Therapeutic targeting of factor D and MASP3 in complement‐mediated diseases: Lessons learned from mouse studies

• Published in: European journal of immunology 2024-09, Vol.54 (9), p.e2350845-n/a
• Main Authors: Mohammadyari, Eshagh, Miwa, Takashi, Golla, Madhu, Song, Wen‐Chao
• Format: Article
• Language: English
• Subjects: Adipose tissue; Alternative pathway; Animal models; Animals; Blood levels; Complement activation; Complement Activation - drug effects; Complement Activation - immunology; Complement factor D; Complement Factor D - antagonists & inhibitors; Complement Factor D - metabolism; Complement Pathway, Alternative - drug effects; Complement Pathway, Alternative - immunology; Complement system; Disease Models, Animal; Factor D; Humans; Mannose; Mannose-Binding Protein-Associated Serine Proteases - antagonists & inhibitors; Mannose-Binding Protein-Associated Serine Proteases - metabolism; MASP3; Mice; Monoclonal antibodies; Proenzymes; Proteinase inhibitors; Serine proteinase; Therapeutic targets
• ISSN: 0014-2980; 1521-4141; 1521-4141
• DOI: 10.1002/eji.202350845

The alternative pathway (AP) plays a major role in many complement‐mediated human diseases. Factor D (FD), a rate‐limiting enzyme in AP complement activation, is an attractive therapeutic target. Unlike other complement proteins, FD is synthesized primarily in adipose tissue, and its levels in human blood are relatively low. However, because of FD's high turnover rate, therapeutic targeting with monoclonal antibodies and chemical inhibitors has been challenging. The recent discovery that FD activity is regulated by mannose‐binding lectin‐associated serine protease 3 (MASP3), through conversion of a zymogen to mature FD, has sparked interest in MASP3 inhibition as a new way to block FD function and AP complement activity. Here, we review studies of mouse models of FD and MASP3 inhibition. We additionally discuss the lessons learned from these studies and their implications for therapeutic targeting of human FD and MASP3. Factor D (FD) and MASP3 are two proteases that are critical for alternative pathway complement activation and represent attractive therapeutic targets for complement‐mediated human diseases.