泛 HLA-DR mAb 44H10 的人源化取决于抗体框架中的关键残基

IF 3 Q3 IMMUNOLOGY
Antibodies Pub Date : 2024-07-16 DOI:10.3390/antib13030057
Audrey Kassardjian, Danton Ivanochko, Brian Barber, Arif Jetha, Jean-Philippe Julien
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引用次数: 0

摘要

降低动物源性单克隆抗体(mAbs)用于人体的免疫原性,对于最大限度地提高治疗效果和避免潜在的不良反应至关重要。传统的人源化方法主要是将抗体互补决定区(CDR)嫁接到同源的人类抗体支架上,但框架区也能在抗原结合中发挥重要作用。在这里,我们描述了泛 HLA-DR mAb 44H10 的人源化过程,这是一种框架区在抗原结合中发挥重要作用的鼠类抗体。我们采用一种结构引导的方法,识别并还原了直接与抗原相互作用或通过塑造抗体旁位间接调节抗原结合的框架残基,并设计出了一种在亲和力、生物物理特征和分子结合基础方面与亲代 44H10 mAb 相当的人源化抗体。作为人源化分子,该抗体有望成为开发 MHC II 类靶向疗法和疫苗的支架。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Humanization of Pan-HLA-DR mAb 44H10 Hinges on Critical Residues in the Antibody Framework
Reducing the immunogenicity of animal-derived monoclonal antibodies (mAbs) for use in humans is critical to maximize therapeutic effectiveness and preclude potential adverse events. While traditional humanization methods have primarily focused on grafting antibody Complementarity-Determining Regions (CDRs) on homologous human antibody scaffolds, framework regions can also play essential roles in antigen binding. Here, we describe the humanization of the pan-HLA-DR mAb 44H10, a murine antibody displaying significant involvement of the framework region in antigen binding. Using a structure-guided approach, we identify and restore framework residues that directly interact with the antigen or indirectly modulate antigen binding by shaping the antibody paratope and engineer a humanized antibody with affinity, biophysical profile, and molecular binding basis comparable to that of the parental 44H10 mAb. As a humanized molecule, this antibody holds promise as a scaffold for the development of MHC class II-targeting therapeutics and vaccines.
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来源期刊
Antibodies
Antibodies IMMUNOLOGY-
CiteScore
7.10
自引率
6.40%
发文量
68
审稿时长
11 weeks
期刊介绍: Antibodies (ISSN 2073-4468), an international, peer-reviewed open access journal which provides an advanced forum for studies related to antibodies and antigens. It publishes reviews, research articles, communications and short notes. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. Full experimental and/or methodical details must be provided. Electronic files or software regarding the full details of the calculation and experimental procedure - if unable to be published in a normal way - can be deposited as supplementary material. This journal covers all topics related to antibodies and antigens, topics of interest include (but are not limited to): antibody-producing cells (including B cells), antibody structure and function, antibody-antigen interactions, Fc receptors, antibody manufacturing antibody engineering, antibody therapy, immunoassays, antibody diagnosis, tissue antigens, exogenous antigens, endogenous antigens, autoantigens, monoclonal antibodies, natural antibodies, humoral immune responses, immunoregulatory molecules.
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