Characterization of VRDN-001, a High Affinity and Potent anti-Insulin-like Growth Factor-1 Receptor (IGF-1R) Inhibitory Antibody for the Treatment of Thyroid Eye Disease (TED)

Abstract

Purpose : VRDN-001 is an antagonist antibody to IGF-1R under development by Viridian Therapeutics for treatment of patients with TED, a condition driven by Thyroid Stimulating Hormone Receptor (TSHR) agonistic autoantibodies and crosstalk between TSHR and IGF-1R. TED is characterized by recruitment of fibrocytes that express IGF-1R and TSHR into orbital tissues, where they mediate deposition of hyaluronan and expansion of orbital muscle and fat. Blockade of IGF-1R has been shown to improve TED symptoms in randomized clinical trials. To assess its potential for treating TED, we evaluated the binding characteristics of VRDN-001 to IGF-1R and its potency for inhibition of IGF-1R phosphorylation.

Methods : Binding characteristics of VRDN-001 were investigated using surface plasmon resonance where antibodies were immobilized and recombinant IGF-1R extracellular domain (ECD) was used as analyte. Kinetic parameters and equilibrium dissociation constant were derived by global fitting of data. Binding to cell-surface expressed IGF-1R was assessed by flow cytometry. For cell-based potency testing, IGF-1R expressing primary human ocular choroid fibroblasts (HOCF) and A549 lung carcinoma cells were stimulated with IGF-1, and IGF-1R antibodies were evaluated for inhibition of receptor autophosphorylation using a commercial ELISA kit.

Results : VRDN-001 bound IGF-1R ECD with high affinity (equilibrium dissociation constant K_D = 0.57 nM) and exhibited slow dissociation of IGF-1R (off rate k_d = 5X10^-5 s^-1). These results were consistent with dose-response of binding to cell surface IGF-1R. In IGF-1 stimulated HOCFs and A549 cells, VRDN-001 inhibited IGF-1R phosphorylation in a dose-dependent manner. VRDN-001 IC50 values were ~0.1 nM and greater than 95% inhibition of phosphorylation was observed with VRDN-001 concentrations in the 1-10 nM range (0.15-1.5 µg/mL).

Conclusions : VRDN-001 bound IGF-1R with high affinity and inhibited IGF-1R signaling with high potency. VRDN-001 shut down IGF-1R signaling at concentrations that can be achieved with moderate clinical doses. The in vitro profile of VRDN-001 suggests favorable efficacy and exposure requirements for treatment of TED patients. A phase 1/2 trial for VRDN-001 in healthy volunteers and TED patients is underway (NCT050176639).

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.