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

用于优化糖基化代谢途径以实现狭窄且有针对性的糖型分布的平台

• 批准号: BB/I017011/1
• 负责人: Karen Polizzi
• 金额: $ 93.17万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI017011%2F1
• 关键词: platform; optimisation; metabolic; pathways; glycosylation

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.

最近，新疾病的治疗方法的发展已经从传统的化学化合物转向蛋白质治疗（生物药物），如用于治疗癌症的抗体和用于慢性疾病的激素。近70%的蛋白质治疗剂具有天然附着的糖分子，这会影响它们的功能以及它们在体内停留的时间。由于糖对药物功能非常重要，因此其生产中最大的问题之一是如何控制添加的糖（糖型）并确保生产的所有蛋白质具有相同的糖（均匀的糖型分布）。目前的生产方法产生糖型的非均匀混合物。此外，不同的糖型以不同的方式与免疫系统相互作用，因此能够产生某些糖型而不是其他糖型将是有益的，这取决于药物是什么以及它是如何发挥作用的。我们的目标是开发技术，以快速确定不同生产方法对糖型产生的影响以及糖型谱的均匀性。为了做到这一点，我们将开发在细胞内产生的蛋白质，这些蛋白质也会产生生物药物，这些生物药物会报告已知会影响糖型的营养物质浓度。此外，我们将开发一个细胞代谢的计算机模型，可以预测产生哪些糖型。结合使用这两种方法，我们应该能够为细胞设计新的培养基，从而产生更均匀的糖型谱，我们可以根据细胞的喂养情况进行改变。我们还可以建议对细胞进行遗传改变，这将进一步帮助我们产生单一的设计糖型。这可能导致生产更安全且需要更低剂量的药物，因为它们具有最适合该药物功能的单一糖型。

项目成果

In situ monitoring of intracellular glucose and glutamine in CHO cell culture.

• DOI: 10.1371/journal.pone.0034512
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Behjousiar A;Kontoravdi C;Polizzi KM
• 通讯作者: Polizzi KM

FIBS-enabled noninvasive metabolic profiling.

支持 FIBS 的无创代谢分析。

• DOI: 10.3791/51200
• 发表时间: 2014
• 期刊: JoVE
• 作者: Behjousiar A

27th European Symposium on Computer Aided Process Engineering

第 27 届欧洲计算机辅助过程工程研讨会

• DOI: 10.1016/b978-0-444-63965-3.50376-7
• 发表时间: 2017
• 作者: Filho P

A theoretical estimate for nucleotide sugar demand towards Chinese Hamster Ovary cellular glycosylation.

• DOI: 10.1038/srep28547
• 发表时间: 2016-06-27
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Del Val IJ;Polizzi KM;Kontoravdi C
• 通讯作者: Kontoravdi C

An improved model framework linking the extracellular environment to antibody glycosylation

• DOI: 10.1186/1753-6561-9-s9-p28
• 发表时间: 2015-12-14
• 期刊: BMC Proceedings
• 作者: Jedrzejewski PM;Polizzi KM;Kontoravdi C
• 通讯作者: Kontoravdi C