PFI-TT: A High-Throughput Instrument for Measuring the Stability of Liquid Formulations of Therapeutic Proteins

PFI-TT：用于测量治疗性蛋白质液体制剂稳定性的高通量仪器

• 批准号: 1919083
• 负责人: Paul Cremer
• 金额: $ 25万
• 依托单位: Pennsylvania State Univ University Park
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1919083&HistoricalAwards=false
• 关键词: PFI; TT; Throughput; Instrument; Measuring

The broader impact/commercial potential of this Partnerships for Innovation-Technology Translation (PFI-TT) project is the development of an instrument that will reduce the time required to screen the stability of therapeutic proteins, which have revolutionized the ability to fight diseases like cancer, Alzheimer's disease, and arthritis. The stability of these protein-based drugs is a major concern for ensuring a 2-year shelf-life for liquid formulations under refrigerated temperatures. Currently, the industry assessment standard involves 1-month long stability tests under stressed storage conditions. Improving the efficiency and accuracy of alternative pre-formulation and formulation screening tools should reduce the time required for phase 1 of drug development and make it possible to explore more proteins and more solution conditions. It is expected that the incorporation of this technology into the formulation workflow should help increase the number of therapeutic proteins that can be brought to market and reduce the cost of the products being sold. The proposed project involves the construction of a device designed to measure the susceptibility of a therapeutic protein to phase separation. Like oil and water, concentrated therapeutic protein solutions can separate into two distinct phases below a phase separation temperature, where the solution becomes cloudy. The phase separation temperature and the kinetics of the phase separation provide valuable metrics for instability and can be monitored by simple light scattering measurements via dark-field microscopy. Herein, we outline the development of hardware and software for a temperature gradient microfluidics device that can induce phase separation and extract parameters describing the underlying protein-protein interactions of the phase transition. The goals of this project are to engineer an automated system for controlling the temperature gradient, optical instrumentation, and data analysis. Ultimately, these research and development efforts will provide a prototype version of the temperature gradient microfluidics technology that can be implemented for measuring the stability of a variety of therapeutic proteins. Such high-throughput measurements will enable the exploration of pH, salt, buffers, and protein chemistries that contribute to formulation instability.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

这种伙伴关系对创新技术翻译（PFI-TT）项目的更广泛的影响/商业潜力是开发一种仪器，该工具将减少筛选治疗蛋白稳定性所需的时间，这些蛋白质的稳定性彻底改变了抗击诸如癌症，阿尔茨海默氏病和关节炎等疾病的能力。这些基于蛋白质的药物的稳定性是确保在冷藏温度下确保液体制剂的2年保质期的主要问题。目前，行业评估标准涉及在压力储存条件下进行1个月的稳定性测试。提高替代预制和配方筛选工具的效率和准确性应减少药物开发的第一阶段所需的时间，并使探索更多蛋白质和更多溶液条件成为可能。预计将该技术纳入配方工作流程应有助于增加可以将其推向市场并降低所售产品成本的治疗蛋白的数量。提出的项目涉及构建旨在测量治疗蛋白对​​相分离的敏感性的设备。像油和水一样，浓缩的治疗蛋白溶液可以在相分离温度下方分成两个不同的阶段，在该温度下，溶液变得多云。相分离温度和相位分离的动力学为不稳定性提供了有价值的指标，可以通过暗场显微镜通过简单的光散射测量来监测。本文中，我们概述了温度梯度微流体设备的硬件和软件的开发，该设备可以诱导相位分离并提取描述相变的基本蛋白质 - 蛋白质相互作用的参数。该项目的目标是设计一个自动化系统，以控制温度梯度，光学仪器和数据分析。最终，这些研究和开发工作将提供温度梯度微流体技术的原型版本，可以实施用于测量各种治疗蛋白的稳定性。这种高通量测量将使pH，盐，缓冲液和蛋白质化学分配能够探索有助于配方不稳定性的pH，盐，缓冲液和蛋白质化学分配。该奖项反映了NSF的法定任务，并认为通过基金会的智力优点和更广泛的影响来通过评估进行评估，以评估值得支持。