Development and Pharmacology of Novel Lipidic rAHF

新型脂质rAHF的开发及药理学

基本信息

批准号：
7196813
负责人：
SATHY VENKAT BALU-IYER
金额：
$ 27.14万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7196813
关键词：
A Mouse Abbreviations Antibodies Antibody Formation Antigen-Presenting Cells Antigens Area Under Curve Binding Binding Sites Blood Circulation C2 Domain Calcium ion Cell Culture Techniques Choline Circular Dichroism Complex Complication Dendritic Cells Development Dimyristoylphosphatidylcholine Disease Management Dose Drug Formulations Drug Kinetics Drug or chemical Tissue Distribution Encapsulated Epitopes Ethanolamines Ethylene Glycols Exogenous Factors Factor VIII Frequencies Generations Goals Half-Life Hemophilia A Immune response Immune system In Vitro Inflammatory Response Injection of therapeutic agent Knockout Mice LDL-Receptor Related Protein 1 Lead Lipid Binding Lipids Lipopolysaccharides Liposomes Mediating Micelles Modification Molecular Molecular Sieve Chromatography Mus Particle Size Particulate Patients Pharmacologic Substance Pharmacology Phosphatidic Acid Phospholipids Plasma Play Preparation Process Property Protein Binding Protein Engineering Proteins Recombinants Replacement Therapy Research Personnel Reticuloendothelial System Role Serine Structure Surface T-Cell Activation T-Lymphocyte Testing Therapeutic Therapeutic Agents Time Factors Treatment Efficacy base cytokine density design dioleoyl-N-(monomethoxypolyethylene glycol succinyl)phosphatidylethanolamine ethanolamine ethylene glycol immunogenic immunogenicity improved in vivo inhibitor/antagonist liver metabolism molecular assembly/self assembly mouse model nano novel particle prevent programs protein aggregation receptor receptor density recombinant antihemophilic factor VIII research study therapeutic protein uptake von Willebrand Factor

项目摘要

DESCRIPTION (provided by applicant): Advances in protein engineering have led to the development of proteins as therapeutic agents. However, a common complication is the reduction of efficacy due to antibody response. Factors that influence antibody response include protein aggregation, immunogenic sequences within the protein and the frequency of administration. The broad objective of this proposal is to improve therapeutic efficacy of biopharmaceuticals by developing lipid-protein complexes that will reduce immunogenicity and decrease the clearance of the protein, thereby reducing frequency of administration. Factor VIII (FVIII) offers an excellent opportunity to investigate such approaches, as the administration of exogenous FVIII leads to development of inhibitory antibody responses in 15-30% of Hemophilia A patients, complicating replacement therapy. The long term goal of the project is to develop lipidic complexes of FVIII that positively modulate immunogenicity and clearance. During the previous project period, rational approaches led to the development of FVIIIPhosphoserine (PS) complexes that showed reduction in immune response against the protein following its injection in Hemophilia A mice and improved physical stability. The molecular interaction of PS with FVIII and calcium ions was exploited to develop lipid based nano/micro particulates including liposomes and novel condensed and nano-cochleate structures for FVIII delivery. In this proposal, we propose to investigate (1) the mechanism of reduction in immune response mediated by FVIM-PS complexes (2) the effect of low density receptor related protein and von Willebrand factor mediated clearance of FVIII and FVIII-PS complexes and (3) the effect of antibody response on clearance of FVIII and FVIII-PS complexes. The studies aimed at understanding the pharmacology of FVIII-PS complexes will be carried out in Hemophilia A mice model and in vitro with antigen presenting cells such as dendritic cells and T-cells. We propose to investigate key steps in the processing of protein antigen by the immune system in general, which include uptake and processing of FVIII by antigen presenting cells and subsequent presentation and expansion of Tcells. We will investigate the role of PS in modulating the immunogenicity of FVIII (Specific Aim 1). The pharmacokinetic properties of FVIII are complex due to intrinsic protein binding and we will investigate the disposition of FVIII and FVIII-PS complexes mediated by liver metabolism and immune system. In specific aim 2, we will investigate the effect of PS binding and lipid molecular assemblies on pharmacokinetic parameters such as half-life, area under the curve and clearance. Finally, in specific aim 3, we will investigate the effect of antibody response and disposition of FVIII. The results obtained from these studies will be useful to develop optimal dosing and efficient management of the disease and therapy.

描述（由申请人提供）：蛋白质工程的进展导致蛋白质作为治疗剂的发展。但是，常见的并发症是抗体反应引起的疗效降低。影响抗体反应的因素包括蛋白质聚集，蛋白质内的免疫原性序列和给药频率。该建议的广泛目的是通过开发脂质蛋白质复合物来提高生物药物的治疗功效，从而降低免疫原性并降低蛋白质的清除率，从而降低给药频率。因子VIII（FVIII）提供了一个很好的机会来研究这种方法，因为外源性FVIII的给药会导致15-30％的血友病A患者的抑制性抗体反应发展，从而使替代疗法变得复杂。该项目的长期目标是开发FVIII的脂质复合物，从而积极调节免疫原性和清除率。在上一个项目期间，有理方法导致了FVIIIPHosperine（PS）复合物的发展，该复合物在其在血友病A中注射后针对蛋白质的免疫反应降低并改善了身体稳定性。利用PS与FVIII和FVIII和钙离子的分子相互作用开发基于脂质的纳米/微粒颗粒，包括脂质体和新型冷凝和纳米粉和纳米粉状结构进行FVIII递送。在这一建议中，我们建议研究（1）FVIM-PS复合物介导的免疫反应的减少机制（2）低密度受体相关蛋白和Von Willebrand因子介导的FVIII和FVIII-PS复合物的清除率的影响以及FVIIIIIIIIII-PS-PS-PS-PS-PS-PS-PS-PS-PS-PS-PS-PS-PS-PS-PS）的影响。旨在理解FVIII-PS复合物的药理学的研究将在血友病A模型中进行，并在体外与抗原呈递细胞（例如树突状细胞和T细胞）进行。我们建议研究免疫系统处理蛋白质抗原的关键步骤，其中包括通过抗原呈递细胞对FVIII的摄取和加工，以及随后的TCELL呈现和扩展。我们将研究PS在调节FVIII的免疫原性中的作用（特定目标1）。由于固有的蛋白结合，FVIII的药代动力学特性很复杂，我们将研究由肝脏代谢和免疫系统介导的FVIII和FVIII-PS复合物的处置。在特定目标2中，我们将研究PS结合和脂质分子组件对药代动力学参数的影响，例如半衰期，曲线下的面积和间隙。最后，在特定的目标3中，我们将研究FVIII抗体反应和处置的影响。从这些研究中获得的结果将有助于开发对疾病和治疗的最佳剂量和有效治疗。