Inhibiting the C5-C5a receptor axis

Woodruff, Trent M., Nandakumar, Kutty S. and Tedesco, Francesco (2011) Inhibiting the C5-C5a receptor axis. Molecular Immunology, 48 14: 1631-1642. doi:10.1016/j.molimm.2011.04.014

Author Woodruff, Trent M.
Nandakumar, Kutty S.
Tedesco, Francesco
Title Inhibiting the C5-C5a receptor axis
Journal name Molecular Immunology   Check publisher's open access policy
ISSN 0161-5890
Publication date 2011-08
Sub-type Critical review of research, literature review, critical commentary
DOI 10.1016/j.molimm.2011.04.014
Volume 48
Issue 14
Start page 1631
End page 1642
Total pages 12
Editor Suzan Rooijakkers
Leendert Trouw
Place of publication East Park, Kidlington, Oxford, U.K.
Publisher Pergamon
Collection year 2012
Language eng
Formatted abstract
Activation of the complement system is a major pathogenic event that drives various inflammatory responses in numerous diseases. All pathways of complement activation lead to cleavage of the C5 molecule generating the anaphylatoxin C5a and, C5b that subsequently forms the terminal complement complex (C5b-9). C5a exerts a predominant pro-inflammatory activity through interactions with the classical G-protein coupled receptor C5aR (CD88) as well as with the non-G protein coupled receptor C5L2 (GPR77), expressed on various immune and non-immune cells. C5b-9 causes cytolysis through the formation of the membrane attack complex (MAC), and sub-lytic MAC and soluble C5b-9 also possess a multitude of non-cytolytic immune functions. These two complement effectors, C5a and C5b-9, generated from C5 cleavage, are key components of the complement system responsible for propagating and/or initiating pathology in different diseases, including paroxysmal nocturnal hemoglobinuria, rheumatoid arthritis, ischemia–reperfusion injuries and neurodegenerative diseases. Thus, the C5–C5a receptor axis represents an attractive target for drug development. This review provides a comprehensive analysis of different methods of inhibiting the generation of C5a and C5b-9 as well as the signalling cascade of C5a via its receptors. These include the inhibition of C5 cleavage through targeting of C5 convertases or via the C5 molecule itself, as well as blocking the activity of C5a by neutralizing antibodies and pharmacological inhibitors, or by targeting C5a receptors per se. Examples of drugs and naturally occurring compounds used are discussed in relation to disease models and clinical trials. To date, only one such compound has thus far made it to clinical medicine: the anti-C5 antibody eculizumab, for treating paroxysmal nocturnal hemoglobinuria. However, a number of drug candidates are rapidly emerging that are currently in early-phase clinical trials. The C5–C5a axis as a target for drug development is highly promising for the treatment of currently intractable major human diseases.

Highlights: ► We review the therapeutic options to inhibit the C5–C5a receptor axis. ► We examine methods to inhibit C5 cleavage via targeting C5a convertases or C5 itself. ► We review methods to block C5a or the C5a receptors, CD88 and C5L2. ► Examples of drugs used are discussed in relation to disease models and clinical trials.
Keyword Complement C5
C5a receptor
C5 antibodies
C5a antagonists
Paroxysmal-nocturnal hemoglobinuria
Terminal complement complex
Ischemia-reperfusion injury
Collagen-induced arthritis
Percutaneous coronary intervention
Experimental allergic-asthma
Hemolytic-uremic syndrome
Antigen-induced arthritis
Tubular epithelial-cells
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Special Issue: "XIII European Meeting on Complement in Human Disease Leiden, The Netherlands, August 21st–24th 2011". This paper was commissioned as a complementary article to the Proceedings, and was not presented at the Conference.

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collections: Official 2012 Collection
School of Biomedical Sciences Publications
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Citation counts: TR Web of Science Citation Count  Cited 102 times in Thomson Reuters Web of Science Article | Citations
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