Development and pharmacology of novel lipidic rAHF

新型脂质rAHF的开发和药理学

基本信息

批准号：
8471155
负责人：
SATHY VENKAT BALU-IYER
金额：
$ 38万
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 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8471155
关键词：
A Mouse Address Adoptive Transfer Affect Animal Model Animals Antibodies Antibody Formation Antigen Presentation Pathway B-Lymphocytes Biological Biological Assay Biophysics Blood Circulation Blood coagulation Cell Culture Techniques Clinical Clinical Trials Complex Complication Dendritic Cells Deposition Development Disease Drug Formulations Drug Kinetics Exogenous Factors Experimental Designs Factor VIII Frequencies Functional disorder Goals Half-Life Hemophilia A Hemorrhage Hemostatic Agents Image Immune Tolerance Immune response Immunology Injection of therapeutic agent Interleukin-10 Interleukin-17 Interleukin-6 Knock-out Lipids Lymphatic Macaca Mediating Modeling Modification Mus Outcome Patients Pharmacodynamics Pharmacology Phosphatidylglycerols Phosphatidylinositols Phosphatidylserines Phospholipids Play Positron-Emission Tomography Preparation Primates Process Property Proteins Public Health Replacement Therapy Research Role Route Safety Signal Transduction Specificity T-Lymphocyte Tail Techniques Tertiary Protein Structure Testing Therapeutic Time Time Factors Tissues Treatment Efficacy Tweens Up-Regulation Veins Work absorption base clinically relevant clinically significant design immunogenic immunogenicity improved in vivo interdisciplinary approach lymph nodes nanoscale novel particle protein complex recombinant antihemophilic factor VIII residence response therapeutic protein uptake

A Mouse Address Adoptive Transfer Affect Animal Model Animals Antibodies Antibody Formation Antigen Presentation Pathway B-Lymphocytes Biological Biological Assay Biophysics Blood Circulation Blood coagulation Cell Culture Techniques Clinical Clinical Trials Complex Complication Dendritic Cells Deposition Development Disease Drug Formulations Drug Kinetics Exogenous Factors Experimental Designs Factor VIII Frequencies Functional disorder Goals Half-Life Hemophilia A Hemorrhage Hemostatic Agents Image Immune Tolerance Immune response Immunology Injection of therapeutic agent Interleukin-10 Interleukin-17 Interleukin-6 Knock-out Lipids Lymphatic Macaca Mediating Modeling Modification Mus Outcome Patients Pharmacodynamics Pharmacology Phosphatidylglycerols Phosphatidylinositols Phosphatidylserines Phospholipids Play Positron-Emission Tomography Preparation Primates Process Property Proteins Public Health Replacement Therapy Research Role Route Safety Signal Transduction Specificity T-Lymphocyte Tail Techniques Tertiary Protein Structure Testing Therapeutic Time Time Factors Tissues Treatment Efficacy Tweens Up-Regulation Veins Work absorption base clinically relevant clinically significant design immunogenic immunogenicity improved in vivo interdisciplinary approach lymph nodes nanoscale novel particle protein complex recombinant antihemophilic factor VIII residence response therapeutic protein uptake

