Collaborative Research: GOALI: Nanoparticle analysis of antibody colloidal interactions and their influence on viscoelastic properties of concentrated antibody solutions

目前最畅销的药物大多是单克隆抗体，用于治疗各种各样的人类疾病。抗体是一种分子，作为自然免疫系统的一部分，它与体内的物体有特异性的相互作用。药物开发成本高的一个原因是寻找合适分子的过程漫长而不可预测。许多被试过的分子都不起作用。它们失败的一种方式是药物溶液变得太稠，无法输送到患者体内。该项目旨在开发技术，快速而廉价地确定哪些候选药物有这个问题，以及如何修改药物使其更有效。这些发现可能会降低药物开发成本，从而降低患者使用新药的成本。浓缩抗体溶液的粘性是由抗体之间的成对和高阶相互作用造成的。在这个项目中，这些抗体的相互作用将使用研究人员先前开发的基于纳米粒子的技术进行测量。通过对抗体表面的溶剂暴露区域进行工程改变，并测量总的有效分子间相互作用，将确定抗体表面的不同部分如何结合在一起，从而产生整体行为。抗体溶液的粘性响应也将使用抗体相互作用测量作为计算机模拟的输入来预测。研究人员还将使用计算机模拟来确定抗体相互作用如何导致异常高的溶液粘度。实验和计算相结合的结果有望为预测抗体序列和结构的变化如何影响粘度提供更好的方法。因此，该项目在合理设计具有药物性质的新抗体分子方面具有重大潜力。该项目将在从分子到宏观的尺度上培养物理科学和工程的关键方面的本科生和研究生。这项工作的另一个重点是为代表性不足的少数民族学生发展外展项目。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Most of the best-selling drugs today are monoclonal antibodies, which are being used to treat a wide range of human disorders. Antibodies are molecules that interact specifically with objects in the body as part of the natural immune system. One reason for the high cost of drug development is the long and unpredictable process of trying to find the right molecule. Many molecules that are tried do not work. One way in which they fail is that the drug solutions become so thick that they cannot be delivered to the patient. This project aims to develop technologies for rapidly and cheaply determining which drug candidates have this problem as well as how to modify drugs to make them more effective. These findings can potentially lower drug development costs and thereby the cost of new drugs to patients.The viscous nature of concentrated antibody solutions results from pairwise and higher order interactions between antibodies. In this project, these antibody interactions will be measured using a nanoparticle-based technique previously developed by the investigators. By engineering changes to solvent-exposed regions on the antibody surface and measuring the total effective intermolecular interaction, it will be determined how different parts of the antibody surface combine together to give rise to the overall behavior. The viscous response of antibody solutions will also be predicted using antibody interaction measurements as inputs to computer simulations. The investigators will also use computer simulations to determine how antibody interactions cause abnormally high solution viscosities. The combined experimental and computational findings are expected to lead to better methods for predicting how changes in antibody sequence and structure impact viscosity. Therefore, this project holds significant potential to enable the rational design of new antibody molecules with drug-like properties. The project will train undergraduate and graduate students in key aspects of physical science and engineering at scales ranging from molecular to macroscopic. Another key focus of this work is the development of outreach programs to underrepresented minority students.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.