Synthetic Biology Platform for CHO Cell Engineering

CHO细胞工厂的发展过程仍然依赖于广泛使用一组非常有限的、功能不明确的遗传成分(如病毒启动子)和反复筛选来鉴定具有理想制造特征的细胞。这些过程完全不符合MedImmune的要求，即生产和测试各种下一代生物制药产品组合，这些产品组合是非天然的工程蛋白形式(如双特异性单抗和其他融合蛋白)，具有不可预测的可制造性。为了显著缩短开发时间并显著提高这些新产品的产量，迫切需要从筛选主导转向设计主导技术；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的速度。目前还不存在使我们能够利用支撑合成生物学的核心概念(标准化、设计、预测)来开发下一代生物制药制造系统的技术。这一点开发出来是至关重要的：我们需要消除目前一些产品“难以表达”(DTE)的概念，取而代之的是“设计师产品”需要一个不依赖于筛选天然生物变异功能的“设计师细胞工厂”的概念。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、强大的分子的能力的限制。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的基因系统。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，该平台将允许我们创建定制的合成CHO细胞工厂，其中包含以最佳设计的化学计量比运行的多个遗传成分，能够执行目前不可能实现的复杂制造功能。这将使(I)对现有稳定的电池工厂进行反向工程以使不合格的产品可制造，以及(Ii)对新的电池工厂和具有可预测制造特性的产品进行正向工程。

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.