Preclinical pharmacological characterization of a novel complement C3 inhibitor antibody fragment for geographic atrophy (GA), including binding affinity to C3/C3b/C3 variants, inhibition of membrane attack complex (MAC) formation across all three complement pathways, and Bruch's membrane (BrM) permeation — compared against the compstatin derivative APL-1 and a pegcetacoplan-similar molecule.
The antibody fragment bound C3 ligands with picomolar affinity (vs. single-digit nanomolar for APL-1) and inhibited MAC formation with IC50 of 79 nM (classical pathway), 344 nM (alternative pathway), and 67 nM (lectin pathway) — outperforming APL-1 on the classical and lectin pathways. It also showed greater BrM permeation than the pegcetacoplan-similar molecule.
All experiments are preclinical and in vitro or ex vivo; pegcetacoplan itself could not be sourced and was replaced by a similar molecule and APL-1 surrogate for comparisons; no sample size or human pharmacokinetic data are reported.
This C3-targeting antibody fragment shows stronger binding and pathway inhibition than current compstatin-class comparators and crosses Bruch's membrane more readily — supporting its ongoing clinical investigation in GA patients. Clinicians should watch for emerging trial data on this agent as a potential new option for geographic atrophy.
