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The renaissance of complement therapeutics.

ABSTRACT: 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.

SUBMITTER: Ricklin D

PROVIDER: S-EPMC5805379 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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The renaissance of complement therapeutics.

Ricklin Daniel D Mastellos Dimitrios C DC Reis Edimara S ES Lambris John D JD

Nature reviews. Nephrology 20171204 1

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 var ...[more]

PMID: 29199277

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Project description:The complement system consists of a network of plasma and membrane proteins that modulate tissue homeostasis and contribute to immune surveillance by interacting with the innate and adaptive immune systems. Dysregulation, impairment or inadvertent activation of complement components contribute to the pathogenesis of some autoimmune neurological disorders and could even contribute to neurodegenerative diseases. In this Review, we summarize current knowledge about the main functions of the complement pathways and the involvement of complement in neurological disorders. We describe the complex network of complement proteins that target muscle, the neuromuscular junction, peripheral nerves, the spinal cord or the brain and discuss the autoimmune mechanisms of complement-mediated myopathies, myasthenia, peripheral neuropathies, neuromyelitis and other CNS disorders. We also consider the emerging role of complement in some neurodegenerative diseases, such as Alzheimer disease, amyotrophic lateral sclerosis and even schizophrenia. Finally, we provide an overview of the latest complement-targeted immunotherapies including monoclonal antibodies, fusion proteins and peptidomimetics that have been approved, that are undergoing phase I–III clinical trials or that show promise for the treatment of neurological conditions that respond poorly to existing immunotherapies. In this Review, Dalakas et al. discuss the complement system, the role it plays in autoimmune neurological disease and neurodegenerative disease, and provide an overview of the latest therapeutics that target complement and that can be used for or have potential in neurological disorders. Key points Complement has an important physiological role in host immune defences and tissue remodelling. The physiological role of complement extends to the regulation of synaptic development. Complement has a key pathophysiological role in autoimmune neurological diseases and mediates the actions of pathogenic autoantibodies, such as acetylcholine receptor antibodies and aquaporin 4 antibodies. For some autoimmune neurological diseases, such as myasthenia gravis and neuromyelitis optica spectrum disorders, approved complement-targeted treatments are now available. Complement also seems to be of pathogenic relevance in neurodegenerative diseases such as Alzheimer disease, in which innate immune-driven inflammation is receiving increasing attention. The field of complement-targeted therapeutics is rapidly expanding, with several FDA-approved agents and others currently in phase II and phase III clinical trials.

Dataset Information

The renaissance of complement therapeutics.

Publications

The renaissance of complement therapeutics.

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