Lonigutamab inhibits hyaluronan production by reducing IGF-1R levels in thyroid eye disease orbital fibroblasts

CONTEXT: In thyroid eye disease (TED), the connective tissue behind the eye becomes inflamed and expands, partly due to excessive deposition of hyaluronan (HA), which absorbs water, leading to osmotic swelling. Orbital fibroblasts (OFs) from patients with TED overexpress insulin-like growth factor 1 receptor (IGF-1R), a receptor that promotes cell survival, proliferation, and HA production. These processes contribute to orbital tissue remodeling and expansion, as well as to the inflammation and fibrosis characteristic of TED. Therapeutic options remain limited, highlighting the need for additional targeted therapies. Lonigutamab is a next-generation anti-IGF-1R monoclonal antibody that binds to a distinct epitope on IGF-1R with high affinity, eliciting a novel mechanism of action. OBJECTIVE: To evaluate whether lonigutamab inhibits HA production and characterize its mechanism of action using TED OFs. METHODS: TED OFs were treated with lonigutamab in the presence or absence of IGF-1. HA was measured by ELISA and agarose gel electrophoresis. IGF-1R levels were assessed by flow cytometry and Western blot. The proteasome inhibitor MG132 and the lysosome/autophagy inhibitor bafilomycin were used to probe lonigutamab-mediated degradation pathways. RESULTS: Lonigutamab significantly reduced basal and IGF-1-induced HA production across all evaluated TED OF strains. Lonigutamab also decreased mature IGF-1R protein levels in a time- and dose-dependent manner by promoting IGF-1R internalization and subsequent degradation through proteasomal and lysosomal pathways. CONCLUSIONS: These findings suggest that lonigutamab suppresses HA production in TED OFs via efficient IGF-1R internalization and degradation, supporting its unique mechanism of action and potential as a therapeutic option for TED.