Table Info

Table 3.

Selected diseases with suspected complement involvement for which no complement therapeutics have been FDA approved

Disease or condition	Preclinical complement involvement	Clinical complement involvement	Other treatment options
AD	Shown in multiple mouse models [132]. Genome wide associations of complement proteins (clusterin, CR1) with AD [133]. Complement proteins present in plaques [134] and are upregulated in CSF [133].	No clinical data	Lecanemab [135] aducanumab [136]
MS	Complement C3d fragments deposited in lesions and contribute to myelin destruction [137, 138]. C3, C1q, and CR1 are associated with visual acuity loss in patients with MS [139]. Reducing complement activation is protective in multiple EAE models [140].	No clinical data	Anti-CD20 antibodies (rituximab, ocrelizumab, ofatumumab, and ublituximab) [141], IFN-1α, IFN-1β, glatiramer acetate, natalizumab, fingolimod, and dimethyl fumarate [142].
Select secondary TMAs	Some drug-induced TMAs are suggested to be complement related [143]. In TMAs associated with autoimmune conditions (SLE, catastrophic APS, scleroderma)—complement activation is present in some patients. The CP and the AP are triggered by anti-phospholipid antibodies in vascular and obstetric APS [144]. There is strong evidence for complement activation in TMAs after organ transplant (see text).	Eculizumab showed promising data in patients with SLE/APS in the treatment of TMA and improved kidney function [145]. In catastrophic APS and scleroderma, eculizumab treatment showed promising results [146, 147]. A more recent study showed the efficacy of eculizumab in patients with scleroderma renal crisis [148]. Eculizumab is frequently used off label in TMA secondary to transplantation [149]. Narsoplimab (OMS721) administration resulted in improvement of organ function in phase 2 trial in patients with HSCT-TMA [109].	Multiple depending on disease, most often steroids and primary disease specific treatments.
NAFLD including MASH	Complement is postulated to be activated in NAFLD (C3 fragments, C4d, and MBL/C1q) [150]. An increase in complement components C3, C5, CFB, and C3a was associated with an increased risk and severity of NAFLD [151]. The role of AP activation in MASH has been reported [152].	No clinical data but complement has been proposed as a therapeutic target [150].	NR1A2 agonist—resmetirom [153].
Insulin resistance and obesity	The level of C3 is increased proportionately to the total amount of adipose tissue and blood glucose levels [154]. C3adesArg might trigger a cytokine response and induce inflammation leading to insulin resistance [155]. C5aR1 signaling in obesity has also been linked to insulin resistance in muscle cells [156]. Complement activation might be occurring in T1D, and Genetic variants of C2, CFB, C4A, and C4B appear to play a role in T1D risk [157].	No clinical data	Anti-GLP-1 antibodies are the leading drug class for the treatment of obesity and also improves blood glucose levels [158].
Acute and long COVID-19	Patients with long COVID-19 were shown to have increased MAC [159], iC3b, and Ba generation, suggesting AP activation [160]. Complement system activation plays a major role in acute COVID-19 [70, 161–163].	AMY-101 tested in patients with acute COVID-19 showed some efficacy [100]. Ravulizumab and zilucoplan were also tested in patients with acute COVID-19 with limited efficacy [164]. Vilobelimab showed a reduction in mortality at 28 days in patients on mechanical ventilation and has emergency authorization [90].	Corticosteroids (particularly dexamethasone), interleukin-6 receptor antagonists (e.g., tocilizumab), and Janus kinase inhibitors (e.g., baricitinib), molnupiravir, nirmatrelvir/ritonavir, and remdesivir.
LN	Complement protein deficiencies can lead to SLE (C1q, C1r, C1s, C4, C2). Multiple animal models suggest that complement drives the pathogenesis of SLE [165]. The LP might be activated in LN [166]. C3d/creatinine levels can discriminate between active and inactive LN, while C3d alone correlates with SLE disease activity index [167].	Iptacopan (NCT05268289) Narsoplimab (NCT02682407) Ravulizumab (NCT04564339)	Glucocorticoids, MMF, cyclophosphamide, cyclosporin A, rituximab [168], belimumab, and voclosporin [169].
RA	Antibodies against citrullinated proteins activate both the CP and the AP in vitro [170, 171]. Multiple animal models using knockout mice suggest a pathogenic role of complement [172–174]. TT32 (CR1/CR2 fusion protein) and inhibitor of AP, CP, and LP showed efficacy in 2 animal models of arthritis reducing disease activity [175].	Blocking C5aR1 using PMX53 did not decrease synovial inflammation and did not change biomarkers associated with clinical efficacy in patients with RA [176].	TNF-α inhibitors, rituximab, tocilizumab, and nintedanib [177].

AD: Alzheimer’s disease; APS: antiphospholipid syndrome; GLP-1: glucagon-like peptide-1; LN: lupus nephritis; MASH: metabolic dysfunction-associated steatohepatitis; MMF: mycophenolate mofetil; MS: multiple sclerosis; NAFLD: non-alcoholic fatty liver disease; RA: rheumatoid arthritis; SLE: systemic lupus erythematosus; TMA: thrombotic microangiopathy; AP: alternative pathway; CFB: complement factor B; COVID-19: coronavirus disease 2019; CP: classical pathway; CR1: complement receptor 1; CR2: complement receptor 2; HSCT-TMA: hematopoietic stem cell transplantation-associated thrombotic microangiopathy; IFN-1α: interferon 1α; LP: lectin pathway; MAC: membrane attack complex; MBL: mannan-binding lectin; TNF-α: tumour necrosis alpha

Declarations

Acknowledgments

Authors want to thank Matt Ferenc for his suggestions in improving the manuscript.

Author contributions

MK: Conceptualization. MK and KNR: Writing—original draft. MY, AP, and PD: Writing—review & editing. All authors agree with the contents of the manuscript.

Conflict of interest

KNR, MY, AP, PD and MK are employees and shareholders at Apellis Pharmaceuticals Inc. Apellis researches, produces, and markets products that inhibit the complement system.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

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