Modular approach for the delivery of antibodies into the cytoplasm of cells
将抗体递送到细胞质中的模块化方法
基本信息
- 批准号:9975797
- 负责人:
- 金额:$ 36.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-10 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:ABCC1 geneAffinityAmino AcidsAntibodiesAntigensAspartic AcidAutomobile DrivingBindingBinding SitesCationsCell membraneCellsChargeChimeric ProteinsClinicCytoplasmCytosolDependenceDevelopmentDoxorubicinDrug KineticsElectroporationEngineeringEnzymesEpitopesExcipientsExhibitsFormulationGene DeliveryGlutamic AcidGoalsGoatHeavy-Chain ImmunoglobulinsHumanImmunoglobulin GImmunoglobulin Variable RegionLibrariesLigand BindingLigandsLipidsLipofectamineLiposomesMalignant NeoplasmsMediatingMembraneMicroinjectionsMusNatureOryctolagus cuniculusPharmaceutical PreparationsPropertyProteinsRAS inhibitionRattusReagentReportingResearchSafetySiteSpecificityStructureSystemTacrolimus Binding Protein 1ATechniquesTechnologyTestingTherapeuticTherapeutic Monoclonal AntibodiesTimeToxic effectTransfectionTranslatingbasecytotoxicitydruggable targetfluorexonhigh throughput screeningin vivonanoformulationnanoparticlenovelpolypeptidepreservationprotein degradationprotein functionsmall moleculesuccesstherapeutic targettumorunnatural amino acids
项目摘要
ABSTRACT
Many intracellular targets are not susceptible to small molecule drugs because they lack natural ligands or even
ligand binding sites. Moreover, even if a small molecule drug can bind a desirable target protein, it may not be
effective in inhibiting protein function. Small molecules drugs capable of disrupting interactions between two
proteins have been particularly difficult to identify. Further, even in cases where a small molecule drug is
identified, it must be capable of reaching its target site with good pharmacokinetic properties and minimal off-
target toxicity. These stringent requirements have led to long development times and a very small fraction of
small molecule drugs that have been successfully translated into the clinic, despite decades of research and
countless high-throughput screens.
Therapeutic monoclonal antibodies have had considerable success as cancer therapeutics, but their inability to
cross cell membranes has restricted their targets to secreted or membrane-associated antigens. If antibodies
could be efficiently delivered into the cytosol of living cells, it would significantly increase the number of possible
druggable targets. Antibodies can be developed to bind nearly any exposed protein epitope, with high specificity
and affinity. There are a countless number of therapeutic possibilities that could be pursued if antibodies could
be effectively delivered into cells, from inhibiting protein function, to driving proteins interactions, to tagging
proteins for proteosomal degradation. Not surprisingly, numerous attempts have been made to deliver antibodies
into cells, but a robust and efficient approach has yet to be identified. The overall goal of this proposal is to
develop a modular approach to efficiently deliver antibodies into the cytoplasm of living cells.
Recently, we developed a novel bioconjugation strategy that enables the site-specific and covalent attachment
of small molecules, proteins, and enzymes to IgG. Utilizing this technology, we screened a variety of IgG
conjugates in their ability to be delivered into the cytosol of living cells and identified conjugates that could be
cytoplasmically delivered with a ~60% efficiency at sub-micromolar concentrations of IgG with minimal
cytotoxicity. The modular nature of our approach not only allows for any `off-the-shelf' IgG to be easily swapped
into our system, but also preserves the binding affinity of the IgG variable region.
In this proposal, we plan to further optimize our antibody-delivery technology and evaluate the ability of antibodies
delivered into the cytoplasm to inhibit normal intracellular function or target intracellular proteins for degradation.
The specific aims for this proposal are: Aim 1. Optimize IgG conjugates and conditions for maximum cytoplasmic
delivery; Aim 2. Develop IgG conjugates that can target intracellular proteins for degradation; Aim 3. Develop
and optimize formulations for cytoplasmic delivery of antibodies in vivo.
摘要
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)
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Andrew Tsourkas其他文献
Andrew Tsourkas的其他文献
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{{ truncateString('Andrew Tsourkas', 18)}}的其他基金
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磁泳与光动力联合治疗TNBC
- 批准号:
10426358 - 财政年份:2021
- 资助金额:
$ 36.65万 - 项目类别:
Combined magnetophoresis and photodynamic therapy for the treatment of TNBC
磁泳与光动力联合治疗TNBC
- 批准号:
10586052 - 财政年份:2021
- 资助金额:
$ 36.65万 - 项目类别:
Combined magnetophoresis and photodynamic therapy for the treatment of TNBC
磁泳与光动力联合治疗TNBC
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10297166 - 财政年份:2021
- 资助金额:
$ 36.65万 - 项目类别:
Image-guided surgery and sonodynamic therapy with stroma-targeted theranostic nanoclusters
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- 批准号:
10541160 - 财政年份:2020
- 资助金额:
$ 36.65万 - 项目类别:
Image-guided surgery and sonodynamic therapy with stroma-targeted theranostic nanoclusters
使用基质靶向治疗诊断纳米簇进行图像引导手术和声动力治疗
- 批准号:
9886512 - 财政年份:2020
- 资助金额:
$ 36.65万 - 项目类别:
Image-guided surgery and sonodynamic therapy with stroma-targeted theranostic nanoclusters
使用基质靶向治疗诊断纳米簇进行图像引导手术和声动力治疗
- 批准号:
10318642 - 财政年份:2020
- 资助金额:
$ 36.65万 - 项目类别:
Modular approach for the delivery of antibodies into the cytoplasm of cells
将抗体递送到细胞质中的模块化方法
- 批准号:
10414929 - 财政年份:2019
- 资助金额:
$ 36.65万 - 项目类别:
Modular approach for the delivery of antibodies into the cytoplasm of cells
将抗体递送到细胞质中的模块化方法
- 批准号:
10218119 - 财政年份:2019
- 资助金额:
$ 36.65万 - 项目类别:
Modular approach for the delivery of antibodies into the cytoplasm of cells
将抗体递送到细胞质中的模块化方法
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10654576 - 财政年份:2019
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Preparation of site-specific antibody-drug conjugates by proximity-based sortase ligation
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