权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

An integrated cell and protein engineering approach to generate enhanced CHO cell platforms for manufacture of difficult to express biopharmaceuticals

一种集成的细胞和蛋白质工程方法，用于生成增强的 CHO 细胞平台，用于制造难以表达的生物制药

基本信息

批准号：
BB/R001731/1
负责人：
Christopher Smales
金额：
$ 43.65万
依托单位：
University of Kent
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FR001731%2F1
关键词：
integrated cell protein engineering approach

项目摘要

Recombinant biotherapeutics are medicines for diagnosis and treatment of disease. Those of interest in this project are proteins that are built (by cells acting as programmed factories) from knowledge of the body's own macromolecules and are redesigned for the treatment of specific diseases. For example, versions of insulin (for treatment of diabetes) have been designed that have given diabetics much greater control of their health. Other natural molecules (antibodies) are being synthesized to treat cancer and autoimmune diseases. The ability to make biotherapeutics has been driven by industry with the potential for life-changing treatments balanced against the commercial costs of production. A new generation of biotherapeutics (with the potential to treat an increased range of diseases with much greater effectiveness than the existing biotherapeutics) are in development. The new generation is being designed by taking bits of natural molecules and building novel molecules (in modular structures) for production in cell factories. This is what is called synthetic biology, the engineering of new genetic materials for valuable functions. Whilst this has incredible promise and potential, the ability to produce novel biotherapeutics is far from optimal (due to the manner in which the cell factories handle such unnatural products). To harvest the full potential of these novel medicines, there is a need to more fully understand the processes that take place in the cell factory and, with knowledge of those processes, to enhance their production. This project aims to address the fundamentals that will determine the effectiveness of production of novel biotherapeutics and provide new systems that allow the production of these potentially powerful new medicines at a yield and quality not currently possible. In this study, we will investigate these problems using biotherapeutic products that exemplify the pipeline of real potential products under development at UCB (a company that is at the forefront of technologies to manufacture novel biotherapeutics).Overall, the project aims to investigate and determine how the cell factory responds to the challenge of production of a series of novel biotherapeutics. We also aim to redesign the molecules themselves, by adding into the molecules the ability to have sugars modify specific parts of the molecule, to drive quality control mechanisms in the cell factory that will allow the better assembly and production of the target molecules. We will also use the latest approaches to modifying the cell factory itself, so termed genome editing approaches, to allow us to unravel the 'roadblocks' in the cell factory that prevent production of the molecules of interest and that also allow us to manipulate the cell factory in an attempt to overcome any observed roadblocks. Thus, we will generate an understanding of why the cell factory does not produce difficult to express molecules, how the additional of sugars onto the molecule may help the cell factory recognise 'badly made' material and correct this, and new cell factory systems for industrial application for the manufacture of these new medicines. In delivering the project we will bring together two world-leading laboratories studying cell factories and their manipulation and the needs of UCB towards production of novel biotherapeutics. The understanding that will arise from the project has wide-scale potential for (i) fundamental understanding of the manner in which cell factories operate and their selective control of production of biotherapeutics of different structure and (ii) for translation of findings into industrial practice (at UCB and wider) for more rapid, more certain and less costly production of new medicines. The approach developed by this project will have widespread value across the entire commercial sector and will have direct relevance to the potential to treat many clinical conditions.

重组生物疗法是诊断和治疗疾病的药物。对这个项目感兴趣的是蛋白质，这些蛋白质(由细胞作为程序工厂)从人体自身的大分子知识中构建出来，并被重新设计用于治疗特定疾病。例如，设计的胰岛素版本(用于治疗糖尿病)使糖尿病患者能够更好地控制自己的健康。人们正在合成其他天然分子(抗体)来治疗癌症和自身免疫性疾病。制造生物疗法的能力一直是由工业推动的，改变生活的治疗方法的潜力与生产的商业成本相平衡。新一代生物疗法(有可能以比现有生物疗法更大的效率治疗更多的疾病)正在开发中。新一代是通过提取少量的天然分子并构建新的分子(以模块化结构)在细胞工厂生产而设计的。这就是所谓的合成生物学，即为有价值的功能设计新的遗传物质。虽然这有令人难以置信的前景和潜力，但生产新的生物疗法的能力远远不是最佳的(由于细胞工厂处理这些非天然产品的方式)。为了充分发挥这些新型药物的潜力，需要更充分地了解细胞工厂中发生的过程，并在了解这些过程的情况下，提高它们的产量。该项目旨在解决将决定新型生物疗法生产有效性的基本因素，并提供新的系统，使这些潜在强大的新药能够以目前无法实现的产量和质量生产。在这项研究中，我们将使用生物治疗产品来调查这些问题，这些产品是UCB(一家处于制造新型生物治疗药物技术前沿的公司)正在开发的真正潜在产品的流水线。总体而言，该项目旨在调查和确定细胞工厂如何应对生产一系列新型生物治疗药物的挑战。我们还打算重新设计分子本身，在分子中加入糖修饰分子特定部分的能力，以推动细胞工厂的质量控制机制，使目标分子能够更好地组装和生产。我们还将使用最新的方法来修改细胞工厂本身，即所谓的基因组编辑方法，以使我们能够解开细胞工厂中阻止目标分子产生的“障碍”，并允许我们操纵细胞工厂，试图克服任何观察到的障碍。因此，我们将理解为什么细胞工厂不生产难以表达的分子，额外的糖如何帮助细胞工厂识别“劣质”材料并纠正这一点，以及新的细胞工厂系统用于工业应用，生产这些新药。在实施该项目时，我们将汇集两个世界领先的实验室，研究细胞工厂及其操作，以及UCB对生产新型生物疗法的需求。该项目将产生的理解具有广泛的潜力：(I)从根本上了解细胞工厂的运作方式及其对不同结构生物疗法生产的选择性控制，以及(Ii)将研究结果转化为工业实践(在UCB和更广泛的地方)，以更快、更确定和更低成本地生产新药。该项目开发的方法将在整个商业部门具有广泛的价值，并将与治疗许多临床疾病的潜力直接相关。