S-Space College of Medicine/School of Medicine (의과대학/대학원) Program in Cancer Biology (협동과정-종양생물학전공) Theses (Ph.D. / Sc.D._협동과정-종양생물학전공)
An antibody to a novel epitope on mouse complement C5 β-chain potently neutralizes C5 cleavage
마우스 보체 C5 β-chain에 특이적인 C5 활성 중화 항체 개발
- 의과대학 협동과정 종양생물학전공
- Issue Date
- 서울대학교 대학원
- 학위논문 (박사)-- 서울대학교 대학원 : 의학과 종양생물학전공, 2017. 2. 정준호.
- 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.