The complement system, a complex network of proteins, is a component of the body’s immune defense. It identifies and eliminates foreign invaders like bacteria, and clears damaged cells. While beneficial, its overactivity or dysregulation can damage tissues and contribute to various diseases. In such cases, complement inhibition aims to control these harmful responses.
Understanding the Complement System
The complement system is part of the innate immune system, the body’s immediate protective response. It comprises about 50 proteins circulating in blood and tissues, usually inactive. When activated, these proteins trigger a cascade reaction.
This cascade targets foreign invaders, activates inflammatory responses, and removes unwanted elements. It also clears microbes, damaged cells, and immune complexes. These functions enhance the body’s ability to maintain health.
When Complement Contributes to Disease
While normally protective, uncontrolled complement activation can harm the body’s own tissues. This dysregulation causes the system to mistakenly target healthy cells or overreact. Such activation can trigger excessive inflammation, which, if prolonged or misdirected, can damage organs and systems.
Overactivity of the complement system is implicated in various conditions. These include inflammatory disorders, where persistent inflammation harms tissues, and autoimmune diseases, where the immune system attacks the body’s own cells. Examples include kidney conditions like C3 glomerulopathy and atypical hemolytic uremic syndrome (aHUS), a rare disorder affecting blood vessels. Complement dysregulation is also associated with rheumatoid arthritis and systemic lupus erythematosus (SLE).
How Complement Inhibition Works
Complement inhibition targets specific components or steps within the complement cascade to prevent harmful effects. This approach aims to restore balance when the system is overactive and damaging tissues. Inhibitors can block the cascade’s progression at various points.
One strategy involves blocking key proteins like C5, which promotes inflammation and forms damaging complexes when cleaved. Preventing this cleavage reduces inflammatory responses and protects cells. Other inhibitors may target different components, like C3, Factor B, or Factor D, each with a distinct role. These targets allow precise intervention, mitigating tissue damage while preserving beneficial immune functions.
Current and Emerging Therapies
Complement inhibition therapies have transformed treatment for several diseases. Eculizumab, a C5 inhibitor, was approved for paroxysmal nocturnal hemoglobinuria (PNH) in 2007 and atypical hemolytic uremic syndrome (aHUS) in 2011, improving patient outcomes. This drug prevents C5 cleavage, inhibiting the formation of the membrane attack complex (MAC) that can damage cells.
Other C5 inhibitors like ravulizumab are also approved for PNH and aHUS, offering similar benefits. The field expands with new agents targeting different points in the complement cascade. For instance, pegcetacoplan, a C3 inhibitor, is approved for PNH and geographic atrophy (GA), an ophthalmic condition, by targeting an earlier stage. Emerging therapies include small molecules and gene therapies, such as an intravitreal gene therapy to enhance CD59 expression and protect retinal cells, showing promising results for geographic atrophy. Research also explores inhibitors of C1s, Factor B, and Factor D, broadening the scope of complement-targeted treatments for inflammatory and autoimmune conditions.