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项目摘要

DESCRIPTION (provided by applicant): The development of antibody responses against therapeutic proteins such as Factor VIII (FVIII) is a major clinical complication that compromises the safety and efficacy of protein based therapeutics. Our goal is to improve upon the therapeutic efficacy of proteins by developing non-immunogenic forms of the molecules. FVIII is a multi-domain protein that plays a critical role in blood coagulation cascade. The deficiency and dysfunction of FVIII causes Hemophilia A, a bleeding disorder. Administration of recombinant FVIII is the first line of therapy for Hemophilia A (HA) patients. The safety and efficacy of this replacement therapy is severely compromised by the development of inhibitory antibody responses that occur in 15-30% of HA patients treated with FVIII. We have established that the antibody response to FVIII is reduced significantly by complexing the protein with phosphatidylserine (FVIII-PS) or phosphatidylinositol (FVIII-PI). To exploit this novel finding for developing a more therapeutically effective form of FVIII, and to determine how such lipid modifications may be used with other therapeutic proteins, it is imperative to determine the mechanisms by which the reduction of immunogenicity is achieved. Therefore, in Aim 1 we propose to establish whether the decrease in the antibody response is due to the lipid complexes' ability to alter antigen processing and presentation of the protein, resulting in active induction of immunological tolerance in HA mice. Alternatively we will determine whether it is due to a passive process that results from lipid shielding of immunogenic determinants. These studies will reveal the robustness, specificity, safety and durability of the reduced antibody responses observed, and will establish the degree to which the lipid complexes reduce or eliminate an already-established anti-FVIII antibody response. Because the frequency of administration increases immunogenic response, long acting lipid-FVIII complexes that reduce the frequency of administration are useful. In Aim 2, the effect of lipid headgroup and PEG modification upon the pharmacokinetics (PK) of FVIII will be investigated. PK properties, such as circulation half-life, mean residence time and exposure of FVIII following iv or sc injection, will be established by quantifying and comparing the FVIII levels achieved with lipidic FVIII formulations to those observed with FVIII alone. The haemostatic efficacy of FVIII is the key endpoint of clinical significance. Aim 3 will establish how lipid complexation affects the pharmacodynamics and therapeutic efficacy of the lipid- complexed FVIII by using an in vivo standardized tail vein transection assay. In SA 4, the translational utility of reduction in immunogenicity and PK of FVIII-lipid complex will be tested in a primate model, Macaque mulatta. These studies are expected to elucidate the mechanistic basis by which lipidic FVIII complexes decrease immunogenicity, and improve pharmacokinetics and therapeutic efficacy in animal models, so that this observation may be extended to clinical trial, and applied also to the design, formulation and delivery of other therapeutic proteins, so as to overcome issues that negatively impact their clinical use.

描述（由申请人提供）：针对治疗蛋白（例如因子VIII（FVIII））的抗体反应的发展是损害基于蛋白质疗法的安全性和功效的主要临床并发症。我们的目标是通过开发分子的非不良形式来提高蛋白质的治疗功效。 FVIII是一种多域蛋白，在血液凝结级联反应中起关键作用。 FVIII的缺乏和功能障碍会导致血友病A，一种出血障碍。重组FVIII的给药是血友病A（HA）患者的第一道治疗。这种替代疗法的安全性和功效严重损害了通过FVIII治疗的15-30％的HA患者发生的抑制性抗体反应。我们已经确定，通过将蛋白质与磷脂酰丝氨酸（FVIII-PS）或磷脂酰肌醇（FVIII-PI）复杂化，从而显着降低了对FVIII的抗体反应。为了利用这一新发现来开发更有效的FVIII形式，并确定如何将这种脂质修饰与其他治疗蛋白一起使用，必须确定可实现免疫原性的机制。因此，在AIM 1中，我们建议确定抗体反应的降低是否是由于脂质复合物改变抗原加工和蛋白质的表现的能力，从而导致HA小鼠中的免疫耐受性积极诱导。另外，我们将确定是否是由于免疫决定因素脂质屏蔽产生的被动过程。这些研究将揭示观察到的抗体反应减少的鲁棒性，特异性，安全性和耐用性，并将确定脂质复合物降低或消除已经建立的抗FVIII抗体反应的程度。由于给药的频率增加了免疫原性反应，因此降低给药频率的长作用脂质-FVIII复合物很有用。在AIM 2中，将研究脂质头组和PEG修饰对FVIII药代动力学（PK）的影响。 PK特性（例如循环半衰期，静脉注射或SC注射后的平均停留时间和FVIII的暴露）将通过量化和比较与单独使用FVIII观察到的脂质FVIII公式的FVIII水平来确定。 FVIII的止血功效是临床意义的关键终点。 AIM 3将通过使用体内标准化的尾静脉透射测定法来确定脂质络合如何影响脂质络合FVIII的药效学和治疗功效。在SA 4中，将在灵长类动物模型Macaque Mulatta中测试免疫原性和PK的降低的转化实用性。预计这些研究将阐明脂质FVIII复合物可降低免疫原性的机理基础，并提高动物模型中的药代动力学和治疗功效，从而可以将这种观察扩展到临床试验中，并应用于其他治疗蛋白的设计，表述和交付，以克服其临床问题，从而对其进行临床效果。