6580 Inhibition of IGF-1 Receptor Signaling and Ocular Fibroblast Cell Growth by VRDN-001 vs Teprotumumab

Abstract Disclosure: R. Newell: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. T. Nguyen: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. V. Bedian: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. Introduction: Clinical data have shown that IGF-1 receptor (IGF-1R) antagonism reduces the inflammation and proptosis that occur in thyroid eye disease (TED), while preclinical data have shown that VRDN-001 provides more complete inhibition of IGF-1R autophosphorylation and downstream phosphorylation of AKT than teprotumumab. Here we assess the extent to which these antibodies inhibit another distal end point of IGF-1R signaling—phosphorylation of ERK, part of the mitogen-activated protein kinase (MAPK) pathway, and ocular fibroblast growth. Methods: Antagonist characteristics were determined by assessing dose-responses of 1) inhibition of biotinylated IGF-1 binding to IGF-1R-expressing FreeStyle™ 293-F cells using flow cytometry, 2) inhibition of IGF-1-mediated ERK phosphorylation in primary human ocular choroid fibroblasts (HOCF), and 3) inhibition of IGF-1-mediated cell growth measured by a) ATP released from metabolically active cells and b) imaging data in HOCF cells. Results: Over the dose ranges tested, VRDN-001 inhibited both the binding of biotinylated IGF-1 to cells and IGF-1-mediated MAPK activation to a greater extent than teprotumumab. At concentrations ≥30 nM, VRDN-001 provided near-complete inhibition of ERK phosphorylation vs partial inhibition by teprotumumab. Further, VRDN-001 inhibited IGF-1-mediated cell growth, a downstream functional effect of the MAPK pathway, more fully than teprotumumab. Conclusion: Prior in vitro research showed that compared with teprotumumab, VRDN-001 provided more complete inhibition of IGF-1R autophosphorylation and AKT phosphorylation (PI3K signaling pathway). The current research extends these findings by showing that VRDN-001 also provides more complete inhibition of IGF-1-mediated ERK phosphorylation (MAPK signaling pathway activation) and fibroblast cell growth. While teprotumumab and VRDN-001 share a similar mechanism of action, their binding properties are distinct, which may explain the differences in ligand blocking, antagonism of signaling, and inhibition of functional activity. Ongoing Phase 3 clinical trials will assess the clinical efficacy and safety of VRDN-001 in patients with active and chronic TED. Presentation: 6/1/2024