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首页> 外文期刊>Journal of Molecular Biology >Structure-Guided Combinatorial Engineering Facilitates Affinity and Specificity Optimization of Anti-CD81 Antibodies
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Structure-Guided Combinatorial Engineering Facilitates Affinity and Specificity Optimization of Anti-CD81 Antibodies

机译：结构引导的组合工程有助于抗CD81抗体的亲和力和特异性优化

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摘要

Hepatitis C viral infection is the major cause of chronic hepatitis that affects as many as 71 million people worldwide. Rather than target the rapidly shifting viruses and their numerous serotypes, four independent antibodies were made to target the host antigen CD81 and were shown to block hepatitis C viral entry. The single-chain variable fragment of each antibody was crystallized in complex with the CD81 large extracellular loop in order to guide affinity maturation of two distinct antibodies by phage display. Affinity maturation of antibodies using phage display has proven to be critical to therapeutic antibody development and typically involves modification of the paratope for increased affinity, improved specificity, enhanced stability or a combination of these traits. One antibody was engineered for increased affinity for human CD81 large extracellular loop that equated to increased efficacy, while the second antibody was engineered for cross-reactivity with cynomolgus CD81 to facilitate animal model testing. The use of structures to guide affinity maturation library design demonstrates the utility of combining structural analysis with phage display technologies. (C) 2018 Elsevier Ltd. All rights reserved.
机译：丙型肝炎病毒感染是慢性肝炎的主要原因，影响全世界的7100万人。而不是靶向快速移位的病毒及其许多血清型，也使四种独立抗体靶向宿主抗原CD81，并显示为阻断丙型肝炎病毒进入。每种抗体的单链可变片段与CD81大细胞外环结晶，以通过噬菌体显示器引导两个不同抗体的亲和力成熟。使用噬菌体展示的抗体的亲和力成熟已被证明对治疗性抗体发育至关重要，并且通常涉及修饰占状完善，改善的特异性，增强稳定性或这些性状的组合的分析。设计了一种抗体，用于对人CD81大细胞外环的亲和力增加，所述疗效等同于疗效增加，而第二抗体被设计用于与Cynomolgus CD81的交叉反应性以促进动物模型测试。使用结构引导亲和力成熟库设计演示了与噬菌体展示技术相结合的结构分析的效用。 （c）2018年elestvier有限公司保留所有权利。

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  • 来源
    《Journal of Molecular Biology》 |2018年第14期|共14页
  • 作者

    Nelson Bryce; Adams Jarrett; Kuglstatter Andreas; Li Zhijian; Harris Seth F.; Liu Yang; Bohini Sandya; Ma Han; Klumpp Klaus; Gao Junjun; Sidhu Sachdev S.;

  • 作者单位

    Univ Toronto Banting &

    Best Dept Med Res Donnelly Ctr Cellular &

    Biomol Res 160 Coll St Toronto;

    Univ Toronto Banting &

    Best Dept Med Res Donnelly Ctr Cellular &

    Biomol Res 160 Coll St Toronto;

    Hoffmann La Roche Inc Palo Alto CA 94304 USA;

    Univ Toronto Banting &

    Best Dept Med Res Donnelly Ctr Cellular &

    Biomol Res 160 Coll St Toronto;

    Hoffmann La Roche Inc Palo Alto CA 94304 USA;

    Hoffmann La Roche Inc Palo Alto CA 94304 USA;

    Hoffmann La Roche Inc Palo Alto CA 94304 USA;

    Hoffmann La Roche Inc Palo Alto CA 94304 USA;

    Hoffmann La Roche Inc Palo Alto CA 94304 USA;

    Hoffmann La Roche Inc Palo Alto CA 94304 USA;

    Univ Toronto Banting &

    Best Dept Med Res Donnelly Ctr Cellular &

    Biomol Res 160 Coll St Toronto;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子生物学;
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