Abstract Background: Gastric cancer remains a significant and growing cause of morbidity and mortality globally, with nearly 1 million newly diagnosed patients each year. Treatment paradigms are limited to checkpoint inhibitors, angiogenic blockade, and conventional chemotherapy, with few patients achieving durable responses. HER2 and CLDN18.2 directed therapies represent breakthroughs but substantial unmet need remains. CDH17 represents one of the most widely expressed tumor-associated antigens, offering the potential to treat 50-60% of patients with gastric cancer, including a substantial population of those without HER2 or CLDN18.2 expression. Methods: A single domain VHH anti-CDH17 antibody was engineered using BigHat’s Milliner platform for optimal internalization, humanized, and subsequently conjugated to MMAE via a site-specific and serum-stable, enzyme-cleavable linker using GlycoConnect SYNstatin E technology. The antibody drug conjugate (ADC) was subsequently interrogated in vitro and in vivo, including in cynomolgus macaques as part of a comprehensive preclinical therapeutic research program. Results: BHB810 is fully cross-reactive to human, cyno, and rodent orthologues and features robust and maximized internalization within 24 hours. The VHH-Fc fusion was conjugated to achieve a homogeneous DAR 4 with remarkable serum stability, providing a significantly enhanced therapeutic window compared to typical maleimide-vedotin conjugates. Compared to a benchmark clinical-stage CDH17-directed IgG ADC that rapidly loses payload via retro-Michael addition, BHB810 features no detectable deconjugation, payload transfer, or payload loss in human serum. The humanised VHH-Fc fusion backbone of BHB810 is 50% smaller than a typical IgG, resulting in superior tissue penetration. In PDX models, BHB810 leads to complete or near-complete tumor clearance in a panel of 13 different primary gastric cancers, including those with low and heterogeneous antigen densities. Preclinical modeling of pharmacokinetics and safety demonstrate a multi-day half-life, superior tolerability, and no evidence of on-target toxicities in non-malignant organ systems compared to benchmarks. In vivo imaging demonstrates robust target engagement and on-target ADC accumulation with reduced plasma exposure. BHB810 was evaluated in a 1 month GLP primate toxicity study exploring doses up to 5 mg/kg q2w (10 mg/kg of a conventional IgG ADC). No MTD was reached. Conclusion: BHB810 is a novel, potentially best-in-class CDH17-directed ADC for the treatment of advanced gastric and other GI malignancies. The molecule was engineered on BigHat Biosciences’s AI/ML-powered antibody design platform to maximise ADC internalization and potency against cells that express CDH17. First-in-human studies are planned for 2026, prioritizing patients with gastric cancer. Citation Format: Ryan Henrici, Timothy Park, Melanie Montgomery, Barbara Steurer, Danielle Barreras, Natalie Alba, Srujan Vadlamudi, Hunter Elliott, Jon Wojciak, John Corbin, Peyton Greenside, . BHB810: A novel site-specific CDH17-directed VHH-Fc ADC for gastric cancer 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 6922.
Henrici et al. (Fri,) studied this question.