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The complement system plays a key role in pathogen immunosurveillance and tissue homeostasis. However, subversion of its tight regulatory control can fuel a vicious cycle of inflammatory damage that exacerbates pathology. The clinical merit of targeting the complement system has been established for rare clinical disorders such as paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome. Evidence from preclinical studies and human genome-wide analyses, supported by new molecular and structural insights, has revealed new pathomechanisms and unmet clinical needs that have thrust a new generation of complement inhibitors into clinical development for a variety of indications. This review critically discusses recent clinical milestones in complement drug discovery, providing an updated translational perspective that may guide optimal target selection and disease-tailored complement intervention.

The complement system is recognised as a protector against blood-borne pathogens and a controller of immune system and tissue homoeostasis. However, dysregulated complement activity is associated with unwanted or non-resolving immune responses and inflammation, which induce or exacerbate the pathogenesis of a broad range of inflammatory and autoimmune diseases. Although the merit of targeting complement clinically has long been acknowledged, the overall complement drug approval rate has been modest. However, the success of the humanised anti-C5 antibody eculizumab in effectively treating paroxysmal nocturnal haemoglobinuria and atypical haemolytic syndrome has revitalised efforts to target complement therapeutically. Increased understanding of complement biology has led to the identification of novel targets for drug development that, in combination with advances in drug discovery and development technologies, has resulted in a surge of interest in bringing new complement therapeutics into clinical use. The rising number of approved drugs still almost exclusively target rare diseases, but the substantial pipeline of up-and-coming treatment options will possibly provide opportunities to also expand the clinical targeting of complement to common diseases.

Key Points Complement is a key component of immunity with crucial inflammatory and opsonic properties; inappropriate activation of complement triggers or exacerbates inflammatory disease. Complement dysregulation is a core feature of some diseases and contributes to pathology in many others. Approved agents have been developed for and are highly effective in some orphan applications, but their progress to use in more common diseases has been slow. Numerous challenges, such as target concentration or high turnover, limit the efficacy of these agents in humans. Numerous novel agents targeting different parts of the complement system in different ways are now emerging from pre-clinical studies and are entering Phase I/II trials; these agents bring the potential for more-effective and more-specific anti-complement therapies in disease. Other agents, both biologic and small molecule, are in Phase II or III trials for both rare and common diseases — administration routes include localized (for example, intravitreal) and systemic routes. There is an urgent need to develop biomarkers and imaging methods that enable monitoring of the effects and efficacy of anti-complement agents. The complement cascade, a key regulator of innate immunity, is a rich source of potential therapeutic targets for diseases including autoimmune, inflammatory and degenerative disorders. Morgan and Harris discuss the progress made in modulating the complement system and the existing challenges, including dosing, localization of the drug to the target and how to interfere with protein–protein interactions. The complement system is a key innate immune defence against infection and an important driver of inflammation; however, these very properties can also cause harm. Inappropriate or uncontrolled activation of complement can cause local and/or systemic inflammation, tissue damage and disease. Complement provides numerous options for drug development as it is a proteolytic cascade that involves nine specific proteases, unique multimolecular activation and lytic complexes, an arsenal of natural inhibitors, and numerous receptors that bind to activation fragments. Drug design is facilitated by the increasingly detailed structural understanding of the molecules involved in the complement system. Only two anti-complement drugs are currently on the market, but many more are being developed for diseases that include infectious, inflammatory, degenerative, traumatic and neoplastic disorders. In this Review, we describe the history, current landscape and future directions for anti-complement therapies.

Pegcetacoplan (Empaveli™) is a PEGylated pentadecapeptide developed by Apellis Pharmaceuticals for the treatment of complement-mediated diseases. It binds to complement component 3 (C3) and its activation fragment C3b, controlling the cleavage of C3 and the generation of the downstream effectors of complement activation and thus both C3b-mediated extravascular haemolysis and terminal complement-mediated intravascular haemolysis. Pegcetacoplan is the first C3-targeted paroxysmal nocturnal haemoglobinuria (PNH) therapy to be approved (in May 2021) in the USA, where it is indicated for the treatment of adults with PNH, including those switching from C5 inhibitor therapy with eculizumab and ravulizumab. A regulatory assessment of pegcetacoplan for the treatment of PNH is currently underway in the EU and Australia. Pegcetacoplan is also being investigated as a therapeutic option in other complement-mediated diseases, including age-related macular degeneration, C3 glomerulopathy and autoimmune haemolytic anaemia. The recommended dosage regimen of pegcetacoplan is 1080 mg twice weekly, administered as a subcutaneous infusion via an infusion pump with a ≥ 20 mL reservoir. This article summarizes the milestones in the development of pegcetacoplan leading to this first approval for the treatment of adults with PNH.

