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

项目总结： 抗癌疫苗可以成为一种非常有吸引力的肿瘤保护和治疗方法，因为 有可能提供长期免疫，副作用很少。然而，它一直是极具挑战性的 研发成功的抗癌疫苗。由于肿瘤抗原的固有免疫原性较低，因此至关重要。 免疫原性载体可有效增强对肿瘤抗原的免疫应答。 IASO治疗公司是一家从密歇根州立大学剥离出来的初创公司。国际会计准则组织的使命是 通过靶向一类重要的肿瘤抗原，即肿瘤相关抗原，开发下一代疫苗 碳水化合物和糖结合抗原。在这项申请中，IASO旨在开发一种独特的专有运营商 以噬菌体Qβ为基础的递送肿瘤抗原的系统，如肿瘤相关粘蛋白- 1(TMUC1)，并产生优越的免疫力以对抗乳腺癌。 粘蛋白-1蛋白是抗癌疫苗开发的一个极具吸引力的靶点，因为它与肿瘤相关 TMUC1糖肽由于其不同的糖链结构而被认为是新的抗原。 正常细胞上的对应物。此外，tMUC1在许多类型的肿瘤细胞上高水平表达，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 抗tMUC1抗体水平高的患者预后和无病生存期明显较好。 然而，开发有效的基于tMUC1的抗癌疫苗来诱导 足够水平的抗tMUC1免疫可以起到保护作用。 在这个第一阶段项目的目标1中，我们将在发现tMUC1关键保护性表位的基础上， 工程噬菌体Qβ传递tMUC1Ig，并激发更好的抗体反应。此外，新的 将开发方法来激活针对乳腺癌抗原的特异性T细胞，从而使两种 体液和细胞免疫来对抗乳腺癌。在目标2中，先导Qβ-肿瘤抗原结合物的疗效 将在类似于三重阴性乳腺癌的自发小鼠乳腺癌模型中进行评估 人类病人。此外，由于癌症转移是癌症死亡的主要原因，小鼠的乳房模型 肿瘤转移的发展和先导Qβ-肿瘤抗原结合物的能力降低 转移将被确定。由于Qβ具有诱导强大免疫的能力，因此可以保护 预防乳腺癌发展和复发的免疫宿主。 整体影响。一种新的Qβ疫苗平台大大优于目前可用的载体，旨在 传递肿瘤抗原，激发高水平的抗体和T细胞免疫反应，以减少乳腺侵袭 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.