Design and Testing of New Additives for the Stabilization of Biopharmaceuticals

性状（申请人提供）：生物药物，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。水溶液中生物药物的浓度越高，它们越容易聚集。然而，这些药物的优选递送方法涉及在水溶液中尽可能高的浓度。例如，如果可以开发抗体药物的高浓度水性制剂，则它们可以在一次注射中皮下递送，这是一种比典型的静脉内递送途径更优选的递送途径。此外，如果生物药物可以稳定在非常高的浓度，可以使用植入式装置，这将允许它们在一段时间内以受控释放的方式递送。此外，目前稳定生物药物的方法是添加通过试错法选择的小分子，其中试验范围最多使用化学方法指导。我们建议使用基于我们最近开发和出版的理论框架的合理方法开发新的添加剂。这些新的添加剂，称为“中性拥挤剂”，应该大大降低聚集率，而不影响生物药物的其他特性。我们预测，我们的中性人群可以减少生物制药的聚集率的1000倍。该提案的重点是合成和测试一系列添加剂，这些添加剂是假定的中性拥挤剂。此外，我们建议开发一系列试验，以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拥挤剂的作用，以及（2）添加剂是否具有我们的理论所提出的稳定作用。新添加剂的成功开发开辟了可能性的领域，从非常小的数量到潜在的巨大数量。它可能会导致新的输送方法的发展，这将使患者受益匪浅，例如皮下注射，这可以取代静脉内输送和通过植入式设备长期输送的可能性。

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.