Na Li, Nanxin Gong, Baoxin Duan, Yongyan Zhang, Yi Jian, Yanqin Xu, Jinming Liu, Xiaoqian Wang, Xiaoqi Zhang, Mingjuan Du, Feilong Zhou, Jiliang Zhao, Xiangchen Guan, Xiangda Peng, Sheng Wang, Hongkai Zhang, Xin Li
{"title":"一种具有增强 FcγRIIb 结合能力的 pH 敏感抗体可减少循环中的 IgE 和过敏原。","authors":"Na Li, Nanxin Gong, Baoxin Duan, Yongyan Zhang, Yi Jian, Yanqin Xu, Jinming Liu, Xiaoqian Wang, Xiaoqi Zhang, Mingjuan Du, Feilong Zhou, Jiliang Zhao, Xiangchen Guan, Xiangda Peng, Sheng Wang, Hongkai Zhang, Xin Li","doi":"10.1016/j.ymthe.2024.08.029","DOIUrl":null,"url":null,"abstract":"<p><p>Allergen-crosslinked IgE triggers allergy by interacting with its receptor on basophils and mast cells. The anti-IgE monoclonal antibody omalizumab can alleviate allergy by competing with the receptor for IgE binding. However, along with neutralization, omalizumab also inhibits IgE degradation, which is clinically associated with high dose and total IgE accumulation problems. In this study, we have developed an IgE-eliminating antibody on the basis of omalizumab, which has pH-dependent Fabs and an Fc with high affinity for FcγRIIb. In mice, the antibody rapidly eliminated total serum IgE to baseline levels and caused lower free IgE levels than omalizumab. At low dosages, the antibody also exhibited favorable IgE elimination effects. In addition, the antibody can degrade the corresponding allergen with the removal of IgE, addressing the allergy from its source. Introduction of the M252Y/S254T/T256E (YTE) mutation into this antibody prolongs its serum half-life without reducing potency. Thus, this engineered antibody holds a promising therapeutic option for allergy patients. Mechanistic insights are also included in this study.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":null,"pages":null},"PeriodicalIF":12.1000,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Reduction of circulating IgE and allergens by a pH-sensitive antibody with enhanced FcγRIIb binding.\",\"authors\":\"Na Li, Nanxin Gong, Baoxin Duan, Yongyan Zhang, Yi Jian, Yanqin Xu, Jinming Liu, Xiaoqian Wang, Xiaoqi Zhang, Mingjuan Du, Feilong Zhou, Jiliang Zhao, Xiangchen Guan, Xiangda Peng, Sheng Wang, Hongkai Zhang, Xin Li\",\"doi\":\"10.1016/j.ymthe.2024.08.029\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Allergen-crosslinked IgE triggers allergy by interacting with its receptor on basophils and mast cells. The anti-IgE monoclonal antibody omalizumab can alleviate allergy by competing with the receptor for IgE binding. However, along with neutralization, omalizumab also inhibits IgE degradation, which is clinically associated with high dose and total IgE accumulation problems. In this study, we have developed an IgE-eliminating antibody on the basis of omalizumab, which has pH-dependent Fabs and an Fc with high affinity for FcγRIIb. In mice, the antibody rapidly eliminated total serum IgE to baseline levels and caused lower free IgE levels than omalizumab. At low dosages, the antibody also exhibited favorable IgE elimination effects. In addition, the antibody can degrade the corresponding allergen with the removal of IgE, addressing the allergy from its source. Introduction of the M252Y/S254T/T256E (YTE) mutation into this antibody prolongs its serum half-life without reducing potency. Thus, this engineered antibody holds a promising therapeutic option for allergy patients. Mechanistic insights are also included in this study.</p>\",\"PeriodicalId\":19020,\"journal\":{\"name\":\"Molecular Therapy\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":12.1000,\"publicationDate\":\"2024-09-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Therapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.ymthe.2024.08.029\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOTECHNOLOGY & APPLIED MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ymthe.2024.08.029","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
Reduction of circulating IgE and allergens by a pH-sensitive antibody with enhanced FcγRIIb binding.
Allergen-crosslinked IgE triggers allergy by interacting with its receptor on basophils and mast cells. The anti-IgE monoclonal antibody omalizumab can alleviate allergy by competing with the receptor for IgE binding. However, along with neutralization, omalizumab also inhibits IgE degradation, which is clinically associated with high dose and total IgE accumulation problems. In this study, we have developed an IgE-eliminating antibody on the basis of omalizumab, which has pH-dependent Fabs and an Fc with high affinity for FcγRIIb. In mice, the antibody rapidly eliminated total serum IgE to baseline levels and caused lower free IgE levels than omalizumab. At low dosages, the antibody also exhibited favorable IgE elimination effects. In addition, the antibody can degrade the corresponding allergen with the removal of IgE, addressing the allergy from its source. Introduction of the M252Y/S254T/T256E (YTE) mutation into this antibody prolongs its serum half-life without reducing potency. Thus, this engineered antibody holds a promising therapeutic option for allergy patients. Mechanistic insights are also included in this study.
期刊介绍:
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.