Activated complement fragments

Activated complement fragments are the bioactive cleavage products generated during the activation of the complement system via the classical, lectin, or alternative pathways [1]. These fragments, including anaphylatoxins (C3a, C4a, C5a) and opsonins (C3b, iC3b, C4b), play critical roles in the innate immune response by promoting chemotaxis, leukocyte activation, and the marking of pathogens for phagocytosis [2]. While essential for host defense, excessive or dysregulated production of these fragments is a key driver of tissue damage in various inflammatory and autoimmune conditions, such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) [3]. Therapeutic strategies often involve monoclonal antibodies that specifically neutralize fragments like C5a or inhibit the enzymes (convertases) responsible for their generation [4]. Targeting these fragments helps mitigate systemic inflammation and prevent the formation of the terminal membrane attack complex (MAC) [5]. However, therapeutic inhibition of the complement cascade carries a significant risk of increased susceptibility to pyogenic infections, particularly by Neisseria species [6]. Sources: [1] Ricklin D, et al. (2010). Nat Immunol, 11(9), 785-797. [2] Klos A, et al. (2009). Mol Immunol, 46(14), 2753-2766. [3] Merle NS, et al. (2015). Front Immunol, 6, 262. [4] Giamarellos-Bourboulis EJ, et al. (2020). Lancet Rheumatol, 2(10), e590-e598. [5] Hillmen P, et al. (2006). N Engl J Med, 355(12), 1233-1243. [6] Ram S, et al. (2010). N Engl J Med, 362(13), 1192-1204.

Other names

Complement cleavage productsAnaphylatoxinsOpsoninsC3aC3bC4aC4bC5aC5b-9Complement component 5aComplement component 3b

Drugs targeting activated complement fragments primarily work by either directly binding and neutralizing the bioactive fragments (e.g., Vilobelimab binding C5a) or by binding the parent protein (e.g., Eculizumab binding C5) to prevent its cleavage into active fragments like C5a and C5b [1, 4, 5]. This prevents the downstream inflammatory effects mediated by anaphylatoxin receptors and the formation of the terminal membrane attack complex [3].