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

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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.