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
基本信息
- 批准号:9198565
- 负责人:
- 金额:$ 39.54万
- 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 2019-12-31
- 项目状态:已结题
- 来源:
- 关键词:AnimalsAntibodiesAntigensApoptoticAutoimmune DiseasesB-LymphocytesBiological Response Modifier TherapyBiophysicsBlood Coagulation DisordersBlood coagulationCellsCharacteristicsChargeClinicalClinical TrialsComplicationDataDendritic CellsDevelopmentDiseaseDisease modelEngineeringExperimental DesignsF8 geneFactor IXFactor VIIIGenerationsGlucan 1,4-alpha-GlucosidaseGlycogen storage disease type IIGoalsGrantHealthHemophilia AHemophilia BHemorrhageHemostatic AgentsHumanHypersensitivityImmuneImmune ToleranceImmune responseImmunizationImmunologicsImmunosuppressive AgentsKnowledgeLeadLifeLipidsMediatingMemory B-LymphocyteMissionMusOralOutcomeOuter Leaflet of the Lipid BilayerPharmaceutical PreparationsPharmacodynamicsPharmacologyPhasePhenotypePhosphatidylinositolsPhosphatidylserinesPlasmaPre-Clinical ModelPropertyProteinsProtocols documentationPublic HealthRegulatory T-LymphocyteReplacement TherapyResearchRouteSafetySavingsSignal TransductionT-LymphocyteTestingTolerogenTreatment EfficacyTreatment FailureUnited States National Institutes of HealthVesicleWorkbasebiophysical propertiescostdensitydesignenzyme replacement therapyexosomeimmunogenicimmunoregulationimprovedinhibitor/antagonistinnovationinsightneutralizing antibodynovelnovel strategiesoxidationparticlepreventprogramsprotein S precursorpublic health relevanceresponsesuccesstherapeutic proteinvaccination strategyvon Willebrand Disease
项目摘要
DESCRIPTION (provided by applicant) The safety and efficacy of several life-saving protein therapeutics are compromised by unwanted immune responses. Currently there are no viable clinical options to reduce or reverse these responses. Our goal is to develop protein delivery strategies that improve therapeutic efficacy of protein drugs by reducing or reversing unwanted immune responses. During the previous project period, we observed that exposure of mice to protein therapeutics in the presence of phosphatidylserine (PS) resulted in an antigen specific immunological tolerance/hypo-responsiveness towards the protein, leading to our central hypothesis that PS is immune regulatory and has the capacity to convert immunogenic proteins into tolerogens. To fully realize the clinical potential of this observation, it is necessary to determine the structural characteristics of PS that contribute to its ability to convert an immunogen into a tolerogen (SA1), and to use this information to reduce (SA2) and reverse (SA3) unwanted immune responses to therapeutic proteins and improve their therapeutic efficacy. In SA1 we hypothesize that PS converts dendritic cells from an immunogenic to a tolerogenic phenotype, generating regulatory T-cells that in turn suppress antigen-specific T-cells and B-cells. We investigate the structural and biophysical determinants of PS that program dendritic cells to send tolerogenic over immunogenic signals. Since pre-exposure of mice to FVIII in the presence of PS significantly reduced their immune response during re-challenge with FVIII, in SA2, we investigate a similar pre-treatment approach with two other immunogenic therapeutic proteins to prevent or reduce unwanted immune responses to these proteins during therapy. Specifically we will test this approach with acid alpha glucosidase (GAA in Pompe disease, a lysosomal storage disorder) and Factor IX (in Hemophilia B, a bleeding disorder). We will determine the immune cells that are involved in