Optimisation of CHO for Biotherapeutic Manufacture

基于重组DNA技术的生物药物（例如单克隆抗体，MAb）已经改变了对包括癌症、血友病和类风湿性关节炎在内的限制生命的疾病的治疗。生物制剂领域最近的爆炸性增长似乎将继续下去，在精准医学和个性化医疗保健中的应用越来越多，并且在药物发现管道中有许多新的复杂生物制剂（例如双特异性，三特异性和共轭单克隆抗体）。这些拯救生命的药物的内在复杂性对于简单的化学合成来说太具有挑战性，并且需要利用活细胞。迫使细胞产生它们不自然表达的蛋白质是复杂的，并且通常需要长时间的试错细胞操作，使得生物制造过程耗时且非常昂贵，并直接影响向患者提供变革性药物。随着最近编辑哺乳动物基因组的强大工具的显着发展，用于合成大量DNA构建体的新方法和自动化，以及系统生物学提供的背景，现在是时候使用合成生物学来建立一个新的范例，以成本效益的方式生产生物药物。反过来，这将对医药和健康相关行业产生重大影响，并使生物制药价值链更具成本效益。与此项目相关的经济机会规模巨大。英国拥有世界上最具活力和创新性的医疗保健行业之一，并开发了世界前100名销售药物中的20%以上。英国的医疗技术行业由大约2,800家公司组成，雇佣了52,000名员工，每年创造约106亿英镑的营业额。所有药物中越来越多的部分是生物制药，目前估计为20%。2018年，全球生物制剂市场估计价值2515亿美元，预计到2021年将达到3190亿美元。CHO细胞是最广泛使用的工业表达系统，其产生约70%的批准和上市的治疗性重组蛋白，包括多种单克隆抗体（mAb），因此生产效率和质量的任何提高都具有巨大的经济影响。这种繁荣伙伴关系的愿景是利用最先进的研究工具和合成生物学方法来阐明CHO细胞制造平台的复杂性，并将其设计成更具预测性，有效性，成本效益和竞争力的生物治疗药物生产在英国。

Biological drugs (e.g. monoclonal antibodies, MAbs) based on recombinant DNA technology have transformed the treatment of life-limiting diseases including cancer, haemophilia and rheumatoid arthritis. The recent explosive growth in the biologics sector looks set to continue, with growing applications in precision medicine and personalised healthcare, and there are many new complex biologics in the drug discovery pipeline (e.g. bispecific, trispecific, and conjugated MAbs). The intrinsic complexity of these life-saving drugs is too challenging for synthesis by simple chemistry and requires the utilisation of living cells. Forcing cells to produce proteins that they do not naturally express is complex, and often requires a long period of trial and error cell manipulation, making the bio-manufacturing process time-consuming and very expensive and directly impacting on the delivery of transformative medicines to patients. With the recent remarkable development of powerful tools for editing mammalian genomes, new methods and automation for the synthesis of large numbers of DNA constructs, and the context provided by systems biology, the time is now right for using Synthetic Biology to establish a new paradigm for cost-effective manufacture of biologic drugs. In turn this will have a major impact on medicine and the health related industries, and make the biopharmaceutical value chain more cost-efficient.The scale of the economic opportunity associated with this project is enormous. The UK has one of the most dynamic and innovative healthcare industries in the world and has developed over 20% of the world's top 100 selling drugs. The medical technology sector in the UK consists of around 2,800 companies, employing 52,000 people and generating around £10.6bn of turnover annually. An increasing portion of all medicines, currently estimated at 20%, are biopharmaceuticals. The global biologics market was valued at an estimated $251.5 billion in 2018 and is predicted to reach $319 billion by 2021. The CHO cell is the most widely used industrial expression system, which generates ~70% of approved and marketed therapeutic recombinant proteins, including multiple monoclonal antibodies (mAbs), so any enhancement of production efficiency and quality has a huge economic impact. The vision of this prosperity partnership is to utilise state of the art investigational tools and synthetic biology approaches to both elucidate the intricacies of the CHO cell manufacturing platform and engineer it to be more predictive, effective, cost-efficient, and competitive for the production of biotherapeutics in the UK.