Synthetic integrin antibodies discovered by yeast display reveal αV subunit pairing preferences with β subunits.

IF 5.6 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
mAbs Pub Date : 2024-01-01 Epub Date: 2024-06-18 DOI:10.1080/19420862.2024.2365891
Yuxin Hao, Jiabin Yan, Courtney Fraser, Aiping Jiang, Murali Anuganti, Roushu Zhang, Kenneth Lloyd, Joseph Jardine, Jessica Coppola, Rob Meijers, Jing Li, Timothy A Springer
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引用次数: 0

Abstract

Integrins are cell surface receptors that mediate the interactions of cells with their surroundings and play essential roles in cell adhesion, migration, and homeostasis. Eight of the 24 integrins bind to the tripeptide Arg-Gly-Asp (RGD) motif in their extracellular ligands, comprising the RGD-binding integrin subfamily. Despite similarity in recognizing the RGD motif and some redundancy, these integrins can selectively recognize RGD-containing ligands to fulfill specific functions in cellular processes. Antibodies against individual RGD-binding integrins are desirable for investigating their specific functions, and were selected here from a synthetic yeast-displayed Fab library. We discovered 11 antibodies that exhibit high specificity and affinity toward their target integrins, i.e. αVβ3, αVβ5, αVβ6, αVβ8, and α5β1. Of these, six are function-blocking antibodies and contain a ligand-mimetic R(G/L/T)D motif in their CDR3 sequences. We report antibody-binding specificity, kinetics, and binding affinity for purified integrin ectodomains, as well as intact integrins on the cell surface. We further used these antibodies to reveal binding preferences of the αV subunit for its 5 β-subunit partners: β6 = β8 > β3 > β1 = β5.

通过酵母展示发现的合成整合素抗体揭示了 αV 亚基与 β 亚基配对的偏好。
整合素是介导细胞与其周围环境相互作用的细胞表面受体,在细胞粘附、迁移和稳态中发挥着重要作用。24 种整合素中有 8 种与细胞外配体中的三肽 Arg-Gly-Asp (RGD)基团结合,组成了 RGD 结合整合素亚家族。尽管这些整合素在识别 RGD 基序方面具有相似性和一定的冗余性,但它们可以选择性地识别含 RGD 的配体,从而在细胞过程中发挥特定的功能。针对单个 RGD 结合整合素的抗体是研究其特定功能的理想选择,我们从合成的酵母展示 Fab 库中筛选出了这些抗体。我们发现了 11 种对其目标整合素(即 αVβ3、αVβ5、αVβ6、αVβ8 和 α5β1)具有高特异性和亲和力的抗体。其中,六种是功能阻断型抗体,它们的 CDR3 序列中含有配体拟态 R(G/L/T)D 矩阵。我们报告了抗体结合的特异性、动力学以及与纯化的整合素外显子和细胞表面完整整合素的结合亲和力。我们进一步使用这些抗体揭示了αV亚基与其5个β亚基伙伴的结合偏好:β6 = β8 > β3 > β1 = β5。
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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