the induction of tolerance, and establish the impact of such tolerance induction on the efficacy of these two replacement therapies. In SA3, we develop clinical strategies to reverse established responses to FVIII, FIX and GAA, and thereby improve the efficacy of treatments for these bleeding and lysosomal disorders. Since PS is exposed in outer layer of secreted vesicles such as apoptotic bodies and on exosomes released from cells, we propose and will test the hypothesis that lipid particles mimicking these natural vesicles will reverse the established immune responses to therapeutic proteins. Our goal in SA3 is the optimization of immunization protocol and testing of an artificial lipid particle tha mimics the secreted vesicles, to reverse the unwanted established immune responses. These studies are expected to lead to novel clinical strategies to reduce and reverse immune responses to therapeutic proteins and thereby improve the efficacy of several lifesaving protein-based therapies.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
SATHY VENKAT BALU-IYER其他文献
SATHY VENKAT BALU-IYER的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
$ 39.54万 - 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:
$ 39.54万 - 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:
6623164 - 财政年份:2002
- 资助金额:
$ 39.54万 - 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:
$ 39.54万 - 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:
$ 39.54万 - 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:
$ 39.54万 - 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:
$ 39.54万 - 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:
$ 39.54万 - 项目类别:
相似海外基金
Rationally guided discovery platform for monoclonal antibodies against carbohydrate antigens using virus-like particle conjugate immunization and high throughput selection
使用病毒样颗粒缀合物免疫和高通量选择的合理引导的针对碳水化合物抗原的单克隆抗体的发现平台
- 批准号:
10574738 - 财政年份:2023
- 资助金额:
$ 39.54万 - 项目类别:
Assessing the role of liver stage antigens-specific antibodies against Plasmodium falciparum liver stage infection
评估肝期抗原特异性抗体对抗恶性疟原虫肝期感染的作用
- 批准号:
10392870 - 财政年份:2021
- 资助金额:
$ 39.54万 - 项目类别:
Generation of antibodies specific for optimal non-HRP2 malaria diagnostic antigens
生成最佳非 HRP2 疟疾诊断抗原的特异性抗体
- 批准号:
10092930 - 财政年份:2020
- 资助金额:
$ 39.54万 - 项目类别:
Generation of antibodies specific for optimal non-HRP2 malaria diagnostic antigens
生成最佳非 HRP2 疟疾诊断抗原的特异性抗体
- 批准号:
9896170 - 财政年份:2020
- 资助金额:
$ 39.54万 - 项目类别:
Interrogation of cell surface antigens on B lineage cells using structurally unique variable lymphocyte receptor antibodies of the evolutionarily distant sea lamprey
使用进化遥远的海七鳃鳗结构独特的可变淋巴细胞受体抗体询问 B 谱系细胞上的细胞表面抗原
- 批准号:
433456 - 财政年份:2020
- 资助金额:
$ 39.54万 - 项目类别:
Operating Grants
Investigations of interactions between various natural antibodies and food-derived antigens
研究各种天然抗体与食物源性抗原之间的相互作用
- 批准号:
19K15765 - 财政年份:2019
- 资助金额:
$ 39.54万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Identifying Kawasaki Disease-Specific Antibodies and Antigens
识别川崎病特异性抗体和抗原
- 批准号:
9932769 - 财政年份:2018
- 资助金额:
$ 39.54万 - 项目类别:
Novel Scoring Methods for Interactions between Antibodies and Antigens
抗体和抗原之间相互作用的新评分方法
- 批准号:
BB/P504713/1 - 财政年份:2017
- 资助金额:
$ 39.54万 - 项目类别:
Training Grant
Novel Scoring Methods for Interactions between Antibodies and Antigens
抗体和抗原之间相互作用的新评分方法
- 批准号:
1932904 - 财政年份:2017
- 资助金额:
$ 39.54万 - 项目类别:
Studentship
SBIR Phase II: Automated Design Methods of Antibodies Directed to Protein and Carbohydrate Antigens
SBIR II 期:针对蛋白质和碳水化合物抗原的抗体的自动化设计方法
- 批准号:
1632399 - 财政年份:2016
- 资助金额:
$ 39.54万 - 项目类别:
Standard Grant