Abstract 3510: A 2+1 format MUC16 targeting T cell engager induces MUC16-dependent T cell activity and superior anti-tumor efficacy

Abstract T cell engager (TCE) therapies targeting specific tumor associated antigens (TAAs) have shown clinical efficacy in multiple types of solid tumors. Indeed, TCE has been approved to treat melanoma and small cell lung cancer. Nevertheless, it remains necessary and challenging to improve the efficacy and safety profile of TCE to deliver benefits to more cancer patients. Recurrent and chemotherapy resistant ovarian cancer remains an urgent global unmet medical need. These is limited therapeutic options for this highly lethal and refractory disease. Recently, a MUC16 TCE demonstrated promising and durable clinical efficacy against heavily pretreated MUC16-high ovarian cancer, with acceptable safety profile. This underlines the potential to develop a MUC16 TCE with favorable safety profile and enhanced anti-tumor efficacy to possibly expand the benefits to MUC16-medium and MUC16-low ovarian cancer patients. MUC16 is a glycoprotein overexpressed in several types of solid tumors, especially in the majority of ovarian cancer. Here, we developed a 2+1 format MUC16 TCE, with improved tumor cell binding affinity, enhanced tumor cell killing potency, and MUC16-dependent T cell binding and activation. This MUC16 TCE targets membrane-proximal domains of MUC16 and achieves avidity-driven tumor cell binding in the presence of soluble CA125. Moreover, this MUC16 TCE elicited limited T cell binding and activation in the absence of MUC16, compared to benchmark molecule, to minimize off-target activity. This 2+1 format MUC16 TCE also showed favorable pharmacokinetics profile in mice. Functionally, systemic administration of this MUC16 TCE showed superior anti-tumor efficacy, with undetectable toxicity, in xenograft tumor models. Importantly, this MUC16 TCE demonstrated potent and synergistic anti-tumor efficacy in combination with clinically validated therapeutic strategies for ovarian cancer in pre-clinical tumor models. This provides rationale to develop combination therapies in future clinical trials. Indeed, combination of TCE with other therapies, e.g. ADC, chemotherapy, PD1/PDL1 mAb, are being tested clinically. Together, our pre-clinical data demonstrated that a 2+1 MUC16 TCE elicits potent anti-tumor efficacy and minimized off-target T cell activation, with potential to deliver benefits to ovarian cancer patients and patient with other MUC16-positive cancer. Citation Format: Jinyang Li, Yang Li, Nan Gao, Yi Wang, Mengqiang Di, Min Wu, Yiyi Li, Ran Xue, Shiyu Hao, Weiwei Wu, Xiguang Zhang, Li Li, Shuaixiang Zhou, Huizhong Xiong. A 2+1 format MUC16 targeting T cell engager induces MUC16-dependent T cell activity and superior anti-tumor efficacy [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 3510.