Modulation by Botanicals of Antibody Based Cancer Immuno

基于抗体的癌症免疫的植物调节

基本信息

  • 批准号:
    6946043
  • 负责人:
  • 金额:
    $ 28.08万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2005
  • 资助国家:
    美国
  • 起止时间:
    2005-04-01 至 2010-03-31
  • 项目状态:
    已结题

项目摘要

Many botanicals advocated or researched for the treatment of cancer are thought to act via an immune mechanism. Their interaction with antibody-mediated cytotoxicity has not been previously explored. Tumor-specific antibodies now play major roles in the standard treatment of several human cancers, including trastuzumab (Herceptin) for breast cancer, rituximab (Rituxan) and alemtuzumab (Campath) for lymphorina and Cetuximab (Erbitux) for colon cancer. Natural or induced anti-tumor antibodies have also been correlated with favorable clinical outcomes in a number of human cancers. Through antibody, both complement mediated cytotoxicity (CMC) and cell-mediated cytotoxicity (ADCC) have played key roles. Besides Fc receptors, complement receptor 3 (CR3) is now found to be essential for ADCC in both in vitro and in vivo models. Beta-glucan is a major ingredient in many botanicals and when orally administered is transported by gut macrophages to the marrow where the processed carbohydrate is released to allow activation of the CR3 on leukocytes. In the presence of anti-tumor antibodies, this increased avidity of CR3 translates into highly efficient tumor kill. Therapies designed rationally on the basis of this mechanistic knowledge have been highly effective in animal models and early clinical trials. In this grant application, we hypothesize that botanicals can impact on these anti-tumor mechanisms by enhancing effector functions of leukocytes in ADCC through modulation of FcR, CR3 as well as other critical adhesion molecules. We propose to study oral administration of botanicals in combination with intravenous intravenous injection of anti-tumor antibodies in human xenograft models. Botanicals will also be tested for binding to CR3, and in vivo activation of CR3, FcR and integrins on leukocytes, as well as in vivo activation of neutrophil and .macrophage mediated tumor cytotoxicity. CR3-dependent tumor cytotoxicity for both IgM (innate) or IgG (induced) anti-tumor antibodies will be examined. For those botanicals with significant anti-tumor effects, the importance of CR3 will be confirmed using knockout mice. Although initial experiments will be carried out on five botanicals, we expect to screen a total of 46. Our findings will: a) suggest candidate botanicals for clinical trial in combination with antibodies or vaccines; b) form the basis of a general screening tool and quality control; c) provide leads for further research in the other projects that focus on vaccines, dendritic cells, T-cells and NK cells in different disease models.
许多倡导或研究用于治疗癌症的植物药物被认为是通过免疫机制发挥作用的。它们与抗体介导的细胞毒性的相互作用以前还没有被探索过。肿瘤特异性抗体现在在几种人类癌症的标准治疗中发挥着主要作用,包括用于乳腺癌的曲妥珠单抗(Herceptin),用于淋巴管的利妥昔单抗(Rituxan)和阿伦图珠单抗(CamPath),以及用于结肠癌的西妥昔单抗(Erbitux)。在许多人类癌症中,天然或诱导的抗肿瘤抗体也与良好的临床结果相关。补体介导的细胞毒作用(CMC)和细胞介导的细胞毒作用(ADCC)通过抗体发挥了关键作用。除了Fc受体,补体受体3(CR3)在体外和体内的ADCC模型中都被发现是必不可少的。β-葡聚糖是许多植物药的主要成分,口服时是 由肠道巨噬细胞运输到骨髓,在那里处理后的碳水化合物被释放,以允许激活白细胞上的CR3。在抗肿瘤抗体存在的情况下,这种增加的CR3亲和力转化为高效的肿瘤杀伤。在这种机制知识的基础上合理设计的治疗方法在动物模型和早期临床试验中已经非常有效。在这项拨款申请中,我们假设植物药可以通过调节FCR、CR3以及其他关键的黏附分子来增强ADCC中白细胞的效应功能,从而影响这些抗肿瘤机制。我们建议在人类异种移植模型中研究口服植物药与静脉注射抗肿瘤抗体的联合作用。还将测试植物类药物与CR3的结合情况,并在 体内激活CR3、FCR和整合素,以及体内激活中性粒细胞和巨噬细胞介导的肿瘤细胞毒。依赖于CR3的肿瘤细胞对免疫球蛋白M(天然的)或免疫球蛋白(诱导的)抗肿瘤抗体的细胞毒性将被检测。对于那些具有显著抗肿瘤作用的植物药物,CR3的重要性将在基因敲除小鼠中得到证实。虽然初步实验将在五种植物学药物上进行,但我们预计总共将筛选46种。我们的发现将:a)建议结合抗体或疫苗进行临床试验的候选植物药物;b)形成一般筛查工具和质量控制的基础;c)为其他专注于疫苗、树突状细胞的项目的进一步研究提供线索 不同疾病模型中的细胞、T细胞和NK细胞。

