Abstract
Purpose :
Clinical and preclinical studies have demonstrated IGF-1 receptor (IGF-1R) antagonism reduces the inflammation and proptosis that occur in thyroid eye disease (TED). VRDN-001 is a full antagonist antibody to IGF-1R with subnanomolar affinity; VRDN-003 is a next-generation, half-life extended version of VRDN-001 designed to enable subcutaneous administration via a fixed-dose patient-controlled pen. Given that VRDN-003 is identical to VRDN-001 except for the half-life extension modification, we assessed whether they have the same in vitro antagonist characteristics.
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 and 2) inhibition of IGF-1–mediated IGF-1R and AKT phosphorylation (end points of IGF-1–mediated signaling) in primary human ocular choroid fibroblasts.
Results :
Over the dose ranges tested, the potencies and antagonist properties of VRDN-001 and VRDN-003 were indistinguishable. At concentrations ≥50 nM, both antibodies provided near-complete inhibition of IGF-1 binding (>95%). In addition, both antibodies provided similar and near-complete inhibition of IGF-1–induced phosphorylation of IGF-1R (proximal signaling) and phosphorylation of AKT (distal signaling) with IC50s of 0.1–0.2 nM.
Conclusions :
Both VRDN-001 and VRDN-003 provide indistinguishable and near-complete inhibition of IGF-1 binding and IGF-1R signaling. Prior studies with VRDN-001 have shown robust increases in IGF-1 levels in healthy volunteers and patients with TED as well as favorable efficacy signals in a small cohort of TED patients. Given that VRDN-001 and VRDN-003 antagonist properties are the same, VRDN-003 should achieve similar in vivo pharmacodynamics and efficacy.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.