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:6623164
- 负责人:
- 金额:$ 19.01万
- 依托单位:
- 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 2006-03-31
- 项目状态:已结题
- 来源:
- 关键词:biological transport biotherapeutic agent blood /lymphatic pharmacology blood disorder chemotherapy chemical aggregate chemical stability chemical structure function circular dichroism coagulation factor VIII conformation drug design /synthesis /production fluorescence spectrometry hemophilia As immunologic assay /test immunoregulation intermolecular interaction laboratory rat lipids liposomes macrophage molecular shape molecular site pharmacokinetics physical property protein folding recombinant proteins
项目摘要
DESCRIPTION (provided by applicant): Hemophilia A is an inherited bleeding
disorder caused by deficiency of Factor VIII, a blood coagulation protein that
functions as a cofactor in the coagulation cascade. It is transmitted as a
defect on the X chromosome and affects 1 male in 5000. Recent advances in
biotechnology and protein engineering, together with cloning of the gene coding
for Factor VIII, have made it feasible to manufacture recombinant human Factor
VIII (rAHF). The recombinant preparation promises to be a source of unlimited
supply, together with the freedom from the complications of transmission of
blood-borne viruses. However, rAHF induces antibody type immune response or
inhibitors. It has been shown that immune response for a therapeutic protein is
caused by the existence of aggregates, frequent administration and existence of
natural antibodies for specific epitope region of the protein. Furthermore, a
moderately-short circulating half-time limits the duration of pharmacological
effect. The overall goal of this proposal is to develop a lipid-based delivery
vehicle for AHF to overcome the immune response and extend circulating halflife
(Inhibitor Treatment for Hemophilia using Lipid Protein System, ITHELPS). The
rationale to use lipidic protein complexes is three fold: (1) the epitope
region of the protein binds to phospholipids, and thus by engineering a
lipid-protein complex one could shield the epitope region; (2) the lipidic
components can interact with intermediate structures in the
unfolding/denaturation pathway, thus stabilizing protein structure during
storage and reconstitution, thereby avoiding protein aggregate formation, and
(3) the lipid-protein complexes, analogous to liposomal particles, may increase
the circulation half-life of the rAHF, thus reducing the frequency of
administration. In support of these hypotheses, preliminary studies were
carried out to develop rationally a lipidic rAHF. The liposomal vesicles
stabilized the protein against aggregation and a prototype formulation with
lipidic rAHF was achieved. We propose to characterize the molecular topology,
pharmacokinetic behavior and immune response of this novel, rationally
developed lipidic rAHF. Further, we propose to investigate liposomal clearance
mechanisms, including endocytosis and its role in altering the circulation time
and immune response of lipidic rAHF. We also propose to study the epitope
specificity of rAHF antibodies and the mechanism of immune response.
描述(由申请人提供):血友病A是一种遗传性出血
由缺乏凝血因子VIII引起的疾病,凝血因子VIII是一种凝血蛋白,
在凝血级联反应中起辅助因子的作用。它是作为一个
X染色体上的缺陷,每5000名男性中就有1名受到影响。的最新进展
生物技术和蛋白质工程,以及基因编码的克隆
对于因子VIII,已经使得生产重组人因子
VIII(rAHF).重组制剂有望成为一个无限的来源,
供应,以及免受传播并发症的困扰
血液传播的病毒然而,rAHF诱导抗体型免疫应答或
抑制剂的已经表明,对治疗性蛋白质的免疫应答是免疫应答的一部分。
由于聚集体的存在、频繁的给药和
针对蛋白质的特定表位区域的天然抗体。而且有
中短的循环半衰期限制了药理学作用的持续时间,
效果该提案的总体目标是开发一种基于脂质的递送
AHF的载体,以克服免疫应答并延长循环半衰期
(使用脂质蛋白系统的血友病抑制剂治疗,CYCLELPS)。的
使用噬菌体蛋白复合物的基本原理有三个方面:(1)表位
蛋白质的区域结合磷脂,因此通过工程改造,
脂质-蛋白复合物可屏蔽抗原表位区;
组件可以与
解折叠/变性途径,从而稳定蛋白质结构,
储存和重构,从而避免蛋白质聚集体形成,和
(3)类似于脂质体颗粒的脂质-蛋白质复合物可以增加
rAHF的循环半衰期,从而降低了
局为了支持这些假设,进行了初步研究。
为合理开发无菌rAHF进行了研究。脂质体囊泡
稳定蛋白质以防止聚集,并且具有以下的原型制剂:
实现了无菌rAHF。我们提出的分子拓扑结构的特点,
药代动力学行为和免疫应答,合理地
开发了脂质rAHF。此外,我们建议研究脂质体清除率
机制,包括内吞作用及其在改变循环时间中的作用
和rAHF的免疫应答。我们还建议研究表位
rAHF抗体的特异性和免疫应答机制。
项目成果
期刊论文数量(0)
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SATHY VENKAT BALU-IYER其他文献
SATHY VENKAT BALU-IYER的其他文献
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{{ truncateString('SATHY VENKAT BALU-IYER', 18)}}的其他基金
Development of tolerogenic Factor VIII as immunotherapy to prevent inhibitor development in Hemophilia A
开发耐受性因子 VIII 作为免疫疗法来预防 A 型血友病抑制剂的产生
- 批准号:
10594819 - 财政年份:2023
- 资助金额:
$ 19.01万 - 项目类别:
Development and Pharmacology of Novel Lipidic rAHF
新型脂质rAHF的开发及药理学
- 批准号:
6872195 - 财政年份:2002
- 资助金额:
$ 19.01万 - 项目类别:
HL-Development and Pharmacology of novel lipidic rAHF and biotherapeutics
HL-新型脂质性 rAHF 和生物治疗药物的开发和药理学
- 批准号:
9198565 - 财政年份:2002
- 资助金额:
$ 19.01万 - 项目类别:
Development and Pharmacology of Novel Lipidic rAHF
新型脂质rAHF的开发及药理学
- 批准号:
6463657 - 财政年份:2002
- 资助金额:
$ 19.01万 - 项目类别:
Development and Pharmacology of Novel Lipidic rAHF
新型脂质rAHF的开发及药理学
- 批准号:
7196813 - 财政年份:2002
- 资助金额:
$ 19.01万 - 项目类别:
Development and Pharmacology of Novel Lipidic rAHF
新型脂质rAHF的开发及药理学
- 批准号:
7541330 - 财政年份:2002
- 资助金额:
$ 19.01万 - 项目类别:
Development and Pharmacology of Novel Lipidic rAHF
新型脂质rAHF的开发及药理学
- 批准号:
7341719 - 财政年份:2002
- 资助金额:
$ 19.01万 - 项目类别:
Development and pharmacology of novel lipidic rAHF
新型脂质rAHF的开发和药理学
- 批准号:
8471155 - 财政年份:2002
- 资助金额:
$ 19.01万 - 项目类别:
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