Abstract 7316: QL615, a tetraspecific T cell engager with highly restricted activity on MET and EGFR-positive tumors while providing co-stimulation via CD2

Abstract Effective targeting of solid tumors using T cell engagers remains challenging due to the lack of tumor specific antigens (TSA), and the difficulty in achieving sustained anti-tumor response. Frequently, target antigen expression is upregulated on cancer, yet low expression on normal tissues limits the therapeutic window. Moreover, the lack of co-stimulatory signals paired with CD3 in the tumor microenvironment often leads to T cell exhaustion and non-durable responses. To overcome these shortcomings, we have developed a tetraspecific T cell engaging platform, termed TECAD “T Cell Engager with Co-Stimulation Avidity Driven”, to address both tumor selectivity and potency by (1) activating T cells only when bound to tumor cells expressing paired antigens, and (2) providing CD3 co-stimulation via conditional CD2 activation. The latter enhances antitumor immune response and overcomes resistance to immune checkpoint blockade therapies. QL615, our lead TECAD candidate, targets MET and EGFR, two clinically validated targets limited by expression on normal tissues. MET and EGFR are typically expressed on non-overlapping normal tissues but frequently colocalized on tumors cells. We have optimized the affinity of MET and EGFR binding domains such that only dual engagement on the target cell provides high avidity binding AND-gated activation. Cell binding assays showed nanomolar EC50 on tumor cells expressing both MET and EGFR, whereas binding was negligible on cells expressing only low levels of either MET or EGFR. In vitro killing assays demonstrated over a 1000-fold selectivity in the lysis of double-positive tumor cells. The TECAD’s CD2-mediated co-stimulation enhanced in vitro killing of tumor cells ∼30-fold over constructs with CD3 redirection alone and showed superior tumor growth control in vivo. QL615 is currently advancing toward a development decision and clinical evaluation. Citation Format: Yanan Wang, Meihua Luo, Guangjie Guo, Shenda Gu, Joshua Morrissette, Nathan Ngo, Shihao Chen. QL615, a tetraspecific T cell engager with highly restricted activity on MET and EGFR-positive tumors while providing co-stimulation via CD2 [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 7316.