June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Design and Preclinical Characterization of VRDN-003, a Next-Generation, Half-life Extended Antibody to IGF-1 Receptor in Development for Thyroid Eye Disease (TED)
Author Affiliations & Notes
  • Rachel Newell
    Viridian Therapeutics Inc, Waltham, Massachusetts, United States
  • Yang Zhao
    Viridian Therapeutics Inc, Waltham, Massachusetts, United States
  • Vahe Bedian
    Viridian Therapeutics Inc, Waltham, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Rachel Newell Viridian Therapeutics Inc, Code E (Employment), Viridian Therapeutics Inc, Code I (Personal Financial Interest); Yang Zhao Viridian Therapeutics Inc, Code E (Employment), Viridian Therapeutics Inc, Code I (Personal Financial Interest), Viridian Therapeutics Inc, Code P (Patent); Vahe Bedian Viridian Therapeutics Inc, Code E (Employment), Viridian Therapeutics Inc, Code I (Personal Financial Interest), Viridian Therapeutics Inc., Code P (Patent)
  • Footnotes
    Support  Study funded by Viridian Therapeutics Inc.
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 4044. doi:
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    • Get Citation

      Rachel Newell, Yang Zhao, Vahe Bedian; Design and Preclinical Characterization of VRDN-003, a Next-Generation, Half-life Extended Antibody to IGF-1 Receptor in Development for Thyroid Eye Disease (TED). Invest. Ophthalmol. Vis. Sci. 2023;64(8):4044.

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      © ARVO (1962-2015); The Authors (2016-present)

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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.

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