A trispecific GLP-1/anti-GIPR/FGF21 peptibody exhibits favorable metabolic effects in a diet-induced obesity model

BACKGROUND: Metabolic diseases such as obesity and type 2 diabetes are complex disorders involving multiple dysregulated pathways, which may limit the efficacy of single-target therapies. To address this challenge, we developed a trispecific peptibody integrating glucagon-like peptide-1 receptor (GLP-1R) agonism, glucose-dependent insulinotropic polypeptide receptor (GIPR) antagonism, and fibroblast growth factor 21 (FGF21) pathway activation. This study evaluated the pharmacological activity and metabolic effects of the trispecific construct in preclinical models. METHODS: The trispecific peptibody was generated using an antibody-based scaffold and characterized using in vitro binding, receptor activation, and competitive assays. Binding kinetics were assessed by surface plasmon resonance (SPR) and bio-layer interferometry (BLI). In vivo efficacy was evaluated in a diet-induced obesity (DIO) mouse model, including body weight, food intake, glucose tolerance, body composition, and serum biochemical analyses. RESULTS: The trispecific construct retained functional activity across all three targets. In DIO mice, the trispecific peptibody (TA2) significantly reduced body weight, improved glucose tolerance, and ameliorated dyslipidemia. Notably, TA2 was associated with substantial body weight reduction under conditions of generally comparable food intake relative to tirzepatide. Additional improvements were observed in lipid profiles and liver-associated parameters. CONCLUSIONS: These findings demonstrate that the trispecific peptibody exhibits favorable metabolic effects in preclinical models. The observed effects may not be fully explained by reduced food intake alone, suggesting metabolic effects beyond appetite suppression. This study provides a proof-of-concept for multispecific biologics as a potential strategy for the treatment of complex metabolic diseases.