Synthetic Biology Platform for CHO Cell Engineering

CHO细胞工厂开发过程仍然依赖于广泛使用非常有限的一组复杂的、功能不明确的遗传组分（如病毒启动子）和试错筛选，以鉴定具有理想生产特征的细胞。这些工艺完全不符合MedImmune生产和测试下一代生物制药产品的多样化组合的要求，这些产品是非天然的工程蛋白质形式（如双特异性单克隆抗体和其他融合蛋白），具有不可预测的可制造性。为了显著缩短这些新产品的开发时间并显著提高产量，迫切需要从筛选主导型技术转向设计主导型技术;在生物工艺开发的早期阶段嵌入产品可制造性的预测和设计，以加速产品进入临床。使我们能够将合成生物学的核心概念（标准化，设计，预测）应用于下一代生物制药制造系统的开发的技术目前还不存在。这一点非常重要：我们需要消除目前的概念，即一些产品是“难以表达”（DTE），取而代之的是“设计师产品”需要一个“设计师细胞工厂”，不依赖于筛选自然生物变异的功能。生物医学的发展不应该受到制造技术的限制，而应该受到生物分子工程师设计新的有效分子的能力的限制。为了使CHO细胞工厂合成生物学成为现实，有必要从头开始设计和测试用于细胞工程的新遗传系统。在这个项目中，我们将开发一个用于CHO细胞工程的合成生物学平台，这将使我们能够创建定制的合成CHO细胞工厂，以最佳设计的化学计量运行多种遗传成分，能够执行目前不可能的复杂制造功能。这将使得（i）现有稳定的细胞工厂的逆向工程使失败的产品可制造，以及（ii）新的细胞工厂和具有可预测的制造特性的产品的正向工程。

The process of CHO cell factory development still relies upon the widespread use of a very limited set of complex, functionally ill-defined genetic components (such as viral promoters) and trial-and-error screening to identify cells with desirable manufacturing characteristics. These processes are entirely incompatible with MedImmune's requirement to produce and test a diverse portfolio of next-generation biopharmaceutical products that are non-natural, engineered protein formats (such as bispecific MAbs and other fusion proteins) with unpredictable manufacturability. To enable both significant reductions in development times and significant improvements in production yields for these new products, there is an urgent need to shift from screening-led to design-led technologies; embedding prediction and design of product manufacturability at an earlier stage in bioprocess development to speed products into the clinic. Enabling technology that permits us to employ the core concepts underpinning synthetic biology (standardisation, design, prediction) to the development of next-generation biopharmaceutical manufacturing systems does not currently exist. It is vitally important that this is developed: We need to eliminate the current concept that some products are "difficult-to-express" (DTE), replacing this with the concept that a "designer product" requires a "designer cell factory" that does not rely on screening natural biological variation for functionality. Biomedicine development should not be limited by manufacturing technology, but by the ability of biomolecular engineers to design new, potent molecules. To make CHO cell factory synthetic biology a reality, it is necessary to design and test new genetic systems for cell engineering from the ground-up. In this project we will develop a synthetic biology platform for CHO cell engineering that will permit us to create bespoke synthetic CHO cell factories, harbouring multiple genetic components operating at optimal designed stoichiometries, capable of performing complex manufacturing functions that are currently not possible. This will enable both (i) reverse engineering of existing stable cell factories to render failed products manufacturable and (ii) forward engineering of new cell factories and products with predictable manufacturing properties.