Analyzing the "Degree of humanness" of antibody sequences
Analyzing the "Degree of humanness" of antibody sequences
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DOI：
10.1016/j.jmb.2007.02.100
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发表时间：
2007-06-08
影响因子：
5.6
通讯作者：
Martin, Andrew C. R.
中科院分区：
文献类型：
--
作者：
Abhinandan, K. R.;Martin, Andrew C. R.
基因工程小鼠抗体现在普遍用于临床。然而，它们的发展是有限的，因为人类免疫系统倾向于将它们视为外来物，这会引发免疫反应。解决办法是使工程抗体看起来更像人类。在这里，我们提出了一种方法来评估抗体序列的“人性化程度”，提供了一种工具，可能有助于抗原性的预测。我们分析了人和小鼠中属于各种链/类别的抗体的序列。我们基于抗体序列之间的序列同一性百分比的度量分析显示了人和小鼠序列之间的明显差异。基于平均序列同一性和标准偏差，我们计算了从Kabat数据库提取的抗体序列的数据集的Z分数。我们将分析应用于一组人源化和嵌合抗体以及人种系序列。我们的结论是，这种方法可能有助于选择更合适的小鼠可变结构域的抗体工程，使他们更人性化，但在一般情况下，我们发现，典型的序列相比，表达的人类剧目是没有很好的相关性与抗原性。我们提供了一个Web服务器，允许为序列匕首分配人性。(c)2007爱思唯尔有限公司保留所有权利。
Genetically engineered mouse antibodies are now commonly in clinical use. However, their development is limited because the human immune system tends to regard them as foreign and this triggers an immune response. The solution is to make engineered antibodies appear more human. Here, we propose a method to assess the "degree of humanness" of antibody sequences providing a tool that may contribute to predictions of antigenicity. We analyzed sequences of antibodies belonging to various chains/classes in human and mouse. Our analysis of metrics based on percentage sequence identity between antibody sequences shows distinct differences between human and mouse sequences. Based on mean sequence identity and standard deviation, we calculated Z-scores for data sets of antibody sequences extracted from the Kabat database. We applied the analysis to a set of humanized and chimeric antibodies and to human germline sequences. We conclude that this approach may aid in the selection of more suitable mouse variable domains for antibody engineering to render them more human but in general, we find that typicality of a sequence compared with the expressed human repertoire is not well correlated with antigenicity. We have provided a Web server allowing humanness to be assigned for a sequence dagger. (c) 2007 Elsevier Ltd. All rights reserved.