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Editorial
. 2024 Mar 1;109(3):704-708.
doi: 10.3324/haematol.2023.283805.

Understanding pharmacological complement inhibition in paroxysmal nocturnal hemoglobinuria

Antonio M Risitano  1 , Camilla Frieri  2
Affiliations
Editorial

Understanding pharmacological complement inhibition in paroxysmal nocturnal hemoglobinuria

Antonio M Risitano et al. Haematologica. .
No abstract available

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Figures

Figure 1.
Figure 1.
Mechanisms of residual hemolysis in the presence of C5 inhibitors in vitro and in vivo. (A) Complement activation with C5 inhibitors in vitro, spontaneous activation. Spontaneous, Low-grade complement activation results in some degree of Lysis on paroxysmal nocturnal hemoglobinura (PNH) erythrocytes in vitro; in the presence of anti-C5 monoclonal antibody (mAb) this Lysis is almost completely inhibited, but surviving PNH erythrocytes accumulate C3 on their surface. (B) Complement activation with C5 inhibitors in vitro, complement activation. When PNH erythrocytes are exposed to complement activation (i.e., by Lowering the pH) the inhibition seen with anti-C5 mAb is only partial, and C3 deposition is observed in all non-Lysed PNH erythrocytes. More in detail, all PNH erythrocytes suffer from C3 activation; in some cells, the excess of surface-bound C3b Leads to C5b-9 assembly and subsequent Lysis (C3b remains detectable on erythrocyte ghosts), while on some other cells C3b is inactivated and its split fragment C3d remains the only detectable C3 fragment on non-Lysed PNH red blood cells. (C) Complement activation with C5 inhibitors in vivo, complete inhibition. Ideally, anti-C5 mAb are in excess to C5, resulting in complete inhibition of C5 which prevents C5 cleavage and further membrane attack complex (MAC) formation; thus, intravascular hemolysis may be fully blocked in vivo, even if uncontrolled C3 activation accounts for continuous, Low-grade C3 activation which clinically Leads to C3-mediated extravascular hemolysis. However, partial inhibition of C5 may occur, possibly resulting in reappearance of intravascular hemolysis (acute or chronic), which in addition to C3-mediated extravascular hemolysis precludes the best hematologic benefit. (D) Complement activation with C5 inhibitors in vivo, pharmacokinetic breakthrough hemolysis. In the case of sub-therapeutic plasma Levels of anti-C5 mAb, free C5 may become available to C5 convertase for cleavage, eventually resulting in acute hemolytic events that are defined pharmacokinetic breakthrough hemolysis (BTH). (E) Complement activation with C5 inhibitors in vivo, pharmacodynamic breakthrough hemolysis. Similar acute hemolytic events may occur even when C5 is fully saturated by the anti-C5 mAb, due to overt complement activation caused by specific triggers (i.e., complement amplifying conditions). In this case, an excess of C3b results in C3b-rich C5 convertases with enhanced affinity for C5 (eventually competing more efficiently with the anti-C5 mAb for their common target C5), or directly in a conformational change of C5 which may then start C5b-9 assembly; these acute hemolytic events are defined pharmacodynamic BTH. (F) Complement activation with C5 inhibitors in vivo, zilucoplan. Residual hemolysis is also seen with zilucoplan, resembling that seen with anti-C5 mAb in unfavorable pharmacokinetic or pharmacodynamic circumstances. It should be noted that residual hemolysis with zilucoplan seems rather chronic, in contrast to the acute BTH seen with anti-C5 mAb. Even if pharmacokinetic and pharmacodynamic information about zilucoplan is Limited, this might suggest that the phenomenon of chronic, continuous residual intravascular hemolysis is associated with the specific pharmacodynamics of this compound, which may compete Less efficiently with C5 convertase for their common substrate/target C5. Figure created with somersauLt18:24.
See this image and copyright information in PMC

Comment on

  • Phase II trials of zilucoplan in paroxysmal nocturnal hemoglobinuria.
    Kulasekararaj AG, Lehtinen AE, Forsyth C, Gandhi S, Griffin M, Körper S, Mikala G, Muus P, Overgaard U, Patriquin CJ, Pullon H, Shen YM, Spearing R, Szer J, De la Borderie G, Duda PW, Farzaneh-Far R, Ragunathan S, Sayegh CE, Vadysirisack DD, Schrezenmeier H. Kulasekararaj AG, et al. Haematologica. 2024 Mar 1;109(3):929-935. doi: 10.3324/haematol.2022.281780. Haematologica. 2024. PMID: 37534517 Free PMC article. Clinical Trial. No abstract available.

References

    1. Howard JF Jr, Bresch S, Genge A, et al. . Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Neurol. 2023;22(5):395-406. - PubMed
    1. Kulasekararaj AG, Lehtinen A-E, Forsyth C, et al. . Phase II trials of zilucoplan in paroxysmal nocturnal hemoglobinuria. Haematologica. 2024;109(3):927-933. - PMC - PubMed
    1. Risitano AM, Marotta S. Toward complement inhibition 2.0: next generation anticomplement agents for paroxysmal nocturnal hemoglobinuria. Am J Hematol. 2018;93(4):564-577. - PubMed
    1. Risitano AM, Frieri C, Urciuoli E, Marano L. The complement alternative pathway in paroxysmal nocturnal hemoglobinuria: from a pathogenic mechanism to a therapeutic target. Immunol Rev. 2023;313(1):262-278. - PMC - PubMed
    1. Harder MJ, Kuhn N, Schrezenmeier H, et al. . Incomplete inhibition by eculizumab: mechanistic evidence for residual C5 activity during strong complement activation. Blood. 2017;129(8):970-980. - PMC - PubMed

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