AGR2-superantigen vaccine conjugate for the treatment of pancreaticductal adenocarcinoma

AGR2-超抗原疫苗缀合物用于治疗胰导管腺癌

• 批准号: 10857460
• 负责人: Reeder McNeil Robinson
• 金额: $ 78.27万
• 依托单位: LEUKOGENE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-17 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10857460
• 关键词: Adenocarcinoma; Affinity; Animals; Anterior; Antibody titer measurement; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Binding; Biochemistry; Biological Markers; Blood; C57BL/6 Mouse; CTLA4 gene; Cancer Model; Cancer Vaccines; Carrier Proteins; Cell Line; Cells; Clinic; Color; Conjugate Vaccines; Dependence; Detection; Development; Diagnosis; Dose; Drug Metabolic Detoxication; Effector Cell; Enzyme-Linked Immunosorbent Assay; Exotoxins; Family; Firefly Luciferases; Flow Cytometry; Goals; Haemophilus influenzae; Head; Head of pancreas; Histocompatibility Antigens Class II; Histopathology; Human; Immune; Immune Targeting; Immune checkpoint inhibitor; Immune response; Immunohistochemistry; Immunologic Markers; Immunologics; Immunophenotyping; Immunosuppression; Immunotherapy; Implant; Interleukin-6; KPC model; Malignant Neoplasms; Malignant neoplasm of pancreas; Maximum Tolerated Dose; Measures; Mediating; Modeling; Monitor; Mus; Operative Surgical Procedures; Pancreas; Pancreatic Ductal Adenocarcinoma; Patient-Focused Outcomes; Patients; Peptide/MHC Complex; Phase; Pre-Clinical Model; Protein Disulfide Isomerase; Proteins; Radiation therapy; Recombinants; Research; Schedule; Serum; Streptococcus; Streptococcus pyogenes; Superantigens; Surface; Surrogate Markers; Survival Rate; T cell response; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Tissues; Toxic effect; Toxicology; Treatment Protocols; Tumor Antigens; Tumor Markers; Tumor-Infiltrating Lymphocytes; Vaccinated; Vaccination; Vaccines; Work; anti-CTLA4 antibodies; anti-PD-1; anti-cancer; bioluminescence imaging; body system; cancer therapy; checkpoint inhibition; chemotherapy; clinical candidate; clinical development; cytokine release syndrome; drug candidate; effective therapy; immune cell infiltrate; immunogenic; immunogenicity; in vivo; innovation; member; mouse model; mutant; novel; overexpression; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; phase 1 study; phase 2 study; pre-clinical; programs; receptor binding; response; subcutaneous; success; synergism; targeted treatment; theories; therapeutic vaccine; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis; vaccine candidate; vaccine development; vaccine immunotherapy; vaccine strategy

Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer. Poor survival rates are largely due to the late stage at which PDAC is diagnosed and a lack of effective targeted therapies. While the field of immunotherapy has significantly increased overall survival in some malignancies, they have not translated to PDAC. The long-term goal of this research program is to develop a novel cancer vaccine for the treatment of PDAC. Preliminary studies by our group and others have shown that the Anterior Gradient-2 (AGR2) protein, a member of the protein disulfide isomerase (PDI) family, is induced during PDAC oncogenesis and highly expressed in >90% of PDAC patients. AGR2 has intracellular oxidative folding function and is also released from the cell where it localizes to the surface of PDAC cells and is shed into the tumor microenvironment. We hypothesize that AGR2 is an actionable target for the development of a PDAC targeted vaccine and will test that theory using a new immunotherapy drug candidate. Streptococcal Mitogenic Exotoxin Z-2 (SMEZ-2) from Streptococcus pyogenes is a bacterial superantigen (SAg) that binds to MHC II molecules on antigen presenting cells (APCs) with high affinity. In preliminary studies we generated a detoxified AGR2-SMEZ-2 conjugate that we hypothesize will stimulate a robust anti-PDAC immune response. We found in preliminary studies that AGR2- SMEZ-2 generates a robust anti-AGR2 response in mice and displays no overt toxicity. The objectives of Phase 1 of this study are: (1) to demonstrate anti-PDAC efficacy of AGR2-SMEZ-2 in vivo, and (2) to measure B and T cell biomarkers of an anti-AGR2 response in vaccinated mice. Upon success in Phase 1, the objectives of Phase 2 of this study are: (1) to show synergy between AGR2-SMEZ-2 vaccination and checkpoint inhibition in vivo, (2) to compare the superior immunogenicity of SMEZ-2 mediated through MHC II-specific binding over existing vaccine carrier proteins, and (3) to determine the optimal dose, schedule, and toxicology profile of AGR2-SMEZ-2 in vivo. This work is innovative because we will investigate the anti-PDAC mechanism of our proprietary AGR2- SMEZ-2 vaccine and characterize the induced immune response in different mouse models. This work will support the development of a first-in-class vaccine for the treatment of PDAC, a cancer with few existing therapies. In addition, we expect that this study will allow for other immunotherapies (namely checkpoint inhibition) to become effective in providing a PDAC response in patients.

项目概要/摘要 胰腺导管腺癌（PDAC）是最致命的癌症之一。存活率低主要是 由于PDAC诊断时已处于晚期，且缺乏有效的靶向治疗。虽然该领域 免疫疗法显着提高了某些恶性肿瘤的总生存率，但尚未转化为 PDAC。该研究计划的长期目标是开发一种新型癌症疫苗来治疗 PDAC。我们小组和其他人的初步研究表明，前梯度 2 (AGR2) 蛋白是一种 蛋白质二硫键异构酶 (PDI) 家族的成员，在 PDAC 肿瘤发生过程中被诱导，并且高度 在 >90% 的 PDAC 患者中表达。 AGR2具有细胞内氧化折叠功能，也由细胞释放 它定位于 PDAC 细胞表面并脱落到肿瘤微环境中。我们 假设 AGR2 是开发 PDAC 靶向疫苗的可行靶标，并将测试这一点 使用新的免疫治疗候选药物的理论。链球菌有丝分裂外毒素 Z-2 (SMEZ-2) 来自 化脓性链球菌是一种细菌超抗原 (SAg)，可与抗原呈递上的 MHC II 分子结合 细胞（APC）具有高亲和力。在初步研究中，我们生成了一种解毒的 AGR2-SMEZ-2 缀合物， 我们假设会刺激强大的抗 PDAC 免疫反应。我们在初步研究中发现 AGR2- SMEZ-2 在小鼠体内产生强烈的抗 AGR2 反应，并且没有表现出明显的毒性。阶段目标 本研究的 1 项内容是：(1) 证明 AGR2-SMEZ-2 体内的抗 PDAC 功效，以及 (2) 测量 B 和 T 接种疫苗的小鼠中抗 AGR2 反应的细胞生物标志物。第一阶段取得成功后，第一阶段的目标 这项研究的 2 点是：（1）展示 AGR2-SMEZ-2 疫苗接种和体内检查点抑制之间的协同作用， (2) 比较通过 MHC II 特异性结合介导的 SMEZ-2 优于现有的免疫原性 疫苗载体蛋白，(3) 确定 AGR2-SMEZ-2 体内的最佳剂量、时间表和毒理学特征。这项工作具有创新性，因为我们将研究我们专有的 AGR2-的抗 PDAC 机制 SMEZ-2 疫苗并表征不同小鼠模型中诱导的免疫反应。这项工作将 支持开发用于治疗 PDAC 的一流疫苗，PDAC 是一种现有的癌症很少 疗法。此外，我们预计这项研究将允许其他免疫疗法（即检查点疗法） 抑制）以有效地为患者提供 PDAC 反应。