Pharmacological Characterization of a Novel Complement C3 Inhibitor Antibody Fragment

The complement system is a key driver of geographic atrophy (GA), a disease that leads to progressive, irreversible vision loss. Pharmacological preclinical studies characterizing an antibody fragment, which is a novel complement C3 inhibitor under investigation for GA treatment, are presented. Kinetic parameters were determined for the antibody fragment binding to C3, C3b, and C3 variants associated with GA. Inhibition of membrane attack complex (MAC) formation after classical (CP), alternative (AP), and lectin (LP) pathway activation was determined. Comparisons with the second-generation compstatin derivative (APL-1) were made because of the expected similarity of binding behavior and in vitro potency with pegcetacoplan (which could not be sourced at the time of the study). Diffusion through Bruch’s membrane (BrM) was investigated for the antibody fragment and a pegcetacoplan-similar (PEG-s) molecule using enriched porcine BrM in Ussing chamber devices. The antibody fragment showed high (picomolar) affinity for all tested C3 ligands. APL-1 showed lower (single-digit nanomolar) affinity than the antibody fragment, comparable with published values. The antibody fragment exhibited dose-dependent inhibition of MAC formation via CP (half-maximal inhibitory concentration [IC50] 79 nM), AP (344 nM), and LP (67 nM), with enhanced potency for inhibiting CP- and LP-mediated complement activation vs. APL-1. More efficient permeation of the BrM was observed with the antibody fragment than with the PEG-s molecule. The antibody fragment is a potent and specific C3 inhibitor that displays dose-dependent inhibition of MAC formation across all three complement pathways and effectively crosses the BrM. In line with these results, the antibody fragment is being investigated in patients with GA. Graphical abstract available for this article. Geographic atrophy is the late stage of age-related macular degeneration. Geographic atrophy is a disease that causes damage to the retina in the eye and can cause loss of vision and reduce a person’s quality of life. There are currently only a few medicines approved to treat geographic atrophy. The development and progression of geographic atrophy is linked to the components of the immune system that are responsible for inflammation and the formation of destructive protein complexes. This preclinical study used laboratory experiments to investigate how a potential new therapy called an antibody fragment affects these immune system components and to see if it is suitable for the treatment for geographic atrophy. The study found that the antibody fragment bound strongly to its target immune components, and it may prevent the formation of destructive protein complexes. The antibody fragment was also able to readily pass through the membrane found in the eye where the immune components need to be targeted. These promising preclinical results support further investigation of the antibody fragment in people with geographic atrophy.