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（由申请人提供）：水溶液中的生物药物，包括球状蛋白和抗体药物，不稳定。这些药物降解的主要途径是聚集，这会使它们失活，也可能导致免疫原性物质。在水溶液中生物药物的浓度越高，聚集的易感性就越容易受到影响。然而，这些药物的首选递送方法在水溶液中涉及尽可能高的浓度。例如，如果可以开发出高浓度的抗体药物水配方剂，则可以在一次注射中皮下递送，这是一种在典型的静脉输送途径上高度优选的递送途径。此外，如果可以在非常高的浓度下稳定生物药物，则可以使用可植入的设备，这将使它们在一段时间内通过受控释放进行交付。此外，当前的生物药物稳定方法是添加小分子，这是通过试验和误差选择的，其中试验范围充其量是使用启示术的指导。我们建议使用基于我们最近开发和发布的理论框架的理性方法来开发新的添加剂。这些称为“中性人群”的新添加剂应大大降低聚合速率，而不会影响生物制药的其他特性。我们预测，我们的中立人群可以通过1000的因素降低生物制药的聚集率。该提案重点是合成和测试的一系列添加剂，这些添加剂是假定的中立人群。此外，我们建议开发一系列测定法，以测试我们新添加剂的普遍适用活性，以稳定蛋白质，以稳定蛋白质，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正充当中立人群，以及（2）添加剂是否具有我们理论提出的稳定效果。新添加剂的成功开发从很小的数字到潜在的巨大数量开发了可能性领域。它可能导致开发新的分娩方法，这些方法将使患者受益匪浅，例如皮下注射，这可以取代静脉输送，并可能通过可植入的设备长期递送。