Abstract 3514: AZD6621: Improving the therapeutic index for prostate cancer T cell engagers with a next-generation CD8-guided format

Abstract Prostate cancer is the second most common malignancy in males with a 5-year survival rate for metastatic castration-resistant prostate cancer of only 37%. Six-transmembrane epithelial antigen of the prostate 2 (STEAP2) is a metalloreductase with plasma membrane expression that is restricted to the prostate but is highly overexpressed across all stages of prostate adenocarcinoma. This expression profile makes STEAP2 an ideal target for a T cell engager (TCE). Despite promising efficacy, the toxicity profile of current TCEs remains challenging with patients often experiencing cytokine release syndrome and on-target, off-tumor adverse effects. This dose-limiting toxicity profile restricts their therapeutic window and with it the potential for combination therapy. We sought to improve this therapeutic index in 3 ways: 1) targeting the tumor-restricted STEAP2 antigen, 2) affinity-optimizing the CD3 binding domain and 3) integrating a CD8 binding domain to preferentially engage CD8+ T cells over CD4+ T cells, as the latter have been shown to contribute to the risk of cytokine release syndrome. Here we provide preclinical in vitro and in vivo evidence demonstrating that this design can potentially increase the therapeutic index when compared to a conventional TCE. We demonstrate that AZD6621 mediates potent, STEAP2-dependent cytotoxicity in vitro with cytotoxicity EC50 values below 10 pM. AZD6621 also induces preferential activation of CD8+ T cells over CD4+ T cells, with an approximately 5-fold increase in maximal activation of CD8+ T cells, as well as significantly reduced cytokine release compared to a conventional TCE. AZD6621 mediates complete anti-tumor regressions as a monotherapy in the STEAP2-expressing 22Rv1 subcutaneous xenograft model in humanized mice. Anti-tumor activity of AZD6621 in vivo was also observed in a C4-2 intratibial xenograft model. Furthermore, when matched for anti-tumor activity in an intravenous 22Rv1 xenograft model, systemic cytokine levels were significantly reduced in AZD6621-treated mice compared to a conventional TCE. These data provide reason to believe that AZD6621 can improve the therapeutic index of conventional TCEs via CD8-guided, affinity-optimized CD3 engagement of STEAP2 on prostate cancer cells and support a first-in-human clinical trial planned to start in 2025. Citation Format: Suzanne Sitnikova, Natalie Burrows, Nikolaos Ioannou, Even Walseng, Chunning Yang, Nadia Luheshi, Yariv Mazor, Mark Cobbold, Saso Cemerski, Simon Dovedi. AZD6621: Improving the therapeutic index for prostate cancer T cell engagers with a next-generation CD8-guided format [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3514.