Variants of IGT-427 are long-acting, bispecific antibodies for the treatment of degenerative retinal diseases

Abstract

Purpose : Vascular endothelial growth factor (VEGF) inhibitors are standard of care first-line treatment for diabetic macular edema (DME) and wet type age-related macular degeneration (wAMD) although moderate frequency of intraocular administration and the substantial inadequately responding population limit the utility of these treatments. Variants of IGT-427 were designed to address both limitations of the current therapies. The dual function of VEGF inhibition and Tie2 activation is designed to improve the quality of the retinal vasculature and the longer vitreous half-life designed to reduce the frequency of administration compared to the current standard of care. This study set out to evaluate variant's biological and biophysical characteristics.

Methods : The binding affinity was assessed by SPR analysis and the potency in regulating target signaling pathways was assessed in mammalian cell-based assays. Laser-induced choroidal neovascularization (CNV) model in rabbits was employed to examine its in vivo mode of action. In addition, its vitreous pharmacokinetics was measured in a rabbit model.

Results : IGT-427, a bispecific antibody, simultaneously suppressed VEGF signaling and activated Tie2 signaling pathways in heterologous CHO cells and vascular endothelial cells. IGT-427 bound human Tie-2 with Kd < 1 nM in a bivalent interaction, analogous to the cellular surface interaction, and bound human VEGF with a Kd < 10 pM. It displayed comparable high affinities toward rabbit orthologs. Intravitreal IGT-427 reduced vascular leakage in the rabbit CNV model. Engineered variants of IGT-427 were site-specifically PEGyated to increase the apparent molecular weight of the bispecific antibody by > 3-fold. While these variants had slightly reduced apparent affinity for Tie-2 and VEGF, they were similar in activity blocking VEGF and activating Tie-2 in cell-based assays. The extended ocular half-life in rabbit eyes compared to unmodified IGT-427 and Aflibercept will be presented.

Conclusions : IGT-427 has potential as best-in-class therapeutics with superior efficacy compared to agents that only inhibit VEGF, have more potent agonist activity on Tie-2 compared to Ang2 inhibiting agents, and have reduced frequency of intravitreal administration.

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