Abstract
The complement system comprises the frontline of the innate immune system. Triggered by pathogenic surface patterns in different pathways, the cascade concludes with the formation of a membrane attack complex (MAC; complement components C5b to C9) and C5a, a potent anaphylatoxin that elicits various inflammatory signals through binding to C5a receptor 1 (C5aR1). Despite its important role in pathogen elimination, priming and recruitment of myeloid cells from the immune system, as well as crosstalk with other physiological systems, inadvertent activation of the complement system can result in self-attack and overreaction in autoinflammatory diseases. Consequently, it constitutes an interesting target for specialized therapies. The paradigm of safe and efficacious terminal complement pathway inhibition has been demonstrated by the approval of eculizumab in paroxysmal nocturnal hematuria. In addition, complement contribution in rare kidney diseases, such as lupus nephritis, IgA nephropathy, atypical hemolytic uremic syndrome, C3 glomerulopathy, or antineutrophil cytoplasmic antibody-associated vasculitis has been demonstrated. This review summarizes the involvement of the terminal effector agents of the complement system in these diseases and provides an overview of inhibitors for complement components C5, C5a, C5aR1, and MAC that are currently in clinical development. Furthermore, a link between increased complement activity and lung damage in severe COVID-19 patients is discussed and the potential for use of complement inhibitors in COVID-19 is presented.
Highlights
The complement system, as part of the innate immune system [1], comprises several important functions beyond fighting microbial infections, which was assumed to be the only role in the early days following its discovery [2]
Treatment of rare inflammatory kidney diseases consisted of supportive measures, such as plasma exchange [11], or strong nonspecific immunosuppression, including corticosteroids, which is limited by underlying toxicity and adverse events [12], and many patients progressed to end-stage renal disease (ESRD) requiring dialysis a few years after diagnosis [13, 14]
This review focuses on the terminal effector function, i.e., C5 and corresponding cleavage products, and aims at providing an overview on rare inflammatory kidney diseases with complement contribution and the current status of compounds in clinical development that target the terminal pathway of the complement system
Summary
The complement system, as part of the innate immune system [1], comprises several important functions beyond fighting microbial infections, which was assumed to be the only role in the early days following its discovery [2]. Treatment of rare inflammatory kidney diseases consisted of supportive measures, such as plasma exchange [11], or strong nonspecific immunosuppression, including corticosteroids, which is limited by underlying toxicity and adverse events [12], and many patients progressed to end-stage renal disease (ESRD) requiring dialysis a few years after diagnosis [13, 14]. This review focuses on the terminal effector function, i.e., C5 and corresponding cleavage products, and aims at providing an overview on rare inflammatory kidney diseases with complement contribution and the current status of compounds in clinical development that target the terminal pathway of the complement system (see Table 1 and Figure 2 for an overview of clinical studies listed on clinicaltrials.gov). To provide an example of the versatility of complement inhibitors and in light of the outbreak of the COVID-19 pandemic, implications of complement overreaction to infectious diseases are summarized, including the potential of complement therapies in COVID-19 [17, 18]
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