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A Novel Plant Cell Bio-Production Platform for Therapeutic Proteins

用于治疗性蛋白质的新型植物细胞生物生产平台

基本信息

批准号：
7910238
负责人：
DAVID RADIN
金额：
$ 15.12万
依托单位：
BIOSTRATEGIES, LC
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-15 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7910238
关键词：
Agitation Animals Bioreactors CSF3 gene Cell Culture Techniques Cell Density Cells Chemicals Chromatography Clinic Conscious Culture Media Development Devices Disadvantaged Economic Development Economically Deprived Population Effectiveness Environmental Pollution Farming environment Fermentation Global Warming Glycoproteins Goals Government Half-Life Health Health Priorities Hepatitis C virus Hydrophobic Interactions Hydroxyproline Interferons Mammalian Cell Marketing Medical Methods Molecular Molecular Sieve Chromatography Occupations Oxygen Patients Perfusion Pharmaceutical Preparations Pharmacologic Substance Phase Plant Proteins Plants Polishes Population Process Production Productivity Proteins Protocols documentation Recombinant Proteins Recovery Research Safety Serum Small Business Innovation Research Grant Somatropin Speed Suspension Culture System Tandem Repeat Sequences Techniques Technology Testing Time Tobacco Work base commercialization cost design follow-up glycosylation improved innovation meetings microbial novel phase 2 study programs prototype public health relevance scale up success therapeutic protein

项目摘要

DESCRIPTION (provided by applicant): This Small Business Innovation Research Phase I proposal develops a technology that allows bioactive proteins to be synthesized and secreted from cultured plant cells in high yields and with prolonged serum half-life. The innovation of this technology, designated Hyp-Glyco, involves the expression of secreted therapeutic proteins as fusions with a novel hydroxyproline (Hyp)-Glyco tag. The Hyp-Glyco tag also extends serum half-life and facilitates purification of secreted proteins while retaining protein bioactivity. This proposal is focused on scale-up process development of Hyp-Glyco technology in bioreactor cultured tobacco cells expressing interferon 2b and in development of a cost-effective technique for protein recovery/purification. Specific aims of this feasibility Phase I are to 1) Establish bioreactor based high yield interferon protein production in plant cell cultures using Hyp-Glyco technology; 2) Demonstrate that continuous perfusion culture technology will further enhance protein production; and 3) Show that reliable and cost-effective recovery and purification of bioactive interferon protein can be achieved in bioreactor grown plant cell cultures. Success of Phase I will support a follow-up Phase II aimed at establishing cost-effective commercial level production protocols for all phases of this new protein production technology so as to provide the confidence necessary for investing in Phase III commercial development. Protein therapeutics represents a multi-billion-dollar marketplace, but costly manufacturing methods for these drugs currently make them prohibitive for consumers. The broad impact of the proposed work resides in the potential of an alternative less costly platform for enhanced production of therapeutic proteins in plant cells which would, simultaneously, provide the added advantage of improved clinic effectiveness. Because this technology not only produces high-yield secreted proteins but also eliminates the time-consuming and expensive process of chemical derivatization to improve clinic effectiveness, the production costs can be significantly reduced. With the additional safety advantage of substituting plant cells for existing animal cell production, "molecular farming" could become commercially competitive with current mammalian and microbial cell production systems. Importantly, the interferon with extended serum half-life described here would meet a significant demand from 4 million hepatitis C virus (HCV) infected patients in USA and 3% of population worldwide. This technology is also broadly applicable to a wider range of therapeutically important proteins such as hGH, G-CSF and EPO etc, all of which represent billion-dollar markets. The development and success in commercializing the Hyp-Glyco protein manufacturing technology would create job opportunities in economically disadvantaged regions of the US and drive local economic development. PUBLIC HEALTH RELEVANCE: The growing dual threat of environmental pollution and global warming is considered by most health/medical experts and governments as one of the most dangerous and intransigent potential health problems globally. The need for developing new health positive, cost conscious and environmentally sustainable technologies for production of industrial and pharmaceutical products is a high priority of health related research in the U.S. and abroad. This proposal will target this need directly by developing and testing the feasibility of innovative more cost-effective methods for producing therapeutic proteins by using plant-based cultures and bioreactors which will confer the simultaneously benefits of greater safety, energy conservative and environmental sustainability than traditional manufacturing methods.

描述(申请人提供)：这项小型企业创新研究第一阶段提案开发了一种技术，允许从培养的植物细胞中合成和分泌生物活性蛋白质，产量高，血清半衰期长。这项名为Hyp-Glyco的技术的创新涉及到分泌治疗性蛋白质的表达，作为与新型羟脯氨酸(Hyp)-Glyco标签的融合。Hyp-Glyco标签还延长了血清半衰期，并在保持蛋白质生物活性的同时促进了分泌蛋白质的纯化。这项建议的重点是在生物反应器培养的表达干扰素2b的烟草细胞中扩大Hyp-Glyco技术的过程，并开发一种具有成本效益的蛋白质回收/纯化技术。这一可行性阶段第一阶段的具体目标是：1)利用Hyp-Glyco技术在植物细胞培养中建立基于生物反应器的高产干扰素蛋白质生产；2)证明连续灌流培养技术将进一步提高蛋白质产量；以及3)证明在生物反应器培养的植物细胞培养物中可以实现可靠和经济高效的生物活性干扰素蛋白质的回收和纯化。第一阶段的成功将支持后续第二阶段，旨在为这项新的蛋白质生产技术的所有阶段建立具有成本效益的商业级生产方案，以便为投资第三阶段的商业开发提供必要的信心。蛋白质疗法代表着一个数十亿美元的市场，但这些药物的昂贵制造方法目前使消费者望而却步。这项拟议工作的广泛影响在于，有可能找到一种替代的、成本更低的平台，以增强植物细胞中治疗性蛋白质的生产，同时，这将提供改善临床有效性的额外优势。由于该技术不仅可以生产高产率的分泌蛋白，而且还可以省去费时费钱的化学衍生化过程，从而提高临床疗效，从而显著降低生产成本。有了用植物细胞替代现有动物细胞生产的额外安全优势，“分子农业”可能会在商业上与目前的哺乳动物和微生物细胞生产系统竞争。重要的是，这里描述的延长血清半衰期的干扰素将满足美国400万丙型肝炎病毒(HCV)感染患者和全球3%人口的巨大需求。这项技术还广泛适用于更广泛的治疗重要蛋白质，如hGH、G-CSF和EPO等，所有这些都代表着数十亿美元的市场。Hyp-Glyco蛋白质制造技术的开发和商业化成功将为美国经济困难地区创造就业机会，并推动当地经济发展。与公共健康相关：环境污染和全球变暖日益严重的双重威胁被大多数健康/医学专家和各国政府视为全球最危险和最顽固的潜在健康问题之一。为工业和医药产品的生产开发新的健康正面、有成本意识和环境可持续的技术是美国和国外健康相关研究的高度优先事项。这项建议将直接针对这一需求，开发和测试创新的、更具成本效益的方法的可行性，通过使用以植物为基础的培养物和生物反应器来生产治疗性蛋白质，这些方法将同时带来比传统制造方法更安全、节能和环境可持续性的好处。