Blockade of the C5a/C5aR1 axis
C5a is generated in response to C5 cleavage by canonical and non-canonical complement activation. It exerts many of its pro-inflammatory properties through engagement of its cognate G-protein-coupled C5aR1. It also binds to C5aR2, which is uncoupled from G-proteins (Karasu, Nilsson, Kohl, Lambris & Huber-Lang, 2019; Klos, Tenner, Johswich, Ager, Reis & Kohl, 2009). At this point, most strategies to target C5a-mediated effects focus on C5aR1 (Figure 1). The most advanced approach uses a small molecule inhibitor of C5aR1, Avacopan (CCX168) developed by ChemoCentryx that is orally available. Avacopan has been demonstrated efficacy, safety and steroid sparing in a phase II trial for ANCA-associated vasculitis (Jayne et al., 2017) which was recently confirmed in a phase III trial and even showed superiority to standard glucocorticoid therapy. Innate Pharma has developed the fully human antibody advoralimab (IPH-5401), which is currently tested in patients with advanced solid tumors in a phase I trial together with the PD-L1 antibody durvalumab (AstraZeneca). Additional C5aR1 antagonists have been developed, which are still in the preclinical stage including, an allosteric inhibitor of C5aR1 (Dompe), or the cyclic peptide ALS-205 (Alsonex) based on PMX-53, a non-competitive inhibitor of C5aR1, which has been successfully used in several animal models of inflammatory diseases to target C5aR1 (Hawksworth, Li, Coulthard, Wolvetang & Woodruff, 2017). Finally, the C5a mutein A8Δ71-73 has been developed, primarily selected from a phage-display library, that simultaneously targets C5aR1 and C5aR2 (Heller et al., 1999). The antagonistic properties rely on an amino acid replacement at position 69 of C5a with a positively charged amino acid (Otto et al., 2004). This molecule has been shown in a preclinical model of sepsis to be superior to isolated C5aR1 targeting (Rittirsch et al., 2008).
As alternative approach, InflaRx has developed the antibody IFX-1 that specifically targets hC5a (Figure 1). This antibody, which has been licensed to Staidson Biopharmaceutics (BDB-001) is currently used in a multicenter, randomized double blind placebo-controlled trial in mild COVID- 19 patients and an open label two-cohort clinical trial in patients with severe and critical COVID-19. First results were recently released showing a promising curative effect in two severe COVID-19 patients with moderate ARDS or pneumonia (Gao et al., 2020).
The available preclinical data and the few clinical data point toward a key role for C5a in complement-driven ARDS and TMA development in response to highly pathogenic coronavirus infection. The strong differences between C5a serum levels of COVID-19 patients with moderate and severe disease (Gao et al., 2020) indicate that longitudinal monitoring of C5a serum levels in patients with moderate disease might help to identify and stratify patients at risk to develop severe lung injury and TMA. Targeting C5a or C5aR1 might be superior to C5 targeting approaches as it is a more tailored approach that leaves the formation of the MAC intact, which is critical to combat infections with encapsulated bacteria including Neisseria meningitidis . Also, C3-fragment mediated opsonization is still possible. Also, the C5a/C5aR1 axis intersects and amplifies the responses of other innate immune receptors. For example, C5aR1 sets the threshold for IgG Fc receptor (FcγR)-mediated immune cell activation as C5aR1 upregulates the expression of activating FcγRs and downregulates the expression of inhibitory FcγRIIB(Karsten & Kohl, 2012). Of note, a significant association has been described between a SNP in FcγRIIA and the severity of SARS-CoV infection (Yuan et al., 2005). Thus, C5aR targeting might also reduce virus-IgG-driven immune cell activation by activating FcγRs.