complementtargeted

Complement-targeted refers to therapeutic approaches that modulate the complement system, a part of the innate immune system that helps defend against pathogens but can also drive inflammation and tissue injury when dysregulated. These therapies aim to prevent or limit injury by interrupting specific steps in the complement cascade, thereby reducing opsonization, inflammation, and the formation of the membrane attack complex.

The complement system comprises three activation pathways—classical, lectin, and alternative—that converge at C3 and proceed through C5 to form the terminal membrane attack complex. Regulation of these pathways is essential to avoid collateral damage to host tissues. In disease, excessive or misplaced complement activation contributes to conditions such as paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy, certain forms of age-related macular degeneration, and inflammatory or transplant-related injuries. Complement-targeted therapies seek to balance immune defense with control of pathological activation.

Therapeutic strategies include inhibiting key effector points (for example, C3 or C5), blocking the formation of C5a or its receptor, or inhibiting specific pathways such as the lectin pathway. Notable examples are C5 inhibitors (eg, eculizumab, ravulizumab), C3 inhibitors (eg, pegylated C3 inhibitors, AMY-101), and C5a or C5a receptor inhibitors (eg, vilobelimab, avacopan). Other approaches include lectin pathway inhibitors (eg, MASP-2 inhibitors like narsoplimab) and factor D or factor B inhibitors that limit the alternative pathway. Many complement-targeted therapies are approved for specific indications or are in extensive clinical development, often focusing on licensed use in PNH or aHUS and expanding to kidney, ocular, and autoimmune diseases.

Risks include increased susceptibility to infections, notably meningococcal disease, and potential effects on host defense. Vaccination and monitoring of infection risk, laboratory complement activity, and disease-specific markers are common clinical considerations.