The renaissance of complement therapeutics

Abstract

The increasing number of clinical conditions that involve a pathological contribution from the complement system - many of which affect the kidneys - has spurred a regained interest in therapeutic options to modulate this host defence pathway. Molecular insight, technological advances, and the first decade of clinical experience with the complement-specific drug eculizumab, have contributed to a growing confidence in therapeutic complement inhibition. More than 20 candidate drugs that target various stages of the complement cascade are currently being evaluated in clinical trials, and additional agents are in preclinical development. Such diversity is clearly needed in view of the complex and distinct involvement of complement in a wide range of clinical conditions, including rare kidney disorders, transplant rejection and haemodialysis-induced inflammation. The existing drugs cannot be applied to all complement-driven diseases, and each indication has to be assessed individually. Alongside considerations concerning optimal points of intervention and economic factors, patient stratification will become essential to identify the best complement-specific therapy for each individual patient. This Review provides an overview of the therapeutic concepts, targets and candidate drugs, summarizes insights from clinical trials, and reflects on existing challenges for the development of complement therapeutics for kidney diseases and beyond.

Figure 1. Complement involvement in host defence, immune surveillance and disease processes

a | Sensing of microbial intruders by pattern recognition proteins (PRPs) of the complement system leads to opsonization (tagging) of the microorganisms with C3b and/or C4b. In the absence of regulators on the microbial surface, this initial opsonization is rapidly amplified via C3 convertases, leading to the initiation of various effector functions, including cell damage or lysis via the membrane attack complex (MAC), chemoattraction and immune cell activation by anaphylatoxins, shuttling and phagocytosis of opsonized microorganisms via complement receptors and the stimulation of cellular and/or adaptive immune responses. b | Immune surveillance by complement has a role in housekeeping functions, such as the clearance of apoptotic cells following controlled activation of the cascade. Attack of healthy host cells by complement is typically prevented by a set of complement regulators that rapidly resolve bystander activation or probing. c | Cell injury and/or genetic alterations can lead to excessive activation or insufficient regulation of complement. Dysregulated opsonization and generation of complement effectors can contribute to thrombo-inflammatory complications and lead to additional cell damage, which can in turn further activate complement and exacerbate the adverse effects.

Figure 2. Major mechanisms of the pathogenic involvement of complement in systemic and local disorders

Even when the complement system is operating normally, adverse activation can be triggered after exposure to massive amounts of pathogen, damage-associated stimuli or foreign surfaces such as transplanted organs or biomaterials. In many chronic disorders, genetic alterations lead to a systemic or local imbalance of complement that can contribute to inflammation, thrombosis and tissue damage. Ineffective removal of apoptotic cells, debris or immune complexes owing to the clearing capacity of the complement system being exceeded or deficiencies in complement components can induce or exacerbate autoimmune and neurodegenerative diseases. aHUS, atypical haemolytic uraemic syndrome; AMD, age-related macular degeneration; C3G, C3 glomerulopathy; CARPA, complement activation-related pseudo allergy; PNH, paroxysmal nocturnal haemoglobinuria; SIRS, systemic inflammatory response syndrome; SLE, systemic lupus erythematosus; TMA, thrombotic microangiopathy.

Figure 3. Therapeutic intervention in the complement cascade

The complement cascade is initiated via pattern recognition proteins (PRPs) of the classical pathway (CP) and lectin pathway (LP) or via tick-over of the alternative pathway (AP). Formation of C3 convertases by any route leads to cleavage of C3 and opsonization of the activating surface with C3b. The AP also drives amplification of the initial complement response as C3b interacts with factor B (FB) and factor D (FD) to form new convertases. Insufficiently restricted opsonization enables generation of AP C5 convertases that cleave C5 and initiate the terminal pathway (TP), which leads to formation of membrane attack complexes (MACs). Regulator of complement activation (RCA) family proteins attenuate convertase assembly and shape immune responses by acting as cofactors for the regulatory protease factor I (FI) that degrades C3b to iC3b and C3dg. C3b and its degradation products bind to complement receptors and stimulate phagocytosis and/or immune signalling. The release of anaphylatoxins (C3a and C5a) during complement activation mediates the attraction and priming of immune cells and helps to orchestrate downstream inflammatory responses. Therapeutic complement inhibition can be achieved by preventing initiation in a pathway-specific manner, by controlling the activation and amplification of the response at the level of C3 or at the level of the CP and LP C3 convertase or by modulating specific effector pathways or functions. Major targets for complement therapeutics include C3, C5 and C5a receptor 1 (C5aR1). Ab, antibody; Bb, cleavage product formed from the degradation of FB; C2b, cleavage product formed from the degradation of C2; C3aR, C3a receptor; C3w, hydrolysed C3 (C3[H₂O]); C4a, cleavage product formed from the degradation of C4; C4b, cleavage product formed from the degradation of C4; CR1–4, complement receptor type 1–4; C5b, cleavage product formed from the degradation of C5; GPCR, G protein-coupled receptor; MASP, mannose-binding lectin-associated serine protease; MBL, mannose-binding lectin; PAR1, proteinase-activated receptor 1; PAR4, proteinase-activated receptor 4.

Figure 4. The complement drug development pipeline

Complement-targeted drugs and drug candidate that are in preclinical or clinical development as of September 2017 are shown. This schematic is based on publications, conference abstracts and publicly available information on company websites. The major target is listed next to each drug name. In the preclinical section, drug candidates are ordered according to target, and their position does not reflect the stage of development. In the phase I through phase III sections, drugs are ordered according to the start date of the clinical trial; only the most advanced trial is indicated for each candidate drug. C1q, complement C1q; C1s, complement C1s; C2, complement C2; C3, complement C3; C5, complement C5; C5a, anaphylatoxin formed from the degradation of complement C5; C5aR1, C5a receptor 1; FB, factor B; FD, factor D; FH, factor H; MASP, mannose-binding lectin-associated serine protease.