Complement component 3a and Complement component 5a (C3a and C5a) (C3a and C5a)

Complement anaphylatoxins C3a and C5a are potent bioactive peptides generated through the proteolytic cleavage of complement components C3 and C5 during the activation of the complement cascade [4, 5]. These small, cationic molecules function as critical mediators of the innate immune response, primarily by binding to their cognate G protein-coupled receptors, C3aR and C5aR1/C5aR2, on various immune and non-immune cells [1, 3]. Their biological roles include inducing chemotaxis of leukocytes, triggering mast cell degranulation, increasing vascular permeability, and modulating both innate and adaptive immune responses [5, 8]. In pathological states, excessive or chronic production of C3a and C5a contributes to the progression of inflammatory and autoimmune diseases, such as rheumatoid arthritis and lupus, as well as the promotion of an immunosuppressive microenvironment in cancer [2, 15]. Therapeutic strategies targeting this axis include monoclonal antibodies that neutralize the anaphylatoxins (e.g., vilobelimab), inhibitors that prevent the cleavage of precursor proteins (e.g., eculizumab, pegcetacoplan), and small molecule antagonists that block receptor activation (e.g., avacopan) [13, 15]. While effective in treating complement-mediated disorders, these therapies carry a significant safety concern regarding an increased risk of life-threatening infections, particularly by encapsulated bacteria like Neisseria meningitidis [13].

Other names

AnaphylatoxinsComplement anaphylatoxinsC3aC5aComplement component 3aComplement component 5a

Drugs targeting the C3a and C5a axis function by neutralizing the anaphylatoxin ligands directly, inhibiting the enzymatic cleavage of their precursor proteins (C3 and C5) to prevent their generation, or competitively antagonizing their cognate G protein-coupled receptors (C3aR and C5aR1) to block downstream pro-inflammatory signaling cascades.