| Candidate ID: | R1436 |
| Source ID: | DB12159 |
| Source Type: | approved; investigational |
| Compound Type: |
biotech
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| Compound Name: |
Dupilumab
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| Synonyms: |
Dupilumab
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| Molecular Formula: |
--
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| SMILES: |
--
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| DrugBank Description: |
Dupilumab is a fully human monoclonal antibody of the immunoglobulin G4 subclass that binds to the interleukin-4 (IL-4) receptor, inhibiting the receptor signaling pathways. As an interleukin-4 receptor alpha antagonist, dupilumab inhibits the signaling of pro-inflammatory cytokines, called interleukins (IL), that induce inflammatory and immunological reactions in several atopic or allergic conditions, such as eczema, allergic reaction, and rhinosinusitis. Dupilumab was generated by recombinant DNA technology in Chinese Hamster Ovary cell suspension culture.
Dupilumab is commonly marketed as Dupixent®, which is available as a formulation for subcutaneous injection. It was first approved by the FDA in 2017 for patients 12 and older with eczema or atopic dermatitis. Dupilumab is also approved by Health Canada for the same indication and the European Commission for use in atopic dermatitis as well as severe asthma with type 2 inflammation. It is the first biologic therapy to have been approved for the treatment of adult patients with moderate-to-severe AD in the EU and USA. In 2018, FDA approved the use of dupilumab as an add-on maintenance treatment for patients 12 years and older with moderate-to-severe eosinophilic asthma or with oral corticosteroid-dependent asthma. In June 2019, dupilumab was also approved by the FDA as an add-on maintenance treatment for inadequately controlled chronic rhinosinusitis with nasal polyps in adult patients. Dupilumab is currently under investigations for potential therapeutic use in diseases driven by allergic reactions or type 2 inflammation, such as pediatric atopic dermatitis, eosinophilic esophagitis, and chronic obstructive pulmonary disease. It is also being studied in combination with another antibody that which targets IL-33.
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| CAS Number: |
1190264-60-8
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| Molecular Weight: |
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| DrugBank Indication: |
Dupilumab is indicated, as monotherapy or in combination with topical corticosteroids, for the treatment of patients aged 12 years and older with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.
It is also used as an add-on maintenance treatment in patients with moderate-to-severe asthma aged 12 years and older with an eosinophilic phenotype or with oral corticosteroid dependent asthma. It is not indicated for the relief of acute bronchospasm or status asthmaticus.
Dupilumab is indicated as an add-on maintenance treatment in adult patients with inadequately controlled chronic rhinosinusitis with nasal polyposis.
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| DrugBank Pharmacology: |
Dupilumab is an recombinant human IgG4 antibody to the IL-4 receptor that works by inhibiting the activation of certain pro-inflammatory cytokines that are implicated in the pathophysiology of several allergic and atopic conditions, including asthma, chronic rhinosinusitis with nasal polyps, and food and environmental allergies. _In vivo_, dupilumab was shown to reduce the levels of type 2 inflammatory biomarkers associated with atopic dermatitis, such as thymus and activation-regulated chemokine (TARC/CCL17), total serum IgE, allergen-specific IgE, and lactate dehydrogenase (LDH). A decrease in the levels of biomarkers of asthma, such as FeNO, eotaxin-3, IgE, periostin, and eotaxin-3 (CCL26) was also observed. Since dupilumab works to suppress the immune response, it is proposed that it may influence the immune response against some infections, such as helminth infections, by inhibiting IL-4/IL-13 signaling. It is advised that infections are appropriately treated until resolved before initiating dupilumab therapy.
While findings of some _in vitro_ and _in vivo_ studies suggest that some cytokine modulators may influence the expression and activity of specific cytochrome P450 (CYP450) enzymes, an open-label drug-drug interaction study demonstrated that dupilumab displays no significant effect on the activity of CYP450 enzymes studied (CYP3A, CYP2C19, CYP2C9, CYP1A2, and CYP2D6).
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| DrugBank MoA: |
Type 2 inflammatory processes in various allergic and atopic conditions, such as asthma and atopic diseases, involve the type 2 helper T-cell (Th2) immunity. Upregulation of this Type 2/Th2 pathway is commonly observed in other inflammatory conditions and the activation of Th2 cells is linked to the production of Th2-associated cytokines, such as interleukin (IL) 4, IL-5, IL-9, and IL-13. IL-4 and IL-13 play a central role in inducing inflammatory conditions such as allergic rhinitis, asthma, and atopic dermatitis, by regulating Type 2 inflammation and immune function. These inflammatory cytokines work by modulating gene expression downstream of receptor signalling, regulating Th2 cell differentiation, and activating inflammatory cells such as mast cells and macrophages.
There are two types of receptors for IL-4: the type 1 receptor, which is composed of the IL-4 chain (IL-4Rα) and a γ chain (γC), and the type 2 receptor, which is composed of the IL-4Rα chain and the α1 chain of the IL-13 receptor (IL-13Rα1). Essentially, IL‐4Rα is a component shared by the IL‐4 and IL-13 receptor complexes and is ubiquitously expressed on both innate and adaptive immune cells to promote the signaling of IL-4 and IL-13. The type I receptor is primarily expressed on lymphocytes and controls Th2-cell differentiation, whereas the type II receptor is mostly found across resident and myeloid cells. Dupilumab is a fully human monoclonal antibody directed against IL‐4Rα to inhibit the signalling of IL‐4 and IL‐13. Dupilumab inhibits IL-4 signalling via the Type I receptor (IL-4Rα/γc), and both IL-4 and IL-13 signaling through the Type II receptor (IL-4Rα/IL-13Rα). It ultimately downregulates type-2 immunity.
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| Targets: |
Interleukin-4 receptor subunit alpha antagonist
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| Inclusion Criteria: |
Therapeutic strategy associated
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