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

“We were quite surprised with the in vivo experiments—in vitro, we were seeing better results compared [with other] bispecific antibodies, but then we started to see in vivo that even our [trispecific] antibody was effective at 10 times lower concentration than [teclistamab]. I mean, the [data] were very impressive.”

Jessica Encinas Mayoral, PhD, a postdoctoral research fellow in the laboratory of Nikhil C. Munshi, MD, at Dana-Farber Cancer Institute, discussed data from an abstract presented at the 23rd International Myeloma Society Annual Meeting & Exposition evaluating an artificial intelligence (AI)–designed BCMA x FcRL5 (also known as FcRH5) x CD3 trispecific T-cell engager (TriTE) as a strategy to overcome antigen escape and outperform BCMA-directed therapies in relapsed/refractory multiple myeloma (RRMM).

According to Encinas Mayoral, the construct’s dual BCMA/FcRL5 architecture was designed to address the antigen loss and point mutations that limit existing BCMA-directed therapies. In binding studies, she and her colleagues identified 2 BCMA extracellular-domain deletions, Pro34del and Ser30del, previously linked to loss of teclistamab (Tecvayli) recognition; the trispecific antibody’s BCMA-targeting arm still recognized both variants, she said. Pairing that arm with an FcRL5-directed domain, she added, allows the molecule to continue engaging myeloma cells even when BCMA expression is lost entirely.

In vivo, the trispecific antibody achieved efficacy at approximately 10-fold lower concentrations than teclistamab, Encinas Mayoral reported, a finding she called unexpected given the more modest differences observed in vitro. A head-to-head comparison with ramantamig (JNJ-79635322), a BCMA x GPRC5D x CD3 trispecific antibody in phase 1 testing (NCT05652335), showed comparable antitumor activity with longer survival among treated mice, according to Encinas Mayoral. In ex vivo experiments using bone marrow mononuclear cells from patients with myeloma, the antibody selectively killed malignant plasma cells while sparing the healthy mononuclear cell population, she said, and no weight loss was observed in mice during in vivo dosing. Toxicities described for other T-cell–engaging therapies still need to be assessed in humans, Encinas Mayoral noted.

Looking ahead, Encinas Mayoral said the goal is to advance this trispecific approach as an alternative to teclistamab, ramantamig, and BCMA-directed CAR T-cell therapies such as ciltacabtagene autoleucel (Carvykti), particularly for patients whose disease has escaped single-target BCMA therapy. She said she and her colleagues are eager to see how the molecule performs in future clinical investigation.