Abstract 1676: HA-00495: A development candidate ADC featuring a novel protein translation inhibitor payload with broad efficacy and a favorable non human primate safety profile

Abstract Antibody drug conjugates (ADCs) have demonstrated clinical benefit across multiple cancers, yet resistance to existing payload classes, particularly topoisomerase and microtubule inhibitors, remains a major barrier to durable efficacy. To address this limitation, Hexagon Bio is leveraging its natural product discovery platform to identify new ADC payloads with mechanisms of action (MOAs) that are non-overlapping with currently approved payload classes. Enabled by our proprietary natural product library, we identified a protein translation inhibitor as a highly potent ADC payload. We conjugated the payload to a diverse panel of antibodies recognizing tumor-associated antigens and observed consistent ADC-mediated cytotoxicity across cell lines, supporting broad applicability across tumor types. In vivo, ADCs generated using anti-TROP2 (sacituzumab) and anti-HER2 (trastuzumab) antibodies demonstrated deep and durable antitumor activity in bladder, gastric, breast and lung cancer models, including models with known resistance to topoisomerase inhibitor-based ADCs. Here, we provide updated efficacy data across multiple tumor models and, for the first time, report the non-human primate (NHP) safety profile of an ADC incorporating this payload. Our new data include a comprehensive assessment of the HER2 ADC HA-00495 in NHPs, evaluating multiple dose levels as well as repeat-dose regimens. These studies reveal an acceptable safety and tolerability profile. We will present the clinical observations, clinical pathology, histopathology and key findings from these studies.In summary, we have identified a novel protein translation inhibitor payload class for ADCs that demonstrates strong efficacy, activity in resistance settings and a favorable NHP safety profile. These results support the potential of HA-00495 to address critical gaps in current ADC therapies and development activities for this candidate are now underway. Citation Format: Tara L. Arvedson, Victor Cee, Corey Reeves, Madhura Deshpande, Natacha Le Moan, Kyle Dunbar, Amandeep Gakhal, Chris Kimberlin, Cynthia Bailey, Edres Babacarkhial, Nolan Carney, Xufeng Cao, Yi-Ming Chiang, Amber Cornelius, Natalie Duong, Colin Harvey, Yingxia Hu, Dimitri Kharakovsky, Jose Leighton, Dennis Liu, Luca Lizzardo, Octovia Monteiro, Samuel Oteng-Pabi, Bruno Perlatti, Rajani Marthappa Shenoy, Joseph Spraker, Mélanie Uguen, Jakub Vaith, Sandeep Venkataram, Kendra Wheeler, Shiyan Xu, Danielle Yee, Clarence Yeung, Eva Yuan, . HA-00495: A development candidate ADC featuring a novel protein translation inhibitor payload with broad efficacy and a favorable non human primate safety profile [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 1676.