Dr Encinas Mayoral on an AI-Designed BCMA/FcRL5-Targeting TRiTE in Multiple Myeloma

“[Even] in the presence of one of the two targets, our [trispecific] antibody can work. And even if the cells in the patient don’t have BCMA, we still can target the tumor.”

Jessica Encinas Mayoral, PhD, a postdoctoral research fellow in the laboratory of Nikhil C. Munshi, MD, at Dana-Farber Cancer Institute, discussed preclinical data on the design and antigen-independent activity of CB101, an artificial intelligence (AI)–optimized BCMA x FcRL5 (also known as FcRH5) x CD3 trispecific antibody, and the rationale for choosing FcRL5 over GPRC5D as a BCMA-partner target in multiple myeloma.

According to Encinas Mayoral, CB101 was tested against a myeloma cell line with low BCMA and low FcRL5 expression, where the antibody showed no activity, confirming that it requires expression of at least one of the two antigens. When FcRL5 expression was restored, she said, CB101 retained cytotoxic activity while a BCMA-only benchmark bispecific, teclistamab (Tecvayli), did not, demonstrating that CB101 can still eliminate myeloma cells that have lost BCMA.

Encinas Mayoral explained that her group used an effector function–based screening strategy rather than the conventional binding-affinity approach to identify their lead clone. The workflow paired functional cytotoxicity assays with iterative AI-driven optimization across multiple rounds of selection, she said, narrowing an initial panel to 4 or 5 candidates before CB101 emerged as the top performer in final validation based on tumor-killing activity.

Encinas Mayoral noted that although GPRC5D is the antigen most often paired with BCMA in clinical development, agents targeting it, such as talquetamab (Talvey), carry oral, skin, and nail toxicities that prompted her group to evaluate FcRL5 as an alternative BCMA partner. She pointed to ramantamig (JNJ-79635322), a BCMA x GPRC5D x CD3 trispecific antibody that consolidates the teclistamab-talquetamab combination strategy into a single molecule; in a phase 1 trial (NCT05652335) presented at the 2025 ASCO Annual Meeting, ramantamig produced an objective response rate of 100% and a cytokine release syndrome rate of 56.5%, with no grade 3 or higher events, among BCMA- and GPRC5D-inhibitor–naive patients (n = 27) at the recommended phase 2 dose. No study has directly compared ramantamig with the teclistamab-talquetamab combination, Encinas Mayoral said, so how the 2 approaches compare on toxicity remains unclear, but she suggested a single dual-targeting molecule may ultimately prove more practical than administering 2 separate agents.