Protein therapeutics and their lessons: Expect the unexpected when inhibiting the multi‐protein cascade of the complement system

Abstract

Summary Over a century after the discovery of the complement system, the first complement therapeutic was approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). It was a long‐acting monoclonal antibody (aka 5G1‐1, 5G1.1, h5G1.1, and now known as eculizumab) that targets C5, specifically preventing the generation of C5a, a potent anaphylatoxin, and C5b, the first step in the eventual formation of membrane attack complex. The enormous clinical and financial success of eculizumab across four diseases (PNH, atypical hemolytic uremic syndrome (aHUS), myasthenia gravis (MG), and anti‐aquaporin‐4 (AQP4) antibody‐positive neuromyelitis optica spectrum disorder (NMOSD)) has fueled a surge in complement therapeutics, especially targeting diseases with an underlying complement pathophysiology for which anti‐C5 therapy is ineffective. Intensive research has also uncovered challenges that arise from C5 blockade. For example, PNH patients can still face extravascular hemolysis or pharmacodynamic breakthrough of complement suppression during complement‐amplifying conditions. These “side” effects of a stoichiometric inhibitor like eculizumab were unexpected and are incompatible with some of our accepted knowledge of the complement cascade. And they are not unique to C5 inhibition. Indeed, “exceptions” to the rules of complement biology abound and have led to unprecedented and surprising insights. In this review, we will describe initial, present and future aspects of protein inhibitors of the complement cascade, highlighting unexpected findings that are redefining some of the mechanistic foundations upon which the complement cascade is organized.

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

“…However, the clinical use of eculizumab in PNH unexpectedly provided further insight into the disease mechanism and the molecular mechanisms of the AP/AL convertases. The phenomenon of extravascular hemolysis in PNH patients treated with eculizumab was described in 2009 by Risitano et al 50 and this phenomenon is expanded on here by Schmidt and Smith 49 . Due to the lack of CD55 on PNH erythrocytes, in the face of C5 blockade the AP/AL continues to drive opsonization of erythrocytes, resulting in a coating of C3 fragments that facilitate erythro‐phagocytosis in the extravascular spaces in the liver and spleen.…”

“…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.…”

“…Treatment over time has also resulted in expansion of the PNH clone sizes as those cells are no longer lysed by the MAC; the clinical implications of this remain unclear. 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 C5‐blockers 49 . While their article focuses on anti‐C5, other potential therapeutic protein modulators of the AP/AL include those that target the FHR axis 6,19 and the natural control proteins of the AP/AL, FH and FI.…”

“…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. 49 While their article focuses on anti-C5, other potential therapeutic protein modulators of the AP/AL include those that target the FHR axis 6,19 and the natural control proteins of the AP/ AL, FH and FI.…”

Global-feature of autoimmune glomerulonephritis using proteomic analysis of laser capture microdissected glomeruli

“…It is known that C5 is not a stable molecule cleaved by C5 convertase into the C5a, and C5b. C5a further leads to the activation of eosinophils and neutrophils and triggers pro-inflammatory effects, and C5b participates in the formation of the MAC C5b-9 to induce cell injury and kidney diseases ( 29 , 30 ). High level of C5b-9 complexes was found in patients diagnosed with immune Glomerulus diseases ( 31 ).…”