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.

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
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Abstract

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.

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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。
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。
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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.
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