EAGER: Directionally Aligned Macroporous Ceramics with In-Situ Synthesized Functional Polymer Microgels as a Platform for Next Generation Membrane Chromatography

EAGER：定向排列大孔陶瓷与原位合成功能聚合物微凝胶作为下一代膜色谱的平台

基本信息

批准号：
1911972
负责人：
Katherine Faber
金额：
$ 19.46万
依托单位：
California Institute of Technology
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1911972&HistoricalAwards=false
关键词：
EAGER Directionally Aligned Macroporous Ceramics

项目摘要

A monoclonal antibody is a protein capable of specifically binding a targeted molecule or receptor. Through this specific binding, antibodies become highly active drugs with reduced side effects. The market for biopharmaceuticals, such as monoclonal antibodies, is growing rapidly, with worldwide sales expected to reach $125 billion by 2020. The growing demand for antibodies and related biologics has driven up the cost of treatment using these products. As a result, the biopharmaceutical industry is increasingly under pressure from regulators, healthcare providers, and consumers to decrease production and treatment costs. Purification of monoclonal antibodies during bioprocessing is both slow and costly, representing more than 80% of the manufacturing expense. Membrane adsorbers are emerging as more efficient separation systems compared to conventional resin column beds in downstream biopharmaceutical manufacturing. Membrane adsorbers can be operated with much higher flow rates and throughput and, thus, are ideally suited for reducing processing times and production costs. The overarching goal of the EAGER project is to build the foundation for a new generation of macroporous membrane materials and modules that overcome the capacity, selectivity, and throughput limitations of existing commercial membrane adsorbers. To achieve this goal, functional polymers with high protein binding capacity and selectivity will be coupled with high surface area macroporous ceramic scaffolds, which can be configured into scalable modules for continuous bioprocessing. Within the biopharmaceutical manufacturing community, the desired transition to precisely targeted therapeutics based on monoclonal antibodies (mAb) depends on dramatically increasing manufacturing speed and reducing production costs. Although membrane chromatography has demonstrated advantages over standard column chromatography, including higher throughput and lower cost, it is limited by low protein binding capacity and selectivity of commercial membrane adsorbers as well as complex module configurations and fabrication. Consequently, there is a critical need for a new generation of membrane adsorber materials that can be readily configured into scalable modules with high binding capacity and selectivity. This project seeks to build a foundation for the next generation of scalable membrane adsorber materials and modules for downstream biopharmaceutical manufacturing that overcome the limitations of existing commercial membranes. This EAGER project will focus on achieving two specific objectives: the design, preparation, and characterization of 1) salt-tolerant membrane adsorbers with high protein binding capacity for mAb purification; and 2) membrane adsorbers for selective mAb capture and recovery from bioreactor harvests. The strategy to establish the foundation for these membrane adsorbers relies upon the design of a family of macroporous ceramics with tunable pore size, structure, and morphology using directional solution freeze casting. Building upon the porous scaffolds, a two-pronged approach will be undertaken. Firstly, in-situ polymerization and phase-separation micromolding will be employed to prepare functional polymer microgels inside macroporous ceramic scaffolds that contain high concentrations of ligands with large protein binding capacity and selectivity. Secondly, conformal microgel coatings of highly tortuous dendritic pores will be prepared to provide hydrodynamic trapping and adsorption sites inside macroporous scaffolds. Fundamental understanding of the material preparation and functionalization process and protein binding capacity and selectivity will be developed.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

单克隆抗体是一种能够特异性结合靶向分子或受体的蛋白质。通过这种特定的结合，抗体成为高度活性药物，副作用降低。诸如单克隆抗体之类的生物药物市场的市场正在迅速增长，到2020年，全球销售额预计将达到1,250亿美元。对抗体和相关生物制剂的需求不断增长，促进了使用这些产品的治疗成本。结果，生物制药行业越来越受监管机构，医疗保健提供者和消费者降低生产和治疗成本的压力。生物处理过程中单克隆抗体的纯化既缓慢又昂贵，占制造费用的80％以上。与下游生物制药制造中的常规树脂柱床相比，膜吸附者正在成为更有效的分离系统。膜吸附者可以以更高的流速和吞吐量进行操作，因此非常适合减少处理时间和生产成本。急切的项目的总体目标是为克服现有商业膜吸附剂的容量，选择性和吞吐量限制的新一代大型膜材料和模块奠定基础。为了实现这一目标，具有高蛋白质结合能力和选择性的功能聚合物将与高表面积大陶瓷支架相结合，可以将其配置为可扩展的模块，以进行连续生物处理。在生物制药制造社区中，基于单克隆抗体（MAB）的精确靶向治疗剂的期望过渡取决于显着提高制造速度并降低生产成本。尽管膜色谱法证明了与标准色谱柱色谱法相比的优势，包括更高的吞吐量和较低的成本，但它受到蛋白质结合能力低的限制和商业膜吸附剂的选择性，以及复杂的模块构型和制造。因此，新一代的膜吸附材料迫切需要，这些材料可以容易地将其配置为具有高结合能力和选择性的可扩展模块。该项目旨在为下一代可扩展的膜吸附物材料和模块建立基础，用于下游生物制药制造，以克服现有商业膜的局限性。这个急切的项目将着重于实现两个特定的目标：1）具有高蛋白结合能力以纯化的MAB纯化能力的耐盐膜剂的设计，制备和表征； 2）膜吸附剂，用于从生物反应器收获中捕获和恢复的选择性mAb。为这些膜吸附者建立基础的策略依赖于使用定向溶液冻结铸造具有可调孔径，结构和形态的大型陶瓷家族的设计。在多孔脚手架的基础上，将采取两管齐下的方法。首先，将采用原位聚合和相分离微量重要来制备大孔陶瓷支架内的功能性聚合物微凝胶，这些陶瓷支架中含有高浓度的配体具有较大蛋白质结合能力和选择性的配体。其次，将准备高度曲折的树突状孔的保形微凝胶涂层，以便在大孔支架内提供流体动力诱捕和吸附位点。对材料制备和功能化过程以及蛋白质结合能力和选择性的基本理解将得到发展。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子优点和更广泛的影响来通过评估来支持的。