The complement alternative pathway in paroxysmal nocturnal hemoglobinuria: From a pathogenic mechanism to a therapeutic target

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal, not malignant, hematological disease characterized by intravascular hemolysis, thrombophilia and bone marrow failure. While this latter presentation is due to a T-cell mediated auto-immune disorder resembling acquired aplastic anemia, the first two clinical presentations are largely driven by the complement pathway. Indeed, PNH is characterized by a broad impairment of complement regulation on affected cells, which is due to the lack of the complement regulators CD55 and CD59. The deficiency of these two proteins from PNH blood cells is due to the somatic mutation in the phosphatidylinositol Nacetylglucosaminyltransferase subunit A gene causing the disease, which impairs the surface expression of all proteins linked via the glycosylphosphatidylinositol anchor.The lack of the complement regulators CD55 and CD59 on PNH erythrocytes accounts for the hallmark of PNH, which is the chronic, complement-mediated intravascular hemolysis. This hemolysis results from the impaired regulation of the alternative pathway upstream in the complement cascade, as well as of the downstream terminal pathway. PNH represented the first indication for the development of anticomplement agents, and the therapeutic interception of the complement cascade at the level of C5 led to remarkable changes in the natural history of the disease. Nevertheless, the clinical use of an inhibitor of the terminal pathway highlighted the broader derangement of complement regulation in PNH, shedding light on the pivotal role of the complement alternative pathway. Here we review the current understanding of the role of the alternative pathway in PNH, including the emergence of C3-mediated extravascular hemolysis in PNH patients on anti-C5 therapies. These observations provide the rationale for the development of novel complement inhibitors for the treatment of PNH. Recent preclinical and clinical data on proximal complement inhibitors intercepting the alternative pathway with the aim of improving the treatment of PNH are discussed, together with their clinical implications which are animating a lively debate in the scientific community. This article is part of a series of reviews covering The Alternative Pathway or Amplification Loop of Complement appearing in Volume 313 of Immunological Reviews.

The complement alternative pathway in health and disease—activation or amplification?

“…PNH is caused by the clonal expansion of erythrocytes that lack the surface complement regulators CD55 (decay accelerating factor; DAF) and CD59. The pathophysiology and clinical features of PNH are reviewed by Risitano et al 40 Complement inhibitory drugs block the underlying cause of PNH and are now clinically approved for treatment of PNH. Furthermore, the rapid response of PNH to complement inhibition and easily measured clinical biomarkers of this response (increase in hematocrit, decrease in lactate dehydrogenase levels), make PNH well‐suited for testing new complement inhibitory drugs.…”

“…The clinical development path for the next generation of therapeutics was greatly facilitated by the identification of diseases that were driven by the alternative pathway or amplification loop, where clearly defined mechanisms could be identified. In this issue, Risitano et al 40 take us through the development path of drugs with potential to treat PNH. The simplicity of the disease mechanism has resulted in its utility as a test‐bed for many drugs developed over the years and indeed, in development today.…”

“…The first complement drug to be approved for PNH was the anti‐C5 monoclonal antibody, eculizumab (FDA approval 2007), introduced in this issue by Risitano et al 40 and extensively explored from a mechanistic point of view by Schmidt and Smith 49 . Although the disease is driven by the AP/AL, blockade of C5 has a profound effect on the course of disease.…”

“…The first complement drug to be approved for PNH was the anti-C5 monoclonal antibody, eculizumab (FDA approval 2007), introduced in this issue by Risitano et al 40 and extensively explored from a mechanistic point of view by Schmidt and Smith. 49 Although the disease is driven by the AP/AL, blockade of C5 has Schmidt and Smith go on to describe a series of studies suggesting that strong AP/AL activation, due either to either the nature of the surface or the complement activating potential, can drive C5 conformational changes (termed "priming") and activation, even in the absence of proteolytic cleavage and in the presence of C5blockers.…”

Complement‐targeted therapeutics: An emerging field enabled by academic drug discovery

“…At the same time, the availability of a C5 inhibitor in the clinic allowed for a gradual expansion of indications, which now include atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis (gMG), and neuromyelitis optica spectrum disorders (NMOSD). 3 Furthermore, the clinical use of eculizumab also revealed elusive pathogenic mechanisms that remain unaddressed under anti-C5 treatment, 4,5 paving the way for the clinical evaluation and approval of therapeutics that afford broader coverage/benefits in certain diseases, such as C3-targeted therapeutics. 6,7 After a derivative of eculizumab with improved pharmacokinetic properties (ravulizumab; Ultomiris, Alexion) was introduced in 2018, 8 the past 2 years finally saw the approval of novel complement inhibitor classes that are distinct in their points of intervention, application routes, and indication areas.…”