High Efficiency Purification of Immunotherapeutics with Nanoporous Composite Memb

描述(申请人提供)：单抗(MAb)疗法已经成为制药行业正在开发的大多数药物，因为它们能够靶向和治疗特定的疾病细胞。近年来，生物反应器设计和宿主细胞工程的改进导致了更高的滴度计数，在很大程度上满足了大规模生产的需求。遗憾的是，下游加工是单抗生产的一大瓶颈，目前占单抗生产成本的80%以上。此外，高滴度可导致抗体聚集物的形成，已知抗体聚集物具有抗原性，并可能导致患者不良的免疫反应。因此，非常需要可扩展的方法来有效提高mAbs的纯化，特别是从多聚体聚集体中提纯mAbb。 我们建议使用一种高效的纳米多孔复合膜来纯化单抗，并展示其相对于现有膜的优越性。与当前的膜工艺相比，这些纳米多孔复合膜将提供快速的加工和高纯度，从而显著提高纯度，并减少从多聚体中纯化单抗所需的额外时间、劳动力和成本密集的提纯。 在第一阶段，我们将使用具有高孔密度和窄孔径分布的纳米孔复合膜从多聚体mAb聚集体中提纯出模型mAb。我们将比较这种提纯方法在聚集体去除和单体单抗回收方面的效果，并与具有相似标称孔径的商业膜进行比较。在第二阶段，我们将把这一演示扩展到一个原型制造过程，并研究过滤条件和污垢对净化的影响。我们还将与一个商业合作伙伴合作，将我们的膜整合到一个完整的净化过程中。 与公众健康相关：在过去的二十年中，改进的制造方法导致了诸如单抗(MAbs)等生物制药生产的显著改善；然而，由此产生的高滴度流含有更多的杂质，而目前的下游加工技术难以处理这些杂质。因此，下游加工已成为单抗生产成本的巨大比例，降低这些成本和提高效率的改进将能够显著改善单抗生产，从而加快试验进展，最终改善患者的健康。膜分离是最便宜和最有效的净化工艺之一，提高它们的净化能力可以减少或消除对其他更昂贵和更耗时的工艺的需要。

DESCRIPTION (provided by applicant): Monoclonal antibody (mAb) therapeutics have become the majority of drugs being developed by the pharmaceutical industry, due to their ability to target and treat specific diseased cells. In recent years, improvements in bioreactor design and host cell engineering have resulted in much higher titer counts, largely keeping up with the demand for large scale production. Unfortunately, downstream processing, is a large bottleneck in mAb production, and currently accounts for more than 80% of mAb production cost. In addition, high titers can lead to the formation of antibody aggregates, which are known to exhibit antigenic activity and can lead to undesirable immune responses in patients. As such, scalable methods that efficiently improve the purification of mAbs, especially from multimeric aggregates, are highly desired. We propose to demonstrate the purification of mAbs using a high-efficiency nanoporous composite membrane and to demonstrate their superiority to current membranes. These nanoporous composite membranes will offer rapid processing and high purity relative to current membrane processes, thereby dramatically improving purity and reducing the amount of additional time, labor and cost intensive purification needed to achieve purification of mAbs from multimeric aggregates. In Phase I, we will purify a model mAb from multimeric mAb aggregates using a nanoporous composite membrane, which will have a high pore density and a narrow pore size distribution. We will compare the efficacy of this purification, in terms of aggregate removal and recovery of monomeric mAb, to that of selected commercial membranes with similar nominal pore sizes. In Phase II, we will extend this demonstration to a prototype manufacturing process and investigate the effects of filtration conditions and fouling on the purification. We will also work with a commercial partner to integrate our membrane into a complete purification process. PUBLIC HEALTH RELEVANCE: In the last twenty years, improved manufacturing methods have led to a marked improvement in the production of biopharmaceuticals such as monoclonal antibodies (mAbs); however, the resulting high titer streams have greater amounts of impurities which current downstream processing techniques struggle to handle. Consequently, downstream processing has become a huge percentage of mAb production costs, and improvements that reduce these costs and increase efficiency will be able to dramatically improve mAb production, thereby speeding progress through trials and ultimately improving patient health. Membrane separations are one of the least expensive and most efficient purification processes, and improving their purification ability reduces or eliminates the need for other more costly and time consuming processes.