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. [unreadable] [unreadable] [unreadable]