PFI-RP: Scalable Plant-Based Production of Affordable Protein Drugs

创新研究伙伴关系（PFI-RP）项目的更广泛影响/商业潜力是一个新的植物生物制造平台，用于生产罕见疾病的治疗药物，这将帮助患者，降低美国的医疗保健成本，并开辟新的商业市场机会。据估计，大约有7000种已知的罕见病或“孤儿”病，大多数都有遗传基础，这些疾病总共影响着美国2500万至3000万人（约占人口的8%），而fda批准的孤儿药只有350种。即使有孤儿药，它们通常也非常昂贵，每年每个病人的费用在10万到40万美元之间。随着美国试图降低医疗成本，迫切需要新的基于植物的生物制造平台，以实现低成本、可扩展的“孤儿”生物制剂（即基于蛋白质的治疗药物）的生产。作为概念验证，该团队选择了α -1抗胰蛋白酶（AAT）作为目标产品，这是一种人类血液蛋白，已被证明在传统哺乳动物和细菌宿主中有效制造极具挑战性。拟议的项目将建立一个新的生物制造范式，克服在植物生产系统中实现高水平生产（500 mg/kg植物鲜重）功能性完整的人类血液蛋白的先前挑战。该项目将侧重于在封闭设施中利用寄主植物——本烟属植物（Nicotiana benthamiana）的短暂农业渗透生产重组AAT的工艺开发。本烟属植物是烟草的亲戚。由于本项目将评估的新型表达载体、宿主工程载体和生物处理策略是通用的（例如，AAT基因可以替换为其他治疗性蛋白质的基因），因此它是一种可应用于许多生物产品的平台技术。PFI-RP项目的具体目标是提高功能性和完整的天然AAT、抗氧化AAT变体和AAT- fc融合蛋白的生产；建立AAT生产一致性和产品质量；随着工艺的优化，适应和修改硅工艺技术经济模型，以评估生产成本、资本投资以及对规模化生产设施的环境、健康和安全影响。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。

The broader impact/commercial potential of this Partnerships for Innovation – Research Partnerships (PFI-RP) project is a new plant-based biomanufacturing platform for the production of treatments for rare diseases that will help patients, reduce U.S. healthcare costs, and open up new commercial market opportunities. It is estimated that there are about 7,000 known rare or “orphan” diseases, most with a genetic basis, that collectively affect between 25-30 million people in the United States (about 8% of the population) and only 350 FDA-approved orphan drugs. Even when orphan drugs are available they are often extremely expensive, costing between $100,000 and $400,000 per patient annually. As the U.S. tries to reduce healthcare costs, new plant-based biomanufacturing platforms that enable low cost, scalable production of “orphan” biologics (i.e., protein-based therapeutics) are urgently needed. As a proof-of-concept, the team has selected alpha-1 antitrypsin (AAT), a human blood protein that has proven to be extremely challenging to make efficiently in traditional mammalian and bacterial hosts, as a target product. The proposed project will establish a new biomanufacturing paradigm that overcomes prior challenges associated with achieving high level production (500 mg/kg plant fresh weight) of functional, fully intact human blood proteins in plant production systems. This project will focus on process development for recombinant AAT production using transient agroinfiltration of a host plant, Nicotiana benthamiana, a relative of tobacco, in a contained facility. Since the novel expression vectors, host engineering vectors, and bioprocessing strategies that will be evaluated in this project are generic (e.g. the AAT gene can be swapped out for genes for other therapeutic proteins), it is a platform technology that can be applied to many biologic products. The specific aims of the PFI-RP project are to improve production of functional and intact native AAT, oxidation-resistant AAT variants, and AAT-Fc fusion proteins; establish AAT production consistency and product quality; and adapt and modify in silico process technoeconomic models as the process is optimized to evaluate manufacturing costs, capital investments, and environment, health and safety impacts for scaled-up production facilities.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.