AIHA, The Role of Complement in AIHA and The Potential for C3 Inhibition

The complement system is an essential and powerful part of our immune defense system. Its main function is to coordinate the destruction and removal of infectious organisms, known and pathogets, or damaged cells in our body that need to be replaced.1 The complement system may be activated by three different pathways - the alternative, classical and lectin pathways that all run through Complement C3, the central protein in the cascade.1 C3 serves as the master switch controlling all downstream effectors that ultimately cause destruction of the cell. In situations where the complement system becomes over activated, it results in immune attack, the destruction of healthy cells, and ultimately causes illness and damage to the body.1
Autoimmune hemolytic anemia (AIHA) is a group of rare autoimmune disorders characterized by the premature destruction (hemolysis) of red blood cells (RBCs) by autoantibodies at a rate faster than they can be replaced.2 Most cases of AIHA are classified as either warm antibody (wAIHA, 60% to 70% of cases) or cold agglutinin disease (CAD, 20% to 25% of cases), depending upon the temperature at which the autoantibodies show maximum binding.2
In wAIHA, IgG antibodies improperly bind to self-proteins on the surface of red blood cells, activating the classical complement pathway, which causes C3b to attach to the cell surface, resulting in extravascular hemolysis, the destruction of red blood cells in the liver and spleen.2
In CAD, IgM antibodies improperly bind to self-proteins on the surface of red blood cells, causing them to clump together, strongly activating the classical complement pathway which leads to the accumulation of C3b on the cell surface, resulting in extravascular hemolysis. In severe CAD, C3b activates the whole complement cascade, causing the formation of membrane attack complexes, known as MACs, which form holes in the surface of red blood cells, resulting in hemolysis inside blood vessels, called intravascular hemolysis.
APL-2 is an investigational therapy designed to help restore normal complement activity and reduce inflammation. By targeting C3, APL-2 has the potential to block complement activation and prevent both intravascular and extravascular hemolysis, protecting the body from further complement-mediated immune attack.3
Learn more at aihaclinicaltr...
1. Murphy K, Weaver C. Innate immunity: the first lines of defense. In: Janeway's Immunobiology. 9th ed. London, UK: Garland Science; 2016.
2. Barcellini W. New insights in the pathogenesis of autoimmune hemolytic anemia. Transfus Med Hemother. 2015;42(5):287-293.
3. Data on file, Apellis Pharmaceuticals.