Design and Testing of New Additives for the Stabilization of Biopharmaceuticals

用于稳定生物制药的新添加剂的设计和测试

• 批准号: 7314659
• 负责人: BERNHARDT L TROUT
• 金额: $ 19.43万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-09 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7314659
• 关键词: Affect; Antibodies; Arginine; Biological Assay; Circular Dichroism Spectroscopy; Class; Complex; Condition; Densitometry; Development; Devices; Differential Scanning Calorimetry; Drug Delivery Systems; Drug Formulations; Effectiveness; Event; Excipients; Freeze Drying; Funding Mechanisms; Goals; High Pressure Liquid Chromatography; Injectable; Injection of therapeutic agent; Intravenous; Ions; Kinetics; Lead; Learning; Libraries; Life; Liquid substance; Marketing; Measures; Methodology; Methods; Modeling; Molecular Conformation; Molecular Sieve Chromatography; Molecular Weight; Monitor; N-substituted Glycines; Numbers; Patients; Peptide Library; Peptides; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Powder dose form; Principal Investigator; Process; Property; Protein Binding; Proteins; Publishing; Range; Rate; Research Personnel; Research Project Grants; Resources; Rewards; Risk; Route; S Phase; Salmo trutta; Salts; Series; Site; Solid; Solutions; Spectrometry, Mass, Electrospray Ionization; Spectrum Analysis; Structure; Testing; Therapeutic antibodies; Time; Validation; Work; analytical ultracentrifugation; aqueous; base; clinical application; controlled release; cost; design; globular protein; heuristics; immunogenic; implantable device; improved; light scattering; novel; prevent; programs; protein aggregation; protein folding; protein protein interaction; research and development; size; small molecule; solute; sugar; theories; tool

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.

描述(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。这些药物的主要降解途径是聚集，这会使它们失活，也会导致免疫原性物质的产生。水溶液中生物药物的浓度越高，它们越容易聚集。然而，这些药物的首选给药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溶液配方，它们可以在一次注射中被皮下注射，这种给药途径比典型的静脉给药方式更受欢迎。此外，如果生物药物可以稳定在非常高的浓度，可以使用植入性装置，这将使它们能够在一段时间内以受控释放的方式输送。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，其中试验的范围充其量是使用启发式指导的。我们建议在我们最近开发和发表的理论框架的基础上，使用合理的方法开发新的添加剂。这些新的添加剂被称为“中性聚集物”，应该会大大降低聚集率，而不会影响生物制药的其他性质。我们预测，我们的中性人群可以使生物药物的聚集率降低1000倍，S。这项建议集中在合成和测试一系列可能的中性人群的添加剂。此外，我们建议开发一系列检测方法，以测试我们的新添加剂稳定蛋白质抗聚集的普遍适用活性，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了中性人群的作用，以及(2)这些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，从非常小的数字到潜在的巨大数字。这可能会导致新的给药方法的开发，这些方法将使患者受益匪浅，例如皮下注射，可以取代静脉给药，以及通过植入性设备进行长期给药的可能性。