Abstract Prostate cancer remains a major global burden, ranking second in incidence among men, and outcomes are particularly poor once disease progresses to metastatic castration resistance. Six-transmembrane epithelial antigen of the prostate 2 (STEAP2) is a metalloreductase present on the plasma membrane whose expression is largely confined to prostate tissue and is markedly upregulated across all stages of prostate adenocarcinoma, positioning it as a tumor-associated antigen highly amenable for T cell-based targeting. T cell engagers (TCE) have recently demonstrated promising potential to deliver robust efficacy but their safety profile is often constrained by cytokine release syndrome (CRS) and on-target, off-tumor toxicities, producing dose-limiting adverse events that narrow the therapeutic window and hinder combination strategies. Here we introduce AZD8359, a TCE based on the Target-Induced-T-cell-Activating-Nanobody (TITAN) format which is engineered around two hypotheses intended to widen the therapeutic index: 1) reducing the risk of off-tumor activity by targeting the tumor-restricted antigen STEAP2 and 2) mitigating the CRS risk by incorporating a CD8 binding domain to bias activity toward CD8+ T cells in order to reduce cytokine release while preserving cytotoxicity. Here, we present preclinical in vitro and in vivo findings showing that this format can potentially widen the therapeutic index relative to a conventional TCE. In vitro, AZD8359 drove potent, STEAP2-dependent tumor cell killing while dampening cytokine release by 40% relative to a conventional TCE benchmark. Functional profiling in vitro, in vivo and using live cell imaging showed preferential activation of CD8+ T cells compared to CD4+ T cells with a 4 fold increase in maximal activation of CD8+ T cells in vitro. In immune-humanized mice, AZD8359 demonstrated potent antitumor activity with complete regressions observed in both STEAP2-positive 22Rv1 subcutaneous and C4-2 intratibial xenograft models. In an intravenous 22Rv1 setting, when efficacy was matched to a conventional TCE, systemic cytokine release by AZD8359 was reduced by more than 10-fold. These results collectively support the concept that CD8-biased, low-affinity TCR engagement of the tumor-restricted antigen STEAP2 by AZD8359 confers a wider preclinical therapeutic index compared to conventional TCEs in prostate cancer. This preclinical package underpins the clinical evaluation of AZD8359 planned in 2026. Citation Format: Suzanne I. Sitnikova, Elodie Grockowiak, Mar Cabeza Cabrerizo, Even Walseng, Chunning Yang, Natalie Burrows, Nikolaos Ioannou, Ryan Golden, Nadia Luheshi, Yariv Mazor, Mark Cobbold, Saso Cemerski, Simon J. Dovedi. AZD8359: A novel CD8-biased T cell engager designed to deliver a wider therapeutic window in prostate cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr ND02.
Sitnikova et al. (2026) studied this question.