Selective activation of pro-anti-IL-1β antibody enhances specificity for autoinflammatory disorder therapy

Abstract Canakinumab is a fully human monoclonal antibody that specifically neutralizes human interleukin (IL)-1β and has been approved by the US Food and Drug Administration for treating different types of autoinflammatory disorders such as cryopyrin-associated periodic syndrome, tumor necrosis fac...

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Autores principales:	Wen-Wei Lin, Yun-Chi Lu, Bo-Cheng Huang, Chih-Hung Chuang, Yi-An Cheng, I.-Ju Chen, Hui-Ju Liu, Kai-Wen Ho, Tzu-Yi Liao, En-Shuo Liu, Ting-Yi Wu, Long-Sen Chang, Shih-Ting Hong, Tian-Lu Cheng
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cbc2120056d34be588820d88d63a8a3e
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spelling	oai:doaj.org-article:cbc2120056d34be588820d88d63a8a3e2021-12-02T17:55:13ZSelective activation of pro-anti-IL-1β antibody enhances specificity for autoinflammatory disorder therapy10.1038/s41598-021-94298-y2045-2322https://doaj.org/article/cbc2120056d34be588820d88d63a8a3e2021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-94298-yhttps://doaj.org/toc/2045-2322Abstract Canakinumab is a fully human monoclonal antibody that specifically neutralizes human interleukin (IL)-1β and has been approved by the US Food and Drug Administration for treating different types of autoinflammatory disorders such as cryopyrin-associated periodic syndrome, tumor necrosis factor receptor-associated periodic syndrome and systemic juvenile idiopathic arthritis. However, long-term systemic neutralization of IL-1β by Canakinumab may cause severe adverse events such as serious upper respiratory tract infections and inflammation, thereby decreasing the quality of life of patients. Here, we used an IgG1 hinge as an Ab lock to cover the IL-1β-binding site of Canakinumab by linking with matrix metalloprotease 9 (MMP-9) substrate to generate pro-Canakinumab that can be specifically activated in the inflamed regions in autoinflammatory diseases to enhance the selectivity and safety of treatment. The Ab lock significantly inhibited the IL-1β-binding by 68-fold compared with Canakinumab, and MMP-9 completely restored the IL-1β neutralizing ability of pro-Canakinumab within 60 min and blocked IL-1β-downstream signaling and IL-1β-regulated genes (i.e., IL-6). It is expected that MMP-9 cleavable and efficient Ab lock will be able to significantly enhance the selective reaction of Canakinumab at the disease site and reduce the on-target toxicities of Canakinumab during systemic circulation, thereby showing potential for development to improve the safety and quality of life of patients with autoinflammatory disorders in the future.Wen-Wei LinYun-Chi LuBo-Cheng HuangChih-Hung ChuangYi-An ChengI.-Ju ChenHui-Ju LiuKai-Wen HoTzu-Yi LiaoEn-Shuo LiuTing-Yi WuLong-Sen ChangShih-Ting HongTian-Lu ChengNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Wen-Wei Lin Yun-Chi Lu Bo-Cheng Huang Chih-Hung Chuang Yi-An Cheng I.-Ju Chen Hui-Ju Liu Kai-Wen Ho Tzu-Yi Liao En-Shuo Liu Ting-Yi Wu Long-Sen Chang Shih-Ting Hong Tian-Lu Cheng Selective activation of pro-anti-IL-1β antibody enhances specificity for autoinflammatory disorder therapy
description	Abstract Canakinumab is a fully human monoclonal antibody that specifically neutralizes human interleukin (IL)-1β and has been approved by the US Food and Drug Administration for treating different types of autoinflammatory disorders such as cryopyrin-associated periodic syndrome, tumor necrosis factor receptor-associated periodic syndrome and systemic juvenile idiopathic arthritis. However, long-term systemic neutralization of IL-1β by Canakinumab may cause severe adverse events such as serious upper respiratory tract infections and inflammation, thereby decreasing the quality of life of patients. Here, we used an IgG1 hinge as an Ab lock to cover the IL-1β-binding site of Canakinumab by linking with matrix metalloprotease 9 (MMP-9) substrate to generate pro-Canakinumab that can be specifically activated in the inflamed regions in autoinflammatory diseases to enhance the selectivity and safety of treatment. The Ab lock significantly inhibited the IL-1β-binding by 68-fold compared with Canakinumab, and MMP-9 completely restored the IL-1β neutralizing ability of pro-Canakinumab within 60 min and blocked IL-1β-downstream signaling and IL-1β-regulated genes (i.e., IL-6). It is expected that MMP-9 cleavable and efficient Ab lock will be able to significantly enhance the selective reaction of Canakinumab at the disease site and reduce the on-target toxicities of Canakinumab during systemic circulation, thereby showing potential for development to improve the safety and quality of life of patients with autoinflammatory disorders in the future.
format	article
author	Wen-Wei Lin Yun-Chi Lu Bo-Cheng Huang Chih-Hung Chuang Yi-An Cheng I.-Ju Chen Hui-Ju Liu Kai-Wen Ho Tzu-Yi Liao En-Shuo Liu Ting-Yi Wu Long-Sen Chang Shih-Ting Hong Tian-Lu Cheng
author_facet	Wen-Wei Lin Yun-Chi Lu Bo-Cheng Huang Chih-Hung Chuang Yi-An Cheng I.-Ju Chen Hui-Ju Liu Kai-Wen Ho Tzu-Yi Liao En-Shuo Liu Ting-Yi Wu Long-Sen Chang Shih-Ting Hong Tian-Lu Cheng
author_sort	Wen-Wei Lin
title	Selective activation of pro-anti-IL-1β antibody enhances specificity for autoinflammatory disorder therapy
title_short	Selective activation of pro-anti-IL-1β antibody enhances specificity for autoinflammatory disorder therapy
title_full	Selective activation of pro-anti-IL-1β antibody enhances specificity for autoinflammatory disorder therapy
title_fullStr	Selective activation of pro-anti-IL-1β antibody enhances specificity for autoinflammatory disorder therapy
title_full_unstemmed	Selective activation of pro-anti-IL-1β antibody enhances specificity for autoinflammatory disorder therapy
title_sort	selective activation of pro-anti-il-1β antibody enhances specificity for autoinflammatory disorder therapy
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/cbc2120056d34be588820d88d63a8a3e
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Selective activation of pro-anti-IL-1β antibody enhances specificity for autoinflammatory disorder therapy

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