AAV vectorized antibody-mediated dual complement pathway inhibition for the treatment of AMD

Abstract

Purpose : Age-related macular degeneration (AMD) is a common, complex disease that is the leading cause of central vision loss in individuals 60 years of age and older. In geographic atrophy (GA), an advanced form of AMD, metabolic and inflammatory stresses in the retina lead to the death of photoreceptors and retinal pigment epithelial cells, the appearance of atrophic lesions, and eventual blindness. Human genetic variants in complement pathway genes are among the most common and strongest genetic risk factors associated with AMD and implicate roles for both the classical and alternative pathways in disease pathogenesis.

Methods : Here, we describe an AAV-mediated gene therapy approach to inhibit proximal steps in both the classical and alternative complement pathways through sustained expression of vectorized antibody fragments targeting active C1s (aC1s) and Factor Bb in the eye. In addition to its benefit as a potential one-time treatment for GA, this bifunctional strategy has potential to show improved efficacy compared to approaches that target downstream components in the complement pathway because it will broadly inhibit both proximal and terminal mediators of inflammation, phagocytosis, and membrane attack complex-mediated cell lysis.

Results : To inhibit both the classical and alternative pathways, we designed a novel AAV vector AAV-aC1s_scFab-Bb_scFab that co-expresses anti-aC1s and anti-Bb single-chain antibody fragments (scFabs). The vector derived scFabs demonstrate target engagement and inhibitory activity for their respective targets and pathways in vitro. AAV-aC1s_scFab-Bb_scFab was evaluated in vivo following intravitreal (IVT) administration in wild-type C57BL/6 mice and cynomolgus monkeys. At multiple dose levels and timepoints following IVT delivery, the AAV-aC1s_scFab-Bb_scFab vector transduces the retina and expresses transcripts encoding both scFabs. Vector-derived scFabs secreted from transduced cells are detectable in the aqueous and vitreous humors, maintain target engagement capacity, and improve clinical indicators in an NHP model of ocular inflammation.

Conclusions : Overall, these data demonstrate that dual complement pathway inhibition through IVT delivery of vectorized antibody fragments has potential as a one-time treatment for GA secondary to AMD.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.