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

项目摘要 为了响应NCI的FOA PAR-20 - 292，用于转化癌症研究的早期和概念阶段，我们 NIH R21资助申请旨在生成和验证一种新形式的条件活性T细胞 接合双特异性抗体（T-biAb），其被设计用于在肿瘤微环境中的蛋白水解活化， 实体恶性肿瘤因此，所提出的T-biAb形式允许靶向肿瘤相关抗原 由于它们在健康细胞上的基础表达水平， 重要器官。虽然这样的条件活性T-biAb具有广泛的治疗效用，但我们将重点关注我们的研究。 在卵巢癌的体外、体内和离体模型中严格验证新形式的拟议研究 癌这包括卵巢癌细胞系（体外和体内）和原发性肿瘤细胞系（体外和体内）的实验。 来自卵巢癌患者的细胞（离体）。公共卫生迫切需要一种概念上新的 卵巢癌的治疗在目前患有卵巢癌的约235，000名美国女性中， 将存活5年。2020年，约22，000名美国女性将被新诊断，约14，000名将死于卵巢癌 癌我们将检验靶向TAA EGFR、HER2和HER3的条件活性T-biAb是否能够抑制肿瘤细胞增殖的假设。 FOLR1在卵巢癌中均过表达，可介导有效且安全的肿瘤根除 细胞随着激励先进的临床前研究的总体目标，我们将提供 用于探测TAA靶向的创新工具和技术， 一般实体恶性肿瘤和卵巢癌肿瘤微环境中的蛋白水解活化 特别的。

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.