High Efficiency Purification of Immunotherapeutics with Nanoporous Composite Memb

使用纳米多孔复合膜高效纯化免疫治疗药物

• 批准号: 7999034
• 负责人: Bradford Allen Pindzola
• 金额: $ 13.74万
• 依托单位: TIAX, LLC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-06 至 2011-09-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7999034
• 关键词: Accounting; Antibodies; Antibody Formation; Area; Bioreactors; Buffers; Cells; Colorectal Cancer; Crohn' s disease; Development; Disease; Drug Industry; Excision; Exhibits; FDA approved; Film; Filtration; Graft Rejection; Health; Immune response; Immunotherapeutic agent; Lead; Malignant Neoplasms; Marketing; Membrane; Methods; Modeling; Monoclonal Antibodies; Non-Hodgkin' s Lymphoma; Patients; Performance; Pharmaceutical Preparations; Phase; Process; Production; Productivity; Recovery; Relative (related person); Rheumatoid Arthritis; Side; Speed; Stream; Techniques; Therapeutic; Thick; Time; Ultrafiltration; Work; base; cellular engineering; comparative efficacy; cost; density; design; experience; improved; large scale production; malignant breast neoplasm; manufacturing process; membrane flux; neoplastic cell; protein purification; prototype; public health relevance

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.

描述（由申请人提供）：单克隆抗体（mAb）治疗剂由于其靶向和治疗特定病变细胞的能力，已成为制药行业开发的大多数药物。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，在很大程度上跟上了大规模生产的需求。不幸的是，下游加工是mAb生产中的一个大瓶颈，目前占mAb生产成本的80%以上。此外，高滴度可导致抗体聚集体的形成，已知抗体聚集体表现出抗原活性并可导致患者中不期望的免疫应答。因此，高度期望有效地改善mAb的纯化，特别是从多聚体聚集体中纯化的可扩展方法。 我们建议使用高效的纳米多孔复合膜来证明mAb的纯化，并证明其优于当前的膜。这些纳米多孔复合膜将提供相对于当前膜方法的快速加工和高纯度，从而显著提高纯度并减少实现从多聚体聚集体纯化mAb所需的额外时间、劳动力和成本密集型纯化的量。 在阶段I中，我们将使用纳米多孔复合膜从多聚体mAb聚集体中纯化模型mAb，所述纳米多孔复合膜将具有高孔密度和窄孔径分布。我们将比较这种纯化的有效性，在聚集体去除和单体mAb的回收方面，与具有相似标称孔径的选定商业膜的有效性。在第二阶段，我们将把这一示范推广到原型制造工艺，并研究过滤条件和污垢对净化的影响。我们还将与商业合作伙伴合作，将我们的膜集成到一个完整的纯化过程中。 公共卫生相关性：在过去的二十年中，改进的制造方法已经导致生物药物如单克隆抗体（mAb）的生产的显著改进;然而，所得的高滴度流具有更大量的杂质，当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mAb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mAb生产，从而加快试验进展并最终改善患者健康。膜分离是最便宜和最有效的纯化方法之一，并且提高其纯化能力减少或消除了对其他更昂贵和耗时的方法的需要。