项目成果

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NAI-KONG V CHEUNG其他文献

NAI-KONG V CHEUNG的其他文献

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{{ truncateString('NAI-KONG V CHEUNG', 18)}}的其他基金

Dual targeting of tumoral microenvironment and tumoral cells by blocking the IL-33/ST2 pathway
通过阻断 IL-33/ST2 通路双重靶向肿瘤微环境和肿瘤细胞
  • 批准号:
    10228863
  • 财政年份:
    2020
  • 资助金额:
    $ 28.08万
  • 项目类别:
Targeting Neuroblastoma with armed T cells
用武装 T 细胞靶向神经母细胞瘤
  • 批准号:
    9325268
  • 财政年份:
    2016
  • 资助金额:
    $ 28.08万
  • 项目类别:
Targeting Neuroblastoma with armed T cells
用武装 T 细胞靶向神经母细胞瘤
  • 批准号:
    9344287
  • 财政年份:
    2016
  • 资助金额:
    $ 28.08万
  • 项目类别:
Targeting Neuroblastoma with armed T cells
用武装 T 细胞靶向神经母细胞瘤
  • 批准号:
    8760348
  • 财政年份:
    2014
  • 资助金额:
    $ 28.08万
  • 项目类别:
Targeting Neuroblastoma with armed T cells
用武装 T 细胞靶向神经母细胞瘤
  • 批准号:
    8926911
  • 财政年份:
    2014
  • 资助金额:
    $ 28.08万
  • 项目类别:
Phase I Study of Humanized 3F8 Monoclonal Antibody (Hu3F8) in Patients with High-
人源化 3F8 单克隆抗体 (Hu3F8) 在高危人群中的 I 期研究
  • 批准号:
    8270451
  • 财政年份:
    2011
  • 资助金额:
    $ 28.08万
  • 项目类别:
Phase I Study of Humanized 3F8 Monoclonal Antibody (Hu3F8) in Patients with High-
人源化 3F8 单克隆抗体 (Hu3F8) 在高危人群中的 I 期研究
  • 批准号:
    8189124
  • 财政年份:
    2011
  • 资助金额:
    $ 28.08万
  • 项目类别:
A novel set of molecular markers to measure metastatic neuroblastoma
一套用于测量转移性神经母细胞瘤的新型分子标记物
  • 批准号:
    7023377
  • 财政年份:
    2006
  • 资助金额:
    $ 28.08万
  • 项目类别:
A novel set of molecular markers to measure metastatic neuroblastoma
一套用于测量转移性神经母细胞瘤的新型分子标记物
  • 批准号:
    7268042
  • 财政年份:
    2006
  • 资助金额:
    $ 28.08万
  • 项目类别:
Project 4
项目4
  • 批准号:
    7129450
  • 财政年份:
    2005
  • 资助金额:
    $ 28.08万
  • 项目类别:

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独特抗体受体延长血液IgY半衰期的机制研究及其在禽类免疫增强中的应用
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细胞内抗体受体 TRIM21 的先天免疫功能
  • 批准号:
    nhmrc : GNT1124162
  • 财政年份:
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  • 项目类别:
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Innate immune functions of the intracellular antibody receptor TRIM21
细胞内抗体受体 TRIM21 的先天免疫功能
  • 批准号:
    nhmrc : 1124162
  • 财政年份:
    2017
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Mechanism and engineering of IgG-based monoclonal antibody/receptor interactions
基于 IgG 的单克隆抗体/受体相互作用的机制和工程
  • 批准号:
    9300976
  • 财政年份:
    2015
  • 资助金额:
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Mechanism and engineering of IgG-based monoclonal antibody/receptor interactions
基于 IgG 的单克隆抗体/受体相互作用的机制和工程
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增强嵌合抗体受体定向 T 细胞治疗癌症
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  • 财政年份:
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  • 资助金额:
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Augmenting Chimeric Antibody Receptor Directed T cell Therapy for Cancer
增强嵌合抗体受体定向 T 细胞治疗癌症
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Augmenting Chimeric Antibody Receptor Directed T cell Therapy for Cancer
增强嵌合抗体受体定向 T 细胞治疗癌症
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  • 财政年份:
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Augmenting Chimeric Antibody Receptor Directed T cell Therapy for Cancer
增强嵌合抗体受体定向 T 细胞治疗癌症
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  • 财政年份:
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Small Grants for Exploratory Research: Separation of Cells and Biological Macromolecules by Antibody Receptor Coated Magnetic Vesicles and Ferritin Conjugates
探索性研究小额资助:通过抗体受体包被的磁囊和铁蛋白缀合物分离细胞和生物大分子
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  • 财政年份:
    1991
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    $ 28.08万
  • 项目类别:
    Standard Grant
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