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Coronavirus disease 2019 (COVID-19) is a disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in a pandemic 1 . The C5a complement factor and its receptor C5aR1 (also known as CD88) have a key role in the initiation and maintenance of several inflammatory responses by recruiting and activating neutrophils and monocytes 1 . Here we provide a longitudinal analysis of immune responses, including phenotypic analyses of immune cells and assessments of the soluble factors that are present in the blood and bronchoalveolar lavage fluid of patients at various stages of COVID-19 severity, including those who were paucisymptomatic or had pneumonia or acute respiratory distress syndrome. The levels of soluble C5a were increased in proportion to the severity of COVID-19 and high expression levels of C5aR1 receptors were found in blood and pulmonary myeloid cells, which supports a role for the C5a–C5aR1 axis in the pathophysiology of acute respiratory distress syndrome. Anti-C5aR1 therapeutic monoclonal antibodies prevented the C5a-mediated recruitment and activation of human myeloid cells, and inhibited acute lung injury in human C5aR1 knock-in mice. These results suggest that blockade of the C5a–C5aR1 axis could be used to limit the infiltration of myeloid cells in damaged organs and prevent the excessive lung inflammation and endothelialitis that are associated with acute respiratory distress syndrome in patients with COVID-19. Blockade of the C5a–C5aR1 axis using anti-C5aR1 monoclonal antibodies prevented inflammation associated with COVID-19.

Tumors often resist immune-mediated destruction because of the presence of suppressor cells. Lambris and colleagues show that activated complement C5a helps mediate this effect by recruiting myeloid suppressor cells to the tumor microenvironment. The involvement of complement-activation products in promoting tumor growth has not yet been recognized. Here we show that the generation of complement C5a in a tumor microenvironment enhanced tumor growth by suppressing the antitumor CD8 + T cell–mediated response. This suppression was associated with the recruitment of myeloid-derived suppressor cells into tumors and augmentation of their T cell–directed suppressive abilities. Amplification of the suppressive capacity of myeloid-derived suppressor cells by C5a occurred through regulation of the production of reactive oxygen and nitrogen species. Pharmacological blockade of the C5a receptor considerably impaired tumor growth to a degree similar to the effect produced by the anticancer drug paclitaxel. Thus, our study demonstrates a therapeutic function for complement inhibition in the treatment of cancer.

The pathogenesis of highly pathogenic Middle East respiratory syndrome coronavirus (MERS-CoV) remains poorly understood. In a previous study, we established an hDPP4-transgenic (hDPP4-Tg) mouse model in which MERS-CoV infection causes severe acute respiratory failure and high mortality accompanied by an elevated secretion of cytokines and chemokines. Since excessive complement activation is an important factor that contributes to acute lung injury after viral infection, in this study, we investigated the role of complement in MERS-CoV-induced lung damage. Our study showed that complement was excessively activated in MERS-CoV-infected hDPP4-Tg mice through observations of increased concentrations of the C5a and C5b-9 complement activation products in sera and lung tissues, respectively. Interestingly, blocking C5a production by targeting its receptor, C5aR, alleviated lung and spleen tissue damage and reduced inflammatory responses. More importantly, anti-C5aR antibody treatment led to decreased viral replication in lung tissues. Furthermore, compared with the sham treatment control, apoptosis of splenic cells was less pronounced in the splenic white pulp of treated mice, and greater number of proliferating splenic cells, particularly in the red pulp, was observed. These data indicate that (1) dysregulated host immune responses contribute to the severe outcome of MERS; (2) excessive complement activation, triggered by MERS-CoV infection, promote such dysregulation; and (3) blockade of the C5a-C5aR axis lead to the decreased tissue damage induced by MERS-CoV infection, as manifested by reduced apoptosis and T cell regeneration in the spleen. Therefore, the results of this study suggest a new strategy for clinical intervention and adjunctive treatment in MERS-CoV cases.

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.

