1324-OR: A β-klotho Antibody Conjugated to GLP-1/GCG/GIP Triple Agonist Demonstrates Robust Body Weight Reduction and Metabolic Improvement in Obese Rodents and Nonhuman Primates

Introduction and Objective: Obesity is a major driver of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), conditions with substantial unmet medical need. This study aimed to characterize XWDAPC-1, a novel long-acting β-klotho antibody-GLP-1/GCG/GIP quadragonist, for its metabolic efficacy and pharmacological profile. Methods: The in vitro activity of XWDAPC-1 was evaluated using cell-based assays expressing β-klotho, GLP-1 receptor (GLP-1R), glucagon receptor (GCGR), or glucose-dependent insulinotropic polypeptide receptor (GIPR). In vivo efficacy was assessed in diet-induced obese (DIO) mice and obese male cynomolgus monkeys. Pharmacokinetic (PK) properties were evaluated in male cynomolgus monkeys. Results: XWDAPC-1 exhibited robust agonist activity across β-klotho, GLP-1R, GCGR, and GIPR assays. In DIO mice, a single dose of XWDAPC-1 induced sustained and greater body weight reduction compared with MariTide. In obese cynomolgus monkeys, XWDAPC-1 consistently produced substantial body weight control and modulation of plasma metabolic biomarkers. PK analysis in cynomolgus monkeys demonstrated profiles comparable to MariTide, supporting monthly dosing interval. Conclusion: XWDAPC-1 demonstrates strong in vitro potency, robust in vivo metabolic efficacy, and favorable pharmacokinetic properties. These findings support XWDAPC-1 as a promising therapeutic candidate for the treatment of obesity and related metabolic liver diseases, including MASLD and MASH. Disclosure H. Zou: Employee; Current; Sciwind Biosciences. Y. Wang: Employee; Current; Sciwind Biosciences. R. Zhu: Employee; Current; Sciwind Biosciences. J. Zhao: Employee; Current; Sciwind Biosciences. D. Jia: Employee; Current; Sciwind Biosciences. J. Deng: Employee; Current; Sciwind Biosciences. X. Wu: Employee; Current; Sciwind Biosciences.