T-cell engaging bispecific antibodies designed for proteolytic activation in the tumor microenvironment

T 细胞接合双特异性抗体，专为肿瘤微环境中的蛋白水解激活而设计

基本信息

批准号：
10290191
负责人：
CHRISTOPH RADER
金额：
$ 14.49万
依托单位：
SCRIPPS FLORIDA
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：
2021-07-20 至 2022-04-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10290191
关键词：
Acute Lymphocytic Leukemia Antigen Targeting Applications Grants Autologous Binding Biopsy Bispecific Antibodies CD19 gene CD3 Antigens Cancer Patient Cancer cell line Carcinoma Cell Surface Receptors Cells Cleaved cell Clinical Trials Development Disulfides Drug Kinetics ERBB2 gene Engineering Epidermal Growth Factor Receptor Epithelial Cells FDA approved FOLR1 gene Fab domain Generations Goals Heart Hematologic Neoplasms Hematology Human Immune Immune system Immunocompetent In Vitro Incentives Investigation Kidney Liver Lung Lymphoid Cell Malignant - descriptor Malignant Neoplasms Malignant neoplasm of ovary Mediating Modality Modeling Monoclonal Antibodies Mus Mutation Myeloid Cells Newly Diagnosed Organ Peptide Hydrolases Pilot Projects Primary Neoplasm Proteins Public Health Recruitment Activity Refractory Relapse Research Serine Protease Site Solid T-Lymphocyte Techniques Testing Therapeutic Therapeutic Index Tissues Toxic effect Tumor Antigens Tumor-Derived United States National Institutes of Health Validation Woman Xenograft procedure anti-PD-1 anti-PD-L1 arm base cancer cell cancer immunotherapeutics cancer immunotherapy cancer therapy cell killing design experimental study in vivo innovation matriptase men neoplastic cell novel overexpression pre-clinical recruit response tool translational cancer research tumor tumor eradication tumor microenvironment

项目摘要

PROJECT SUMMARY In response to NCI’s FOA PAR-20-292 for early and conceptual stages of translational cancer research, our NIH R21 grant application seeks the generation and validation of a new format of conditionally active T-cell engaging bispecific antibodies (T-biAbs) designed for proteolytic activation in the tumor microenvironment of solid malignancies. As such, the proposed T-biAb format permits the targeting of tumor-associated antigens (TAAs) that prohibit interrogation by conventional T-biAbs due to their basal expression levels on healthy cells of vital organs. While such conditionally active T-biAbs have broad therapeutic utility, we will focus our proposed studies on rigorously validating the new format in in vitro, in vivo, and ex vivo models of ovarian cancer. This includes experiments with both ovarian cancer cell lines (in vitro and in vivo) and primary tumor cells from ovarian cancer patients (ex vivo). There is an urgent public health need for conceptually new treatments for ovarian cancer. Less than half of the ~235,000 U.S. women currently living with ovarian cancer will survive 5 years. In 2020, ~22,000 U.S. women will be newly diagnosed and ~14,000 will die of ovarian cancer. We will test the hypothesis that conditionally active T-biAbs targeting the TAAs EGFR, HER2, and FOLR1, all of which are overexpressed in ovarian cancer, can mediate potent and safe eradication of tumor cells. With the overall objective of incentivizing advanced preclinical investigations, we will deliver both innovative tools and techniques for probing TAA targeting with conditionally active T-biAbs designed for proteolytic activation in the tumor microenvironment of solid malignancies in general and ovarian cancer in particular.

项目概要为了响应 NCI 针对转化癌症研究早期和概念阶段的 FOA PAR-20-292，我们 NIH R21 拨款申请寻求生成和验证一种新形式的有条件活性 T 细胞参与双特异性抗体（T-biAbs），设计用于肿瘤微环境中的蛋白水解激活因此，所提出的 T-biAb 形式可以靶向肿瘤相关抗原。 (TAA) 由于其在健康细胞上的基础表达水平而禁止传统 T-biAb 的询问虽然这种有条件活性的 T-biAb 具有广泛的治疗用途，但我们将重点关注我们的研究。拟议的研究严格验证新格式的体外、体内和离体卵巢模型这包括卵巢癌细胞系（体外和体内）和原发性肿瘤的实验。来自卵巢癌患者的细胞（离体）公共卫生方面迫切需要新概念的细胞。目前患有卵巢癌的约 235,000 名美国女性中不到一半。到 2020 年，大约 22,000 名美国女性将被新诊断出卵巢癌，大约 14,000 人将死于卵巢癌。我们将检验以下假设：条件活性 T-biAb 靶向 TAA EGFR、HER2 和 FOLR1 在卵巢癌中过度表达，可以介导有效且安全的肿瘤根除为了激励先进的临床前研究，我们将提供这两项研究。用于利用条件活性 T-biAb 探测 TAA 靶向的创新工具和技术，专为一般实体恶性肿瘤和卵巢癌肿瘤微环境中的蛋白水解激活特别的。