Design and Testing of New Additives for the Stabilization of Biopharmaceuticals

描述（由申请人提供）：生物药品，包括球状蛋白和抗体药物，在水溶液中不稳定。这些药物降解的主要途径是聚集，这使它们失活，也可能导致免疫原性物质。生物药品在水溶液中的浓度越高，越容易发生聚集。然而，这些药物的首选递送方法是在水溶液中尽可能高的浓度。例如，如果可以开发出高浓度的抗体药物水制剂，它们可以一次注射皮下给药，这种给药途径比典型的静脉给药途径更受欢迎。此外，如果生物制药可以在非常高的浓度下稳定，可以使用植入式装置，这将允许它们在一段时间内以可控的释放被递送。此外，目前稳定生物制药的方法是添加小分子，通过试验和错误选择，其中试验范围最好使用启发式指导。我们建议使用基于我们最近开发和发表的理论框架的合理方法开发新的添加剂。这些新的添加剂，被称为“中性聚合剂”，应该会在不影响生物制药的其他特性的情况下大大降低聚合速度。我们预测，我们的中性crowders可以将生物制药的聚集率降低1000倍。本课题主要是合成和测试一系列假定为中性添加剂的添加剂。此外，我们建议开发一系列的试验来测试我们的新添加剂的普遍适用的活性，以稳定蛋白质的聚集，并阐明这些添加剂的作用。因此，我们应该能够测试(1)我们设计的添加剂是否真的起到中性增稠剂的作用，(2)添加剂是否具有我们理论所提出的稳定作用。新添加剂的成功开发打开了可能性的领域，从非常小的数量到潜在的巨大数量。这可能会导致新的输送方式的发展，将极大地造福患者，如皮下注射，它可以取代静脉输送和通过植入式装置长期输送的可能性。

DESCRIPTION (provided by applicant): Biopharmaceuticals, including globular protein and antibody drugs, are unstable in aqueous solution. The major route of degradation of these drugs is aggregation, which deactivates them and can also lead to immunogenic substances. The higher the concentration of biopharmaceuticals in aqueous solution, the more susceptible they are to aggregation. Yet the preferred methods of delivery of these drugs involve as high a concentration as possible in aqueous solution. For example, if high concentration aqueous formulations of antibody drugs could be developed, they could be delivered subcutaneously in one injection, a delivery route which is highly preferred over the typical route of intravenous delivery. In addition, if biopharmaceuticals could be stabilized at very high concentrations, implantable devices could be used, which will allow them to be delivered over a period of time with controlled release. Furthermore, the current approach to stabilization of biopharmaceuticals is to add small molecules, chosen via trial and error, where the ranges of trials are at best guided using heuristics. We propose to develop new additives using a rational approach based on a theoretical framework that we recently developed and published. These new additives, called "neutral crowders," should substantially reduce the rate of aggregation without affecting other properties of the biopharmaceuticals. We predict that our neutral crowders could reduce the rate of aggregation of biopharmaceuticals by factors of 1000's. This proposal focuses on synthesizing and testing series of additives that are putative neutral crowders. In addition, we propose to develop a series of assays to test the generally applicable activity for our new additives to stabilize proteins against aggregation and to elucidate the action of these additives. We should thus be able to test (1) whether the additives that we designed really act as neutral crowders and (2) whether the additives have the stabilizing effect that our theories propose. The successful development of new additives opens up the realm of possibility from a very small number to a potentially huge number. It could lead to the development of new delivery approaches that will benefit patients tremendously, such as subcutaneuous injection, which could replace intravenous delivery and the possibility of long term delivery through inplantable devices.