Compendium of current complement therapeutics

Zelek, Wioleta M.; Xie, Long; Morgan, B. Paul; Harris, Claire L.

doi:10.1016/j.molimm.2019.07.030

Cited by 110 publications

(108 citation statements)

References 72 publications

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“…In trials of eculizumab for PNH, myasthenia gravis and NMOSD 146,192 , safety profiles have been very good, but some aspects need attention. For example, eculizumab impairs host defences against Neisseria spp.…”

Section: Safety Of Complement-targeted Therapiesmentioning

confidence: 99%

Complement in neurological disorders and emerging complement-targeted therapeutics

2020

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The human complement system is an effector of innate and adaptive humoral immunity. The system comprises soluble membrane-bound proteins (opsonins) that act collectively to recognize pathogens and non-self material and subsequently initiate opsonization and phagocytosis or lysis of pathogens. The proteolytic fragments that derive from complement activation can be targeted by white blood cells and endothelial cells, leading to extravasation and migration of immune cells at the sites of inflammation. Other physiological functions of complement include timely removal of altered and senescent self, tissue remodelling, cell lysis, chemotaxis, opsonization, inflammation and immune cell stimulation 1-4. Complement activation products link the innate and adaptive immune systems by acting directly on receptors on T cells and B cells or by modulating dendritic cell functions 5-8. Disruption of the delicate coordination required for complement activation and control is fundamental in the pathogenic mechanism of several autoimmune neurological disorders, and is even emerging as a contributor in some neurodegenerative diseases. As a result, interest is increasing in targeting complement as a therapeutic approach to prevent ongoing tissue destruction in several difficult-to-treat neurological diseases. In this Review, we provide an overview of the main components of the initial complement activation pathways, the lytic pathway and the factors associated with inappropriate complement activation or control in disease initiation and progression. We consider the role of complement in the tissue destruction that is responsible for the genesis of the most common autoimmune neurological diseases, including complement-mediated myopathies, myasthenia gravis, neuropathies and CNS disorders. We also discuss the role of complement in some neurodegenerative disorders, including Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), Huntington disease, traumatic brain injury and even schizophrenia. Finally, we discuss emerging complement-targeted therapies, such as monoclonal antibodies, fusion proteins and cyclic peptides, that inhibit the functions of individual complement proteins, especially therapies that disrupt the lytic pathway. Some of these therapeutic agents have been approved or are being tested in phase I-III clinical trials and promise to change the therapeutic armamentarium for treatment of neurological conditions that respond poorly to existing immunotherapies.

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Section: Safety Of Complement-targeted Therapiesmentioning

confidence: 99%

Complement in neurological disorders and emerging complement-targeted therapeutics

2020

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“…Complement is a key component of the immune system, evolved to protect from bacterial infections; however, dysregulation of complement drives inflammation and leads to pathology in many diseases. 1,2 Activation of complement by way of classical, lectin or alternative pathways triggers enzymatic cascade reactions that all result in formation of C3-cleaving enzymes (convertases) and subsequently C5 convertases; these cleave C5 into C5a, a potent anaphylatoxin, and C5b, which nucleates formation of membrane attack complex (MAC) by sequentially binding C6 and C7. The C5b67 complex binds membranes and sequentially recruits C8 and C9 to complete the MAC.…”

Section: Introductionmentioning

confidence: 99%

“…2 The first disease targets for anti-complement drugs were rare complement-driven diseases caused by complement gene mutations or polymorphisms, notably paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome, [4][5][6][7] but complement is also implicated in many more common diseases, including age-related macular degeneration, myasthenia gravis, and in multiple central nervous system diseases including Alzheimer's disease, neuromyelitis optica and multiple sclerosis. 1,8 In haemolytic uraemic syndrome and paroxysmal nocturnal haemoglobinuria, blocking MAC assembly with the anti-C5 mAb eculizumab prevents pathology and transforms patient outcomes. [4][5][6][7] The evidence underpinning the rapid developments in complement therapeutics has come from animal studies; a large proportion of these studies have used the same key agent, a function-blocking anti-C5 mAb BB5.1.…”

Section: Introductionmentioning

confidence: 99%

Characterizing the original anti‐C5 function‐blocking antibody, BB5.1, for species specificity, mode of action and interactions with C5

et al. 2020

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“…The possible primary and perpetuating causes of complement dysregulation and inflammation in schizophrenia and other mental disorders are unclear, but maternal immune activation ( Conway and Brown, 2019 ), exposure to infections ( Kneeland and Fatemi, 2013 ), the microbiome ( Severance and Yolken, 2019 ) and other environmental factors such as childhood adversity ( Danese and J Lewis, 2017 ) and substance use ( Miller et al, 2018 ) are potential contributing factors. Drugs targeting the complement system are available and others in active development ( Carpanini et al, 2019 ; Druart and Le Magueresse, 2019 ; Ricklin et al, 2018 ; Zelek et al, 2019 ), but whether they may prove useful in the treatment or prevention of psychotic disorders will require extensive preclinical testing before human trials.…”

Section: Discussionmentioning

confidence: 99%

Peripheral complement proteins in schizophrenia: A systematic review and meta-analysis of serological studies

Mongan

Sabherwal

Susai

et al. 2020

Schizophrenia Research

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Background There is renewed focus on the complement system in the pathogenesis of schizophrenia. In addition to providing aetiological insights, consistently dysregulated complement proteins in serum or plasma may have clinical utility as biomarkers. Methods We performed a systematic literature review searching PubMed, Embase and PsycINFO for studies measuring complement system activity or complement protein concentrations in serum or plasma from patients with schizophrenia compared to controls. Random-effects meta-analyses were performed to calculate pooled effect estimates (Hedges' g standardised mean difference [SMD]) for complement proteins whose concentrations were measured in three or more studies. The review was pre-registered on the PROSPERO database (CRD42018109012). Results Database searching identified 1146 records. Fifty-eight full-text articles were assessed for eligibility and 24 studies included. Seven studies measured complement system activity. Activity of the classical pathway did not differ between cases and controls in four of six studies, and conflicting results were noted in two studies of alternative pathway activity. Twenty studies quantified complement protein concentrations of which complement components 3 (C3) and 4 (C4) were measured in more than three studies. Meta-analyses showed no evidence of significant differences between cases and controls for 11 studies of C3 (SMD 0.04, 95% confidence interval [CI] -0.29–0.36) and 10 studies of C4 (SMD 0.10, 95% CI -0.21–0.41). Conclusions Serological studies provide mixed evidence regarding dysregulation of the complement system in schizophrenia. Larger studies of a longitudinal nature, focusing on early phenotypes, could provide further insights regarding the potential role of the complement system in psychotic disorders.

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Compendium of current complement therapeutics

Cited by 110 publications

References 72 publications

Complement in neurological disorders and emerging complement-targeted therapeutics

Complement in neurological disorders and emerging complement-targeted therapeutics

Characterizing the original anti‐C5 function‐blocking antibody, BB5.1, for species specificity, mode of action and interactions with C5

Peripheral complement proteins in schizophrenia: A systematic review and meta-analysis of serological studies

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