Engineering bacteriophage Qβ conjugates with tumor associated carbohydrate antigens as multi-component anti-cancer vaccines

工程噬菌体 Qβ 与肿瘤相关碳水化合物抗原缀合物作为多组分抗癌疫苗

基本信息

  • 批准号:
    10358502
  • 负责人:
  • 金额:
    $ 44.74万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-01-01 至 2023-12-31
  • 项目状态:
    已结题

项目摘要

Project Summary Targeting tumor-associated carbohydrate antigens (TACAs) for anticancer vaccines is exceptionally attractive because many TACAs are highly expressed on multiple types of cancer cells with no or negligible expression on normal cells. While passive immunity utilizing anti-TACA monoclonal antibodies has achieved clinical success, developing a TACA based immunogen to elicit effective anti-cancer immunity has been extremely difficult due to the notoriously low immunogenicity of TACAs. To address this challenge, exciting preliminary results have been obtained showing that TACA-based vaccines can significantly reduce cancer induced death by delivering a prototypical TACA, the Tn antigen, using virus like particle bacteriophage Qβ. In this proposal, new ground in TACA based cancer vaccine design will continue to be broken by engineering Qβ to generate powerful anti-cancer immune responses. Building on the exciting preliminary results, in Aim 1, an important tumor associated glycopeptide antigen human MUC-1 bearing Tn glycan will be targeted. Using Qβ as the carrier, super-high titers of IgG antibodies were elicited against MUC1-Tn, which significantly reduced tumor growth in mice, even in transgenic mice tolerant to human MUC1. Besides Tn and tumor associated MUC1 glycopeptides, other TACAs including GD2 and SSEA-3 will be investigated as vaccine targets to reduce the risk of tumor escape from immune surveillance and to kill purported cancer stem cells, a possible cause for resistance to traditional treatments such as chemotherapy. In addition, guided by the crystal structure of Qβ, Qβ mutants will be developed to reduce undesirable anti-Qβ antibodies and further boost desired anti- TACA responses. Cytotoxic T cells can also kill cancer cells. In Aim 2, Qβ will be engineered to deliver cytotoxic T cell epitopes and built-in adjuvants in addition to generating anti-TACA IgG antibodies. The comprehensive antibody and cytotoxic T cell immune responses induced by Qβ-TACA-cytotoxic T cell epitope conjugate should provide superior protection to immunized host against tumor development. To lay the groundwork for future translation, in Aim 3, the vaccine efficacy in treating canine cancer patients will be established. Canines can naturally develop cancer, which are clinically relevant large animal models for human diseases due to their high similarities to human cancer. This will be the first of its kind trial of such TACA based vaccine constructs in canine patients. Overall impacts: This project will establish a Qβ vaccine platform vastly superior to currently available carriers to deliver both TACAs and cytotoxic T cell epitopes, which will elicit long-lasting anti-TACA IgG antibodies and cytotoxic T cells for cancer treatment. Deeper understanding of the connections between structural features of Qβ-TACA conjugates and anti-tumor immunity will exert a sustained impact on cancer vaccine design and is essential for successful TACA-based anti-cancer vaccines.
项目摘要 靶向肿瘤相关的碳水化合物抗原(TACA)抗癌疫苗是异常的 有吸引力,因为许多塔卡斯都在多种类型的癌细胞上高度表达,没有或可以忽略不计 在正常细胞上的表达。利用抗TACA单克隆抗体的被动免疫学已实现 临床成功,开发基于TACA的免疫原来引起有效的抗癌免疫,已经是 由于塔卡斯的臭名昭著的低免疫原性,极其困难。为了应对这一挑战,令人兴奋 已经获得了初步结果,表明基于TACA的疫苗可以显着减少癌症 通过使用粒子细菌等病毒Qβ的病毒传递原型TACA,TN抗原诱导死亡。 在此提案中,基于TACA的癌症疫苗设计中的新基础将继续被打破 工程Qβ生成强大的抗癌免疫反应。以令人兴奋的初步结果为基础 在AIM 1中,将靶向一个重要的肿瘤抗原抗原抗原抗原人us-1轴承。 使用Qβ作为载体,对MUC1-TN引起IgG抗体的超高滴度,这显着 小鼠的肿瘤生长降低,即使在耐受人MUC1的转基因小鼠中。除了TN和肿瘤 相关的MUC1糖磷酸酯,包括GD2和SSEA-3在内的其他TACAS将作为疫苗靶标进行研究 为了降低肿瘤逃脱免疫监测的风险并杀死所谓的癌症干细胞, 导致对传统疗法(例如化学疗法)的抵抗。另外,在晶体结构的指导下 Qβ,将开发Qβ突变体以减少难以释放的抗Qβ抗体,并进一步增强所需的抗抗体 塔卡(Taca)的回应。细胞毒性T细胞也可以杀死癌细胞。在AIM 2中,将设计Qβ以提供细胞毒性 T细胞表位和内置调节器除了产生抗TACA IgG抗体。综合 Qβ-TACA-胞毒性T细胞表位结合物诱导的抗体和细胞毒性T细胞免疫复杂应应 为免疫宿主提供了较高的保护,以防止肿瘤发育。为未来奠定基础 在AIM 3中,将建立AIM 3的翻译疫苗效率。犬罐 自然发展的癌症,由于癌症是人类疾病的临床大型动物模型 与人类癌症的相似之处。这将是此类基于TACA的疫苗结构的同类试验中的第一个试验 犬类患者。 总体影响:该项目将建立一个Qβ疫苗平台,大大优于当前可用的 携带者可以提供塔卡斯和细胞毒性T细胞表位,这将引起持久的抗TACA IgG 用于癌症治疗的抗体和细胞毒性T细胞。更深入地了解 Qβ-TACA结合物和抗肿瘤免疫的结构特征将对癌症产生持续影响 疫苗设计,对于成功的基于TACA的抗癌疫苗至关重要。

