OR31-06 Lonigutamab (Anti-IGF-1R Monoclonal Antibody) Induces Efficient Degradation of IGF-1R in Thyroid Eye Disease Orbital Fibroblasts

Abstract Disclosure: B. Welch: 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. A. Nyborg: 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 driven by overexpression and aberrant stimulation of the insulin-like growth factor 1 receptor (IGF-1R) pathway. IGF-1R is a clinically validated therapeutic target for TED. Lonigutamab is a high-affinity, subcutaneously administered, next-generation anti-IGF-1R monoclonal antibody that showed proof of concept efficacy in a phase 1/2 study in patients with TED (1) and is advancing to phase 3 randomized registrational trials. Uniquely, relative to other anti-IGF-1R therapeutic antibodies, lonigutamab binds to IGF-1R non-competitively with IGF-1. It was previously shown to induce rapid internalization of IGF-1R in a human breast cancer cell line (2). Here, we describe studies in the context of TED orbital fibroblasts (OFs), which establish that lonigutamab mediates IGF-1R degradation in these cells. Methods: Primary human OFs were obtained from patients with TED who underwent orbital decompression surgery. These cells were then treated with lonigutamab (or vehicle control) in the absence or presence of ligand (IGF-1) stimulation. Total cellular IGF-1R was assessed by Western blot to measure IGF-1R protein degradation; mRNA levels were assessed by RT-qPCR. To assess the mechanism of lonigutamab-mediated IGF-1R degradation, TED OFs were treated with a proteasome inhibitor (MG132) and/or an autophagy/lysosome inhibitor (bafilomycin) and analyzed by Western blot. Results: Treatment of TED OFs with 2 μg/mL of lonigutamab reduced total mature IGF-1R levels by ∼75% within 24 hours relative to controls, as measured by Western blot. The reduction in total IGF-1R levels was dependent on lonigutamab concentration (from 0.00001 to 2 μg/mL) and length of time (from 1 to 24 hours). Pro-protein levels of IGF-1R and mRNA levels of IGF1R were unchanged with lonigutamab. The addition of a proteasome (MG132) and/or lysosome (bafilomycin) inhibitor prevented lonigutamab-mediated reduction of IGF-1R levels. Conclusions: Findings from this study demonstrate that lonigutamab, a high-affinity anti-IGF-1R monoclonal antibody, induces efficient internalization and degradation of IGF-1R in TED OFs. Inhibition of the IGF-1/IGF-1R axis through elimination of IGF-1R from the surface of OFs has the potential to provide a meaningful benefit in TED and supports the continued clinical development of lonigutamab. References: 1. Ugradar S, et al. J Endocrine Soc. 2024;8(suppl):bvae163.2040. 2. Akla B, et al. Mol Cancer Ther. 2020;19(1):168-177. Presentation: Monday, July 14, 2025