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.