Control and estimation of glycosylation profile via media supplementation based on intracellular models in mammalian cell cultures

重组单克隆抗体（mAb）在治疗许多疾病中是有效的，包括几种类型的癌症。mAb的有效性与mAb表面的糖修饰模式密切相关。该项目试图了解并最终预测mAb如何在表面的特定位置用糖修饰。这些知识将填补当前mAb质量控制的工业实践中的重大空白，并改善此类治疗性分子的开发和制造。研究团队还将通过本科生研究提供STEM培训机会，招募少数民族学生，开发新的生物制造课程和讲座，并支持K-12学生和公众的外联活动。成功控制和优化单克隆抗体糖基化目前阻碍了有限的了解糖基化如何在体内培养扰动。本研究拟通过探索细胞内代谢机制来解决这一挑战，从而将培养基补充与糖基化联系起来，最终建立一个预测培养物中糖基化变化的模型，并通过培养基补充提供一种控制方法。对糖基化至关重要的细胞生理学的机制见解将通过多组学方法实现。这将为开发细胞内代谢模型铺平道路，该模型将培养基补充剂，细胞内特性和聚糖谱联系起来，并通过培养基补充剂开发聚糖属性的控制策略。如果成功的话，这些结果应该能够重复产生完全活性的单克隆抗体，提高疗效并降低这种重要的人类健康疗法的成本。

Recombinant monoclonal antibodies (mAbs) are effective in curing many diseases, including several types of cancer. The effectiveness of mAbs is closely related to the pattern of decoration of the mAb surface with sugars. This project attempts to understand and ultimately predict how mAbs are decorated with sugars in specific locations on the surface. Such knowledge would fill a significant gap in current industrial practice on mAb quality control and improve the development and manufacturing of such therapeutic molecules. The research team will also provide STEM training opportunities through undergraduate research, recruiting minority students, developing new biomanufacturing courses and lectures, and supporting outreach activities for K-12 students and general public. Successful control and optimization of mAb glycosylation is currently hindered by limited understanding of how glycosylation responds in vivo to culture perturbations. This research proposes to tackle the challenge by exploring intracellular metabolic mechanisms that link media supplementation in to glycosylation.This should eventually lead to the establishment of a model to predict glycosylation variation in cultures and accommodate a control methodology via media supplementation. Mechanistic insights into the cellular physiology critical to glycosylation will be achieved by multi-omics approaches. This will pave the way to developing intracellular metabolic models which connect media supplements, intracellular properties, and glycan profiles, an to developing control strategies for glycan attributes via media supplementation. If successful, these results should enable the reproducible generation of fully active monoclonal antibodies, increasing the efficacy and decreasing the cost of this important human health therapy.