A Fusion System to Prolong Plasma Half-Life of Proteins

延长蛋白质血浆半衰期的融合系统

• 批准号: 6833622
• 负责人: Tauseef R. Butt
• 金额: $ 27.93万
• 依托单位: LIFESENSORS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6833622
• 关键词: beta galactosidase; biotechnology; blood proteins; enzyme linked immunosorbent assay; green fluorescent proteins; interferon alpha; intravenous administration; laboratory rat; pharmacokinetics; protein engineering; protein purification; recombinant proteins; technology /technique development; transfection /expression vector; ubiquitin

DESCRIPTION (provided by applicant): Recombinant proteins are notorious for their short half-lives and reduced bioavailability. As more novel therapeutic proteins are identified from human genome-sequencing projects, there is an increasing need to formulate protein delivery strategies to prolong the half-life of proteins. Many promising protein therapeutics are abandoned at clinical stages for their inability to sustain therapeutic levels of protein in the body. At times process development costs are prohibitive to justify commercialization. Development of technologies that enhance pharmacokinetics profiles of therapeutic proteins or vaccines will be highly advantageous for many candidate proteins. Indeed technologies have been developed that help increase half-lives of proteins, e.g., polyethylene glycol conjugation or fusion to Fc fragments or albumin. However, at times these technologies inactivate proteins or increase cost of goods and development time lines. LifeSensors has developed ubiquitin-like protein SUMO fusion technology to prolong the half-lives of proteins in plasma. SUMO fusion enhances the level of protein production in eukaryotic and prokaryotic cells. SUMO hydrolase efficiently cleaves the junction between SUMO and its fusion protein to generate desired N-termini of a candidate protein. Thus, the SUMO fusion system can be used to generate a therapeutic protein that contains 19 different N-termini. LifeSensors hypothesizes that the plasma half-life of a protein is regulated by the identity of its N-terminus. In addition, the fusion of an unstable protein to a highly stable structure, such as ubiquitin or SUMO, will prolong the half-life of the protein. Development of a new and simple technology that prolongs plasma half-life of proteins will be a major advance in biopharmaceuticals.

描述（由申请人提供）： 重组蛋白因其短半衰期和降低的生物利用度而臭名昭著。从人类基因组测序项目中确定了更新颖的治疗蛋白，因此越来越需要制定蛋白质递送策略以延长蛋白质的半衰期。许多有前途的蛋白质治疗药在临床阶段被放弃，因为它们无法维持体内的蛋白质水平。有时，流程开发成本对商业化的合理性很高。增强治疗蛋白或疫苗的药代动力学谱的技术的开发对于许多候选蛋白而言将非常有利。实际上，已经开发了有助于增加蛋白质半衰期的技术，例如聚乙烯甘油偶联或融合到FC片段或白​​蛋白。但是，有时这些技术会使蛋白质失活或增加商品和开发时间线的成本。救生员已经开发了泛素样蛋白相扑融合技术，以延长血浆中蛋白质的半衰期。相扑融合增强了真核和原核细胞中蛋白质产生的水平。 SUMO水解酶有效地切割了Sumo及其融合蛋白之间的连接，从而产生候选蛋白的所需N末端。因此，Sumo融合系统可用于生成包含19种不同N末端的治疗蛋白。救生器假设蛋白质的血浆半衰期受其N末端的身份调节。另外，不稳定的蛋白质与高度稳定的结构（例如泛素或相扑）的融合将延长蛋白质的半衰期。开发一种延长蛋白质血浆半衰期的新型简单技术将是生物制药的重大进步。