The complement system plays a crucial role in the innate immune response against invading pathogens. The complement fragment C5a is one of its key effector components, activating two receptors: C5aR1 and C5aR2. C5AR1 is the C5a anaphylatoxin chemoattractant receptor 1, also known as C5a-R or CD88. C5aR1 is a typical G protein-coupled receptor that couples to G proteins and the Gαi subtype of β-arrestin proteins (βarrs). It exerts multiple physiological functions by activating C5a receptor 1 (C5aR1) and associated downstream G proteins and β-arrestin signaling pathways. C5aR2 does not exhibit any functional G protein coupling but can robustly recruit βarrs. Dysfunction of the C5a-C5aR1 axis is associated with numerous inflammatory and immune-mediated diseases.
(Data source: Pandey S, et al. Trends Biochem Sci. 2020)
Expression distribution of C5AR1
C5AR1 is mainly expressed in monocytes and is also expressed in small amounts in macrophages, Hofbauer cells, and Kupffer cells.
(Data source: Uniprot)
Structure of C5AR1 and its ligands
C5aR1 is a typical seven-transmembrane (7TM) G protein-coupled receptor (GPCR) that couples to the Gαi subtype of the heterotrimeric G protein. The N-terminus of C5aR1 is located on the extracellular side and is one of the key regions for C5a binding.
Human C5a is composed of four α-helical bundles (residues 1-64) and a C-terminal tail (residues 65-74). C5a recognizes C5aR1 through a three-way binding mechanism. Site 1 is located in the membrane-proximal N-terminal region of C5aR1. Site 2 is located at the C-terminus of C5aR1, and site 3 is located in the extracellular loop (ECL) 2 region of C5aR1. ECL2 at the N-terminus of C5aR1 is a key component of C5aR1 activation. ECL2 can interact with specific regions of the C5a molecule to form a third binding site (site 3), further stabilizing the binding of the receptor to the ligand and participating in conformational changes of the receptor.
(Data source: Feng Y, et al. Cell Res. 2023)
Signaling pathway and regulation of C5AR1
C5aR1 is a classic G protein-coupled receptor (GPCR) that primarily mediates signal transduction through Gα family proteins. It regulates cell growth, motility, metabolism, survival, and cytokine production through downstream signaling via the PI3K or Ras mitogen-activated protein kinase (RAPK) pathways. The recruitment of β-arrestins to C5aR1 primarily leads to the termination of G protein signaling by inducing receptor desensitization and internalization.
(Data source: Trambas IA, et al. Int J Mol Sci. 2023)
C5AR1-targeted therapy
As an important immunoregulatory receptor, C5AR1 has become a key target for the treatment of multiple diseases. Currently, targeted treatments for C5AR1 mainly focus on the research and development of small molecule inhibitors and monoclonal antibodies.
Avacopan is a small molecule drug that was first approved in Japan in September 2021 for the treatment of GPA and MPA. It was approved in China in October 2024 for the adjunctive treatment of adults with severe, active AAV (GPA or MPA) in addition to standard therapy (SOC) containing glucocorticoids, which does not yet offset the use of glucocorticoids.
VIS-954 is a monoclonal antibody targeting C5AR1, developed by Visterra for the treatment of complement-mediated diseases and currently in Phase 1 clinical trials. NCT06212804 is a safety, pharmacokinetics, and pharmacodynamics study of VIS954 in healthy adults.
Izastobart is a monoclonal antibody targeting C5aR1 acquired by Biogen through the acquisition of HI-Bio. It is currently in Phase I clinical trials for the treatment of complement-mediated autoimmune diseases (such as IgA nephropathy, lupus nephritis, etc.).
