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GB12 - 09,一种靶向白细胞介素4受体α(IL4Rα)和白细胞介素31受体α(IL31Rα)用于特应性皮炎治疗的双特异性抗体。

GB12-09, a bispecific antibody targeting IL4Rα and IL31Rα for atopic dermatitis therapy.

作者信息

Deng Feiyan, Qiu Yuxin, Zhang Xiangling, Guo Nining, Hu Junhong, Yang Wenjie, Shang Wei, Liu Bicheng, Qin Suofu

机构信息

Drug Discovery, Center for Research and Development, Kexing BioPharma Co., Ltd, Shenzhen 518057, China.

Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing 999077, China.

出版信息

Antib Ther. 2024 Jan 5;7(1):77-87. doi: 10.1093/abt/tbad032. eCollection 2024 Jan.

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin condition characterized by dysregulated immune responses. The key mediators of AD pathogenesis are T helper 2 (TH2) cells and TH2 cytokines. Targeting interleukin 4 (IL4), IL13 or IL31 has become a pivotal focus in both research and clinical treatments for AD. However, the need remains pressing for the development of a more effective and safer therapy, as the current approaches often yield low response rates and adverse effects. In response to this challenge, we have engineered a immunoglobulin G-single-chain fragment variable (scFv) format bispecific antibody (Ab) designed to concurrently target IL4R and IL31R. Our innovative design involved sequence optimization of VL-VH and the introduction of disulfide bond (VH44-VL100) within the IL31Rα Ab scFv region to stabilize the scFv structure. Our bispecific Ab efficiently inhibited the IL4/IL13/IL31 signaling pathways and reduced serum immunoglobulin E and IL31 levels . Consequently, this intervention led to improved inflammation profiles and notable amelioration of AD symptoms. This research highlighted a novel approach to AD therapy by employing bispecific Ab targeting IL4Rα and IL31Rα with potent efficacy.

摘要

特应性皮炎(AD)是一种慢性炎症性皮肤病,其特征为免疫反应失调。AD发病机制的关键介质是辅助性T细胞2(TH2)和TH2细胞因子。靶向白细胞介素4(IL4)、IL13或IL31已成为AD研究和临床治疗的关键焦点。然而,由于目前的方法往往有效率低且有不良反应,因此开发更有效、更安全的治疗方法的需求仍然紧迫。为应对这一挑战,我们构建了一种免疫球蛋白G-单链可变片段(scFv)形式的双特异性抗体(Ab),旨在同时靶向IL4R和IL31R。我们的创新设计包括VL-VH的序列优化以及在IL31Rα Ab scFv区域内引入二硫键(VH44-VL100)以稳定scFv结构。我们的双特异性抗体有效抑制了IL4/IL13/IL31信号通路,并降低了血清免疫球蛋白E和IL31水平。因此,这种干预改善了炎症状况,并显著减轻了AD症状。这项研究突出了一种通过使用靶向IL4Rα和IL31Rα且具有强大疗效的双特异性抗体来治疗AD的新方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22a7/10873276/13d9d764663b/tbad032f1.jpg

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