对 40 亿个人类抗体可变区的大规模数据挖掘揭示了治疗性抗体与天然抗体之间的趋同性,这限制了生物制剂药物发现的搜索空间。

IF 5.6 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
mAbs Pub Date : 2024-01-01 Epub Date: 2024-06-06 DOI:10.1080/19420862.2024.2361928
Pawel Dudzic, Dawid Chomicz, Jarosław Kończak, Tadeusz Satława, Bartosz Janusz, Sonia Wrobel, Tomasz Gawłowski, Igor Jaszczyszyn, Weronika Bielska, Samuel Demharter, Roberto Spreafico, Lukas Schulte, Kyle Martin, Stephen R Comeau, Konrad Krawczyk
{"title":"对 40 亿个人类抗体可变区的大规模数据挖掘揭示了治疗性抗体与天然抗体之间的趋同性,这限制了生物制剂药物发现的搜索空间。","authors":"Pawel Dudzic, Dawid Chomicz, Jarosław Kończak, Tadeusz Satława, Bartosz Janusz, Sonia Wrobel, Tomasz Gawłowski, Igor Jaszczyszyn, Weronika Bielska, Samuel Demharter, Roberto Spreafico, Lukas Schulte, Kyle Martin, Stephen R Comeau, Konrad Krawczyk","doi":"10.1080/19420862.2024.2361928","DOIUrl":null,"url":null,"abstract":"<p><p>The naïve human antibody repertoire has theoretical access to an estimated > 10<sup>15</sup> antibodies. Identifying subsets of this prohibitively large space where therapeutically relevant antibodies may be found is useful for development of these agents. It was previously demonstrated that, despite the immense sequence space, different individuals can produce the same antibodies. It was also shown that therapeutic antibodies, which typically follow seemingly unnatural development processes, can arise independently naturally. To check for biases in how the sequence space is explored, we data mined public repositories to identify 220 bioprojects with a combined seven billion reads. Of these, we created a subset of human bioprojects that we make available as the AbNGS database (https://naturalantibody.com/ngs/). AbNGS contains 135 bioprojects with four billion productive human heavy variable region sequences and 385 million unique complementarity-determining region (CDR)-H3s. We find that 270,000 (0.07% of 385 million) unique CDR-H3s are highly public in that they occur in at least five of 135 bioprojects. Of 700 unique therapeutic CDR-H3, a total of 6% has direct matches in the small set of 270,000. This observation extends to a match between CDR-H3 and V-gene call as well. Thus, the subspace of shared ('public') CDR-H3s shows utility for serving as a starting point for therapeutic antibody design.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2361928"},"PeriodicalIF":5.6000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11164219/pdf/","citationCount":"0","resultStr":"{\"title\":\"Large-scale data mining of four billion human antibody variable regions reveals convergence between therapeutic and natural antibodies that constrains search space for biologics drug discovery.\",\"authors\":\"Pawel Dudzic, Dawid Chomicz, Jarosław Kończak, Tadeusz Satława, Bartosz Janusz, Sonia Wrobel, Tomasz Gawłowski, Igor Jaszczyszyn, Weronika Bielska, Samuel Demharter, Roberto Spreafico, Lukas Schulte, Kyle Martin, Stephen R Comeau, Konrad Krawczyk\",\"doi\":\"10.1080/19420862.2024.2361928\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The naïve human antibody repertoire has theoretical access to an estimated > 10<sup>15</sup> antibodies. Identifying subsets of this prohibitively large space where therapeutically relevant antibodies may be found is useful for development of these agents. It was previously demonstrated that, despite the immense sequence space, different individuals can produce the same antibodies. It was also shown that therapeutic antibodies, which typically follow seemingly unnatural development processes, can arise independently naturally. To check for biases in how the sequence space is explored, we data mined public repositories to identify 220 bioprojects with a combined seven billion reads. Of these, we created a subset of human bioprojects that we make available as the AbNGS database (https://naturalantibody.com/ngs/). AbNGS contains 135 bioprojects with four billion productive human heavy variable region sequences and 385 million unique complementarity-determining region (CDR)-H3s. We find that 270,000 (0.07% of 385 million) unique CDR-H3s are highly public in that they occur in at least five of 135 bioprojects. Of 700 unique therapeutic CDR-H3, a total of 6% has direct matches in the small set of 270,000. This observation extends to a match between CDR-H3 and V-gene call as well. Thus, the subspace of shared ('public') CDR-H3s shows utility for serving as a starting point for therapeutic antibody design.</p>\",\"PeriodicalId\":18206,\"journal\":{\"name\":\"mAbs\",\"volume\":\"16 1\",\"pages\":\"2361928\"},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2024-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11164219/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"mAbs\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/19420862.2024.2361928\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/6/6 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"mAbs","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/19420862.2024.2361928","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/6/6 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0

