Abstract 7320: KGX105, a conditionally active prodrug of EGFRxCD3 T cell engager induces anti-tumor potency

Abstract T cell engagers (TCEs), are highly potent antitumor therapeutics to trigger T cell cytotoxicity, which have shown clinical benefit in hematologic malignancies while far been less successful in solid tumors. The development of TCEs against solid tumors has been limited by the significant on-target toxicity in normal tissues and cytokine release syndrome. Epidermal growth factor receptor (EGFR) is expressed in a variety of solid tumors. Several EGFR-targeted therapeutics have been approved for the treatment of cancer with either limited efficacy or induction of resistance. EGFR-targeting TCEs offered an alternative solution to overcome these issues. To address these challenges, we have developed KGX105, an EGFRxCD3 TCE prodrug with masked EGFR and CD3 antibody, which could be conditionally activated by tumor-specific proteases, and an albumin binding domain to extend the half-life. This design prevents on-target toxicity in normal tissues and systemic activation of T cells in circulation. Once masks are cleaved by tumor microenvironment (TME)-specific proteases, KGX105 could effectively trigger T cell cytotoxicity toward EGFR-positive tumor cells. To confirm KGX105's masking effect, we compared KGX105 and unmasked KGX105 for their ability in binding, T cell activation and T-cell-induced tumor cytotoxicity. KGX105 showed significantly reduced binding to CD3 and EGFR by >1000-fold and >200-fold, compared to the unmasked KGX105. KGX105 also showed reduced potency by >3000-fold in the T cell activation and by >1000-fold in the tumor cell cytotoxicity, which could be fully recovered after protease digestion, comparable to the unmasked KGX105. Then we conducted in vivo antitumor studies in human colorectal cancer HCT116 and COLO205 xenograft models using hPBMC-reconstituted M-NSG mice. KGX105 showed significant anti-tumor efficacy in both tumor models with the TGI% in HCT116 of 95% at 0.3 mg/kg and the TGI% in COLO205 of 68% at 3 mg/kg. No obvious body weight change was observed during the dosing period. The pilot toxic study to evaluate the safety and toxicokinetics of KGX105 is ongoing in Cynomolgus monkeys. The studies presented herein support KGX105 as a promising novel therapeutic to target a wide range of EGFR-expressing cancers with the potential to avoid the life-threatening on-target toxicities and systemic cytokine release. Citation Format: Yutao Gao, Jing Wang, Shumin Yang, Jie Huang, Hui Chen, Huiping Jiang, Haixiang Wu, Yi Wu, Weidong Jiang. KGX105, a conditionally active prodrug of EGFRxCD3 T cell engager induces anti-tumor potency [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 7320.