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

项目摘要 以肿瘤相关碳水化合物抗原(TACA)为靶点的抗癌疫苗是例外 很有吸引力，因为许多TACA在多种类型的癌细胞上高度表达，而不表达或可以忽略不计 在正常细胞上表达。而利用抗TACA单抗的被动免疫已经实现 临床上取得了成功，开发出了一种基于TACA的免疫原来诱导有效的抗癌免疫 由于TACA的免疫原性低是出了名的，因此非常困难。为了应对这一挑战，令人兴奋 初步结果表明，基于TACA的疫苗可以显著降低癌症 通过使用病毒样颗粒噬菌体Qβ递送典型的TACA，TN抗原来诱导死亡。 在这项提案中，基于TACA的癌症疫苗设计的新领域将继续被 设计Qβ，产生强大的抗癌免疫反应。在令人兴奋的初步结果的基础上， 在目标1中，将以含有TN多糖的重要肿瘤相关糖肽抗原人MUC-1为靶点。 以Qβ为载体，获得了超高滴度的抗MUC1Tn抗体。 减少小鼠的肿瘤生长，即使在耐受人MUC1的转基因小鼠中也是如此。除了TN和肿瘤 相关的MUC1糖肽、包括GD2和SSEA-3在内的其他TACA将被作为疫苗靶标进行研究 为了减少肿瘤逃脱免疫监视的风险并杀死所谓的癌症干细胞，一种可能的方法 导致对化疗等传统疗法产生抵抗力。此外，在晶体结构的指导下， 在Qβ中，将开发Qβ突变体以减少不受欢迎的抗Qβ抗体，并进一步增强所需的抗 塔卡反应。细胞毒性T细胞也可以杀死癌细胞。在AIM 2中，Qβ将被设计为提供细胞毒 T细胞表位和内置佐剂，以及产生抗TACA抗体。全面的 Qβ-TacA-细胞毒性T细胞表位结合物诱导的抗体和细胞毒性T细胞免疫应答 为免疫宿主提供卓越的保护，防止肿瘤的发展。为未来奠定基础 在目标3中，将确定疫苗治疗犬癌患者的疗效。犬类可以 自然发生癌症，这是临床上相关的人类疾病的大型动物模型，因为它们的高 与人类癌症相似。这将是此类基于TACA的疫苗构建的第一次此类试验 犬科病人。 总体影响：该项目将建立一个远远优于目前可用的Qβ疫苗平台 携带TACA和细胞毒性T细胞表位的携带者将产生持久的抗TACA抗体 抗体和细胞毒性T细胞用于癌症治疗。更深入地了解 Qβ-TACA偶联物的结构特征与抗肿瘤免疫对肿瘤的持续影响 疫苗设计是成功的基于TACA的抗癌疫苗的关键。

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.