Dupilumab (REGN-668, SAR-231893) is a potent, fully human IgG4 monoclonal antibody specific for IL-4Rα. Dupilumab blocks interleukin-4 (IL-4) and interleukin-13 (IL-13)-mediated signaling by targeting the shared receptor subunit IL-4Rα[1].
Dupilumab can inhibit intracellular STAT6 signaling induced by IL-4 and IL-13, with IC50 of 9.9 ± 2.7 ng/mL and 9.7 ± 2.5 ng/mL, respectively. Dupilumab inhibits TF-1 cell proliferation induced by cytokines IL-4 or IL-13 in a concentration-dependent manner, with IC50 of 10.8 ± 1.1 and 12.0 ± 2.4 ng/mL, respectively. When primary human peripheral blood mononuclear cells (PBMCs) are stimulated with IL-4 or IL-13 in vitro, thymus and activation-regulated chemokines(TARC) is released into the culture supernatant, and Dupilumab can inhibit the release of TARC[2].
Dupilumab effectively protects mice from house dust mite (HDM)-induced airway hyperresponsiveness (AHR). Dupilumab effectively prevents allergen-induced lung function impairment by preventing pathogenic immune cell-induced lung inflammation and IL-13-driven mucus production (GCM)[1]. Subcutaneous administration of dupilumab (25 mg/kg) to humanized IL-4/IL-4RA (B-hIL4/hIL4RA) mice improved helper T cell (Th2)-driven allergic responses. Compared with hIgG4 isotype control, Dupilumab treatment almost completely abolished the increased number of immune cells (CD45+ hematopoietic cells and eosinophils) and ovalbumin-specific IgE concentrations in the blood, as well as eosinophil infiltration in the lung tissue[2].
References:
[1] Le Floc’h A, Allinne J, Nagashima K, et al. Dual blockade of IL‐4 and IL‐13 with dupilumab, an IL‐4Rα antibody, is required to broadly inhibit type 2 inflammation[J]. Allergy, 2020, 75(5): 1188-1204.
[2] Zhang L, Ding Y, Wang Q, et al. Preclinical immunological characterization of rademikibart (CBP-201), a next-generation human monoclonal antibody targeting IL-4Rα, for the treatment of Th2 inflammatory diseases[J]. Scientific Reports, 2023, 13(1): 12411.
Dupilumab（杜匹鲁单抗，REGN-668，SAR-231893）是一种对IL-4Rα具有特异性的强效全人源IgG4单克隆抗体。Dupilumab通过靶向共享受体亚基IL-4Rα阻断白细胞介素-4（IL-4）和白细胞介素-13（IL-13）介导的信号传导[1]。
Dupilumab可以抑制IL-4和IL-13诱导的细胞内STAT6信号传导，IC50分别为9.9 ± 2.7 ng/mL和9.7 ± 2.5 ng/mL。Dupilumab以浓度依赖性方式抑制细胞因子IL-4或IL-13诱导的TF-1细胞增殖，IC50分别为10.8±1.1和12.0±2.4 ng/mL。原代人外周血单核细胞（PBMCs）在体外用IL-4或IL-13刺激时，会将胸腺和激活调节趋化因子（TARC）释放到培养上清液中，Dupilumab能够抑制TARC的释放[2]。
Dupilumab有效地保护小鼠免受房尘螨（HDM）诱导的气道高反应性（AHR）。Dupilumab通过预防致病性免疫细胞诱导的肺部炎症以及IL-13驱动的粘液产生（GCM）有效防止过敏原诱导的肺功能损害[1]。人源化IL-4/IL-4RA（B-hIL4/hIL4RA）小鼠皮下给予Dupilumab（25 mg/kg），可以改善辅助型T细胞（Th2）驱动的过敏反应。与hIgG4同种型对照相比，Dupilumab处理几乎完全消除了血液中免疫细胞数量增加（CD45+造血细胞和嗜酸性粒细胞）和卵清蛋白特异性IgE浓度，以及肺组织中嗜酸性粒细胞浸润[2]。