B-cell-specific transduction for anti-HIV antibody and B-cell receptor expression
用于抗 HIV 抗体和 B 细胞受体表达的 B 细胞特异性转导
基本信息
- 批准号:10549760
- 负责人:
- 金额:$ 39万
- 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:2019-02-15 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:Amino Acid SequenceAnimal ModelAntibodiesAntibody FormationAntibody TherapyAntigensApplications GrantsAutoantigensAutoimmune DiseasesB cell differentiationB-Cell Antigen ReceptorB-Cell DevelopmentB-Cell Receptor BindingB-LymphocytesBLT miceBindingCell Differentiation processCellsChromosomesCommunicable DiseasesDevelopmentDifferentiation and GrowthExperimental DesignsFactor IXFc domainGene Transduction AgentGenesGenetic RecombinationGenetic TranscriptionGrowthHIV AntibodiesHIV therapyHIV-1Hemophilia AHumanImmuneImmune responseImmunocompetentImmunoglobulin GInfectionIntravenousLentivirus VectorLigandsLongevityMembraneMemory B-LymphocyteMethodsMusMutationPathologyPhysiologicalPlasma CellsPositioning AttributeProliferatingProteinsPublic HealthReagentResearchSerumSignal TransductionSpecificityStructural ProteinSystemTherapeuticTherapeutic EffectTherapeutic antibodiesTimeTissuesTransgenesViral ProteinsViral VectorVirusVirus Replicationcell growthcell typecellular transductioncostenv Gene Productsgene productgene therapyimmunoreactionin vivoin vivo imaginginhibitormouse modelnatural antibodiesneutralizing antibodynovelpromoterreceptor expressiontherapeutic genetherapeutically effectivetooltransgene expressiontransmission processvector
项目摘要
PROJECT SUMMARY
Neutralizing antibodies against HIV-1 are very potent in suppressing HIV-1 replication. However, the serum
concentrations of the antibodies must be kept at therapeutic levels for long periods of time to eliminate
HIV-1-infected cells, because persistently infected cells reside in the deep tissue. Therefore, multiple
administrations of the antibodies are required, which could be expensive and labor-intensive. Gene therapy
vectors can be used to produce therapeutic antibodies. However, transgene expression by any gene therapy
vectors, including lentiviral vectors, can induce immune reactions against the transgenes, thereby decreasing
the therapeutic effects of transgene products and eliminating the transduced cells. Therefore, it is important to
express transgenes in the cell types that can develop tolerance to transgene products. B-cells physiologically
express wide varieties of valuable antibody regions generated by recombination and mutations in genes. B-cells
are known to induce tolerance to the valuable regions. This ability of B-cells was previously used to induce
tolerance to self-antigens for therapy of autoimmune diseases and coagulation factor IX for treatment of
hemophilia. Therefore, transduction of B-cells is likely to generate long-term anti-HIV-1 antibodies without
inducing immune reactions to the antibodies. We have developed lentiviral vectors that can specifically
transduce desired target cell types after systemic administration. The vector can selectively transduces splenic
B-cells without conjugation of any B-cell-targeting ligand. By exploiting this B-cell-specific transduction by our
lentiviral vectors, we will attempt to express anti-HIV-1 proteins specifically in B-cells to develop tolerance to the
transgene products. We will further increase specificity of transgene expression with our targeting vector by
combining it with transcriptional B-cell targeting by a B-cell-specific promoter. Using this highly B-cell-specific
transgene expression system, we will express eCD4-Ig, a highly potent anti-HIV-1 reagent consisting of IgG and
soluble CD4, in immunocompetent mice. We will investigate whether eCD4-Ig expression, specifically in B-cells,
can induce long-term expression of eCD4-Ig by inducing developing tolerance. We will next express both
secretory and membrane-anchored forms of eCD4-Ig in B-cells to generate an anti-HIV-1 B-cell receptor (BCR)
on B-cells. We will investigate whether anti-HIV-1 BCR elicits signals upon binding to the HIV-1 envelope protein,
inducing differentiation and growth of the transduced cells. The growth of transduced B-cells will increase the
serum concentrations of eCD4-Ig. Differentiation of transduced cells to memory B-cells and plasma cells will
extend the period of eCD4-Ig expression by prolonging the life span of transduced B-cells. We will then evaluate
the therapeutic effects of B-cell-specific expression of eCD4-Ig in HIV-1 infection of humanized BLT mice. These
experiments are designed to develop a novel gene therapeutic antibody that can be applied not only to therapy of
HIV-1 infection, but also other types of infectious diseases.
