challenge with limited treatment options. Here, we report the preclinical characterization of W308051, a bispecific T cell engager developed by GSK under license from WuXi, designed to target prostate‐specific membrane antigen (PSMA) on malignant cells and CD3 on T lymphocytes. W308051 demonstrates a higher binding affinity to PSMA compared to the competitor molecules AMG160 and AMG340 with a K D of 16 pM as shown by surface plasmon resonance and also stronger binding in ELISA and cell-based binding assays. However, its affinity for CD3 with a K D of 60 nM is lower than AMG160 but higher than AMG340, a rationale design choice to increase the therapeutic index. In vitro studies reveal that W308051 induces potent cytotoxicity against PSMA‐positive cancer cells, achieving efficacies comparable to AMG160 and surpassing those of AMG340 across multiple cell lines with variable PSMA expression levels. Furthermore, in vivo experiments utilizing a cell line-derived xenograft model with the LNCaP cell line in immunodeficient mice engrafted with human peripheral blood mononuclear cells demonstrated complete tumor growth inhibition at higher dosing regimens, reflective of AMG160's profile. Importantly, in vitro cytokine release associated with W308051 treatment was reduced relative to AMG160 and marginally elevated compared to AMG340, suggesting a potentially improved safety profile and an expanded therapeutic window. Pharmacokinetic analyses indicate that the use of T cell receptor domains for bispecific antibody assembly confers properties akin to those observed with conventional monoclonal antibodies. Collectively, these findings support the further clinical investigation of W308051 as a promising therapeutic modality for mCRPC.