Paroxysmal nocturnal hemoglobinuria (PNH) is a hematological disorder characterized by
complement-mediated
hemolytic anemia,
thrombophilia, and
bone marrow failure. PNH is due to a somatic, acquired mutation in the X-linked
phosphatidylinositol glycan class A (PIG-A) gene, which impairs the membrane expression on affected blood cells of a number of
proteins, including the
complement regulators CD55 and CD59. The most evident clinical manifestations of PNH arise from dysregulated complement activation on blood cells; in fact, the hallmark of PNH is chronic,
complement-mediated,
intravascular hemolysis, which results in
anemia,
hemoglobinuria,
fatigue, and other
hemolysis-related disabling symptoms. In addition, the peculiar thromboembolic risk typical of PNH patients is thought as secondary to the
complement-mediated
hemolysis itself and/or to a
complement-mediated activation of platelets. Thus, as a
complement-mediated disease, PNH was an appropriate medical condition to develop and to investigate therapeutical
complement inhibitors. Indeed, the first
complement inhibitor eculizumab, a humanized anti-C5
monoclonal antibody, has been proven safe and effective for the treatment of PNH patients. Chronic treatment with
eculizumab results in sustained control of
intravascular hemolysis, leading to
hemoglobin stabilization and transfusion independence in more than half of the patients. However, recent observations have demonstrated that residual
anemia may persist in some patients regardless of sustained fluid-phase terminal
complement inhibition. Indeed, persistent dysregulated activation of the early phases of the
complement cascade on PNH erythrocytes may lead to progressive C3 deposition on affected cells, which become susceptible to subsequent
extravascular hemolysis through the reticuloendothelial system. These findings have renewed the interest for the development of novel
complement inhibitors which aim to modulate early phases of complement activation, more specifically at the level of C3 activation. As proof of principle of this concept, an anti-C3
monoclonal antibody has been proven effective in vitro to prevent
hemolysis of PNH erythrocytes. More intriguingly, a human fusion
protein consisting of the
iC3b/ C3d-binding region of
complement receptor 2 and of the inhibitory domain of the CAP regulator
factor H has been recently shown effective in inhibiting, in vitro, both
intravascular hemolysis of and surface C3-deposition on PNH erythrocytes, and is now under investigation in phase 1 clinical trials.