Safety Profile of Monoclonal Antibodies and Subsequent Drug Developments in the Treatment of Paroxysmal Nocturnal Hemoglobinuria

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal stem cell disease characterized by intravascular hemolysis due to the targeting of affected red blood cells by the complement system. Eculizumab and ravulizumab are two monoclonal antibodies that inhibit the complement system's components and have been shown to significantly improve survival and quality of life. This review describes the role of these monoclonal antibodies in the treatment of PNH with an emphasis on their safety profile. The challenges in the use of these drugs and new drugs in various stages of drug development are also described, which may be helpful in addressing some of these challenges.

Keywords: adverse drug reaction; challenges; eculizumab; investigational new drugs; paroxysmal nocturnal hemoglobinuria; ravulizumab.

Figure 1

PNH pathogenesis and mechanism of action of important drugs. The complement cascade is initiated by three different pathways: classical, lectin and alternative. Conversion of C3 to C3b is mediated by C3 convertase, and that of C5 to C5b is mediated by C5 convertase. C5b enables the formation of membrane attack complex (MAC) and leads to cell lysis. CD55 inhibits the enzyme C3 convertase. CD59 inhibits the incorporation of C9 into MAC. In PNH, there is a deficiency of CD55 and CD59. The anti-C5 drugs are eculizumab, ravulizumab and crovalimab. The anti-C3 drug is pegcetacoplan.