Targeting C3b/C4b and VEGF with a bispecific fusion protein optimized for neovascular age-related macular degeneration therapy

Abstract

Antiangiogenesis therapies targeting vascular endothelial growth factor (VEGF) have revolutionized the treatment of neovascular ocular diseases, including neovascular age-related macular degeneration (nAMD). Compelling evidence has implicated the vital role of complement system dysregulation in AMD pathogenesis, implying it as a potential therapeutic strategy for geographic atrophy in dry AMD and to enhance the efficacy of anti-VEGF monotherapies in nAMD. This study reports the preclinical assessment and phase 1 clinical outcomes of a bispecific fusion protein, efdamrofusp alfa (code: IBI302), which is capable of neutralizing both VEGF isoforms and C3b/C4b. Efdamrofusp alfa showed superior efficacy over anti-VEGF monotherapy in a mouse laser-induced choroidal neovascularization (CNV) model after intravitreal delivery. Dual inhibition of VEGF and the complement activation was found to further inhibit macrophage infiltration and M2 macrophage polarization. Intravitreal efdamrofusp alfa demonstrated favorable safety profiles and exhibited antiangiogenetic efficacy in a nonhuman primate laser-induced CNV model. A phase 1 dose-escalating clinical trial (NCT03814291) was thus conducted on the basis of the preclinical data. Preliminary results showed that efdamrofusp alfa was well tolerated in patients with nAMD. These data suggest that efdamrofusp alfa might be effective for treating nAMD and possibly other complement-related ocular conditions.

Diabetic retinopathy in China: Epidemiology, screening and treatment trends—A review

“…Our group previously reported that IBI302, a bispecific fusion protein capable of neutralising both VEGF isoforms and C3b/C4b, showed great potential in the preclinical assessment and phase I clinical outcomes of nAMD. 101 Phase I and II trials of intravitreal IBI302 for DMO treatment are ongoing (CTR20212710). Recently, a phase I clinical trial was initiated for an anti-VEGF/anti-Ang-2 bispecific antibody designed in the form of scFv (singlechain Fv) + VHH (single-domain antibody), coded IBI324, for DMO treatment (CTR20221524).…”

“…In China, various innovative drugs are in phases I‐III clinical trials. Our group previously reported that IBI302, a bispecific fusion protein capable of neutralising both VEGF isoforms and C3b/C4b, showed great potential in the preclinical assessment and phase I clinical outcomes of nAMD 101 . Phase I and II trials of intravitreal IBI302 for DMO treatment are ongoing (CTR20212710).…”

Retinal fluid is associated with cytokines of aqueous humor in age-related macular degeneration using automatic 3-dimensional quantification

“…The role of VEGF in AMD has been strongly supported in several studies (Lee et al, 2018;Yang et al, 2022). VEGF appears to be a major stimulator of neovascularization growth originating from the retinal and choroidal vasculature (Marneros, 2021).…”

Ocular Delivery of Therapeutic Agents by Cell-Penetrating Peptides

“…Another example of success is the dual-blocking strategy. Efdamrofusp alpha/IBI302 (Innovent Biologics, Jiangsu, China) is a bispecific decoy receptor fusion protein for VEGF and complement [ 126 , 148 ]. A randomized, open-label Phase Ib study (NCT04370379) showed that monthly intravitreal injection of efdamrofusp alpha, dosed up to 4 mg, was well tolerated in wet AMD patients, with similar improvement of visual acuity compared to aflibercept [ 127 ].…”