RII Track-2 FEC: Membrane Purification Platform for Continuous Biomanufacturing of Viral Vectors and Virus-like Particles in Arkansas and Beyond

RII Track-2 FEC：阿肯色州及其他地区用于病毒载体和病毒样颗粒连续生物制造的膜纯化平台

• 批准号: 2218054
• 负责人: Xianghong Qian
• 金额: $ 599.98万
• 依托单位: University of Arkansas
• 依托单位国家: 美国
• 项目类别: Cooperative Agreement
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2218054&HistoricalAwards=false
• 关键词: RII; Track; FEC; Membrane; Purification

Biologics are large molecule therapeutics and have been used to treat a variety of diseases, including cancer, diabetes, cardiovascular disease, autoimmune disorders, genetic and ophthalmologic diseases to name a few. Biologics include monoclonal antibodies (mAbs) and other therapeutic proteins, vaccines such as mRNA vaccines, cell and gene therapies products such as stem cells, and viral vectors. The impact of biologics on human health has been tremendous with the success of mRNA vaccines for COVID-19 as an example. The market for biologics is increasing exponentially, reaching over $300 billion as of today. The large demand for biologics places great challenge on the manufacturing process. The total cost for downstream process accounts for up to 80% of the total manufacturing cost. The vision of this RII Track-2 FEC project is to create a membrane-based downstream purification platform for the future large scale biomanufacturing of viral vectors and virus-like particles (VLPs) for gene therapy and vaccine applications. This platform will be used to replace the current processes such as centrifugation and resin-based chromatography that are difficult to scale up. The overall goal of this project is to develop innovative and practical unit operations that could be part of a platform for the downstream purification of these virus particle-based therapeutics. The project brings together multidisciplinary researchers with complementary expertise from three EPSCoR jurisdictions from the University of Arkansas (Arkansas), Clemson University (South Carolina) and University of Kentucky (Kentucky). Each of the three institutions offers unique facilities and resources that can rapidly catalyze the technology development. The economic impact of the proposed activities on the entire state of Arkansas as well as on Kentucky and South Carolina will be significant. Regional incubator centers for biotechnology industry of tomorrow will be established in the three EPSCoR states. Successful development of a high-productivity membrane purification platform is expected to improve human health by improving access to revolutionary treatments for genetic and chronic diseases for mid- and low-income families. Workforce development for the future biotechnology industry, a commitment to diversity through collaborations with Minority-serving Institutions, and a focus on early career faculty mentorship are key components of the project. The project will provide internship opportunities for graduate students and research experiences for undergraduates to develop the STEM workforce in this field. In addition, all three universities will outreach to the respective Minority-serving Institutions in the state to foster collaborative research experiences. Development of cost-effective large scale biomanufacturing for the purification of viral vectors and virus-like particles (VLPs) is a major challenge. Membrane based unit operations are attractive; however, membrane capacity, fouling and lack of commercial membranes as well as the robustness of membrane performance under a range of operating conditions have limited applications by industrial practitioners. This project will address key issues and overcome critical barriers for developing a membrane-based bioprocessing platform for viral vectors and VLPs. The project aims to overcome the technical and economic barriers at multiple fronts and involve close collaborations among researchers at three different institutions in three EPSCoR jurisdictions. More specific research objectives include (1) feedstock production of two common viral vectors for gene therapy applications and VLPs for vaccine applications; (2) advanced microfiltration operations for bioreactor harvesting; (3) high capacity affinity membrane design, fabrication and characterization; (4) downstream membrane chromatography for separating full and empty viral capsids; (5) module design, process optimization and process intensification; (6) employing state-of-the-art bioanalytical methods for detection and quantification; and (7) a technology readiness and acceptance study. Through the project's collaborative research efforts across three universities, researchers will build upon existing infrastructure at each institution, expanding it far beyond current capabilities.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.

生物制剂是大分子疗法，已被用于治疗多种疾病，包括癌症、糖尿病、心血管疾病、自身免疫性疾病、遗传和眼科疾病等。生物制剂包括单克隆抗体（mab）和其他治疗性蛋白质、疫苗（如mRNA疫苗）、细胞和基因治疗产品（如干细胞）以及病毒载体。以新冠病毒mRNA疫苗的成功为例，生物制剂对人类健康的影响是巨大的。生物制剂市场呈指数级增长，目前已超过3000亿美元。对生物制剂的巨大需求给生产过程带来了巨大的挑战。下游工序的总成本占总制造成本的80%。这个RII Track-2 FEC项目的愿景是为未来大规模生物制造病毒载体和病毒样颗粒（vlp）的基因治疗和疫苗应用创建一个基于膜的下游纯化平台。该平台将用于取代目前难以扩大规模的工艺，如离心和树脂基色谱。该项目的总体目标是开发创新和实用的单元操作，这可能是这些基于病毒颗粒的疗法的下游纯化平台的一部分。该项目汇集了来自阿肯色大学（阿肯色州）、克莱姆森大学（南卡罗来纳州）和肯塔基大学（肯塔基州）三个EPSCoR管辖区的多学科研究人员和互补的专业知识。这三个机构都提供了独特的设施和资源，可以迅速促进技术的发展。拟议中的活动对整个阿肯色州以及肯塔基州和南卡罗来纳州的经济影响将是巨大的。未来生物技术产业的区域孵化器中心将在EPSCoR的三个州建立。高生产率膜净化平台的成功开发有望通过改善中低收入家庭获得革命性的遗传病和慢性病治疗方法来改善人类健康。未来生物技术产业的劳动力发展，通过与少数民族服务机构合作实现多样性的承诺，以及关注早期职业教师指导是该项目的关键组成部分。该项目将为研究生提供实习机会，为本科生提供研究经验，以培养该领域的STEM劳动力。此外，这三所大学都将与该州各自的少数民族服务机构建立联系，以促进合作研究经验。开发具有成本效益的大规模生物制造技术纯化病毒载体和病毒样颗粒（vlp）是一项重大挑战。基于膜的单元操作很有吸引力；然而，膜容量、污染和商用膜的缺乏以及在一系列操作条件下膜性能的稳健性限制了工业从业者的应用。该项目将解决关键问题，克服开发基于膜的病毒载体和VLPs生物处理平台的关键障碍。该项目旨在克服多个方面的技术和经济障碍，并涉及三个EPSCoR管辖区三个不同机构的研究人员之间的密切合作。更具体的研究目标包括：(1)用于基因治疗应用的两种常见病毒载体和用于疫苗应用的VLPs的原料生产；(2)用于生物反应器收获的先进微滤操作；(3)高容量亲和膜的设计、制作与表征；(4)下游膜层析分离满、空病毒衣壳；(5)模块设计、工艺优化和工艺强化；（六）采用先进的生物分析方法进行检测和定量；(7)技术准备和验收研究。通过该项目在三所大学之间的合作研究，研究人员将在每个机构现有的基础设施上进行建设，将其扩展到远远超出当前能力的范围。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。