Synthetic Biology Platform for CHO Cell Engineering

CHO细胞工厂发育的过程仍然依赖于广泛使用一组非常有限的复杂的、功能不明确的遗传成分（如病毒启动子）和试错筛选来鉴定具有理想制造特征的细胞。这些工艺与MedImmune生产和测试下一代生物制药产品的多样化组合的要求完全不相容，这些产品是非天然的，工程蛋白格式（如双特异性单克隆抗体和其他融合蛋白），可制造性不可预测。为了显著缩短开发时间并显著提高这些新产品的产量，迫切需要将以筛选为主导的技术转向以设计为主导的技术；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，以加快产品进入临床。目前尚不存在使我们能够将合成生物学（标准化、设计、预测）的核心概念应用于下一代生物制药制造系统开发的技术。这是至关重要的：我们需要消除一些产品“难以表达”（DTE）的当前概念，代之以“设计产品”需要“设计细胞工厂”的概念，该概念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，我们将为CHO细胞工程开发一个合成生物学平台，这将使我们能够创建定制的合成CHO细胞工厂，其中包含多种遗传成分，以最佳设计的化学计量学运行，能够执行目前不可能实现的复杂制造功能。这将使(i)对现有稳定的细胞工厂进行逆向工程以使失败的产品可制造，以及（ii）对具有可预测制造特性的新细胞工厂和产品进行正向工程。

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.