3080-LB: Naturally Derived Fully Human Anti-ACVR2A Antibodies with Superior PK and Functional Benefits for Obesity and Metabolic Disease

Introduction and Objective: Obesity affects >1.1B people globally, increasing risks for CVD, diabetes, and cancer. Current GLP-1 therapies achieve weight loss but fail to preserve muscle, exacerbating “sarcopenic obesity” and mortality risk. ACVR2A regulates muscle and fat metabolism: blocking it reduces adipogenesis while promoting muscle growth. We developed fully human anti-ACVR2A antibodies retaining natural sequences with superior PK, enabling extended dosing intervals for obesity treatment. Methods: ACVR2A-immunized HUGO-eKO mice underwent single B-cell sorting to obtain naturally paired VH/VL sequences. Leads were assessed for ACVR2A/B binding (ELISA/SPR, cell FACS), signaling blockade (reporter assays), PK (C57 mice), efficacy in DIO mice ± semaglutide (MRI body composition), and muscle function (grip strength in CB-17 SCID mice). Results: Lead antibodies showed high affinity for ACVR2A (KD 10-9~10-10 M) with minimal ACVR2B binding, and effectively recognized membrane-bound ACVR2A. They potently blocked ACVR2A-mediated signaling. In PK studies, lead antibodies exhibited significantly prolonged half-life and increased exposure vs. clinical-stage control. In DIO mice, lead antibodies + semaglutide synergistically enhanced weight loss, increased lean mass, and reduced fat mass. In CB-17 SCID mice, lead antibodies significantly improved grip strength (p<0.01). Conclusion: We developed fully human anti-ACVR2A antibodies with high affinity and selectivity. Lead antibodies showed superior PK with prolonged half-life. In DIO mice, they achieved synergistic “fat loss with muscle gain” with semaglutide. In CB-17 SCID mice, they improved grip strength, confirming muscle function enhancement. Targeting ACVR2A with fully human antibodies is a promising approach for obesity and sarcopenic obesity. Y. Liu: None.