Complement C2 is a precursor to the C3 and C5 convertase complex catalytic component of the complement pathway. Component C2 is part of the classical, lectin, and GZMK complement systems. It can cleave into complement C2a and serine protease complement C2b. C2 plays a role in immune defense, immune complex clearance, and the development of autoimmune diseases.

C2 expression distribution

C2 expression is tissue-specific, primarily found in the liver and gallbladder. At the cellular level, it is mainly expressed in mononuclear phagocytes, alveolar cells, renal tubular cells, neurons, ductal cells, and ciliated cells.

(Data source: uniprot)

The structure of C2 and its role in the complement system

C2 consists of 732 amino acids and contains multiple functional domains, including an N-terminal Sushi/CCP domain and a C-terminal serine protease domain. Complement C2 can be cleaved by proteases into two functional fragments, C2b and C2a.

The C2b domain consists of three tandem CCP (complement regulatory protein) domains, serving as the anchoring binding region for C2. It can specifically recognize and bind to C4b, anchoring C2 to the surface of pathogen/damaged cell membranes and participating in the assembly of the proconvertase complex; the spatial arrangement of CCPs determines the specificity and binding stability of the C2-C4b interaction.

C2a domain: This is the core catalytic region, containing the classic serine protease domain. After C2 is cleaved by the protease and anchored to the membrane, C2a undergoes conformational rearrangement, activating protease activity. It assembles with C4b to form the C3 convertase C4b2a, which can further form the C5 convertase, driving the activation of the downstream complement cascade.

(Data source: Milder FJ, et al. Structure. 2006)

C2 is a key serine protease precursor in both the classical complement pathway and the lectin pathway, activated by cleavage from C1s or MASP. Upon activation, it cleaves into C2a and C2b fragments, with C2a retaining enzymatic activity and C2b being released free. C2a and C4b assemble on the target cell membrane to form the C3 convertase-C4b2a complex. C4b2a efficiently cleaves C3 to generate C3a and C3b, initiating a downstream complement cascade amplification reaction. The C3 convertase further generates the C5 convertase, driving the assembly of the membrane attack complex (MAC) and mediating target cell lysis. Abnormal C2 function leads to complement pathway imbalance and is an important target for autoimmune and complement-related diseases.

(Data source: Van de Walle I, et al. Nat Commun. 2025)

C2-targeted therapy

Empasiprubart is a novel humanized IgG1 monoclonal antibody (mAb) that binds to C2, thereby blocking downstream activation of the classical and lectin complement pathways while preserving the alternative pathway. Empasiprubart binds to C2 in a pH- and calcium-dependent manner. Empasiprubart contains mutations in its Fc regions (H433K and N434F) to increase affinity for FcRn, thereby prolonging its half-life. A randomized, double-blind, placebo-controlled trial was reported to evaluate the safety and tolerability of Empasiprubart in 78 healthy subjects, as well as its pharmacokinetics, pharmacodynamics, and immunogenicity (NCT04532125). A single intravenous (IV) dose of empasiprubart reduced circulating C2 levels by up to 99% and dose-dependently inhibited both the classical and lectin pathways. Repeated IV administration of empasiprubart further enhanced the reduction in free C2 levels, which persisted until the 41-week endpoint. This sustained reduction is consistent with the elimination half-life of Empasiprubart (70–88 days). Single and multiple escalation doses of Empasiprubart are generally safe and well-tolerated.

(Data source: Van de Walle I, et al. Nat Commun. 2025)