Introduction and Objective: Obesity is a chronic disease requiring lifelong management, yet peptide agonists face high discontinuation and rebound weight gain due to dosing burdens. Improving therapeutic persistence requires long-acting agents optimized for weight maintenance. Leveraging antibody-based half-life extension, we developed a potent GIPR antagonist. This study evaluates its cellular potency and metabolic durability in DIO models, establishing its role as a superior maintenance-oriented monotherapy and a foundational backbone for next-generation combination regimens. Methods: Our SPID platform employed deep mutational scanning (DMS) to map GIPR-antagonist interactions. Combinatorial mutations were screened for high affinity, pH-sensitive recycling, and stable expression, together with in silico immunogenicity assessment. Selected candidates were validated via cAMP signaling assays and evaluated for weight and glucose control in DIO mice to assess suitability for extended-interval dosing. Results: DMS identified permissive substitutions across all CDRs, yielding a lead GIPR antagonist with 47-fold increased affinity and a 5-fold improvement in cellular potency. The lead candidate demonstrated a superior pharmacokinetic profile, with a 47-day half-life and a 44.3% higher maximum plasma concentration. In the DIO mouse model, the lead candidate achieved superior weight loss (7.4%) compared to the hit (4.2%), despite comparable food intake. Furthermore, IPGTT analysis demonstrated that the lead significantly improved glycemic control (21.8% AUC reduction vs. vehicle), whereas the hit showed no meaningful effect. Histological analysis revealed a 25.7% reduction in adipocyte size, normalized morphology, reduced iWAT and liver mass, and marked attenuation of hepatic steatosis. Conclusion: We demonstrate that the SPID-engineered GIPR antagonist provides durable metabolic control and supports its application as a long-acting maintenance therapy and a backbone for combination strategies. Disclosure J. Jo: Employee; Current; PROTEINA Co., Ltd. H. An: Employee; Current; PROTEINA Co., Ltd. C. Chun: Employee; Current; PROTEINA Co., Ltd. H. Cho: Employee; Current; PROTEINA Co., Ltd. S. Lee: Employee; Current; PROTEINA Co., Ltd. B. Yu: Employee; Current; PROTEINA Co., Ltd. C. Lee: Employee; Current; PROTEINA Co., Ltd. J. Kim: Employee; Current; PROTEINA Co., Ltd. Y. Ban: Employee; Current; PROTEINA Co. Ltd. H. Lee: Employee; Current; PROTEINA Co., Ltd.
JO et al. (Mon,) studied this question.