The humanized monoclonal antibody eculizumab (Soliris ® ) is a complement inhibitor indicated for use in anti-acetylcholine receptor (AChR) antibody-positive adults with generalized myasthenia gravis (gMG) in the USA, refractory gMG in the EU, or gMG with symptoms that are difficult to control with high-dose IVIg therapy or PLEX in Japan. It is the first complement inhibitor to be approved for use in these patients. In the well-designed, 26-week REGAIN study in patients with anti-AChR-positive refractory gMG, although a statistically significant benefit of eculizumab over placebo in the prespecified primary endpoint analysis (change from baseline in MG-activities of daily living (ADL) score assessed by worst-rank ANCOVA) was not formally demonstrated, preplanned and post hoc sensitivity analyses of this outcome, as well as other secondary outcomes supported the efficacy of eculizumab. Overall, patients receiving eculizumab experienced significant improvements in the ADL, muscle strength and health-related quality of life (HR-QOL) parameters relative to patients receiving placebo. Moreover, an ongoing extension of REGAIN showed that treatment benefits with eculizumab were sustained during continued therapy for at least 52 weeks. Eculizumab was generally well tolerated in these studies, with a tolerability profile similar to that reported previously in other indications. Although several questions remain, such as duration of treatment, cost effectiveness and long-term efficacy and tolerability, current evidence indicates that eculizumab is a valuable emerging therapy for patients with refractory gMG.

Eculizumab is the first drug approved for the treatment of complement-mediated diseases, and current dosage schedules result in large interindividual drug concentrations. This review provides insight into the pharmacokinetic and pharmacodynamic properties of eculizumab, both for reported on-label (paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia gravis) and off-label (hematopoietic stem cell transplantation-associated thrombotic microangiopathy) indications. Furthermore, we discuss the potential of therapeutic drug monitoring to individualize treatment and reduce costs.

The terminal complement protein (C5) inhibitor eculizumab (Soliris ® ) is the first agent to be specifically approved in the EU, USA, Canada and Japan for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults who are aquaporin-4 water channel autoantibody (AQP4-IgG) seropositive and (in the EU only) for those with a relapsing course of disease. In the phase III PREVENT trial, eculizumab significantly reduced the risk of adjudicated relapse relative to placebo in patients with AQP4-IgG-seropositive NMOSD, approximately a quarter of whom did not receive concomitant immunosuppressive therapies. The beneficial effect of eculizumab was seen across all patient subgroups analysed and was accompanied by improvements in neurological and functional disability assessments, as well as generic health-related quality of life measures; it was sustained through 4 years of treatment, according to combined data from the PREVENT trial and an interim analysis of its ongoing open-label extension study. The safety profile of eculizumab in AQP4-IgG-seropositive NMOSD was consistent with that seen for the drug in other approved indications. Thus, eculizumab provides an effective, generally well tolerated and approved treatment option for this rare, disabling and potentially life-threatening condition. Video abstract 2qKwCupTrKm1nhKJcp11T2 Video Abstract (MP4 241640 KB)

Crovalimab (派圣凯 ®; PiaSky) is a humanized, anti-complement component C5 (anti-C5) recycling monoclonal antibody developed by Chugai Pharmaceutical, in collaboration with Roche, which is being investigated for the treatment of complement-mediated diseases, including paroxysmal nocturnal haemoglobinuria (PNH), atypical haemolytic uremic syndrome, lupus nephritis and sickle cell disease. Crovalimab targets C5, inhibiting its cleavage to C5a and C5b, thus blocking the terminal complement pathway and preventing intravascular haemolysis in PNH. Crovalimab is designed to bind to the antigen repeatedly, resulting in sustained complement inhibition at a lower dosage, and allowing for once-monthly subcutaneous administration. In February 2024, subcutaneous crovalimab received its first approval in China for the treatment of adolescents and adults (aged ≥ 12 years) with PNH who have not been previously treated with complement inhibitors. Crovalimab has since been approved in Japan in March for use in the treatment of PNH, including in treatment-naïve and previously treated patients. Crovalimab is also under regulatory review for the treatment of naïve and previously treated patients with PNH in multiple countries, including the USA and the European Union. This article summarizes the milestones in the development of crovalimab leading to this first approval in China for the treatment of PNH.

CD55 prevents convertase enzyme formation in the complement cascade, acting as a brake on complement activation. Inactivating mutations in CD55 result in hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy.

A novel coronavirus, SARS‐CoV‐2, has recently emerged in China and spread internationally, posing a health emergency to the global community. COVID‐19 caused by SARS‐CoV‐2 is associated with an acute respiratory illness that varies from mild to the life‐threatening acute respiratory distress syndrome (ARDS). The complement system is part of the innate immune arsenal against pathogens, in which many viruses can evade or employ to mediate cell entry. The immunopathology and acute lung injury orchestrated through the influx of pro‐inflammatory macrophages and neutrophils can be directly activated by complement components to prime an overzealous cytokine storm. The manifestations of severe COVID‐19 such as the ARDS, sepsis and multiorgan failure have an established relationship with activation of the complement cascade. We have collected evidence from all the current studies we are aware of on SARS‐CoV‐2 immunopathogenesis and the preceding literature on SARS‐CoV‐1 and MERS‐CoV infection linking severe COVID‐19 disease directly with dysfunction of the complement pathways. This information lends support for a therapeutic anti‐inflammatory strategy against complement, where a number of clinically ready potential therapeutic agents are available. Graphical Abstract This review offers a balanced view on how the complement system may be engaged in COVID‐19 and suggests therapeutic strategies, some of which already in clinical trials.