Optimization of Protein Therapeutics Formulations

蛋白质治疗制剂的优化

• 批准号: 8253253
• 负责人: Lawrence J Delucas
• 金额: $ 99.64万
• 依托单位: SOLUBLE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8253253
• 关键词: Academia; Address; Antibody Therapy; Area; Binding; Biological Products; Biotechnology; Choline; Chromatography; Chronic Disease; Communicable Diseases; Communities; Complex; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Development; Disease; Drug Formulations; Engineering; Enzymes; Excipients; Experimental Designs; Generations; Government; Human; Human body; Hydrolysis; Industry; Insulin; Marketing; Measures; Membrane Proteins; Monitor; Monoclonal Antibodies; Nucleotides; Osteoporosis; Patients; Peptide Library; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physiologic calcification; Polymers; Process; Protein Binding; Proteins; Publishing; Reporting; Research; Research Personnel; Resources; Science; Silicon Dioxide; Solubility; Solutions; System; Technology; Therapeutic; Time; Tumor necrosis factor receptor 11b; Vaccines; Validation; aqueous; base; cost; drug discovery; improved; meetings; next generation; novel vaccines; phase 1 study; phospholipase D1; prevent; protein complex; protein expression; protein protein interaction; prototype; therapeutic protein; vaccine candidate; validation studies

DESCRIPTION (provided by applicant): This proposal involves the development of a high-throughput self-interaction chromatography (SIC) system that will be used by Soluble Therapeutics, LLC, to improve and accelerate the formulation discovery process for biopharmaceuticals (i.e. vaccines, monoclonal antibodies and other therapeutic proteins). Biopharmaceuticals are used to treat a variety of infectious and chronic diseases. According to a Data-Monitor Report published in June, 2008, protein therapeutics represents the second largest segment in pharmaceutical drug discovery. Since 2000, more than 25% of all new drugs approved have been biopharmaceuticals but there development is a time-consuming and costly endeavor. The development of biopharmaceuticals requires that the protein therapeutic is highly soluble since a substantial amount of the protein must be injected in patients via a small volume of solution. Pharmaceutical and biotechnology companies devote significant time and resources developing suitable formulations that allow the desired protein to be concentrated to high levels without inducing instability in the protein. This process of formulation development is often the major bottleneck in the protein therapeutic discovery process. The HSC technology provides a new paradigm for rapidly improving the solubility and physical stability of biopharmaceuticals. The paradigm was validated in phase-1 studies using vaccine candidates obtained from two pharmaceutical companies as well as the proteins osteoprotegerin (involved in bone mineralization and osteoporosis), the cystic fibrosis transmembrane conductance regulator protein (CFTR), the nucleotide-binding domain-1 of CFTR and phospholipase-D1 (a human enzyme responsible for the hydrolysis of phosphatidyl choline). A prototype 2nd generation system was used to improve the solubility and physical stability of each protein by measuring the second virial coefficient (B-value) for the protein in solutions containing different excipients. In addition to developing the 3rd generation system, a second area with significant commercial potential will simultaneously be validated. This involves use of SIC to optimize stabilization of protein complexes and to screen compound or peptide libraries for those that inhibit or augment protein-protein interactions. The development of a 3rd generation, higher throughput system is needed to meet the market demand demonstrated by Soluble Therapeutics via meetings with pharmaceutical and biotechnology company representatives. The proposed technology will accelerate and improve development of clinically useful biopharmaceutical formulations, research conducted by pharmaceutical, biotechnology, government and academic communities. It will also benefit any protein expression research organization (expressing aqueous or membrane proteins) that desires improved solubility and physical stability of expressed protein. It will reduce the cost and time required to develop new vaccines, monoclonal antibodies and other protein therapeutics. Soluble Therapeutics, LLC intends to support biopharmaceutical research as a CRO by establishing collaborative relationships with researchers from industry, academia and the government. PUBLIC HEALTH RELEVANCE: Protein drugs such as insulin, vaccines and antibody therapies interact with natural biomolecular processes in the human body to prevent and treat disease. A significant number of protein drugs - although identified to be relevant to a disease state - are unable to be taken to market by pharmaceutical companies due to the difficult challenge of identifying a formulation which makes the protein drug physically stable and soluble at high concentration. The proposed research will enable Soluble Therapeutics to more rapidly (and cost effectively) to bring new protein drugs to patients.

描述（由申请人提供）：该提案涉及一种高通量自相互作用色谱（SIC）系统的开发，该系统将被Soluble Therapeutics， LLC用于改进和加速生物制药（即疫苗，单克隆抗体和其他治疗性蛋白质）的配方发现过程。生物制药用于治疗各种传染病和慢性疾病。根据2008年6月发布的一份Data-Monitor报告，蛋白质疗法是医药药物发现的第二大领域。自2000年以来，批准的所有新药中有25%以上是生物制药，但它们的开发是一项耗时且昂贵的努力。生物制药的发展要求治疗性蛋白质具有高度可溶性，因为大量蛋白质必须通过小体积的溶液注射到患者体内。制药和生物技术公司投入大量时间和资源开发合适的配方，使所需的蛋白质浓缩到高水平，而不会引起蛋白质的不稳定性。这一配方开发过程往往是蛋白质治疗发现过程中的主要瓶颈。HSC技术为快速提高生物药品的溶解度和物理稳定性提供了新的范例。该模式在从两家制药公司获得的候选疫苗、骨保护蛋白（涉及骨矿化和骨质疏松症）、囊性纤维化跨膜传导调节蛋白（CFTR）、CFTR的核苷酸结合结构域-1和磷脂酶- d1（一种负责磷脂酰胆碱水解的人类酶）的1期研究中得到验证。采用第二代原型系统，通过测量蛋白质在不同赋形剂溶液中的二次维里系数（b值）来提高每种蛋白质的溶解度和物理稳定性。除了开发第三代系统外，还将同时验证具有重大商业潜力的第二个领域。这包括使用SIC来优化蛋白质复合物的稳定性，并筛选那些抑制或增强蛋白质相互作用的化合物或肽库。可溶性治疗公司通过与制药和生物技术公司代表的会议表明，需要开发第三代、更高通量的系统来满足市场需求。拟议的技术将加速和改善临床有用的生物制药配方的开发，以及制药、生物技术、政府和学术界进行的研究。它也将有利于任何蛋白质表达研究组织（表达水或膜蛋白），希望提高所表达蛋白质的溶解度和物理稳定性。它将减少开发新疫苗、单克隆抗体和其他蛋白质疗法所需的成本和时间。可溶性Therapeutics， LLC打算通过与工业界、学术界和政府的研究人员建立合作关系，作为CRO支持生物制药研究。