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

项目总结 为了回应NCI关于转化性癌症研究的早期和概念性阶段的FOA PAR-20-292，我们的 NIH R21拨款申请寻求产生和验证一种新的条件激活T细胞格式 结合双功能抗体(T-biAbbs)设计用于在肿瘤微环境中激活蛋白 实体恶性肿瘤。因此，建议的T-biAb形式允许靶向肿瘤相关抗原 (TAAs)，由于其在健康细胞上的基本表达水平，禁止传统T-biAbs的询问 重要器官。虽然这种有条件活性的T-biAbs具有广泛的治疗作用，但我们将专注于我们的 建议在体外、体内和体外卵巢模型中严格验证新格式的研究 癌症。这包括对卵巢癌细胞系(体外和体内)和原发肿瘤的实验。 来自卵巢癌患者的细胞(体外)。公共卫生迫切需要一种新的概念 卵巢癌的治疗。在目前患有卵巢癌的约235,000名美国女性中，只有不到一半的人 能存活5年。到2020年，约22,000名美国妇女将被新诊断，约14,000人将死于卵巢 癌症。我们将检验这样的假设，即靶向TAA EGFR、HER2和 FOLR1在卵巢癌中均有过表达，可介导有效而安全的肿瘤根除 细胞。总体目标是激励先进的临床前研究，我们将提供这两项 使用专为以下目的而设计的条件活性T-biAbs探测TAA靶向的创新工具和技术 实体瘤和卵巢癌肿瘤微环境中蛋白水解酶的激活 很特别。

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.