项目总结
针对HIV-1的中和抗体在抑制HIV-1复制方面非常有效。然而,血清
抗体的浓度必须长时间保持在治疗水平才能消除
HIV-1感染细胞,因为持续感染的细胞驻留在深层组织中。因此,多个
注射抗体是必要的,这可能是昂贵和劳动密集型的。基因治疗
载体可用于产生治疗性抗体。然而,通过任何基因治疗的转基因表达
载体,包括慢病毒载体,可以诱导针对转基因的免疫反应,从而减少
转基因产物的治疗效果和转导细胞的清除。因此,重要的是要
在能够对转基因产品产生耐受性的细胞类型中表达转基因。生理上的B细胞
表达由基因重组和突变产生的各种有价值的抗体区域。B细胞
已知会导致对有价值地区的耐受性。B细胞的这种能力以前被用来诱导
自身抗原耐受治疗自身免疫性疾病和凝血因子IX治疗自身免疫性疾病
血友病。因此,B细胞的转导很可能产生长期的抗HIV-1抗体,而不是
诱导对抗体的免疫反应。我们已经开发出慢病毒载体,可以特异性地
全身给药后转导所需的靶细胞类型。该载体可选择性地传导脾
不结合任何B细胞靶向配体的B细胞。通过利用我们的B细胞特异性转导
慢病毒载体,我们将尝试在B细胞中特异性表达抗HIV-1蛋白,以培养对
转基因产品。我们将通过我们的靶向载体进一步提高转基因表达的特异性
将其与B细胞特异性启动子的转录B细胞靶向相结合。使用这种高度特异的B细胞
转基因表达系统,我们将表达eCD4-Ig,一种高效的抗HIV-1试剂,由IgG和
免疫功能正常小鼠体内的可溶性CD_4。我们将研究eCD4-Ig的表达,特别是在B细胞中的表达,
可通过诱导发育耐受而诱导eCD4-Ig的长期表达。接下来我们将对这两种情况进行快递
分泌和膜固定型eCD4-Ig在B细胞中产生抗HIV-1B细胞受体(BCR)
在B细胞上。我们将研究抗HIV-1 BCR与HIV-1包膜蛋白结合后是否会产生信号,
诱导转导细胞分化生长。转导的B细胞的生长将增加
血清eCD_4-Ig浓度。将转导细胞分化为记忆B细胞和浆细胞
通过延长转导B细胞的寿命来延长eCD4-Ig的表达周期。然后我们将评估
B细胞特异性表达eCD4-Ig对人源化BLT小鼠HIV-1感染的治疗作用这些
实验的目的是开发一种新的基因治疗性抗体,这种抗体不仅可以用于治疗
HIV-1感染,也有其他类型的传染病。
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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Koki Morizono其他文献
Koki Morizono的其他文献
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{{ truncateString('Koki Morizono', 18)}}的其他基金
Ablation of HIV-1 infected cells by sustained bNAb expression from B-cells
B 细胞持续表达 bNAb 消除 HIV-1 感染细胞
- 批准号:
10468653 - 财政年份:2020
- 资助金额:
$ 39万 - 项目类别:
Ablation of HIV-1 infected cells by sustained bNAb expression from B-cells
B 细胞持续表达 bNAb 消除 HIV-1 感染细胞
- 批准号:
10614646 - 财政年份:2020
- 资助金额:
$ 39万 - 项目类别:
Ablation of HIV-1 infected cells by sustained bNAb expression from B-cells
B 细胞持续表达 bNAb 消除 HIV-1 感染细胞
- 批准号:
10160821 - 财政年份:2020
- 资助金额:
$ 39万 - 项目类别:
B-cell-specific transduction for anti-HIV antibody and B-cell receptor expression
用于抗 HIV 抗体和 B 细胞受体表达的 B 细胞特异性转导
- 批准号:
10328245 - 财政年份:2019
- 资助金额:
$ 39万 - 项目类别:
B-cell-specific transduction for anti-HIV antibody and B-cell receptor expression
用于抗 HIV 抗体和 B 细胞受体表达的 B 细胞特异性转导
- 批准号:
9753437 - 财政年份:2019
- 资助金额:
$ 39万 - 项目类别:
The roles of phosphatidylserine and its receptors in HIV replication
磷脂酰丝氨酸及其受体在HIV复制中的作用
- 批准号:
8685123 - 财政年份:2013
- 资助金额:
$ 39万 - 项目类别:
The roles of phosphatidylserine and its receptors in HIV replication
磷脂酰丝氨酸及其受体在HIV复制中的作用
- 批准号:
8602737 - 财政年份:2013
- 资助金额:
$ 39万 - 项目类别:
The role of envelope phosphatidylserine in the binding of HIV to target cells
包膜磷脂酰丝氨酸在HIV与靶细胞结合中的作用
- 批准号:
8137989 - 财政年份:2011
- 资助金额:
$ 39万 - 项目类别:
The role of envelope phosphatidylserine in the binding of HIV to target cells
包膜磷脂酰丝氨酸在HIV与靶细胞结合中的作用
- 批准号:
8225125 - 财政年份:2011
- 资助金额:
$ 39万 - 项目类别:
Ablation of HIV-1 infected cells by sustained bNAb expression from B-cells
B 细胞持续表达 bNAb 消除 HIV-1 感染细胞
- 批准号:
9890824 - 财政年份:
- 资助金额:
$ 39万 - 项目类别:
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