H6-IgG Antagonizes LepR Signaling and Attenuates TPA-Induced Cutaneous Inflammation in Mice

Leptin receptor (LepR) signaling contributes to energy homeostasis and inflammatory responses, making LepR antagonism a potential anti-inflammatory strategy. Although H6-derived antibody ligands exhibit LepR agonistic activity, the pharmacological properties of H6 in a full-length immunoglobulin G format (H6-IgG) remain unclear. We evaluated H6-IgG binding, competition with leptin, and signaling activity, examined NanoBiT reporter responses and structural models, and assessed its activity in a 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced acute cutaneous inflammation model in C57BL/6 mice. H6-IgG bound human and mouse LepR and interfered with leptin binding. H6-IgG showed no appreciable agonist activity but inhibited leptin-induced STAT3/STAT5 signaling and NanoBiT reporter responses. Structural modeling suggested distinct membrane-proximal LepR arrangements associated with H6-IgG and leptin. In female mice, H6-IgG (5 mg/kg) significantly reduced TPA-induced ear swelling. These findings identify H6-IgG as a functional LepR antagonist with anti-inflammatory activity in an acute cutaneous inflammation model.