Abstract 3793: Advancing GPC3-positive solid tumor therapy with AZD9793, a novel CD8-guided T cell engager with potent pre-clinical efficacy and superior therapeutic index over GPC3 x CD3 formats

AZD9793 is a novel CD8-guided T cell engager (TCE) being developed for the treatment of Glypican-3 (GPC3)-positive solid tumors, including hepatocellular carcinoma (HCC). It comprises two Fab domains that bind to human GPC3 on the surface of cancer cells, one VHH binding domain that binds to human TCR, and one VHH binding domain that binds to the human CD8 co-receptor expressed on T cells. AZD9793 biological activity was assessed in vitro and in vivo and compared to a conventional GPC3xCD3 TCE. A GLP 1-month cynomolgus monkey toxicity study was also conducted, involving repeated weekly intravenous or subcutaneous administration of AZD9793 at doses ≤ 6 mg/kg/week. In vitro studies showed that AZD9793 preferentially engages CD8+ T cells through CD8/TCR binding, leading to potent HCC cell killing and reduced CD4+ T cell activation. This bias significantly limits the production of Cytokine Release Syndrome (CRS)-related cytokines compared to a conventional GPC3xCD3 TCE, which equally activates CD8+ and CD4+ T cells. Using purified T cell subsets and control TCEs with abrogated binding domains, we demonstrated that CD4+ T cells are the main driver of cytokine production upon TCE engagement, while CD8 guiding enhances cytotoxicity by harnessing the anti-tumor functions of CD8+ T cells. In humanized mouse models, AZD9793 exhibits robust and dose-dependent anti-tumor efficacy against HCC and non-small cell lung cancer xenografts by enhancing T cell infiltration and increasing the CD8/CD4 T cell ratio within tumors. Using mixtures of GPC3-positive and -negative HCC cell lines and PDX models in vivo, we demonstrated that AZD9793 promotes bystander killing of antigen-negative cells via an IFN-γ dependent mechanism and effectively controls tumors that heterogeneously express GPC3. Lastly, in the cynomolgus monkey 1-month toxicity study, AZD9793 induced transient chemokine elevation and T cell margination with limited systemic cytokine secretion. Overall, AZD9793 was well-tolerated, and a NOAEL was established at 6 mg/kg/week. The combined features of bivalent GPC3 binding, CD8-biased engagement, and low-affinity TCR binding enhance AZD9793 cytotoxic potency against tumor cells while minimizing the risk of cytokine release and associated toxicities. These findings support the ongoing clinical evaluation of AZD9793 as a promising therapeutic for patients with GPC3-positive solid tumors. Citation Format: Cristina Bergamaschi, Cerys Lovatt, Upneet K. Sokhi, Christine Youn, Cathryn R. Kelton, Eric Chang, Andrew Yang, Anna Huntley, Eddie Chen, Dimitris Karamitros, Eric Tu, Neil Mody, Bharat Burman, Sterling Payne, Harini Shandilya, Hanzhi Zhang, Richard Stebbings, Christopher Lloyd, Francisca Wollerton, Yariv Mazor, Simon Dovedi, Frederick W. Goldberg, Saso Cemerski, Mark Cobbold, Corinne Cayatte. Advancing GPC3-positive solid tumor therapy with AZD9793, a novel CD8-guided T cell engager with potent pre-clinical efficacy and superior therapeutic index over GPC3 x CD3 formats [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 3793.