The mechanism of eculizumab is effective in the pathophysiology of paroxismal nocturnal haemoglobinuria (PNH). This rare disease is characterised by haemolysis of erythrocytes by the bodies own complement system. The cause of PHN is a genetic defect in one of the natural protecting complement inhibitors, CD59. In a healthy person, the CD59 protects the erythrocyte from the attachment of the membrane attack complex (MAC). Because PNH patients are deficient for CD59, the MAC can attack the erythrocytes and lyse them.

The MAC is the final outcome of the terminal complement system. In the beginning of the pathway, complement C5 is split up by C5 convertase into C5a and C5b. C5a is a strong immunoreactive agents, which increases the permeability of the blood vessels and attracts inflammatory cells by chemotaxis. C5b binds to other complement (C6, C7, and C8). The formed C5b-8 complex is expanded with C9 and is then called

the membrane attack complex (MAC). This MAC can bind the wall of bacteria (e.g. Neisseria) and destroy it.

Eculizumab is a long-acting humanised monoclonal antibody targeted against complement C5. So, eculizumab prohibits the cleavage of C5 into C5a and C5b and with that, it inhibits the entire terminal complement system including the formation of the MAC. In PNH patients, eculizumab strongly decreases haemolysis of erythrocytes, but also reduces the clearance of Neisseria.

PNH patients that will receive eculizumab therapy should thus be vaccinated against Neisseria in advance. Although eculizumab only inhibits the terminal complement system and does not affect the proxismal system, various kinds of infections in urinary, respiratory and gastrointestinal tract are very common adverse effects.

EPAR of eculizumab.