Development and pharmacology of novel lipidic rAHF

新型脂质rAHF的开发和药理学

• 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
• 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

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）：针对治疗性蛋白质（如因子VIII（FVIII））的抗体应答的发展是一种主要的临床并发症，其损害了基于蛋白质的治疗剂的安全性和有效性。我们的目标是通过开发非免疫原性形式的分子来改善蛋白质的治疗功效。FVIII是一种多结构域蛋白，在凝血级联中起关键作用。FVIII的缺乏和功能障碍导致血友病A，一种出血性疾病。重组FVIII给药是血友病A（HA）患者的一线治疗。这种替代疗法的安全性和有效性因15-30%接受FVIII治疗的HA患者出现抑制性抗体应答而严重受损。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）复合，对FVIII的抗体应答显著降低。为了利用这一新的发现来开发治疗上更有效的FVIII形式，并确定这些脂质修饰如何与其他治疗性蛋白质一起使用，必须确定实现免疫原性降低的机制。因此，在目的1中，我们提出确定抗体应答的降低是否是由于脂质复合物改变抗原加工和蛋白质呈递的能力，导致HA小鼠中免疫耐受的主动诱导。或者，我们将确定它是否是由于一个被动的过程，从脂质屏蔽免疫原性决定簇的结果。这些研究将揭示观察到的抗体应答降低的稳健性、特异性、安全性和持久性，并将确定脂质复合物降低或消除已建立的抗FVIII抗体应答的程度。因为施用频率增加免疫原性应答，所以降低施用频率的长效脂质-FVIII复合物是有用的。在目的2中，将研究脂质头基和PEG修饰对FVIII药代动力学（PK）的影响。将通过定量和比较经皮给药FVIII制剂达到的FVIII水平与单独使用FVIII观察到的FVIII水平，确定PK特性，如静脉或皮下注射后FVIII的循环半衰期、平均滞留时间和暴露量。FVIII的止血疗效是具有临床意义的关键终点。目的3将通过使用体内标准化尾静脉横切测定来确定脂质复合如何影响脂质复合FVIII的药效学和治疗功效。在SA 4中，将在灵长类动物模型猕猴（Macaque mulatta）中测试FVIII-脂质复合物的免疫原性和PK降低的转化效用。这些研究有望阐明免疫原性FVIII复合物降低免疫原性的机制基础，并改善动物模型中的药代动力学和治疗功效，从而使该观察结果可扩展至临床试验，并也应用于其他治疗性蛋白质的设计、配制和递送，以克服对其临床使用产生负面影响的问题。