Biological Therapy of Severe Asthma with Dupilumab, a Dual Receptor Antagonist of Interleukins 4 and 13

Abstract

Interleukin-4 (IL-4) and interleukin-13 (IL-13) are key cytokines involved in the pathophysiology of both immune-inflammatory and structural changes underlying type 2 asthma. IL-4 plays a pivotal role in Th2 cell polarization, immunoglobulin E (IgE) synthesis and eosinophil recruitment into the airways. IL-13 synergizes with IL-4 in inducing IgE production and also promotes nitric oxide (NO) synthesis, eosinophil chemotaxis, bronchial hyperresponsiveness and mucus secretion, as well as the proliferation of airway resident cells such as fibroblasts and smooth muscle cells. The biological effects of IL-4 and IL-13 are mediated by complex signaling mechanisms activated by receptor dimerization triggered by cytokine binding to the α-subunit of the IL-4 receptor (IL-4Rα). The fully human IgG4 monoclonal antibody dupilumab binds to IL-4Rα, thereby preventing its interactions with both IL-4 and IL-13. This mechanism of action makes it possible for dupilumab to effectively inhibit type 2 inflammation, thus significantly reducing the exacerbation of severe asthma, the consumption of oral corticosteroids (OCS) and the levels of fractional exhaled NO (FeNO). Dupilumab has been approved not only for the add-on therapy of severe asthma, but also for the biological treatment of atopic dermatitis and nasal polyposis.

Treatment of patients with atopic dermatitis and extremely high immunoglobulin E: world experience and own clinical observation

“…Полностью человеческое моноклональное антитело IgG4 дупилумаб связывается с ИЛ-4Rα, тем самым предотвращая его взаимодействие как с ИЛ-4, так и с ИЛ-13. Этот механизм действия позволяет дупилумабу эффективно ингибировать воспаление Th2-типа [14]. Клинические улучшения, вызванные дупилумабом, связаны с уменьшением дисрегуляции иммунных механизмов.…”

Airway remodelling in asthma and the epithelium: on the edge of a new era

“…Dupilumab binds to the IL-4 receptor α subunit found on lymphocytes, including B- and T-cells, as well as on epithelial cells, blocking both IL-4 and IL-13 signalling [ 155 ]. This may be expected to reduce mucus production, goblet cell hyperplasia, subepithelial fibrosis and collagen deposition [ 14 , 156 ]. In patients with severe asthma, dupilumab improved FEV 1 and other lung function measures both in RCTs [ 157 , 158 ] and a real-world study [ 159 ].…”

Dupilumab in Eosinophilic Esophagitis Refractory to Conventional Management in Pediatrics: Report of Two Cases

“…El dupilumab es un anticuerpo monoclonal humanizado inhibidor dual de la cadena alfa del receptor de IL-4 e IL-13, con impacto muy importante sobre la cascada inflamatoria T h 2 (9,10) . En un ensayo clínico en adolescentes y adultos con esofagitis eosinofílica se demostró la efectividad y seguridad en el tratamiento con dupilumab en dosis de carga de 600 mg, seguido por 300 mg por vía subcutánea (SC) semanal, que mejoró parámetros clínicos, endoscópicos e histológicos después de 12 semanas de tratamiento, comparado con placebo (11) ; en pacientes pediátricos menores de 12 años aún no hay estudios grandes sobre la seguridad y eficacia en esofagitis eosinofílica, pero es considerada una terapia prometedora por las bases fisiopatológicas (8,12) .…”