Abstract
Purpose :
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. We sought to extend this research by determining 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 ATP released from metabolically active cells in primary HOCF cells.
Results :
Over the dose ranges tested, VRDN-001 inhibited binding of biotinylated IGF-1 to cells to a greater extent than teprotumumab. A similar trend was observed in IGF-1–mediated ERK phosphorylation. At concentrations ≥30 nM, VRDN-001 provided near-complete inhibition of ERK phosphorylation, while inhibition by teprotumumab was incomplete. Further, VRDN-001 inhibited IGF-1–mediated cell growth, a downstream functional effect of the MAPK pathway, more fully than teprotumumab.
Conclusions :
VRDN-001 inhibited IGF-1–mediated MAPK pathway activation and cell growth, adding to the previous reports of IGF-1R autophosphorylation and PI3K signaling inhibition. These data suggest that VRDN-001 is a more robust IGF-1R inhibitor than teprotumumab through these distinct pathways in vitro. While teprotumumab and VRDN-001 share a similar mechanism of action, their binding properties are distinct, which may explain the differences in ligand blocking, signaling antagonism, 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.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.