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首页> 外文期刊>Journal of Molecular Biology >Engineering fully human monoclonal antibodies from murine variable regions.
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Engineering fully human monoclonal antibodies from murine variable regions.

机译：从鼠类可变区工程化全人类单克隆抗体。

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摘要

Fully human monoclonal antibodies (mAbs) derived from transgenic mice or human antibody libraries are the current state of the art for reducing the immunogenicity risk of antibody drugs. Here, we describe a novel method for generating fully human mAbs from nonhuman variable regions using information from the human germline repertoire. Central to our strategy is the rational engineering of residues within and proximal to CDRs and the V(H)/V(L) interface by iteratively exploring substitutions to the closest human germline sequences using semi-automated computational methods. Starting from the parent murine variable regions of three currently marketed mAbs targeting CD25, vascular endothelial growth factor, and tumor necrosis factor alpha, we have generated fully human antibodies with 59, 46, and 45 substitutions, respectively, compared to the parent murine sequences. A large number of these substitutions were in the CDRs, which are typically avoided in humanization methods. Antigen affinities of the fully human variants were comparable to the chimeric mAbs in each case. Furthermore, in vitro functional characterization indicated that all retain potency of the chimeric mAbs and have comparable activity to their respective marketed drugs daclizumab, bevacizumab, and infliximab. Based on local and global sequence identity, the sequences of our engineered mAbs are indistinguishable from those of fully human mAbs isolated from transgenic mice or human antibody libraries. This work establishes a simple rational engineering methodology for generating fully human antibody therapeutics from murine mAbs produced from standard hybridoma technology.
机译：源自转基因小鼠或人类抗体文库的完全人类单克隆抗体（mAb）是降低抗体药物免疫原性风险的最新技术。在这里，我们描述了一种使用来自人类种系库的信息从非人类可变区生成完全人类mAb的新颖方法。我们策略的核心是通过使用半自动化计算方法迭代探索对最接近的人种系序列的取代，对CDR和V（H）/ V（L）接口内部和附近的残基进行合理的工程设计。从针对CD25，血管内皮生长因子和肿瘤坏死因子α的三种目前市售单克隆抗体的亲本鼠可变区开始，与亲本鼠序列相比，我们分别产生了59、46和45个取代的完全人源抗体。 CDR中存在大量此类取代，通常在人源化方法中避免使用。在每种情况下，完全人类变异体的抗原亲和力都可与嵌合mAb相媲美。此外，体外功能表征表明，它们均保留了嵌合mAb的效力，并具有与其各自市售药物daclizumab，bevacizumab和infliximab相当的活性。基于局部和全局序列同一性，我们工程改造的mAb的序列与从转基因小鼠或人类抗体文库中分离的完全人类mAb的序列没有区别。这项工作建立了一种简单的合理的工程学方法，可以从标准杂交瘤技术产生的鼠单克隆抗体中产生完整的人抗体治疗剂。

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