Current and Future Pharmacologic Complement Inhibitors

Risitano, Antonio M.

doi:10.1016/j.hoc.2015.01.009

Cited by 30 publications

(22 citation statements)

References 83 publications

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“…At least in some patients and situations, however, complement activation is thought to proceed beyond the C3 stage, causing cleavage of C5 and thereby triggering the terminal complement cascade with formation of the membrane attack complex (MAC) and intravascular haemolysis . This notion is supported by the occurrence of haemoglobinuria in about 15% of the patients (Swiecicki et al, 2013), the rather frequent finding of haemosiderinuria (Stone & Berentsen, 2017), and the modest but statistically significant beneficial effect of therapy with eculizumab (R€ oth et al, 2009, 2015Tjonnfjord et al, 2017).…”

Section: State Of the Art Review ª 2018 John Wiley And Sons Ltdmentioning

confidence: 88%

“…Complement inhibition in CAD should be further documented and developed and, in particular, extended clinical studies of BIVV009 are warranted (Shi et al, 2014;Jaeger, 2017). Other novel complement inhibitors are also being developed (Risitano, 2015;Gertz et al, 2016). Compstatin is a group of low molecular weight peptides that block cleavage of C3 (Mastellos et al, 2015).…”

Section: Future Therapy Perspectivesmentioning

confidence: 99%

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How I manage patients with cold agglutinin disease

Berentsen

2018

Br J Haematol

111

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Cold agglutinin disease (CAD) is an uncommon autoimmune haemolytic anaemia in which a well-defined, clonal low-grade lymphoproliferative disorder of the bone marrow results in erythrocyte destruction mediated by the classical complement pathway. The pathogenesis, clinical features and diagnostic criteria are reviewed. Although anaemia is mild in some patients, approximately one-third of untreated patients have a haemoglobin level of ≤80 g/l, and about 50% have been considered transfusion dependent for shorter or longer periods. Therapy has improved greatly during the last 15 years. Mild disease can be managed by avoidance of cold and adequate precautions in specific situations, without drug therapy. Corticosteroids should not be used to treat CAD. Patients requiring pharmacological therapy should be considered for prospective trials. Outside clinical studies, the rituximab-bendamustine combination or rituximab monotherapy is recommended in the first line, depending on individual patient characteristics. Second-line options are rituximab-fludarabine in fit patients or, although less strongly documented, a bortezomib-based regimen. Therapies targeting the classical complement pathway are promising, and the complement C1s inhibitor, BIVV009, has shown favourable results in preliminary studies.

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Section: State Of the Art Review ª 2018 John Wiley And Sons Ltdmentioning

confidence: 88%

Section: Future Therapy Perspectivesmentioning

confidence: 99%

How I manage patients with cold agglutinin disease

Berentsen

2018

Br J Haematol

111

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“…However, C5 blockers are currently in use in clinical and pre-clinical studies for a number of other diseases. Eculizumab (Soliris ® ), a humanized anti-C5 monoclonal antibody, prevents C5 from being cleaved into C5a and C5b by C5 convertase, and is currently in trials for paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), with plans to extend its use to age-related macular degeneration, myasthenia gravis, optic neuritis, early septic organ dysfunction, and prevention of rejection of kidney transplants (Melis et al, 2015; Risitano, 2015; Horiuchi and Tsukamoto, 2016). In addition to C5 antibodies, peptidic and non-peptidic C5aR antagonists are in clinical trials, and some have been proven efficacious (Morgan and Harris, 2015).…”

Section: Discussionmentioning

confidence: 99%

C5a Regulates IL-1β Production and Leukocyte Recruitment in a Murine Model of Monosodium Urate Crystal-Induced Peritonitis

Khameneh

Laudisi

et al. 2017

Front. Pharmacol.

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Gouty arthritis results from the generation of monosodium urate (MSU) crystals within joints. These MSU crystals elicit acute inflammation characterized by massive infiltration of neutrophils and monocytes that are mobilized by the pro-inflammatory cytokine IL-1β. MSU crystals also activate the complement system, which regulates the inflammatory response; however, it is unclear whether or how MSU-mediated complement activation is linked to IL-1β release in vivo, and the various roles that might be played by individual components of the complement cascade. Here we show that exposure to MSU crystals in vivo triggers the complement cascade, leading to the generation of the biologically active complement proteins C3a and C5a. C5a, but not C3a, potentiated IL-1β and IL-1α release from LPS–primed MSU-exposed peritoneal macrophages and human monocytic cells in vitro; while in vivo MSU–induced C5a mediated murine neutrophil recruitment as well as IL-1β production at the site of inflammation. These effects were significantly ameliorated by treatment of mice with a C5a receptor antagonist. Mechanistic studies revealed that C5a most likely increased NLRP3 inflammasome activation via production of reactive oxygen species (ROS), and not through increased transcription of inflammasome components. Therefore we conclude that C5a generated upon MSU-induced complement activation increases neutrophil recruitment in vivo by promoting IL-1 production via the generation of ROS, which activate the NLRP3 inflammasome. Identification of the C5a receptor as a key determinant of IL-1-mediated recruitment of inflammatory cells provides a novel potential target for therapeutic intervention to mitigate gouty arthritis.

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“…The first clinically approved complement-targeted drugs, anti-C5 (Eculizumab; Soliris, Alexion) and C1-inhibitor (C1-INH; various manufacturers) are now used for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), and for hereditary angioedema, respectively [40]. Additional candidate drugs for modulating complement activity at various points of the cascade are under development ranging from large biological biomolecules (antibodies and engineered proteins) to interfering RNA, aptamers and low-molecular-weight inhibitors and antagonists [38, 41, 42]. With close to 50 molecules involved in the cascade, the complement system offers numerous potential targets for pharmacological interference.…”

Section: Therapeutic Complement Inhibitorsmentioning

confidence: 99%

Complement inhibition in pre-clinical models of periodontitis and prospects for clinical application

Hajishengallis

Kajikawa

et al. 2016

Seminars in Immunology

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Periodontitis is a dysbiotic inflammatory disease leading to the destruction of the tooth-supporting tissues. Current therapies are not always effective and this prevalent oral disease continues to be a significant health and economic burden. Early clinical studies have associated periodontitis with elevated complement activity. Consistently, subsequent genetic and pharmacological studies in rodents have implicated the central complement component C3 and downstream signaling pathways in periodontal host-microbe interactions that promote dysbiosis and inflammatory bone loss. This review discusses these mechanistic advances and moreover focuses on the compstatin family of C3 inhibitors as a novel approach to treat periodontitis. In this regard, local application of the current lead analog Cp40 was recently shown to block both inducible and naturally occurring periodontitis in non-human primates. These promising results from non-human primate studies and the parallel development of Cp40 for clinical use highlight the feasibility for developing an adjunctive, C3-targeted therapy for human periodontitis.

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Current and Future Pharmacologic Complement Inhibitors

Cited by 30 publications

References 83 publications

How I manage patients with cold agglutinin disease

How I manage patients with cold agglutinin disease

C5a Regulates IL-1β Production and Leukocyte Recruitment in a Murine Model of Monosodium Urate Crystal-Induced Peritonitis

Complement inhibition in pre-clinical models of periodontitis and prospects for clinical application

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