Complement in paroxysmal nocturnal hemoglobinuria: exploiting our current knowledge to improve the treatment landscape

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder associated with an acquired deficiency in glycophosphatidylinositol-anchor biosynthesis that renders erythrocytes susceptible to complement attack. Intravascular hemolysis via the membrane attack complex is a clinical hallmark of the disease, and C5 blockade is currently the only approved treatment for PNH. However, residual anemia is an emerging observation for many PNH patients receiving anti-C5 treatment. A range of complement-targeted therapeutic approaches, encompassing surface-directed inhibition of C3 convertases, blockade of membrane attack complex assembly or C3 interception using peptidic inhibitors, has yielded promising results and offers leverage for even more effective treatment of PNH. This article discusses recent advances in this rapidly evolving field, integrating critical perspectives from preclinical PNH models and diverse complement modulation strategies with genetic insights and therapy response profiles. It also evaluates the relative efficacy, limitations and benefits afforded by C3 or C5 inhibition in the context of PNH therapeutics.

Keywords: AMY-101; C3 inhibitors; C5 blockade; Cp40; MAC; PNH; complement therapeutics; eculizumab; extravascular hemolysis.

Figures

Figure 1. Schematic illustration of the fine interplay between complement activation, regulation and PNH pathophysiology

(A) Complement activation is effectively contained on the surface of normal erythrocytes that express the GPI-linked regulators CD55 (DAF) and CD59. Opsonic C3b may be generated by spontaneous (tick-over) or bystander activation (e.g., due to an infection) but is readily degraded by the plasma enzyme factor I (FI) in concert with the complement regulators factor H (FH), CD55 and CR1 (CD35). Furthermore, CD59 prevents the assembly of the MAC and protects the erythrocyte from autologous complement-mediated lysis (intravascular hemolysis) (B) Lack of GPI-linked CD55 and CD59 leads to the functional ‘dismantling’ of normal complement regulatory activity on the PNH erythrocyte surface, rendering the cell susceptible to autologous complement attack. Complement activation triggered by: spontaneous C3 hydrolysis (via tick-over mechanism); bystander activation; or specific (yet unknown) triggering mechanisms on PNH erythrocyte surfaces leads to C3b generation and surface opsonization that, in the absence of CD55, culminates in uncontrollable C3 fragment opsonization via amplification of the complement response through the alternative pathway and, eventually, in MAC-mediated intravascular hemolysis (i.e., due to the absence of CD59).

Figure 2. Overview of the complement cascade with an emphasis on therapeutic targets, drug leads and intervention strategies for the treatment of PNH

(A) Simplified schematic overview of the complement cascade illustrating points of therapeutic intervention in paroxysmal nocturnal hemoglobinuria. i) At the level of C3: Cp40, the Cp40-based therapeutic AMY-101 and APL-1/2 block activation of C3 by any convertases, thereby abrogating generation of C3b (opsonization), amplification via formation of C3 convertases and downstream effector pathways. TT30 and mini-FH target C3 convertases and C3b, accelerating convertase decay and C3b degradation, thereby also inhibiting AP amplification. ii) At the C5 level: Eculizumab, Coversin and SOBI002 all bind to and inhibit cleavage of C5, thereby blocking terminal pathway activation and preventing formation of the MAC. (B) Benefits and limitations of complement-targeted therapeutic strategies for treating PNH. i) Complement modulation at the level of C3 prevents C3 deposition (opsonization) and all downstream effector functions, including lytic pathway activation and MAC-mediated intravascular hemolysis. On the other hand, complement inhibition at the level of C5, prevents MAC-mediated hemolysis (intravascular hemolysis) but allows C3 fragment opsonization to persist, possibly leading to C3-mediated extravascular hemolysis (via engulfment and immune clearance of C3-opsonized PNH erythrocytes by complement receptor bearing macrophages in the hepatosplenic system). AP: Alternative pathway; CP: Classical pathway; FB: Factor B; Fcn: Ficollin; FD: Factor D; FP: Properdin; LP: Lectin pathway; MAC: Membrane attack complex; MASP: Mannose-binding protein-associated serine protease; MBL: Mannose-binding lectin.