Development of scoring functions for antibody sequence assessment and optimization.
Development of scoring functions for antibody sequence assessment and optimization.
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DOI：
10.1371/journal.pone.0076909
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Seeliger D
中科院分区：
文献类型：
--
作者：
Seeliger D
抗体开发仍然伴随着巨大的风险和困难，因为单个突变可以从根本上改变分子特性，如热力学稳定性、溶解度或粘度。由于抗体生成方法无法选择和优化对生物技术应用很重要的分子特性，因此需要仔细的序列分析和优化来开发满足未来药物雄心勃勃的要求的抗体。虽然从底层获取不需要的分子特性的物理原理的努力变得越来越有力，但大量公开可用的抗体序列提供了另一种方法来使用统计方法开发抗体的早期评估策略，这也是本文的目的。在这里，公开可用的序列被用来开发人类和鼠源抗体的重链和轻链框架区的启发潜力。这些势不仅考虑了单个氨基酸的位置依赖性概率，而且还考虑了序列评估和优化不可避免的条件概率。结果表明，源自人类序列的电位可以清楚地区分人类序列和小鼠序列，因此可以用作人性的衡量标准，将给定序列与人类序列的表型库进行比较，而不是将序列同一性与种系基因进行比较。沿着这条线，证明了，利用开发的潜力，抗体的人源化可以被描述为一个简单的数学优化问题，并且在预测的免疫原性方面，计算机生成的框架变体与天然序列非常相似。
Antibody development is still associated with substantial risks and difficulties as single mutations can radically change molecule properties like thermodynamic stability, solubility or viscosity. Since antibody generation methodologies cannot select and optimize for molecule properties which are important for biotechnological applications, careful sequence analysis and optimization is necessary to develop antibodies that fulfil the ambitious requirements of future drugs. While efforts to grab the physical principles of undesired molecule properties from the very bottom are becoming increasingly powerful, the wealth of publically available antibody sequences provides an alternative way to develop early assessment strategies for antibodies using a statistical approach which is the objective of this paper. Here, publically available sequences were used to develop heuristic potentials for the framework regions of heavy and light chains of antibodies of human and murine origin. The potentials take into account position dependent probabilities of individual amino acids but also conditional probabilities which are inevitable for sequence assessment and optimization. It is shown that the potentials derived from human sequences clearly distinguish between human sequences and sequences from mice and, hence, can be used as a measure of humaness which compares a given sequence with the phenotypic pool of human sequences instead of comparing sequence identities to germline genes. Following this line, it is demonstrated that, using the developed potentials, humanization of an antibody can be described as a simple mathematical optimization problem and that the in-silico generated framework variants closely resemble native sequences in terms of predicted immunogenicity.
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影响因子：
5.6
作者：
Guerois, R;Nielsen, JE;Serrano, L
通讯作者：
Serrano, L
影响因子：
5.6
作者：
Abhinandan, K. R.;Martin, Andrew C. R.
通讯作者：
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影响因子：
120.1
作者：
Nelson, Aaron L.;Dhimolea, Eugen;Reichert, Janice M.
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影响因子：
4.8
作者：
Fodor, AA;Aldrich, RW
通讯作者：
Aldrich, RW
DOI：
10.1073/pnas.1202866109
发表时间：
2012-07-03
影响因子：
11.1
作者：
Dudgeon, Kip;Rouet, Romain;Christ, Daniel
通讯作者：
Christ, Daniel