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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：
7341719
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/7341719
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 Phosphoserine 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

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 FVIII- Phosphoserine (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 T- cells. 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.

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