Elsevier

Molecular Immunology

Volume 48, Issue 14, August 2011, Pages 1631-1642
Molecular Immunology

Review
Inhibiting the C5–C5a receptor axis

https://doi.org/10.1016/j.molimm.2011.04.014Get rights and content

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.

Introduction

The complement system is an evolutionarily ancient and important component of the innate immunity that has reached a high level of complexity in primates and humans. More than 30 components and regulators have been identified that are widely distributed in the circulation and in tissues, where they are synthesized and secreted by a number of cells under various stimuli, including cytokines and hormones. The system plays an important role in host defence against bacteria, and in the removal of immune complexes and apoptotic cells, as indicated by the finding that individuals with inherited and acquired complement deficiencies are susceptible to bacterial infections and immune complex diseases (Botto et al., 2009). Over the last few years, other important functions of complement have been disclosed, including regulation of the adaptive immune response, promotion of tissue regeneration and angiogenesis, mobilization of stem cells, proper development of the central nervous system, and control of embryo implantation (Ricklin et al., 2010).

Despite the lack of specificity that characterizes the components of the acquired immune system, complement recognizes selectively foreign noxae and altered self, using the recognition molecules of the classical, lectin and alternative pathways. As a result of activation, several biologically active products are released, including small peptides and large complexes, that directly kill the targets or favour their removal by recruiting and activating other components of both innate and acquired immunity. Unfortunately, the effector function of the system is not focused solely on the targets to neutralize, but may also involve bystander cells. The end results depend on the extent and the persistence of the activation process. Should this be limited, the undesired effects of complement activation are easily controlled by several complement regulators acting at different steps of the cascade and these present in the fluid phase as well as on the surface of tissue and circulating cells (Zipfel and Skerka, 2009). Conversely, unrestricted complement activation can easily overcome the protection of the complement regulators and may result in extensive tissue damage. This situation is often encountered in acute pathological conditions, such as sepsis or ischemia–reperfusion, or in chronic diseases sustained and amplified by complement, activated by an ongoing inflammatory process and/or by apoptotic/necrotic cells. Hence, a great research effort has been made over the last 10–15 years to devise therapeutic strategies to prevent and/or control the damaging effect of complement, taking advantage of the animal models of human diseases that have been developed. The important issue that is still debated is which component to neutralize, in order to obtain beneficial effects, and to avoid harm to patients, following the classical Latin rule in therapy; “primum non nocere”… above all, do no harm.

C5 is an ideal target to neutralize, particularly in chronic diseases based on the large body of evidence supporting its contribution to complement-mediated cell and tissue damage. Patients with inherited complement deficiencies are susceptible to meningococcal infection, suggesting that chronic C5 inhibition may increase susceptibility to meningococcal disease; however, this can in part be prevented by vaccination strategies. Alternatively, more targeted inhibition can be achieved by targeting the major by-products of C5 cleavage, such as C5a and its targets, C5a receptors. In this article we shall review the compounds that have been developed to neutralize the biological effect of C5, acting either on the molecule to prevent its cleavage, or on its activation product, C5a, and its two known receptors, namely (1) CD88 and (2) C5L2.

Section snippets

Structure of C5, and formation of C5a and C5b

C5 is the initiator of the effector phase of the complement system and shares with C3, C4, and other proteins of the α2-macroglobulin super-family, the molecular structure consisting of two chains—α and β, linked by disulfide bonds, with the only difference that C5 does not contain an internal thio-ester bond. The C5 molecule is cleaved into C5a and C5b at the position Arg751-Leu752 on the α chain by the convertases of the classical/lectin (C4b2a3b) and alternative pathways (C3bBb3b). These

Strategies to control the undesired effects of C5 and C5a receptors

There are a plethora of molecules described to date, which target the inhibition of C5, C5a and/or C5a receptors. The majority of these compounds are either synthetic molecules, or antibodies directed against these specific factors; however, a few are derived from natural sources. For example, the pathogenic gram-positive bacteria S. aureus and group A Streptococcus produce multiple peptides capable of inhibiting C5/C5a at multiple steps, in order to evade complement attack (see Laarman et al.,

Conclusions

There is now clear and seemingly unambiguous evidence that activation of the C5–C5a receptor axis is important in a multitude of human pathologies. Targeting the generation of C5a and C5b, or inhibiting the two C5a receptors, therefore remains an attractive target for drug development. The anti-C5 antibody eculizumab remains the only specific complement inhibitor approved for human clinical use; however, there is a multitude of C5–C5a targeted therapeutics in current clinical development aimed

Acknowledgement

The authors would like to thank Prof. Steve Taylor for his helpful suggestions.

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