The Simultaneous Inhibition of IL‐4 and IL‐13 by Dupilumab

Interleukins (IL) IL-4 and IL-13 are key players in diseases in which the Type 2 immune response is predominant, such as atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyposis (CRSwNP), that are currently being treated with dupilumab. Dupilumab is a fully human IgG4 monoclonal antibody that targets the IL-4 receptor alpha chain (IL-4Rα), preventing both IL-4 and IL-13 mediated signaling. This mini-review summarizes the IL-4 receptor system as well as the mechanism of action of dupilumab.


Introduction
Cytokines are secreted glycoproteins that act as intercellular messengers to control the hematopoietic and immune systems along with the inflammatory response [1,2]. They are structurally distinct factors that bind cellular receptors belonging to at least seven families, which signal through very different pathways [1][2][3].The major cytokine families are: the Type I/II cytokines, the Abstract Interleukins (IL) IL-4 and IL-13 are key players in diseases in which the Type 2 immune response is predominant, such as atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyposis (CRSwNP), that are currently being treated with dupilumab. Dupilumab is a fully human IgG4 monoclonal antibody that targets the IL-4 receptor alpha chain (IL-4Rα), preventing both IL-4 and IL-13 mediated signaling. This mini-review summarizes the IL-4 receptor system as well as the mechanism of action of dupilumab. Tumor Necrosis Factor (TNF) family, the IL-1 family, the IL-17 cytokines family, the stem cell factor/receptor tyrosine kinase cytokines, the Transforming Growth Factor Beta (TGF-β) family, and the chemokines family [1][2][3]. Type I/II cytokines signal through the Janus Kinase (JAK) and the Signal Transducer and Activator of Transcription (STAT) pathway [1][2][3].
The expression of the secondary chains (γc and IL-13Rα1) varies among different cell types [5][6][7][8]. Lymphocytes express only low levels of IL-13Rα1 and relatively large amounts of γc [6][7][8]. In non-hematopoietic cells, γc expression is low or absent, whereas higher amounts of IL-13Rα1 are expressed. By contrast, T cells do not express IL-13Rα1. Actually, only T helper 17 cells seem to express IL-13Rα1 [6,8]. Cells of myeloid origin (such as dendritic cells) as well as B cells express both Type I and Type II IL-4R [6,8].
Therefore, Type I IL-4R is expressed on hematopoietic (lymphoid and myeloid) cells and binds IL-4 exclusively [6][7][8]. On the other hand, the Type II IL-4R is expressed on both hematopoietic and non-hematopoietic cells and can bind IL-4 and IL-13 [5][6][7][8]. Of course, differences in the expression of the Type I and Type II IL-4R subtypes result in differences in the sensitivity of the cells to IL-4 and IL-13 [6][7][8].
As high amounts of IL-13Rα1 are expressed in non-hematopoietic cells (such as fibroblasts, endothelial cells, as well as the airway and skin epithelium), IL-13 seems to be the key cytokine driving Type 2 inflammation in the periphery [6][7][8].

Dupilumab: molecule overview and mechanism of action
Dupilumab is a recombinant, fully human IgG4 monoclonal antibody, with a molecular mass of 147 Kilodaltons, produced in Chinese Hamster Ovary cells via recombinant DNA technology [9].
The drug is administered through subcutaneous injections in doses of 200 or 300 mg. The maximum serum concentration is achieved one week after the initial injection, with a bioavailability of 64%.Following the administration of subsequent doses, steady-state concentrations are reached by week 16 and turns non detectable for about 10-13 weeks after last administration [10,11].
In relation to immunogenicity, the incidence of anti-drug antibodies is usually low. It was reported approximately 7% of patients using dupilumab for 16 weeks developed anti-drug antibodies, of which only 30% were classified as neutralizing [10].
In moderate-to-severe AD, subcutaneous injections of dupilumab (as monotherapy or with concomitant topical corticosteroids) demonstrated improved AD skin lesions, symptoms, and quality of life, with a favorable safety profile, in adults and children (with 6 years old or more) [10,[13][14][15]. Differences in gene expression following administration of dupilumab include downregulation of markers of epidermal proliferation, downregulation of inflammatory mediators, upregulation of structural proteins, upregulation of lipid metabolism proteins, and upregulation of epidermal barrier proteins resulting in normalization of skin [10]. The most common adverse events in all trials were nasopharyngitis, upper respiratory tract infection, injection site reactions, skin infections, and conjunctivitis [10,[13][14][15].
Beyond AD, dupilumab is under investigation for several other dermatological conditions, including prurigo nodularis, chronic spontaneous urticaria, bullous pemphigoid, allergic contact dermatitis, chronic hand eczema, and alopecia areata [16,17], which indicates this drug can be, in a near future, an important player in the chronic skin diseases treatment arsenal.

Conclusion
Aberrant Type 2 immune responses underlie not only AD but also other diseases such as asthma and CRSwNP, which can be
Specifically in dermatology, the sustained efficacy and favorable safety profile of dupilumab observed up to 3 years in adults with AD support the long-term continuous use of the drug for treating this chronic and debilitating disease [13]. There fore, Dermatologists should understand the mechanism of action of dupilumab, which besides to being used to treat moderate-tosevere AD [10,[13][14][15], has great potential for the treatment of several other inflammatory skin diseases [16][17].