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.

Keywords: ANCA-associated vasculitis; C3 glomerulopathy; C5 antagonist; C5aR1 antagonist; IgA nephropathy; aHUS; complement system; lupus nephritis.

Figure 1

Schematic overview of the complement cascade. The classical pathway is initiated upon binding to antibody-antigen complexes and the mannose-binding lectin pathway is triggered by mannose residues on foreign surfaces. Through recruitment of serine proteases and splitting of C2 and C4, C3 convertase is formed, which splits C3 into C3a and C3b. The alternative pathway is constantly hydrolyzing and cleaving C3 on a low level to allow for rapid self-amplification of the signal. C3b associates with C3 convertase to form C5 convertase, which splits C5 into C5a and C5b. Serine proteases of the coagulation system can independently cleave C3 and C5. C5b recruits C6, C7, C8, and several C9 units to form the membrane attack complex, which inserts into cell membranes to induce cell lysis. C3a and C5a bind to their respective receptors C3aR and C5aR1 to execute various effector functions in different physiological systems. C5aR1, C5a receptor 1; MASP, MBL-associated serine protease; MBL, mannose-binding lectin; FB, factor B; FD, factor D; FXa, factor Xa; FXIa, factor XIa.

Figure 2

Overview of the clinical status of compounds (including target and compound class) targeting terminal complement effector functions. Studies completed or terminated before 2017 are not depicted. AAV, antineutrophil cytoplasmic antibody-associated vasculitis; aHUS, atypical hemolytic uremic syndrome; ALS, amyotrophic lateral sclerosis; AMD, age-related macular degeneration; CHAPLE, complement hyperactivation, angiopathic thrombosis, protein losing enteropathy; COVID-19, coronavirus disease 2019; ESRD, end-stage renal disease; GA, geographic atrophy; GMG, generalized myasthenia gravis; HELLP, hemolysis, elevated liver enzyme, low platelet; HS, hidradenitis suppurativa; IgAN, IgA nephropathy; IPCV, idiopathic polypoidal choroidal vasculopathy; mAB, monoclonal antibody; NMOSP, neuromyelitis optica spectrum disorder; PNH, paroxysmal nocturnal hemoglobinuria; SM, small molecule; TAM, Transplant-associated microangiopathy.