Complement inhibition in medicine: Hematology and beyond; complement inhibition in hematology: PNH and beyond

This special issue of the American Journal of Hematology is devoted to complement inhibition in the treatment of various human disorders. It was made possible by support from Apellis. Eight articles in these issues cover the complex complement cascade system from its description to the last update of its inhibition by the most recent targeted therapies, at the terminal and proximal levels. The complement system is part of innate immunity. It has always remained very difficult to apprehend for many generations of hematologists, similar to the “coagulation cascade”. And this appears even more true nowadays, since extreme sub-specialization moved apart immunology and hematology, while they have been embedded when our masters dissected the biology of this immune mechanism. This special issue aims to put together clinical processes with the biological mechanisms underlying clinical findings. Dr Duval & Fremeaux-Bacchi in «Complement biology for hematologist»1 nicely (and comprehensively) describe the robust and efficient proteolytic cascades resulting in opsonization and lysis of the pathogen, as well as in the generation of the inflammatory response. The authors also describe how an increased activation or a loss of the regulation of this fine-tuned cascade is involved in a variety of hematological diseases (as well as in many others). Among complement-mediated disorders, paroxysmal nocturnal hemoglobinuria (PNH) still remains the prototypic model of complement dysregulation disease. Dr. Panse in «Paroxysmal Nocturnal Hemoglobinuria: where we stand»2 describes how anti-C5 therapies have revolutionized the management and prognosis of PNH in the last 2 decades. As discussed in this article, from demonstrating control of intravascular hemolysis, thrombosis protection, and eventually overall survival improvement, hematologists have learned to use eculizumab (Soliris) and to manage patients with PNH receiving anti-C5 inhibition. A plethora of new drugs interfering with the proximal complement cascade are under recent development and they are discussed by Dr. Kulasekararaj in «Paroxysmal Nocturnal Hemoglobinuria: where are we going».3 The first “proof-of-principle” proximal complement inhibitor targeting C3 approved in 2021 (Pecgetacoplan; Aspavelli) is discussed in detail, as well as novel agents, such as factor B and factor D inhibitors, under study at the moment but with very promising results. All these new agents have advanced the field of complement therapeutics eventually demonstrating that even the proximal pathway of the complement cascade may be effectively inhibited, making quite broader the potential applications of such therapies in medicine. Beyond PNH, overactivation of the complement alternative pathway drives the pathogenesis of primary atypical hemolytic uremic syndrome (aHUS). Leon et al. in «Complement-driven hemolytic uremic syndrome»4 elegantly describe genetically-determined or acquired dysregulation of the complement in patients with aHUS, pregnancy-related hemolytic uremic syndrome (HUS), and severe hypertension-associated HUS. The complicated (and still not clear) physiopathology of those disorders is largely addressed, as well as the treatment approach. Transplant-associated thrombotic microangiopathy (TA-TMA) is also a challenging situation for clinicians, which is reviewed by Jodele and Salbuski in «Reeling in Complement in Transplant-Associated Thrombotic Microangiopathy: You're Going to Need a Bigger Boat».5 The current understanding of the pathophysiology of TA-TMA is presented and discussed, particularly as it pertains to complement activation, endothelial injury, and clinical management. Novel complement-blocking therapies currently under investigation for use in TA-TMA are also addressed. We have to remark that both HUS and TA-TMA should be considered still hematological, but multi-organ diseases; thus, many of the considerations discussed for these two conditions may be extended to a number of additional complement-mediated diseases which may affect the kidneys or even other organs. Indeed, complement is a key player in protective immunity against pathogens, but its excessive or deregulated activation may result in collateral tissue injury. It is thus not a surprise the complement system has central in the pathophysiology of the COVID-19 pandemic. Calado et al. describe in «Hyper-inflammation and complement in COVID-19»6 the participation of the complement in the worsening of symptoms during COVID infection. The pathophysiology, clinical trials, as well as single observations using the complement inhibition approach, are summarized. All the data discussed here paved the way for broad involvement of the complement cascade in different systemic, hyper-inflammatory conditions, which may include complications of different infectious diseases (mostly viral), but also iatrogenic conditions (e.g., cytokine storms appearing after cell-or antibody-based immune therapies). At the end of the supplement, the last 2 articles deal with the development and optimization of therapeutic complement inhibition from different perspectives. Lamers et al. in «Complement-Targeted Therapeutics: An Emerging Field Enabled by Academic Drug Discovery»7 recall the difficulties that researchers in the field had to face to pioneer and then develop complement inhibitors. Concerns about the safety of complement-targeted interventions, the large number and high plasma concentrations of target proteins, and the complexity of the complement system's engagement in biological processes are among other factors that kept complement off the drug-discovery radar for decades. In their paper, Lamers et al. document this extraordinary development using examples and aim to venture some predictions about where this promising field may be headed to. In this manuscript, the authors also highlight the challenges coming from the interaction between academic scientists and for-profit entities, which eventually drive the development of candidate therapies and shape their actual successful clinical translation. Finally, Prof. Luzzatto in «closing remarks»8 takes advantage of his long-lasting contribution to the field to share his vision about current and future complement inhibition in medicine. Indeed, Luzzatto recalls some old and more recent concepts of complement biology and hematological diseases, eventually describing how all these therapeutic achievements have advanced hematology and medicine. Luzzatto also discusses some peculiarities of complement-targeted treatment in PNH, eventually introducing the question of whether the best complement-targeted strategy should intercept the cascade at single or multiple well-chosen check points. Should we aim at absolute blockage using possible several compounds for a single patient or trying to find the best, more convenient, single agent? And, in addition to PNH and anti-complement agents, Luzzatto provides sharp comments and considerations which pertain to the development of any treatment strategy in medicine: we believe they are quite informative, especially for the younger generations of scientists and physicians. Several questions are still open in this fascinating field. We do hope that the AJH readers will find these eight articles both instructive and clinically relevant in their daily practice. Our hope is that they can also inspire researchers to further advance a field, which has appeared as a gold mine for scientists (and investors) in the last few decades. Régis Peffault de Latour has received research support from Alexion, Novartis, Pfizer, and Amgen; lecture fees from Alexion, Novartis, Pfizer, and Apellis/SOBI; served as member of advisory/investigator board for Alexion, Apellis/SOBI, Biocryst, Novartis, Roche, Samsung; and served as consultant for Alexion, Novartis, and Apellis. Antonio M. Risitano has received research support from Alexion, Novartis, Alnylam, and Rapharma; lecture fees from Alexion, Novartis, Pfizer, and Apellis/SOBI; served as a member of advisory/investigator board for Alexion, Achillion, Apellis/SOBI, Biocryst, Novartis, Roche, Samsung, and Sanofi; and served as consultant for Amyndas, Novartis, and Omeros.