IN SILICO DESIGN OF HIGH-AFFINITY RECOMBINANT ANTIBODIES

高亲和力重组抗体的计算机模拟设计

• 批准号: 2342674
• 金额: --
• 依托单位: University of Strathclyde
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2342674
• 关键词: SILICO; DESIGN; AFFINITY; RECOMBINANT; ANTIBODIES

Currently there is a trend to move from small drug molecule therapy to use of biologics such as monoclonal antibodies (mAb). MAb therapy uses highly specific antibodies to bind to particular cells or proteins, in order to stimulate the immune system to destroy or neutralise those components that may be involved in disease progression. In a natural immune response, early antibodies bind with low affinity and are less specific about which antigen they bind to. As the immune response continues and there is long-term exposure to an antigen, the antibodies "mature", as a result of mutations in the binding regions of the antibodies. This leads to an increase or decrease in binding affinity. This provides a blueprint for the computational design of effective antibodies, with the advantage that we do not need to rely on purely random mutations but can be guided by our understanding of the interactions between biomolecules and antigens.In this project we will use a variety of biomolecular simulation techniques to study the binding process, and to design mutated structures to optimise the binding of the antibody to its antigen, whilst maintaining selectivity. The designed antibody structure will be produced recombinantly and tested experimentally, and if successful our strategy will yield new technology of immense impact. The industrial partner for this project will be able to utilise the technology in their portfolio of antibodies.

目前，存在从小药物分子治疗转向使用生物制剂如单克隆抗体（mAb）的趋势。单克隆抗体疗法使用高度特异性的抗体与特定的细胞或蛋白质结合，以刺激免疫系统破坏或中和那些可能参与疾病进展的成分。在自然免疫应答中，早期抗体以低亲和力结合，并且对它们结合的抗原的特异性较低。随着免疫应答的持续并且长期暴露于抗原，由于抗体结合区的突变，抗体“成熟”。这导致结合亲和力的增加或减少。这为有效抗体的计算设计提供了蓝图，其优点是我们不需要依赖纯粹的随机突变，而是可以通过我们对生物分子和抗原之间相互作用的理解来指导。在这个项目中，我们将使用各种生物分子模拟技术来研究结合过程，并设计突变结构以优化抗体与其抗原的结合，同时保持选择性。设计的抗体结构将通过重组产生并进行实验测试，如果成功，我们的策略将产生具有巨大影响的新技术。该项目的工业合作伙伴将能够在其抗体组合中利用该技术。