摘要

从理论上讲,人类原始抗体库中可利用的抗体估计超过 1015 种。从这一令人望而却步的巨大空间中找出可能存在治疗相关抗体的子集,对这些制剂的开发非常有用。以前的研究表明,尽管存在巨大的序列空间,但不同的个体可以产生相同的抗体。研究还表明,治疗性抗体通常遵循看似不自然的发展过程,但也可以独立自然地产生。为了检查探索序列空间的方式是否存在偏差,我们对公共资料库进行了数据挖掘,确定了 220 个生物项目,总计 70 亿个读数。其中,我们创建了一个人类生物项目子集,并将其作为 AbNGS 数据库(https://naturalantibody.com/ngs/)提供。AbNGS 包含 135 个生物项目,其中有 40 亿个有结果的人类重变区序列和 3.85 亿个独特的互补决定区 (CDR) -H3。我们发现,有 27 万个(占 3.85 亿个的 0.07%)独特 CDR-H3 高度公开,因为它们至少出现在 135 个生物项目中的 5 个中。在 700 个独特的治疗 CDR-H3 中,共有 6% 在 27 万个小集合中直接匹配。这一观察结果也延伸到了 CDR-H3 与 V 基因调用之间的匹配。因此,共享("公共")CDR-H3 子空间可作为治疗性抗体设计的起点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Large-scale data mining of four billion human antibody variable regions reveals convergence between therapeutic and natural antibodies that constrains search space for biologics drug discovery.

The naïve human antibody repertoire has theoretical access to an estimated > 1015 antibodies. Identifying subsets of this prohibitively large space where therapeutically relevant antibodies may be found is useful for development of these agents. It was previously demonstrated that, despite the immense sequence space, different individuals can produce the same antibodies. It was also shown that therapeutic antibodies, which typically follow seemingly unnatural development processes, can arise independently naturally. To check for biases in how the sequence space is explored, we data mined public repositories to identify 220 bioprojects with a combined seven billion reads. Of these, we created a subset of human bioprojects that we make available as the AbNGS database (https://naturalantibody.com/ngs/). AbNGS contains 135 bioprojects with four billion productive human heavy variable region sequences and 385 million unique complementarity-determining region (CDR)-H3s. We find that 270,000 (0.07% of 385 million) unique CDR-H3s are highly public in that they occur in at least five of 135 bioprojects. Of 700 unique therapeutic CDR-H3, a total of 6% has direct matches in the small set of 270,000. This observation extends to a match between CDR-H3 and V-gene call as well. Thus, the subspace of shared ('public') CDR-H3s shows utility for serving as a starting point for therapeutic antibody design.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
mAbs
mAbs 工程技术-仪器仪表
CiteScore
10.70
自引率
11.30%
发文量
77
审稿时长
6-12 weeks
期刊介绍: mAbs is a multi-disciplinary journal dedicated to the art and science of antibody research and development. The journal has a strong scientific and medical focus, but also strives to serve a broader readership. The articles are thus of interest to scientists, clinical researchers, and physicians, as well as the wider mAb community, including our readers involved in technology transfer, legal issues, investment, strategic planning and the regulation of therapeutics.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信