YMN-V115: a novel humanized BCMA/GPRC5D/CD3 trispecific antibody in relapsed/refractory multiple myeloma

Background Multiple myeloma (MM) is a hematologic malignancy characterized by a high relapse rate despite recent therapeutic advances. B-cell maturation antigen (BCMA) and G protein-coupled receptor class C group 5 member D (GPRC5D) are two well-validated targets, with Food and Drug Administration-approved bispecific antibodies demonstrating clinical efficacy; however, their effectiveness is often limited by antigen escape and immune evasion. Methods This study presents a novel humanized trispecific antibody, YMN-V115, designed in a 1+1+1 format with one binding site each for BCMA, GPRC5D, and CD3. This structural configuration was strategically selected to maximize tumor-specific T cell engagement through dual-antigen targeting while minimizing the risk of CD3-mediated off-tumor toxicity. Results YMN-V115 exhibited superior cytotoxic activity against MM cells in both in vitro and in vivo models, outperforming its bispecific counterparts. Notably, its efficacy was maintained under soluble BCMA-saturated conditions, demonstrating resistance to decoy inhibition. Moreover, YMN-V115 effectively addressed antigenic heterogeneity by targeting both BCMA + and GPRC5D + tumor subsets, resulting in enhanced T-cell activation and durable tumor control. Conclusions YMN-V115 represents a next-generation trispecific T-cell engager that effectively addresses antigenic heterogeneity and immune evasion in MM. These preclinical findings support its further clinical development as a promising therapeutic strategy for relapsed or refractory MM.