A Novel Vaccine Strategy to Target Breast Cancer Enabled by Proprietary Mutant Bacteriophage Qbeta-Tumor Antigen Conjugates

项目概要： 抗癌疫苗可以是用于肿瘤保护和治疗的高度有吸引力的方法，这是由于其具有良好的免疫原性。 提供长期免疫力的潜力，副作用少。然而， 研制出成功的抗癌疫苗。由于肿瘤抗原固有的低免疫原性， 免疫原性载体可以有效地增强对肿瘤抗原的免疫反应。 Iaso Therapeutics是一家从密歇根州立大学分拆出来的初创公司。Iaso的使命是 通过靶向一类重要的肿瘤抗原，即，肿瘤相关 碳水化合物和糖缀合物抗原。在这一应用中，Iaso旨在开发一种独特的专有载体， 基于噬菌体Qβ的系统递送癌抗原，如肿瘤相关粘蛋白所代表的， 1（tMUC 1），并产生对抗乳腺癌的上级免疫力。 粘蛋白-1是一个非常有吸引力的抗癌疫苗开发的目标，作为肿瘤相关的 tMUC 1糖肽被认为是新抗原，因为它们与新抗原相比具有不同的聚糖结构。 正常细胞上的对应物。此外，tMUC 1在许多类型的肿瘤细胞上以高水平表达，例如 乳腺癌胰腺癌结肠癌和肺癌临床研究表明，包括乳腺癌在内的患者 具有高水平抗tMUC 1抗体的患者具有显著更好的预后和无病生存。 然而，开发有效的基于tMUC 1的抗癌疫苗来诱导肿瘤细胞凋亡是非常具有挑战性的。 足够水平的抗tMUC 1免疫是保护性的。 在第一阶段项目的目标1中，我们将在发现tMUC 1关键保护性表位的基础上， 改造噬菌体Qβ以递送tMUC 1并引发上级IgG抗体应答。此外，新 将开发一种方法来激活对乳腺癌抗原特异性的T细胞， 体液和细胞免疫来对抗乳腺癌。在目的2中，研究了前导Qβ-肿瘤抗原缀合物的功效。 将在类似于三阴性乳腺癌的自发性小鼠乳腺癌模型中进行评价， 人类病人此外，由于癌症转移是癌症死亡率的主要原因，因此，乳腺癌的小鼠模型 并且前导Qβ-肿瘤抗原缀合物降低肿瘤转移的能力。 将建立转移。由于其诱导有效免疫的能力，Qβ构建体可以保护 免疫宿主预防乳腺癌发展和复发。 总体影响。开发了一种新的Qβ疫苗平台，大大上级目前可用的载体， 递送肿瘤抗原，引发高水平的抗体和T细胞免疫应答，以减少侵袭性乳腺癌 癌症的发生和转移。

Project summary: Anti-cancer vaccines can be a highly attractive approach for tumor protection and treatment due to the potential for providing long term immunity with few side effects. However, it has been highly challenging to develop successful anti-cancer vaccines. Due to the low inherent immunogenicity of tumor antigens, it is critical that immunogenic carriers are available to powerfully boost the immune responses to tumor antigens. Iaso Therapeutics is a startup company spun out of Michigan State University. The mission of Iaso is to develop next generation vaccines by targeting an important class of tumor antigens, i.e., tumor associated carbohydrate and glyco-conjugate antigens. In this application, Iaso aims to develop a unique proprietary carrier system based on bacteriophage Qβ to deliver cancer antigens, as represented by the tumor associated mucin- 1 (tMUC1), and to generate superior immunity to combat breast cancer. Mucin-1 protein is a highly attractive target for anti-cancer vaccine development, as tumor associated tMUC1 glycopeptides are considered neoantigens due to their different glycan structures compared to the counterpart on normal cells. Furthermore, tMUC1 is expressed at high levels on many types of tumor cells, such as breast, pancreatic, colon and lung cancers. Clinical studies have shown that patients including breast cancer patients with high levels of anti-tMUC1 antibodies have significantly better prognosis and disease-free survival. However, it has been highly challenging to develop effective tMUC1 based anti-cancer vaccines to induce sufficient levels of anti-tMUC1 immunity to be protective. In aim 1 of this Phase I project, based on the discovery of key protective epitope of tMUC1, we will engineer bacteriophage Qβ to deliver tMUC1 and elicit superior IgG antibody responses. Furthermore, new methodologies will be developed to activate T cells specific against breast cancer antigens, thus engaging both humoral and cellular immunity to fight breast cancer. In aim 2, the efficacy of the lead Qβ-tumor antigen conjugate will be evaluated in a spontaneous mouse breast cancer model resembling triple negative breast cancer in human patients. Furthermore, as cancer metastasis is a major cause of cancer mortality, mouse models of breast cancer metastasis will be developed and the capability of the lead Qβ-tumor antigen conjugate to reduce metastasis will be established. With its ability to induce potent immunity, the Qβ construct can protect the immunized host from breast cancer development and recurrence. OVERALL IMPACT. A new Qβ vaccine platform vastly superior to currently available carriers is developed to deliver tumor antigens, eliciting high levels of antibody and T cell immune responses to reduce invasive breast cancer occurrence and metastasis.