Optimization of Protein Therapeutics Formulations

描述(由申请人提供)：这项提案涉及开发一种高通量自作用层析(SIC)系统，该系统将被Sole Treateutics LLC使用，以改进和加快生物制药(即疫苗、克隆抗体和其他治疗性蛋白质)的配方发现过程。生物制药被用来治疗各种传染病和慢性病。根据2008年6月发布的一份数据监测报告，蛋白质疗法是药物发现的第二大领域。自2000年以来，所有批准的新药中有超过25%是生物制药，但开发生物制药是一项既耗时又昂贵的工作。生物制药的发展要求蛋白质疗法是高度溶解的，因为大量的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，使所需的蛋白质能够在不引起蛋白质不稳定的情况下浓缩到高水平。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物的溶解度和物理稳定性提供了一种新的范式。这一范例在一期研究中得到了验证，使用的是从两家制药公司获得的候选疫苗，以及骨保护素(与骨矿化和骨质疏松有关)、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)。通过测量蛋白质在含有不同辅料的溶液中的第二维里系数(B值)，使用了原型第二代系统来改善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。这涉及到使用碳化硅来优化蛋白质复合体的稳定性，并为那些抑制或增强蛋白质-蛋白质相互作用的化合物或肽库筛选。需要开发第三代、更高吞吐量的系统，以满足可溶性治疗公司通过与制药和生物技术公司代表的会议所展示的市场需求。这项拟议的技术将加速和改进临床有用的生物制药配方的开发，这是由制药、生物技术、政府和学术界进行的研究。这也将有利于任何希望提高所表达蛋白质的溶解性和物理稳定性的蛋白质表达研究组织(表达水或膜蛋白)。它将减少开发新疫苗、单抗和其他蛋白质疗法所需的成本和时间。可溶性治疗公司打算通过与工业界、学术界和政府的研究人员建立合作关系，支持作为CRO的生物制药研究。 公共卫生相关性：胰岛素、疫苗和抗体疗法等蛋白质药物与人体内的自然生物分子过程相互作用，以预防和治疗疾病。相当数量的蛋白质药物--尽管被确定为与疾病状态相关--无法被制药公司推向市场，因为寻找一种使蛋白质药物在物理上稳定并在高浓度下可溶的配方是一项艰巨的挑战。拟议的研究将使可溶性治疗公司能够更快(也更具成本效益)地将新的蛋白质药物带给患者。

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.