Glioblastoma (GBM) poses a serious challenge due to its aggressive nature and poor prognosis. Tumor mesenchymal stem-like cells (tMSLCs) secrete complement component 5a (C5a), altering the tumor microenvironment (TME) and promoting tumor progression. This study investigated W54011, a C5a antagonist, to counteract C5a-induced malignancy in GBM tumorspheres. We assessed GBM tissues for C5a receptor 1 (C5aR1) expression using gene profiling and survival analysis. GBM tumorspheres were cultured in C5a-enriched conditioned medium (CM) from tMSLCs to induce tumor stimulation. We evaluated proliferation, invasion, and stemness of GBM tumorspheres using WST/ATP, matrigel invasion assay, and limiting dilution assays. Results were validated via western blotting and RNA sequencing. Additionally, findings were corroborated in an in vivo xenograft mouse model. High C5aR1 expression correlated with increased TME, inflammation-related gene expression, and poorer patient outcomes. CM treatment increased GBM tumorsphere proliferation, invasion, and stemness, which were reversed by W54011. CM also induced the epithelial-mesenchymal transition, whereas W54011 restored spherical morphology and induced apoptosis. In xenograft models, CM-treated GBM tumorspheres led to larger tumors and decreased survival, whereas W54011 decreased tumor size and improved survival. This study suggests a potential role for C5a in GBM progression and supports further investigation of W54011 as a therapeutic candidate.

▪ Abstract  The complement system not only represents an effective innate immune mechanism of host defense to eradicate microbial pathogens, but it is also widely involved in many forms of acute and chronic inflammatory diseases including sepsis, acute lung injury, ischemia-reperfusion injury, and asthma, to give just a few examples. The complement-activated product, C5a, displays powerful biological activities that lead to inflammatory sequelae. C5a is a strong chemoattractant and is involved in the recruitment of inflammatory cells such as neutrophils, eosinophils, monocytes, and T lymphocytes, in activation of phagocytic cells and release of granule-based enzymes and generation of oxidants, all of which may contribute to innate immune functions or tissue damage. Accumulating data suggest that C5a provides a vital bridge between innate and adaptive immune functions, extending the roles of C5a in inflammation. Herein, we review human and animal data describing the cellular and molecular mechanisms of C5a in the development of inflammatory disorders, sepsis, acute lung injury, ischemia-reperfusion injury, and asthma.

Epidermolysis Bullosa Acquisita (EBA) is an autoimmune blistering dermatosis characterized by autoantibodies (AAbs) against type VII collagen (COL7) located at the dermal epidermal junction (DEJ). Local complement activation drives C5a generation associated with neutrophil recruitment and activation resulting in skin lesions and inflammation. Here we tested the impact of C5a/C5adesArg, C5 or combined C5 and alternative pathway (AP) targeting on disease development and skin inflammation in a preclinical mouse model mimicking the effector phase of EBA. C57BL/6 mice were treated subcutaneously with purified rabbit anti-mouse-COL7 IgG in the presence of IgG1 mAbs directed against murine C5a/C5adesArg (M031), C5 (mBB5.1), a bifunctional protein comprising mBB5.1 fused to an active fragment of the AP inhibitor factor H (M014) or an IgG1 isotype control mAb. Formation of skin lesions was evaluated 12 days every other day. On day 12, DEJ separation, IgG AAb and C3b deposition and neutrophil infiltration was assessed. Isotype IgG1-treated mice developed first skin lesions on day 4 peaking on day 12. Prophylactic treatment with either M031 or M014 markedly reduced the development of skin lesions, the dermal/epidermal separation and neutrophil recruitment. Surprisingly, C5 or combined AP/C5 inhibition by M014 but not C5a/C5adesArg-targeting by M031 reduced the development of skin lesions and dermal/epidermal separation in the setting of therapeutic treatment. IgG and C3b deposition was not affected by either treatment. Importantly, direct comparison of isolated C5 targeting by mBB5.1 vs. combined AP/C5 inhibition by M014 revealed that M014 reduced the development of skin lesions earlier and more pronounced than mBB5.1. Our findings identify combined C5/AP targeting as a novel therapeutic option for autoimmune blistering dermatoses.

