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针对治疗性抗体筛选的半合成 vNAR 文库主要提供抗独特型结合物。

Semi-synthetic vNAR libraries screened against therapeutic antibodies primarily deliver anti-idiotypic binders.

机构信息

Institute for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Alarich-Weiss-Strasse 4, D-64287, Darmstadt, Germany.

Merck Lab @ Technische Universität Darmstadt, Alarich-Weiss-Strasse 8, D64287, Darmstadt, Germany.

出版信息

Sci Rep. 2017 Aug 29;7(1):9676. doi: 10.1038/s41598-017-10513-9.

DOI:10.1038/s41598-017-10513-9
PMID:28852148
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5575089/
Abstract

Anti-idiotypic binders which specifically recognize the variable region of monoclonal antibodies have proven to be robust tools for pharmacokinetic studies of antibody therapeutics and for the development of cancer vaccines. In the present investigation, we focused on the identification of anti-idiotypic, shark-derived IgNAR antibody variable domains (vNARs) targeting the therapeutic antibodies matuzumab and cetuximab for the purpose of developing specific capturing ligands. Using yeast surface display and semi-synthetic, CDR3-randomized libraries, we identified several highly specific binders targeting both therapeutic antibodies in their corresponding variable region, without applying any counter selections during screening. Importantly, anti-idiotypic vNAR binders were not cross-reactive towards cetuximab or matuzumab, respectively, and comprised good target recognition in the presence of human and mouse serum. When coupled to magnetic beads, anti-idiotypic vNAR variants could be used as efficient capturing tools. Moreover, a two-step procedure involving vNAR-functionalized beads was employed for the enrichment of potentially bispecific cetuximab × matuzumab antibody constructs. In conclusion, semi-synthetic and CDR3-randomized vNAR libraries in combination with yeast display enable the fast and facile identification of anti-idiotypic vNAR domains targeting monoclonal antibodies primarily in an anti-idiotypic manner.

摘要

抗独特型结合物特异性识别单克隆抗体的可变区，已被证明是研究抗体治疗药药代动力学和开发癌症疫苗的有力工具。在本研究中，我们专注于鉴定抗独特型鲨鱼来源的 IgNAR 抗体可变区（vNAR），以针对治疗性抗体马妥珠单抗和西妥昔单抗开发特异性的捕获配体。我们使用酵母表面展示和半合成、CDR3 随机化文库，在筛选过程中不进行任何反筛选的情况下，在相应的可变区中针对这两种治疗性抗体鉴定出了几个具有高特异性的结合物。重要的是，抗独特型 vNAR 结合物分别与西妥昔单抗或马妥珠单抗没有交叉反应性，并且在存在人血清和鼠血清的情况下仍具有良好的靶标识别能力。当与磁珠偶联时，抗独特型 vNAR 变体可作为有效的捕获工具。此外，还采用两步法，涉及 vNAR 功能化的珠子，用于富集潜在的双特异性西妥昔单抗×马妥珠单抗抗体构建体。总之，半合成和 CDR3 随机化 vNAR 文库与酵母展示相结合，可快速简便地鉴定出主要以抗独特型方式针对单克隆抗体的抗独特型 vNAR 结构域。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/af27/5575089/ebb5bf8c6b53/41598_2017_10513_Fig7_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/af27/5575089/ebb5bf8c6b53/41598_2017_10513_Fig7_HTML.jpg
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