项目成果

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Xuefei Huang其他文献

Xuefei Huang的其他文献

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{{ truncateString('Xuefei Huang', 18)}}的其他基金

Synthetic glycan conjugates with bacteriophage Qbeta for broad spectrum anti-salmonella vaccines
用于广谱抗沙门氏菌疫苗的合成聚糖与噬菌体 Qbeta 缀合物
  • 批准号:
    10432065
  • 财政年份:
    2019
  • 资助金额:
    $ 44.74万
  • 项目类别:
Synthetic glycan conjugates with bacteriophage Qbeta for broad spectrum anti-salmonella vaccines
用于广谱抗沙门氏菌疫苗的合成聚糖与噬菌体 Qbeta 缀合物
  • 批准号:
    9978709
  • 财政年份:
    2019
  • 资助金额:
    $ 44.74万
  • 项目类别:
Synthetic glycan conjugates with bacteriophage Qbeta for broad spectrum anti-salmonella vaccines
用于广谱抗沙门氏菌疫苗的合成聚糖与噬菌体 Qbeta 缀合物
  • 批准号:
    10201474
  • 财政年份:
    2019
  • 资助金额:
    $ 44.74万
  • 项目类别:
Synthetic glycan conjugates with bacteriophage Qbeta for broad spectrum anti-salmonella vaccines
用于广谱抗沙门氏菌疫苗的合成聚糖与噬菌体 Qbeta 缀合物
  • 批准号:
    10653943
  • 财政年份:
    2019
  • 资助金额:
    $ 44.74万
  • 项目类别:
Engineering bacteriophage Qβ conjugates with tumor associated carbohydrate antigens as multi-component anti-cancer vaccines
工程噬菌体 Qβ 与肿瘤相关碳水化合物抗原缀合物作为多组分抗癌疫苗
  • 批准号:
    9473167
  • 财政年份:
    2018
  • 资助金额:
    $ 44.74万
  • 项目类别:
Stereoselective Assembly of Challenging Glycosidic Linkages with Earth-Abundant Metal Catalysts
用地球上丰富的金属催化剂立体选择性组装具有挑战性的糖苷键
  • 批准号:
    9546030
  • 财政年份:
    2018
  • 资助金额:
    $ 44.74万
  • 项目类别:
Stereoselective Assembly of Challenging Glycosidic Linkages with Earth-Abundant Metal Catalysts
用地球上丰富的金属催化剂立体选择性组装具有挑战性的糖苷键
  • 批准号:
    10173059
  • 财政年份:
    2018
  • 资助金额:
    $ 44.74万
  • 项目类别:
Engineering bacteriophage Qβ conjugates with tumor associated carbohydrate antigens as multi-component anti-cancer vaccines
工程噬菌体 Qβ 与肿瘤相关碳水化合物抗原缀合物作为多组分抗癌疫苗
  • 批准号:
    10540343
  • 财政年份:
    2018
  • 资助金额:
    $ 44.74万
  • 项目类别:
Virus like particles as carriers for carbohydrate based anti-Salmonella vaccines
病毒样颗粒作为碳水化合物抗沙门氏菌疫苗的载体
  • 批准号:
    9118056
  • 财政年份:
    2015
  • 资助金额:
    $ 44.74万
  • 项目类别:
Virus like particles as carriers for carbohydrate based anti-Salmonella vaccines
病毒样颗粒作为碳水化合物抗沙门氏菌疫苗的载体
  • 批准号:
    8823965
  • 财政年份:
    2015
  • 资助金额:
    $ 44.74万
  • 项目类别:

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Engineering bacteriophage Qβ conjugates with tumor associated carbohydrate antigens as multi-component anti-cancer vaccines
工程噬菌体 Qβ 与肿瘤相关碳水化合物抗原缀合物作为多组分抗癌疫苗
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Engineering bacteriophage Qβ conjugates with tumor associated carbohydrate antigens as multi-component anti-cancer vaccines
工程噬菌体 Qβ 与肿瘤相关碳水化合物抗原缀合物作为多组分抗癌疫苗
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