Human-likeness of antibody biologics determined by back-translation and comparison with large antibody variable gene repertoires.
Human-likeness of antibody biologics determined by back-translation and comparison with large antibody variable gene repertoires.
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通过反翻译和与大抗体可变基因曲目进行比较确定的抗体生物制剂的人类风格。
DOI：
10.1080/19420862.2020.1758291
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发表时间：
2020-01
期刊：
影响因子：
5.3
通讯作者：
Meiler J
中科院分区：
文献类型：
--
作者：
Schmitz S;Soto C;Crowe JE Jr;Meiler J
抗体 (Ab) 种系基因对可变 (V)、多样性 (D) 和连接 (J) 基因片段的重排以及体细胞超突变产生了人 Ab 可变基因序列库。通常通过与物种特异性野生型种系基因比对来表征可变区的单核苷酸频率。下一代测序在免疫组库研究中的应用越来越多，导致了越来越多的大型适应性免疫组受体组库数据集的编制。我们开发了一种方法，可将目标抗体的序列映射到包含 3.26 亿条人类抗体序列的免疫组数据集上。为此，我们创建了位置和基因特异性评分矩阵 (PGSSM) 及其相应的抗体相似性评分。我们对 PGSSM 评分进行了表征，发现它与 GenBank 中 20 个物种的 181,355 个 Ab 序列的系统发育距离密切相关。仅在PGSSM和Ab的氨基酸序列的情况下，就获得了最有可能的人类核苷酸回译，人类重链和轻链的核苷酸序列回收率分别为95.9%和97.2%。总之，我们的反向翻译评分是对 Ab 序列与自然人类序列相似性的有价值的估计。正如预期的那样，从人类来源开发的抗体治疗分子与工程抗体相比表现出更高的相似性。因此，这里介绍的 PGSSM 指标可用于设计类人抗体疗法。
The antibody (Ab) germline gene rearrangement of variable (V), diversity (D), and joining (J) gene segments, as well as somatic hypermutation, give rise to the human Ab variable gene sequence repertoire. It is common to characterize single nucleotide frequencies of the variable region by alignment to species-specific wildtype germline genes. The increasing application of next-generation sequencing to immune repertoire studies has led to the compilation of increasing large adaptive immunome receptor repertoire datasets. We have developed a method that maps the sequence of a target Ab onto an immunome dataset of 326 million human Ab sequences. For this purpose, we created a position- and gene-specific scoring matrix (PGSSM) and its corresponding antibody similarity score. We characterized our PGSSM score and found that it strongly correlated with the phylogenetic distance of 181,355 Ab sequences from GenBank across 20 species. The most likely human nucleotide back-translation was obtained given only PGSSMs and the amino acid sequence of an Ab achieving a nucleotide sequence recovery of 95.9% and 97.2% for human heavy and light chains, respectively. In conclusion, the scoring of our back-translation is a valuable estimate for the similarity of an Ab sequence to the natural human repertoire. As expected, Ab therapeutic molecules developed from a human source showed a higher similarity to the repertoire than engineered Abs. Thus, the PGSSM metric introduced here can be used to engineer human-like Ab therapeutics.
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影响因子：
8.7
作者：
Corrie BD;Marthandan N;Zimonja B;Jaglale J;Zhou Y;Barr E;Knoetze N;Breden FMW;Christley S;Scott JK;Cowell LG;Breden F
通讯作者：
Breden F
影响因子：
4.3
作者：
Adolf-Bryfogle, Jared;Kalyuzhniy, Oleks;Dunbrack, Roland L., Jr.
通讯作者：
Dunbrack, Roland L., Jr.
影响因子：
5.6
作者：
Abhinandan, K. R.;Martin, Andrew C. R.
通讯作者：
Martin, Andrew C. R.
影响因子：
3.5
作者：
Gao, Sean H.;Huang, Kexin;Adler, Adam S.
通讯作者：
Adler, Adam S.
影响因子：
4.4
作者：
Kovaltsuk, Aleksandr;Leem, Jinwoo;Krawczyk, Konrad
通讯作者：
Krawczyk, Konrad