A platform for the optimisation of metabolic pathways for glycosylation to achieve a narrow and targeted glycoform distribution

最近，新疾病的治疗方法的发展已经从传统的化合物转向蛋白质疗法(生物药物)，如用于治疗癌症的抗体和用于治疗慢性病的激素。近70%的蛋白质疗法中有糖分子自然附着在它们身上，这会影响它们的功能和它们在体内停留的时间。由于糖对药物功能非常重要，其生产中最大的问题之一是如何控制添加什么糖(糖型)，并确保生产的所有蛋白质都有相同的糖(均一型糖型)。目前的生产方法产生的糖型混合物并不均匀。此外，不同的糖型与免疫系统以不同的方式相互作用，因此根据药物是什么以及它的作用方式，能够产生某些糖型而不是其他糖型将是有益的。我们的目标是开发技术，以快速确定不同生产方法对糖型的影响，以及糖型分布的均质性。为了做到这一点，我们将开发在细胞内产生的蛋白质，这些蛋白质也在生产生物药物，报告已知的影响糖形式的营养物质的浓度。此外，我们还将开发一种细胞新陈代谢的计算机模型，该模型可以预测哪些糖形式会产生。将这两者结合起来，我们应该能够为细胞设计新的培养基来使用，从而产生更均匀的糖型，我们可以根据细胞的喂养方式来改变这种糖型。我们还可以建议对细胞进行基因改变，这将进一步帮助我们产生一种单一的、设计好的糖类。这可能导致生产更安全和需要较低剂量的药物，因为它们带有一种最适合该药物功能的单一糖型。

Recently, the development of treatments for new disease has shifted away from traditional chemical compounds and towards protein therapeutics (biopharmaceuticals) like antibodies for the treatment of cancer and hormones for chronic diseases. Nearly 70% of these protein therapeutics have sugar molecules attached to them naturally which affect their function and how long they remain in the body. Because the sugars are so important for the drug function, one of the biggest problems in their manufacture is how to control what sugars are added (glycoform) and to ensure that all the proteins produced have the same sugars on them (homogeneous glycoform profile). Current production methods yield a non-homogeneous mix of glycoforms. Also, different glycoforms interact with the immune system in different ways, so it would be of benefit to be able to produce certain glycoforms over others depending on what the drug is and how it is meant to function. Our goal is to develop technology to rapidly determine the effects of different production methods on which glycoforms are produced and how homogeneous the glycoform profile is. To do this we will develop proteins which are produced inside the cells that are also producing the biopharmaceutical that report the concentrations of nutrients that are already known to influence glycoforms. Alongside, we will develop a computer model of the metabolism of the cells which can predict which glycoforms are produced. Using these two together, we should be able to design new media for the cells to use that result in a more homogeneous glycoform profile which we can change based on what the cells are fed with. We can also suggest genetic changes to the cells that would further help us produce a single, designed glycoform. This could lead to the production of drugs that are safer and require lower doses because they have a single glycoform attached which is the most appropriate for the function of that drug.