Drug discovery and translation are normally based on optimizing efficacy by increasing receptor affinity, functional potency, drug-likeness (rule-of-five compliance) and oral bioavailability. Here we demonstrate that residence time of a compound on its receptor has an overriding influence on efficacy, exemplified for antagonists of inflammatory protein complement C5a that activates immune cells and promotes disease. Three equipotent antagonists (3D53, W54011, JJ47) of inflammatory responses to C5a (3nM) were compared for drug-likeness, receptor affinity and antagonist potency in human macrophages, and anti-inflammatory efficacy in rats. Only the least drug-like antagonist (3D53) maintained potency in cells against higher C5a concentrations and had a much longer duration of action ( t 1/2  ~ 20 h) than W54011 or JJ47 ( t 1/2  ~ 1–3 h) in inhibiting macrophage responses. The unusually long residence time of 3D53 on its receptor was mechanistically probed by molecular dynamics simulations, which revealed long-lasting interactions that trap the antagonist within the receptor. Despite negligible oral bioavailability, 3D53 was much more orally efficacious than W54011 or JJ47 in preventing repeated agonist insults to induce rat paw oedema over 24 h. Thus, residence time on a receptor can trump drug-likeness in determining efficacy, even oral efficacy, of pharmacological agents.

Vilobelimab, a first-in-class, human–mouse chimeric immunoglobulin G4 (IgG4) kappa monoclonal antibody, targets human complement component 5a (C5a) in plasma. Unlike upstream complement inhibitors, vilobelimab does not inhibit the generation of the membrane attack complex (C5b-9), necessary to mitigate certain infections. C5a is a strong anaphylatoxin and chemotactic agent that plays an essential role in both innate and adaptive immunity. Elevated levels of C5a have been associated with pathologic processes, including sepsis and inflammatory respiratory disorders such as acute respiratory distress syndrome (ARDS). Blocking C5a with vilobelimab has shown therapeutic promise. A randomized, multicenter placebo-controlled Phase III study of vilobelimab in patients with severe COVID-19 (PANAMO) found that patients treated with vilobelimab had a significantly lower risk of death by day 28 and 60. Based on this study, the United States Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for Gohibic® (vilobelimab) injection for the treatment of COVID-19 in hospitalized adults when initiated within 48 h of receiving invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO). In January 2025, the European Commission (EC) granted marketing authorization for Gohibic® (vilobelimab) for the treatment of adult patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced ARDS who are receiving systemic corticosteroids as part of standard of care and receiving IMV with or without ECMO. Herein, we review the mechanism of action of vilobelimab in selectively inhibiting C5a-induced inflammation, outlining its bench-to-bedside development from the fundamental biology of the complement system and preclinical evidence through to the clinical data demonstrating its life-saving potential in the management of COVID-19–induced ARDS.

BackgroundBreast cancer is the most diagnosed malignancy and a leading cause of cancer-related deaths among women globally. Cuproptosis plays a significant role in tumor progression and therapeutic response. Increasing studies suggest that targeting cuproptosis presents a promising strategy for cancer therapy, such as through the development of copper nanoparticles as therapeutic agents. However, resistance to cuproptosis has emerged as a critical hallmark of cancer. Therefore, it is essential to further investigate the mechanisms underlying cuproptosis resistance to enhance its therapy effect.MethodsThe relationship between breast cancer progression and the C5a/C5aR pathway or cuproptosis was determined by single-cell RNA sequencing analyses, RNA-sequence analyses, bioinformatic analyses, survival analyses and immunohistochemistry. The antitumor effects of CuS nanoparticles and C5a receptor antagonists (C5aRA) were assessed by in vitro and in vivo strategies including cell counting kit-8, colony formation assay, relative reactive oxygen species level assay, western blots, real-time quantitative PCR, immunohistochemistry, immunofluorescence assay, flow cytometry and the xenograft mice models. Complement system activation by CuS nanoparticles was tested by ELISA.ResultsOur results indicated that activation of the C5a/C5aR pathway contributes to cuproptosis resistance by upregulating ATP7B expression via the Wnt/β-catenin pathway. Consequently, combining CuS nanoparticles with lazer treatment and C5aRA markedly enhanced the antitumor efficacy of CuS nanoparticles by overcoming cuproptosis resistance, leading to a synergistic effect in cancer therapy that included cuproptosis-targeting therapy, immunotherapy, and photothermal therapy.ConclusionsThis study reports, for the first time, proved C5a/C5aR pathway-mediated cuproptosis resistance in cancer cells, and combining CuS nanoparticles and C5aRA offers a superior and novel therapeutic strategy for cancer.