| Candidate ID: | R1063 |
| Source ID: | DB06612 |
| Source Type: | approved; investigational |
| Compound Type: |
biotech
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| Compound Name: |
Mepolizumab
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| Synonyms: |
Mepolizumab
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| Molecular Formula: |
--
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| SMILES: |
--
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| DrugBank Description: |
Eosinophils are involved in inflammatory immune responses, and prolonged hypereosinophilia (typically defined as absolute eosinophil levels of 1500/mm<sup>3</sup> or more) is associated with a spectrum of diseases, including severe asthma, eosinophilic granulomatosis with polyangiitis (EGPA), and hypereosinophilic syndrome (HES). The pathogenesis of eosinophilia is complex, but IL-5 is recognized as a key cytokine involved in the differentiation, recruitment, activation, and prolonged survival of eosinophils in peripheral tissue. Activated eosinophils further stimulate an inflammatory response and also induce tissue lesions and promote fibrosis, all of which contribute to the multifactorial symptomatology of hypereosinophilic diseases.
Mepolizumab is a fully-humanized recombinant IgG1 kappa monoclonal antibody directed against IL-5 produced in Chinese hamster ovary cells. Mepolizumab was first approved by the FDA on November 4, 2015, as an add-on therapy for severe asthma and marketed under the brand name Nucala by GlaxoSmithKline. This indication was subsequently expanded to cover EGPA on December 12, 2017, and HES on September 25, 2020.
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| CAS Number: |
196078-29-2
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| Molecular Weight: |
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| DrugBank Indication: |
Mepolizumab is an anti-IL-5 IgG1 kappa monoclonal antibody indicated as an add-on maintenance treatment in patients aged six years and older with severe eosinophilic asthma and as a treatment in adult patients for eosinophilic granulomatosis with polyangiitis (EGPA). Mepolizumab is also indicated for the treatment of hypereosinophilic syndrome (HES) in patients aged 12 and older in whom eosinophilia is present for at least six months without an identifiable non-hematologic secondary cause.
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| DrugBank Pharmacology: |
Mepolizumab is a monoclonal antibody that acts through interleukin-5 (IL-5) antagonism to reduce blood eosinophil levels, generally in the range of 60-90% of baseline depending on dose, which in turn offers therapeutic benefit in the specific conditions for which mepolizumab is indicated. Mepolizumab has a relatively long half-life of between 16 and 22 days, which allows for long-lasting therapeutic benefit and a four-week dosing schedule. Despite a good demonstrated safety profile, mepolizumab use does act to depress part of the immune system and may be associated with increased infections, such as with herpes zoster virus; pre-existing helminth infections should be treated before starting mepolizumab therapy. Inhaled and oral corticosteroids should not be discontinued after starting mepolizumab but may be tapered as appropriate. Mepolizumab should not be used to treat acute bronchospasms or status asthmatics. Finally, hypersensitivity reactions, including anaphylaxis, have been reported in patients; mepolizumab should be discontinued in patients with suspected or confirmed hypersensitivity.
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| DrugBank MoA: |
Hypereosinophilia is typically considered as an absolute eosinophil count of 1500/mm<sup>3</sup> or higher and is associated with aberrant immune responses in several conditions, including severe asthma, eosinophilic granulomatosis with polyangiitis, and the variable spectrum of hypereosinophilic syndrome (HES). Eosinophils are involved in the inflammatory response by secretion of molecules such as MBP, leukotrienes, matrix metalloproteinases, transforming growth factor-β, nitric oxide, and other reactive oxygen species. Interleukin-5 (IL-5) is the primary cytokine associated with the differentiation of bone marrow progenitor cells into mature inflammatory neutrophils and the subsequent migration, activation, and prolonged survival of activated neutrophils. In concert with other cells, including lymphocytes, neutrophils, mast cells, and macrophages, which themselves can secrete additional pro-inflammatory molecules, high concentrations of neutrophils are associated with tissue damage and fibrosis, leading to the symptoms of eosinophilic diseases.
Typically, eosinophils arise from both CD34<sup>+</sup> and dual CD34<sup>+</sup>, IL-5 receptor-positive (IL-5R<sup>+</sup>) progenitor cells, which is in part mediated by the cytokines IL-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Although there exists a population of eosinophils that are insensitive to IL-5 levels, the main population of inflammatory eosinophils proliferates and migrates into the tissue in response to IL-5. Mepolizumab is a fully-humanized monoclonal IgG1 kappa antibody that binds IL-5 with a dissociation constant of 100 pM, preventing IL-5 from binding to and subsequently activating IL-5R<sup>+</sup> cells. This reduction lowers circulating blood eosinophil levels and therefore exerts a beneficial effect in eosinophilic disease; the exact mechanistic nature of mepolizumab action has not been definitively determined. Not all patients will benefit from mepolizumab treatment, such as those with milder asthma or those with a sub-type of HES that is independent of IL-5 signalling.
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| Targets: |
Interleukin-5 antagonist
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| Inclusion Criteria: |
Therapeutic strategy associated
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