Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway

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.

Epigenetic scores for the circulating proteome as tools for disease prediction

“…The EpiScore for Complement Component 5 (C5) was associated with the onset of five morbidities, the highest number for any EpiScore. Elevated levels of C5 peptides have been associated with severe inflammatory, autoimmune and neurodegenerative states (Ma et al, 2019; Mantovani et al, 2014; Morgan & Harris, 2015) and a range of C5-targetting therapeutic approaches are in development (Alawieh et al, 2018; Brandolini et al, 2019; Hawksworth et al, 2017; Hernandez et al, 2017; Morgan & Harris, 2015; Ort et al, 2020). EpiScores that occupy central hubs in the disease-prediction framework may therefore provide evidence of early methylation signatures common to the onset of multiple diseases.…”

Pediatric Atypical Hemolytic Uremic Syndrome Advances

“…This mitigates the proinflammatory effects of C5a, prevents the formation of C5b-9, and protects the functionality of upstream innate immune complement factors, such as C3a and C3b. [ 4 , 58 ]. Table 5 highlights four of the trials for Eculizumab.…”

“…Eculizumab is ineffective in patients with polymorphic forms of C5, as it is unable to bind to C5 variants; hence, it is unable to block the cleavage of C5 in patients. Due to a greater risk of infection from encapsulated bacteria, such as meningococcal infections, pediatric aHUS patients require prophylactic vaccinations [ 58 , 61 ]. Eculizumab is commonly used today for the treatment of aHUS, and has paved the way for the development of other aHUS therapeutics such as Ravulizumab.…”

“…Through modifications in amino acids, this drug enhances the rate at which the mAb:C5 complex dissociates in the acidic early endosome at pH 6.0 and increases antibody recycling of the neonatal Fc receptor, both of which increase the life of terminal complement inhibition. Ravulizumab has a half-life 4-fold greater than that of Eculizumab, allowing patients to receive infusions every 2–8 weeks rather than bi-monthly, as with Eculizumab [ 58 ].…”

Human Neutrophils Respond to Complement Activation and Inhibition in Microfluidic Devices

“…At the same time, excessive and deregulated activation of complement has been implicated in the pathogenesis of numerous inflammatory and immunological diseases (1,2), including sepsis (3)(4)(5), acute respiratory distress syndrome (6), rheumatoid arthritis (7), glomerulonephritis (8), multiple sclerosis (9), ischemia-reperfusion injury (10), asthma (11), and antineutrophil cytoplasmic antibody-associated-(ANCA) vasculitis (12). Consequently, several anti-inflammatory strategies have emerged based on drugs designed to target upstream, central, and terminal components of the complement cascade, each having advantages and potential risks (13)(14)(15). Eculizumab (ECU, Soliris, Alexion Pharmaceuticals, Boston, MA) was the first approved therapy specifically inhibiting the complement pathway.…”