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

由专有突变噬菌体 Qbeta 肿瘤抗原缀合物实现的针对乳腺癌的新型疫苗策略

• 批准号: 10081294
• 负责人: Herbert Wanjala Kavunja
• 金额: $ 30万
• 依托单位: IASO THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-18 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10081294
• 关键词: Active Immunization; Antibodies; Antibody Response; Antigen Targeting; Antigens; B-Lymphocyte Epitopes; Bacteriophages; Biotechnology; Breast; Breast Cancer Model; Breast Cancer Patient; Breast cancer metastasis; Cancer Etiology; Cancer Patient; Cancer Vaccine Related Development; Cancer Vaccines; Carbohydrates; Cause of Death; Cellular Immunity; Chemosensitization; Chemotherapy and/or radiation; Clinical; Clinical Research; Clinical Trials; Colon Carcinoma; Crystallization; Data; Development; Disease-Free Survival; Encapsulated; Engineering; Epitopes; Generations; Glycopeptides; Goals; Gold; Human; Humoral Immunities; Immune; Immune response; Immunity; Immunization; Immunize; Immunoglobulin G; Immunotherapy; Keyhole Limpet Hemocyanin; Lead; Legal patent; Licensing; Long-Term Effects; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mediation; Memory; Metastatic Neoplasm to the Lung; Methodology; Michigan; Mission; Modeling; Monoclonal Antibodies; Mucin 1 protein; Mus; National Cancer Institute; Neoplasm Metastasis; Normal Cell; Operative Surgical Procedures; Patients; Phase; Polysaccharides; Prevention therapy; Process; Production; Protein Engineering; Recurrence; Resolution; Small Business Innovation Research Grant; Structure; Surface; System; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; Technology; Therapeutic; Transgenic Mice; Tumor Antigens; Tumor Immunity; Universities; Vaccines; Work; anti-cancer; base; breast cancer vaccine; cancer cell; cancer prevention; cancer recurrence; cancer therapy; chimeric antigen receptor T cells; clinically relevant; combat; fighting; head-to-head comparison; immune checkpoint; immunogenic; immunogenicity; innovation; malignant breast neoplasm; mortality; mouse model; mutant; neoantigens; neoplastic cell; novel; novel vaccines; outcome forecast; preclinical study; prevent; quantum; response; side effect; standard of care; success; three dimensional structure; triple-negative invasive breast carcinoma; tumor

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.

项目概要： 抗癌疫苗可能是一种极具吸引力的肿瘤保护和治疗方法，因为 具有提供长期免疫力且副作用很少的潜力。然而，这一直是极具挑战性的 开发成功的抗癌疫苗。由于肿瘤抗原固有的低免疫原性，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反应。 Iaso Therapeutics 是一家从密歇根州立大学分离出来的初创公司。 Iaso 的使命是 通过针对一类重要的肿瘤抗原（即肿瘤相关抗原）开发下一代疫苗 碳水化合物和糖缀合物抗原。在此应用中，Iaso 旨在开发一种独特的专有载体 基于噬菌体 Qβ 的系统可传递癌症抗原，以肿瘤相关粘蛋白为代表 1 (tMUC1)，并产生卓越的免疫力来对抗乳腺癌。 Mucin-1 蛋白是抗癌疫苗开发中极具吸引力的靶点，因为它与肿瘤相关 tMUC1 糖肽被认为是新抗原，因为与其他糖肽相比，它们的聚糖结构不同。 正常细胞上的对应物。此外，tMUC1 在许多类型的肿瘤细胞中高水平表达，例如 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率明显更好。 然而，开发基于 tMUC1 的有效抗癌疫苗以诱导 足够水平的抗 tMUC1 免疫力具有保护作用。 在本期项目的目标1中，基于tMUC1关键保护表位的发现，我们将 设计噬菌体 Qβ 来传递 tMUC1 并引发优异的 IgG 抗体反应。此外，新 将开发方法来激活针对乳腺癌抗原的特异性 T 细胞，从而使两者都参与 体液和细胞免疫来对抗乳腺癌。在目标 2 中，先导 Qβ-肿瘤抗原缀合物的功效 将在类似于三阴性乳腺癌的自发小鼠乳腺癌模型中进行评估 人类患者。此外，由于癌症转移是癌症死亡的主要原因，乳腺癌小鼠模型 癌症转移将会发展，并且先导 Qβ-肿瘤抗原缀合物能够减少癌症转移 将建立转移。凭借其诱导强效免疫的能力，Qβ 构建体可以保护 免疫宿主免受乳腺癌的发展和复发。 总体影响。开发出一种新的 Qβ 疫苗平台，远远优于目前可用的载体 传递肿瘤抗原，引发高水平的抗体和 T 细胞免疫反应，以减少侵入性乳腺 癌症的发生和转移。