An antibody to a novel epitope on mouse complement C5 β-chain potently neutralizes C5 cleavage

Abstract

Complement is a system of interacting proteins that supports the elimination of pathogens and forms an important component of innate immunity. C5 is the final gatekeeper for regulating the terminal pathway in the complement cascade. It has been the main therapeutic target for complement-related disorders. Many attempts have been made in the past to target these components by developing therapeutic agents

however, only a few drugs are available on the market.

Eculizumab is the only approved therapeutic antibody drug for patients suffering from paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). Eculizumab binds to MG7 domain of α-chain for preventing C5 cleavage by C5 convertase, and it is a highly effective therapy for patients with rare diseases. According to the New England Journal of Medicine, minor PNH patients have a SNP (R885H/C), which shows a poor response to eculizumab. To this end, it is important to develop a new C5 targeting therapy for the minor PNH patient group that has a low response to the conventional eculizumab treatment.

In this study, we proposed a novel epitope binding antibody (moC5-72) that inhibits complement C5 cleavage via MG4 domain of β chain. This antibody also demonstrated clinical efficacy in a mouse model of nephritis. Thus, MG4 domain also plays a critical role in C5 cleavage. It is a distinct target for developing a novel therapeutic antibody to inhibit C5 cleavage in humans.