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

今天最畅销的药物大多是单克隆抗体，它们被用于治疗各种人类疾病。抗体是作为天然免疫系统的一部分与体内物体特异性相互作用的分子。药物开发成本高的一个原因是试图找到正确分子的漫长而不可预测的过程。许多尝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如此粘稠，以至于它们不能被输送到患者体内。该项目旨在开发技术，以快速和廉价地确定哪些候选药物有这个问题，以及如何修改药物，使它们更有效。这些发现可以潜在地降低药物开发成本，从而降低新药对患者的成本。浓缩抗体溶液的粘性是由抗体之间的成对和更高阶相互作用引起的。在这个项目中，这些抗体相互作用将使用研究人员先前开发的基于纳米颗粒的技术来测量。通过工程化改变抗体表面上的溶剂暴露区域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联合收割机结合在一起以产生整体行为。还将使用抗体相互作用测量作为计算机模拟的输入来预测抗体溶液的粘性响应。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。结合实验和计算结果，预计将导致更好的方法来预测抗体序列和结构的变化如何影响粘度。因此，该项目具有重要的潜力，能够合理设计具有药物样特性的新抗体分子。该项目将在从分子到宏观的尺度上对物理科学和工程的关键方面的本科生和研究生进行培训。这项工作的另一个重点是发展外展计划，以代表性不足的少数民族学生。这个奖项反映了NSF的法定使命，并已被认为是值得通过评估使用基金会的智力价值和更广泛的影响审查标准的支持。

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.