A Fusion System to Prolong Plasma Half-Life of Proteins

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。随着人类基因组测序项目中发现更多新型治疗蛋白，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剂在临床阶段被放弃，因为它们不能维持体内蛋白质的治疗水平。有时，工艺开发成本过高，无法证明商业化的合理性。增强治疗性蛋白质或疫苗的药代动力学特征的技术的开发将对许多候选蛋白质非常有利。事实上，已经开发了有助于增加蛋白质半衰期的技术，例如，聚乙二醇缀合或融合至Fc片段或白蛋白。然而，有时这些技术会使蛋白质变性或增加商品成本和开发时间。LifeSensors开发了泛素样蛋白SUMO融合技术，以延长血浆中蛋白质的半衰期。SUMO融合提高了真核和原核细胞中蛋白质的生产水平。SUMO水解酶有效地切割SUMO与其融合蛋白之间的连接以产生候选蛋白的所需N-末端。因此，SUMO融合系统可用于产生含有19个不同N-末端的治疗性蛋白质。LifeSensors假设蛋白质的血浆半衰期由其N-末端的特性调节。此外，将不稳定的蛋白质融合到高度稳定的结构，如泛素或SUMO，将延长蛋白质的半衰期。开发一种新的和简单的技术，延长蛋白质的血浆半衰期将是生物制药的一个重大进展。

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.