Abstract 5464: A novel T-cell-engager targeting BCMA and GPRC5D with balanced killing efficacy to overcome potential resistance mechanisms in multiple myeloma treatment

Abstract B-cell maturation antigen (BCMA) and G protein-coupled receptor class C group 5 member D (GPRC5D) are critical surface markers expressed on multiple myeloma (MM) cells. BCMA-targeting T cell engagers (TCEs) and CAR-T therapies have achieved significant success in late-line MM treatment. However, antigen loss or downregulation, as well as point mutations, can result in relapse and resistance. Presence of soluble BCMA in circulation due to protein shedding also jeopardized the efficacy of BCMA-targeted therapies. GPRC5D exhibits both overlapping and independent expression profiles with BCMA, making it a compelling complementary target. Dual-targeting strategies leveraging these two antigens thus offer a promising approach to overcome resistance, improve therapeutic durability, and enhance clinical outcomes. Here, we developed a novel tri-specific TCE targeting BCMA, GPRC5D, and CD3 to optimize T cell-mediated cytotoxicity in MM. This molecule exhibited potent and selective tumor cell lysis in T cell-directed killing assays. Notably, it demonstrated balanced killing activity in cells expressing either BCMA or GPRD5D, reducing dependency on a single target antigen. Moreover, the molecule maintained its efficacy and potency in the presence of high levels of soluble BCMA (sBCMA) and overcame resistance associated with BCMA point mutations observed in patients treated with current approved TCEs. The molecule displayed potent anti-tumor efficacy in vivo in RPMI8226 cell-derived-xenograft models with hPBMC reconstitution. In addition, the molecule was well tolerated in cynomolgus monkeys with favorable pharmacokinetics and deep B cell depletion. In summary, this dual-target TCE offers a promising therapeutic option for addressing resistance of current approved TCEs, and further improving clinical outcomes in MM patients. Citation Format: Xiaochuan Ma, Hanxiao Ying, Chunhong Yu, Ting Qiu, Shu Wang, Pu Pu, Zhibin Xu, Zhendong Xue, Shuyu Cai, Jun Feng, Min Hu, Feng He. A novel T-cell-engager targeting BCMA and GPRC5D with balanced killing efficacy to overcome potential resistance mechanisms in multiple myeloma treatment [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 5464.