Bispecific T cell engagers for the treatment of pancreatic ductal adenocarcinoma

用于治疗胰腺导管腺癌的双特异性 T 细胞接合器

基本信息

批准号：
10324881
负责人：
Nathan G. Dolloff
金额：
$ 36.21万
依托单位：
LEUKOGENE THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-24 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10324881
关键词：
Affinity Anterior Bacteriophages Binding Biological Assay Blood CD3 Antigens Cancer Model Cell Culture Techniques Cell model Cell-Mediated Cytolysis Cells Collaborations Complementarity Determining Regions Complex Data Dependence Development Diagnosis Enzyme-Linked Immunosorbent Assay Family Genetically Engineered Mouse Goals Human Immune Immunoglobulin Fragments Immunologics Immunotherapeutic agent Immunotherapy In Vitro Interferon Type II KRASG12D Lead Libraries Liquid substance Literature Malignant Neoplasms Malignant neoplasm of pancreas Measures Methods Modeling Muromonab-CD3 Mus Mutation Oligonucleotide-Directed Mutagenesis Pancreas Pancreatic Ductal Adenocarcinoma Parents Patients Phage Display Phase Positioning Attribute Pre-Clinical Model Protein Disulfide Isomerase Proteins Receptor Signaling Research Sampling Specificity Surface Surface Plasmon Resonance Survival Rate T-Cell Activation T-Cell Receptor T-Lymphocyte TNF gene Testing Therapeutic Thermodynamics Tissue Microarray Tissues Translations Treatment Protocols Validation Work Xenograft Model anti-PD-1 anti-tumor immune response bi-specific T cell engager cancer therapy cell killing clinical candidate clinical development commercialization drug candidate effective therapy established cell line experimental study extracellular humanized mouse immune checkpoint blockade improved in vivo in vivo evaluation innovation knock-down member model development mouse model mutant neoplastic cell novel therapeutics overexpression pancreas development pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model pancreatic neoplasm pre-clinical programs protein folding screening subcutaneous targeted treatment theories treatment strategy tumor tumor growth tumor microenvironment tumorigenesis

项目摘要

---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 therapies. The long-term goal of this research program is to discover new immunotherapeutic approaches 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 PDAC targeted immunotherapies and will test that theory using a new immunotherapy drug candidate. In preliminary studies we generated a proprietary anti-AGR2 single chain antibody fragment (scFv) by phage display screening and constructed a bispecific T-cell engager (BiTE) that binds to AGR2 and CD3, which is a subunit of the T cell receptor complex. We found that BiTE engagement stimulates T cell receptor signaling, T cell activation/proliferation, and T cell induced killing of AGR2-positive PDAC cells in cellular models. The specific objectives of this study are: (1) to improve the AGR2 binding affinity of our scFv via affinity maturation, and (2) to demonstrate high potency T cell dependent killing of PDAC cells by an optimized BiTE molecule in vitro and in genetically engineered mouse models (GEMMs) of PDAC. These aims are built on clear rationale from the existing literature and strong preliminary data. This work is innovative because we will investigate the activity and mechanism of a new immunotherapy drug candidate for the treatment of PDAC, which is a cancer in need of new therapies. In addition we expect that this study will reveal new methods and mechanisms for generating an anti-tumor immune response in PDAC, for which existing immunotherapies have thus far been ineffective.

---项目总结/摘要 ---- 胰腺导管腺癌（PDAC）是最致命的癌症之一。存活率很低很大程度上是由于PDAC诊断时已处于晚期且缺乏有效的治疗方法。长期目标该研究计划的目的是发现治疗 PDAC 的新免疫治疗方法。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，也被释放它从细胞中定位到 PDAC 细胞表面并脱落到肿瘤微环境中。我们假设 AGR2 是开发 PDAC 靶向免疫疗法的可行靶点，并且将使用一种新的免疫治疗候选药物来测试该理论。在初步研究中，我们生成了通过噬菌体展示筛选专有的抗AGR2单链抗体片段（scFv）并构建了双特异性 T 细胞接合器 (BiTE)，与 AGR2 和 CD3 结合，后者是 T 细胞受体复合物的亚基。我们发现 BiTE 参与刺激 T 细胞受体信号传导、T 细胞活化/增殖和 T 细胞在细胞模型中诱导杀死 AGR2 阳性 PDAC 细胞。本研究的具体目标是：（1）通过亲和力成熟提高我们的 scFv 的 AGR2 结合亲和力，以及 (2) 证明高效能 T 通过优化的 BiTE 分子在体外和基因工程中对 PDAC 细胞进行细胞依赖性杀伤 PDAC 的小鼠模型 (GEMM)。这些目标建立在现有文献的明确理由之上强有力的初步数据。这项工作是创新的，因为我们将研究一个用于治疗 PDAC 的新免疫治疗候选药物，PDAC 是一种需要新疗法的癌症。在此外，我们期望这项研究将揭示产生抗肿瘤药物的新方法和机制 PDAC 中的免疫反应，迄今为止现有的免疫疗法对此无效。