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抗，这种抗体正被用来治疗各种人类疾病。抗体是作为自然免疫系统的一部分，与身体中的物体特定地相互作用的分子。药物开发成本高的一个原因是试图找到合适的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。他们失败的一个原因是药物溶液变得如此稠密，以至于它们无法传递给患者。该项目旨在开发技术，以快速和廉价地确定哪些候选药物存在这一问题，以及如何修改药物以使其更有效。这些发现可以潜在地降低药物开发成本，从而降低患者的新药成本。浓缩抗体溶液的粘性源于抗体之间的成对和高阶相互作用。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颗粒的技术来测量。通过工程改变抗体表面暴露于溶剂的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结合在一起产生整体行为。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反应。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溶液粘度异常高。将实验和计算结果结合起来，有望产生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，使合理设计新的抗体分子具有药物样性质。该项目将在从分子到宏观的范围内，在物理科学和工程的关键方面培训本科生和研究生。这项工作的另一个重点是为代表不足的少数族裔学生制定外展计划。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.