Therapeutic complement inhibition in complement-mediated hemolytic anemias: Past, present and future

Risitano, Antonio M.; Marotta, Serena

doi:10.1016/j.smim.2016.05.001

Cited by 39 publications

(33 citation statements)

References 161 publications

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“…Affected erythrocytes have increased susceptibility to (bystander) complement attack, which leads to their MAC-mediated lysis (intravascular haemolysis) and contributes to thrombotic complications. By impairing C5 activation and subsequent formation of the MAC, eculizumab prevents intravascular haemolysis in most patients with PNH and profoundly changed the hitherto limited options for therapy 62 . With the exception of an increased risk of meningococcal infections, which is curtailed by mandatory vaccination, eculizumab showed an overall beneficial safety profile during clinical trials and long-term post-approval observations 63,64 , thereby raising confidence in the therapeutic approach.…”

Section: Complement-targeting Therapeuticsmentioning

confidence: 99%

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The renaissance of complement therapeutics

et al. 2017

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The increasing number of clinical conditions that involve a pathological contribution from the complement system — many of which affect the kidneys — has spurred a regained interest in therapeutic options to modulate this host defence pathway. Molecular insight, technological advances, and the first decade of clinical experience with the complement-specific drug eculizumab, have contributed to a growing confidence in therapeutic complement inhibition. More than 20 candidate drugs that target various stages of the complement cascade are currently being evaluated in clinical trials, and additional agents are in preclinical development. Such diversity is clearly needed in view of the complex and distinct involvement of complement in a wide range of clinical conditions, including rare kidney disorders, transplant rejection and haemodialysis-induced inflammation. The existing drugs cannot be applied to all complement-driven diseases, and each indication has to be assessed individually. Alongside considerations concerning optimal points of intervention and economic factors, patient stratification will become essential to identify the best complement-specific therapy for each individual patient. This Review provides an overview of the therapeutic concepts, targets and candidate drugs, summarizes insights from clinical trials, and reflects on existing challenges for the development of complement therapeutics for kidney diseases and beyond.

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Section: Complement-targeting Therapeuticsmentioning

confidence: 99%

“…Among patients with PNH, a very small number do not respond owing to a point mutation in the eculizumab epitope on C5 (Arg885His) 72 , but at least one-third remain transfusion-dependent despite eculizumab therapy 62 . A potential factor that might contribute to this insufficient clinical response is .…”

Section: Complement-targeting Therapeuticsmentioning

confidence: 99%

The renaissance of complement therapeutics

et al. 2017

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“…64 A slew of additional agents interfering at various stages of the complement pathway are under development. 65 …”

Section: Therapeuticsmentioning

confidence: 99%

Atypical Hemolytic Uremic Syndrome: A Brief Review

Zhang

Harley

et al. 2017

Hematology Reports

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Atypical hemolytic uremic syndrome (aHUS) is a disease characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury. The histopathologic lesions of aHUS include thrombotic microangiopathy involving the glomerular capillaries and thrombosis involving arterioles or interlobar arteries. Extra-renal manifestations occur in up to 20% of patients. The majority of aHUS is caused by complement system defects impairing ordinary regulatory mechanisms. Activating events therefore lead to unbridled, ongoing complement activity producing widespread endothelial injury. Pathologic mutations include those resulting in loss-of-function in a complement regulatory gene (CFH, CFI, CD46 or THBD) or gain-of-function in an effector gene (CFB or C3). Treatment with the late complement inhibitor, eculizumab – a monoclonal antibody directed against C5 – is effective.

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“…In vitro , it prevents hemolysis of PNH erythrocytes (102). In an open label, non-comparative clinical trial, Coversin reducing serum lactic dehydrogenase, will be tested in patients with PNH and proven resistance to eculizumab due to C5 polymorphisms (NCT02591862).…”

Section: Therapymentioning

confidence: 99%

“…Several preclinical trials are testing this strategy (102), and it is particularly useful in diseases where a specific complement pathway has a dominant pathogenic role. Examples would be the AP in PNH or the CP in antibody-mediated hemolytic anemias.…”

Section: Therapymentioning

confidence: 99%

Complement in Non-Antibody-Mediated Kidney Diseases

2017

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The complement system is part of the innate immune response that plays important roles in protecting the host from foreign pathogens. The complement components and relative fragment deposition have long been recognized to be strongly involved also in the pathogenesis of autoantibody-related kidney glomerulopathies, leading to direct glomerular injury and recruitment of infiltrating inflammation pathways. More recently, unregulated complement activation has been shown to be associated with progression of non-antibody-mediated kidney diseases, including focal segmental glomerulosclerosis, C3 glomerular disease, thrombotic microangiopathies, or general fibrosis generation in progressive chronic kidney diseases. Some of the specific mechanisms associated with complement activation in these diseases were recently clarified, showing a dominant role of alternative activation pathway. Over the last decade, a growing number of anticomplement agents have been developed, and some of them are being approved for clinical use or already in use. Therefore, anticomplement therapies represent a realistic choice of therapeutic approaches for complement-related diseases. Herein, we review the complement system activation, regulatory mechanisms, their involvement in non-antibody-mediated glomerular diseases, and the recent advances in complement-targeting agents as potential therapeutic strategies.

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Therapeutic complement inhibition in complement-mediated hemolytic anemias: Past, present and future

Cited by 39 publications

References 161 publications

The renaissance of complement therapeutics

The renaissance of complement therapeutics

Atypical Hemolytic Uremic Syndrome: A Brief Review

Complement in Non-Antibody-Mediated Kidney Diseases

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