MON-360 Lonigutamab (Anti-IGF-1R Monoclonal Antibody) Reduces IGF-1-Mediated Hyaluronan Production in Thyroid Eye Disease Orbital Fibroblasts

Abstract Disclosure: A. Nyborg: ACELYRIN, INC. E. Roztocil: National Institutes of Health, National Eye Institute, ValenzaBio, Inc./ACELYRIN, INC. F. Husain: National Institutes of Health, National Eye Institute, ValenzaBio, Inc./ACELYRIN, INC. S.E. Feldon: Alliance for Eye and Vision Research (AEVR)/National Alliance for Eye and Vision Research (NAEVR), Empire Discovery Institute, Excell Partners, National Institutes of Health, National Eye Institute, ValenzaBio, Inc./ACELYRIN, INC. B. Welch: ACELYRIN, INC. S. Mpofu: ACELYRIN, INC. C.F. Woeller: National Institutes of Health, National Eye Institute, ValenzaBio, Inc./ACELYRIN, INC.. Background: Thyroid eye disease (TED) is a chronic debilitating condition characterized by aberrant stimulation of the insulin-like growth factor 1 receptor (IGF-1R) pathway. IGF-1R signaling promotes TED pathogenesis, in part through activating orbital fibroblasts (OFs) to produce excessive hyaluronan (HA) and other glycosaminoglycans, leading to interstitial edema and extraocular muscle expansion. Lonigutamab is a high-affinity, subcutaneously administered, next-generation anti-IGF-1R monoclonal antibody (1) that binds to IGF-1R non-competitively with IGF-1 and induces efficient internalization and degradation of IGF-1R from the surface of cells, thus potently blocking IGF-1/IGF-1R signaling. Lonigutamab showed proof of concept efficacy in a phase 1/2 study of patients with TED (2) and is advancing to phase 3 randomized registrational trials. Consistent with the mechanism of action and underlying hypothesis, here we demonstrate that lonigutamab reduces HA production in TED OFs from multiple patients. Methods: Primary human OFs were obtained from patients with TED who underwent orbital decompression surgery. OFs were pretreated with vehicle or lonigutamab for 1 hour, then incubated with vehicle or IGF-1 for 48 to 72 hours. HA from cell supernatants was quantified by enzyme-linked immunosorbent assay and its molecular weight was assessed by agarose gel electrophoresis following digestion with proteinase K. Results: Lonigutamab treatment significantly reduced both basal and IGF-1-induced HA production compared with vehicle across the concentrations tested. Importantly, lonigutamab consistently reduced HA production under varied conditions and across multiple primary TED OF patient samples. Lonigutamab treatment did not alter HA polymer size. Conclusions: In this study, we demonstrated that lonigutamab effectively inhibited the IGF-1-driven production of HA in OFs from multiple patients with TED, highlighting its potential to modulate a crucial pathogenic disease process and providing mechanistic insights that support the observed preliminary clinical activity of lonigutamab in TED. References: 1. Akla B, et al. Mol Cancer Ther. 2020;19(1):168-177. 2. Ugradar S, et al. J Endocrine Soc. 2024;8(suppl):bvae163.2040. Presentation: Monday, July 14, 2025