New concepts on the therapeutic control of complement anaphylatoxin receptors. (September 2017)

• Record Type: Journal Article
• Authors: Hawksworth, Owen A.; Li, Xaria X.; Coulthard, Liam G.; Wolvetang, Ernst J.; Woodruff, Trent M.
• Is Part Of: Molecular immunology. Volume 89(2017:Sep.)
• Page Start: 36
• Page End: 43
• Publication Date: 2017-09
• Subjects: Complement -- C5a -- C5a receptor -- C3a receptor -- Inflammation -- Therapeutics; Immunochemistry -- Periodicals; Molecular biology -- Periodicals; Immunochemistry -- Periodicals; Allergy and Immunology -- Periodicals; Molecular Biology -- Periodicals; Immunochimie -- Périodiques; Biologie moléculaire -- Périodiques; Immunochemistry; Molecular biology; Periodicals; Electronic journals; 571.96
• DOI: 10.1016/j.molimm.2017.05.015
• Languages: English
• ISSNs: 0161-5890

Abstract

Highlights: Complement underlies the pathogenesis of a vast number of inflammatory disorders. Driving the complement inflammatory response are the anaphylatoxins, C5a and C3a. A number of therapeutics have been developed to target anaphylatoxin signaling. This includes drugs targeting C5 and C5a, and the receptors C5aR1, C5aR2, and C3aR. We review these drugs, and their application in clinical and pre-clinical development. Abstract: The complement system is a pivotal driver of innate immunity, coordinating the host response to protect against pathogens. At the heart of the complement response lie the active fragments, C3a and C5a, acting through their specific receptors, C3aR, C5aR1, and C5aR2, to direct the cellular response to inflammation. Their potent function however, places them at risk of damaging the host, with aberrant C3a and C5a signaling activity linked to a wide range of disorders of inflammatory, autoimmune, and neurodegenerative etiologies. As such, the therapeutic control of these receptors represents an attractive drug target, though, the realization of this clinical potential remains limited. With the success of eculizumab, and the progression of a number of novel C5a-C5aR1 targeted drugs to phase II and III clinical trials, there is great promise for complement therapeutics in future clinical practice. In contrast, the toolbox of drugs available to modulate C3aR and C5aR2 signaling remains limited, however, the emergence of new selective ligands and molecular tools, and an increased understanding of the function of these receptors in disease, has highlighted their unique potential for clinical applications. This review provides an update on the growing arsenal of drugs now available to target C5, and C5a and C3a receptor signaling, and discusses their utility in both clinical and pre-clinical development.