PNH, The Role of Complement in PNH, and The Potential of Inhibiting Complement C3

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 pathogens, 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

Paroxysmal nocturnal hemoglobinuria, PNH, is a rare, acquired, potentially life-threatening blood disorder, characterized by chronic, complement-mediated destruction of red blood cells—hemolysis – and formation of life-threatening blood clots, also known as thrombosis.2,3

In PNH, the body’s stem cells acquire a gene mutation which results in the production of abnormal blood cells. These defective red blood cells, white blood cells and platelets, lack the connector, known as GPI, for two important surface proteins – CD55 and CD59 – that regulate complement activity.4 As a result, the complement protein C3 becomes unregulated, triggering all downstream effectors that ultimately cause destruction of blood cells.5,6 In intravascular hemolysis, the formation of the membrane attack complex, known as MAC, creates holes in red blood cells causing them to rupture inside blood vessels. At the same time, extravascular hemolysis is caused by C3b being deposited on the surface of defective red blood cells, tagging them for removal and resulting in their destruction in the liver and spleen. Inhibiting the C3 protein may prevent both intravascular and extravascular hemolysis.7

APL-2 is an investigational therapy designed to help restore normal complement activity and reduce inflammation. By targeting C3, the central protein that serves as the master switch of the complement cascade, APL-2 has the potential to block activation from any complement pathway AND to prevent both intravascular and extravascular hemolysis, reducing the risk of thrombosis and anemia and transfusion dependency in patients with PNH.7

Learn more about the role of the complement system in PNH and the benefits of C3 inhibition in the following video and at https://pnhstudy.com/

1. Murphy K, Weaver C. Innate immunity: the first lines of defense. In: Janeway's Immunobiology. 9th ed. London, UK: Garland Science; 2016.
2. Paroxysmal nocturnal hemoglobinuria (PNH). The Sidney Kimmel Comprehensive Cancer Center Web site. https://www.hopkinsmedicine.org/kimmel_cancer_center/types_cancer/paroxysmal_nocturnal_hemoglobinuria_PNH Accessed May 15, 2018.
3. Besa EC. Paroxysmal nocturnal hemoglobinuria (PNH) MedScape 2017; https://emedicine.medscape.com/article/207468-overview. Accessed May 15, 2018.
4. Rosse WF, Ware RE. The molecular basis of paroxysmal nocturnal hemoglobinuria. Blood. 1995;86(9):3277-3286.
5. Hill A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood. 2013;121(25):4985-4996; quiz 5105.
6. Parker C, Omine M, Richards S, et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood. 2005;106(12):3699-3709.
7. Data on file, Apellis Pharmaceuticals.

Видео PNH, The Role of Complement in PNH, and The Potential of Inhibiting Complement C3 канала Apellis Pharmaceuticals