Abstract 4051: BHB299: An AI/ML-optimized high avidity/low affinity CEACAM6-directed T cell engager for diverse solid tumors

Abstract Background: Solid tumors remain a major cause of global mortality, with millions of new cases annually. Despite a rapidly advancing standard of care, few patients achieve durable responses. CEACAM6 is a cell surface antigen expressed at extremely high levels on CRC (85%), NSCLC (50%), Gastric (30%), Pancreatic (30%) and a variety of other tumor types where it drives tumor metastasis and immune suppression through heterotypic interactions with adjacent cancer and infiltrating immune cells. CEACAM6 has historically been considered undruggable due to its moderate expression on healthy myeloid cells, which act as a peripheral antigen sink and a source of on-target/off-tumor dose-limiting toxicity. Methods: A single domain VHH anti-CEACAM6 antibody was discovered and co-optimized alongside a CD3 binding domain for ultra-fast dissociation and developability using BigHat’s proprietary AI/ML and cell-free protein synthesis (CFPS)-enabled platform. Comprehensive in vitro and in vivo studies of PK, PD, and safety were performed to support the candidacy of BHB299 for first-in-human evaluation. Results: The resulting “2+1” T cell engager binds to cell surfaces with high CEACAM6 densities with high avidity and slow dissociation, but dissociates rapidly from myeloid cells with moderate target densities. This dynamic CD3 and CEACAM6 engagement selectively establishes an immunological synapse between tumor cells and T cells but not healthy myeloid cells, with 10,000x differential in IC50 in vitro using relevant models of cancer and whole blood from human donors. This avidity-based or “IF-BETTER” mechanism also eliminates sensitivity to soluble forms of CEACAM6, which may act as a decoy and antigen sink for high-affinity therapeutics. BHB299 also features a pH conditional CD3 agonist, which further enhances cell killing in the tumor microenvironment to reduce the risk of antigen escape due to low target expression. In vivo, BHB299 leads to complete responses or durable partial responses in multiple models of colon, rectal, lung, and pancreatic tumors, including metastatic PDX models of CRC and lung cancers. In safety studies in humanized mouse models and primates, no MTD was reached, consistent with a substantial therapeutic window. Conclusion: BHB299 is a first-in-class CEACAM6-directed bispecific T cell engager for the treatment of diverse solid tumors, potentially up to 10% of all new cancers in the US each year. The molecule was engineered on BigHat Biosciences’s AI/ML-powered antibody design platform to maximise tumor-specific target engagement. First-in-human studies are supported by the preclinical data package and are planned for 2026. Citation Format: Ryan Henrici, Katrina Stephenson, Rima Sanyal, Melanie Montgomery, Mira Markova, Austin Prater, Barbara Steurer, Timothy Park, Danielle Barreras, Noelle Huskey, Jon Wojciak, John Corbin, Peyton Greenside. BHB299: An AI/ML-optimized high avidity/low affinity CEACAM6-directed T cell engager for diverse solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4051.