Human Anti-Human C5 (Vilobelimab) Monoclonal Antibody, clone Vilobelimab

The complement system plays a critical role in the body's immune defense, particularly in pathogen recognition, immune activation, and regulation of pathological immune responses. Among its key components, complement protein C5 and its cleavage product C5a are essential immune mediators as well as potential pathological inflammatory factors. C5 is generated through activation and cleavage within the complement system, releasing C5a, which, upon binding to the C5a receptor (C5aR/CD88), mediates a series of immune responses, including chemotaxis, increased vascular permeability, and activation of immune cells. However, excessive generation or improper regulation of C5a can lead to a range of diseases such as sepsis, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). While the liver is the primary source of C5, other cells like macrophages can also synthesize and secrete C5, potentially contributing to localized C5a generation. C5a, a potent chemotactic factor and inflammatory mediator, activates various immune cells such as neutrophils and macrophages through its interaction with C5aR. Its role extends beyond early innate immune responses to include subsequent processes like enhanced phagocytosis, respiratory burst, and cytokine release. Despite its critical importance in antimicrobial immunity, excessive C5a generation can lead to pathological inflammation. For instance, overproduction of C5a in sepsis can result in immune dysregulation, weakening the host's immune defense and worsening the condition. Similarly, persistent activation of C5a in chronic inflammatory diseases such as RA and SLE may exacerbate disease progression.

The complement system is closely linked to various autoimmune diseases, particularly RA, SLE, and Sjögren's syndrome, where excessive complement activation can trigger pathological immune responses. In these diseases, complement proteins like C5 and C5a contribute to the formation of immune complexes and local tissue inflammation, leading to chronic tissue damage. The classical complement activation pathway is triggered by antigen-antibody binding, while the alternative pathway is initiated by pathogen surface molecules. Regardless of the activation route, the process converges on the cleavage of C3 and C5, releasing anaphylatoxins such as C5a, which activate downstream immune and inflammatory responses. Dysregulation of complement system regulation may result in excessive tissue inflammation, particularly in RA, where overproduction of C5a is closely associated with synovial inflammation and joint damage. Similarly, in Sjögren's syndrome, complement system imbalance leads to immune-mediated destruction of the salivary and lacrimal glands, worsening disease symptoms. The complement system is tightly regulated, and regulatory proteins such as CD55 (decay-accelerating factor) play a crucial role in inhibiting complement activation. CD55 accelerates the decay of C3 and C5 convertases, preventing excessive release of anaphylatoxins like C5a and maintaining complement system balance. CD55 is highly expressed on various cells, particularly tumor cells, where it prevents nonspecific complement activation and cellular damage. However, in some cases, overexpression of CD55 may inhibit immune recognition and clearance of tumor cells. For example, studies have shown that CD55 expression in ovarian and breast cancer models suppresses C5a release, weakening the antibody-dependent cell-mediated tumor clearance effect. This highlights the complex role of the complement system in tumor immunity, as complement activation may both promote tumor clearance and, through the activation of suppressive immune cells, support tumor growth. C5a plays a dual role in tumor biology. On one hand, research suggests that C5a has potential antitumor effects in tumor immunity. C5a activates neutrophils and macrophages, promoting their phagocytosis and clearance of tumor cells, while also enhancing the release of inflammatory cytokines that improve the function of immune cells infiltrating the tumor. On the other hand, C5a has been found to recruit myeloid-derived suppressor cells (MDSCs), which inhibit CD8+ T-cell antitumor activity, thus supporting tumor growth. The biological effects of C5a within the tumor microenvironment largely depend on its concentration. High levels of C5a often enhance immune suppression, accelerating tumor growth, while lower concentrations may inhibit tumor progression by modulating immune cell infiltration and activation. This concentration-dependent effect suggests that targeting C5a and its related pathways could be a potential therapeutic strategy in future cancer immunotherapies.

Figure 1. The effect of C5a on neutrophil volume and shape and its regulatory signaling mechanisms (Source: Denk S, et al., 2017)

Beyond its critical role in peripheral immunity, C5a also plays an important role in the central nervous system (CNS). C5a generated through complement activation can act on neurons and glial cells via its receptor CD88, modulating neuroinflammatory responses. C5a is thought to be involved in the pathological processes of neurodegenerative diseases such as Alzheimer's disease and multiple sclerosis. One characteristic of these diseases is persistent activation of the complement system within neural tissues, accompanied by C5a generation and dysregulation of local immune responses. However, the role of C5a in the CNS remains controversial. On one hand, the inflammatory mediator functions of C5a may exacerbate neuronal damage and disease progression; on the other hand, the complement system may play a neuroprotective role in clearing aggregated proteins and debris. Thus, the regulatory role of C5a in the CNS depends on its activation level, tissue environment, and pathological conditions. Given C5a's key role in various inflammatory and immune-mediated diseases, C5a receptor antagonists are being explored as potential therapeutic agents. By blocking the interaction between C5a and its receptor, these antagonists can effectively reduce complement-mediated tissue damage and inflammatory responses. Several studies have demonstrated that C5aR antagonists have significant therapeutic effects in disease models such as inflammatory bowel disease, sepsis, and rheumatoid arthritis. Overall, the complement system, particularly C5 and C5a, plays a complex dual role in innate and adaptive immunity. While C5a is critical for immune defense, its excessive activation can lead to pathological inflammation, contributing to a range of diseases. Therefore, regulation of the complement system, especially C5a and its receptor, holds significant clinical promise for therapeutic applications.

Anti-C5 antibody
Vilobelimab
C5 inhibitor monoclonal antibody
Human complement component C5 antibody