Development and Pharmacology of Novel Lipidic rAHF

新型脂质rAHF的开发及药理学

• 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
• 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

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了蛋白质作为治疗剂的发展。然而，一个常见的并发症是由于抗体反应而导致的疗效降低。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。该提案的广泛目标是通过开发脂质-蛋白质复合物来提高生物药物的治疗功效，所述脂质-蛋白质复合物将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）为研究此类方法提供了极好的机会，因为外源性FVIII给药导致15-30%的血友病A患者出现抑制性抗体应答，使替代治疗复杂化。该项目的长期目标是开发能够积极调节免疫原性和清除率的FVIII的免疫复合物。在上一个项目期间，合理的方法导致FVIIIPphosphoserine（PS）复合物的开发，该复合物显示在血友病A小鼠中注射后针对蛋白质的免疫应答降低，并改善了物理稳定性。利用PS与FVIII和钙离子的分子相互作用来开发基于脂质的纳米/微米颗粒，包括脂质体和用于FVIII递送的新型浓缩和纳米卷结构。在该提案中，我们建议研究（1）FVIM-PS复合物介导的免疫应答降低的机制（2）低密度受体相关蛋白和血管性血友病因子介导的FVIII和FVIII-PS复合物清除的作用和（3）抗体应答对FVIII和FVIII-PS复合物清除的作用。旨在了解FVIII-PS复合物药理学的研究将在血友病A小鼠模型中进行，并在体外使用抗原呈递细胞如树突状细胞和T细胞进行。我们建议研究一般免疫系统处理蛋白质抗原的关键步骤，包括抗原呈递细胞对FVIII的摄取和处理以及随后T细胞的呈递和扩增。我们将研究PS在调节FVIII（特异性目的1）免疫原性中的作用。由于固有的蛋白结合，FVIII的药代动力学性质是复杂的，我们将研究肝脏代谢和免疫系统介导的FVIII和FVIII-PS复合物的处置。在具体目标2中，我们将研究PS结合和脂质分子组装体对药代动力学参数如半衰期、曲线下面积和清除率的影响。最后，在具体目标3中，我们将研究抗体应答和FVIII处置的影响。从这些研究中获得的结果将有助于开发疾病和治疗的最佳剂量和有效管理。