Therapeutic control of complement activation at the level of the central component C3

Abstract

The increasing recognition of the complement system's association with diseases of the inflammatory spectrum and with biomaterial and transplant-related complications has generated growing interest in the therapeutic modulation of this innate immune cascade. As a central functional hub that largely drives the activation, amplification, and effector generation of the complement response, the plasma protein C3 has long been recognized as an attractive target. While pharmacological modulation of C3 activation may offer a powerful opportunity to interfere with or even prevent complement-driven pathologies, the development of C3 inhibitors has often been accompanied by concerns regarding the safety and feasibility of this approach. Although no C3-targeted inhibitors have thus far been approved for clinical use, several promising concepts and candidates have emerged in recent years. At the same time, experiences from preclinical development and clinical trials are slowly providing a more detailed picture of therapeutic complement inhibition at the level of C3. This review highlights the current therapeutic strategies to control C3 activation and discusses the possibilities and challenges on the road to bringing C3-targeted therapeutics to the clinic.

Keywords: Alternative pathway; C3; Complement; Convertase; Therapeutics.

Copyright © 2015 Elsevier GmbH. All rights reserved.

Figures

Figure 1. Mechanisms of complement activation and points of therapeutic inhibition at the level of C3

(A) The complement response as a driver of clinical conditions. On a diseased cell surface, damage-associated molecular patterns (DAMPs) and/or (auto)antibodies may trigger complement activation via binding of pattern recognition receptors of the classical (CP) and lectin pathways (LP) or through probing via the tick-over mechanisms of the alternative pathway (AP). The formation of convertases leads to the cleavage of C3 and deposition of C3b, which forms additional convertases and amplifies the response via the AP. C3b deposition also enables the formation of C5 convertases, thereby leading to the generation of membrane attack complexes (MAC) and the inflammatory effector C5a, which can exacerbate tissue damage and fuel an additional complement response. This process is counteracted by regulators of complement activation (RCA) that act on the C3 convertase and mediate the degradation of C3b by factor I (FI), generating opsonin fragments with distinct biological activities. (B) A molecular view of C3 activation and its regulation. Initial deposition of C3b by any route allows the binding of factor B (FB) and formation of the AP C3 convertase after cleavage by factor D (FD). C3 likely binds to the assembled convertase through a dimerization site, thereby enabling the removal of C3a and the generation of additional C3b that can participate in convertase formation. Binding of RCAs to C3bBb leads to accelerated decay of the convertase by competitive removal of Bb and provides a platform for the binding of FI to mediate the cleavage of C3b to iC3b and C3dg. (C) The various concepts to therapeutically control activation of C3. Whereas antibodies against C3b or FB prevent the formation of the pro-convertase (1, 2), mAb- or small molecule-based inhibitors of FD block the conversion to the active convertase (3, 4). C3 inhibitors of the compstatin family protect native C3 by preventing its binding to and cleavage by C3 convertases (5). C3 may also be depleted via cleavage by cobra venom factor or anti-C3 proteases (6, 7). The breakdown of the convertase and C3b can be therapeutically enhanced by adding recombinant FI (8) or by providing purified, recombinant and/or engineered RCA (9). Surfaces may also be coated by entities that recruit factor H (FH) from the circulation (10) or by tethered RCA constructs (11). In panels B and C, the structural figures have been prepared using the crystal structures of C3 (PDB 2A73) (Janssen et al., 2005), C3a (PDB 4HW5) (Bajic et al., 2013), C3b (PDB 2I07) (Janssen et al., 2006), C3d (PDB 1C3D) (Nagar et al., 1998), FB (PDB 2OK5) (Milder et al., 2007), FI (PDB 2XRC) (Roversi et al., 2011), C3bBD (PDB 2XWB) (Forneris et al., 2010), C3b2Bb2SCIN2 (PDB 2WIN) (Rooijakkers et al., 2009), and C3b/FH1-4 (PDB 2WII) (Wu et al., 2009). The complex between C3b, FH1-4, and FI was prepared according to published instructions (Roversi et al., 2011). The hypothetical structure of full-length FH in panel C was composed from multiple copies of FH1-4 derived from the C3b/FH1-4 complex.