Optimisation of CHO for Biotherapeutic Manufacture

基于重组DNA技术的生物药物（如单克隆抗体、单克隆抗体）已经改变了癌症、血友病和类风湿性关节炎等限制生命疾病的治疗方法。随着精准医疗和个性化医疗的应用越来越多，生物制剂行业最近的爆炸式增长似乎将继续下去，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，三特异性和偶联单克隆抗体）。这些拯救生命的药物的内在复杂性是非常具有挑战性的，无法通过简单的化学合成，需要利用活细胞。迫使细胞产生它们不能自然表达的蛋白质是复杂的，通常需要长时间的试验和错误的细胞操作，使生物制造过程耗时且非常昂贵，并直接影响到向患者提供变革性药物。随着最近强大的哺乳动物基因组编辑工具的显著发展，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，现在是利用合成生物学建立具有成本效益的生物药物制造新范例的时候了。反过来，这将对医药和健康相关产业产生重大影响，并使生物制药价值链更具成本效益。与这个项目相关的经济机会规模是巨大的。英国拥有世界上最具活力和创新的医疗保健行业之一，在全球最畅销的100种药物中，有20%以上是英国开发的。英国的医疗技术行业由大约2800家公司组成，雇佣了52000人，每年产生约106亿英镑的营业额。生物制药在所有药物中所占的比例越来越大，目前估计为20%。2018年，全球生物制品市场的价值估计为2515亿美元，预计到2021年将达到3190亿美元。CHO细胞是应用最广泛的工业表达系统，它产生了约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），因此任何生产效率和质量的提高都具有巨大的经济影响。这一繁荣合作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，并将其设计为更具预测性、有效性、成本效益和竞争力的英国生物治疗药物生产。

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.