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)：蛋白质工程的进步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降低了疗效。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。这项提议的广泛目标是通过开发脂质-蛋白质复合体来提高生物药物的治疗效果，这种复合体将降低免疫原性并减少蛋白质的清除，从而减少给药频率。因子(FVIII)为研究这些途径提供了一个极好的机会，因为外源性FVIII的使用会导致15%-30%的血友病A患者产生抑制性抗体反应，从而使替代疗法复杂化。该项目的长期目标是开发FVIII的脂类复合体，积极调节免疫原性和清除性。在之前的项目期间，合理的方法导致了FVIIIPhoserine(PS)复合体的开发，该复合体在注射该蛋白后，在血友病A小鼠中表现出对该蛋白的免疫反应降低，并改善了身体稳定性。利用PS与FVIII和钙离子的分子相互作用，开发了基于脂质的纳米/微粒子，包括脂质体和用于FVIII传递的新型凝聚和纳米蜗体结构。在这项研究中，我们建议研究(1)FVIM-PS复合体介导的免疫应答降低的机制；(2)低密度受体相关蛋白和von Willebrand因子介导的FVIII和FVIII-PS复合体清除的作用；(3)抗体应答对FVIII和FVIII-PS复合体清除的影响。这些研究旨在了解FVIII-PS复合体的药理作用，将在血友病A小鼠模型中进行，并在体外使用抗原提呈细胞，如树突状细胞和T细胞。我们建议研究免疫系统处理蛋白质抗原的关键步骤，包括抗原提呈细胞对FVIII的摄取和处理，以及随后T细胞的提呈和扩增。我们将研究PS在调节FVIII免疫原性中的作用(特异性目标1)。由于固有的蛋白质结合，FVIII的药代动力学特性是复杂的，我们将研究FVIII和FVIII-PS复合体在肝脏代谢和免疫系统中的处置。在具体目标2中，我们将研究PS结合和脂质分子组装对药物动力学参数的影响，如半衰期、曲线下面积和清除度。最后，在特定的目标3中，我们将研究FVIII的抗体应答和处置的影响。从这些研究获得的结果将有助于开发最佳剂量和有效的疾病管理和治疗。