8 Oral - HER2-XPAT, a novel protease-activatable pro-drug T cell engager (TCE), with potent T-cell activation and efficacy in solid tumors and large predicted safety margins in non-human primate (NHP)

Abstract

Background: TCEs are effective at inducing remissions in hematologic cancers but have been challenging in solid tumors due to on-target, off-tumor toxicity. Attempts to circumvent CRS include fractionated or step-up dosing, complex molecular designs, but these have been unsuccessful due to toxicity and/or enhanced immunogenicity. Amunix has developed a conditionally active TCE, XPAT or XTENylated Protease-Activated bispecific T Cell Engager, that exploits the protease activity present in tumors vs. healthy tissue to expand the therapeutic index (TI). The core of the HER2-XPAT (PAT) consists of 2 tandem scFVs targeting CD3 and HER2. Two unstructured polypeptide masks (XTEN) are attached to the core that sterically reduce target engagement and extend T1/2. Protease cleavage sites at the base of the XTEN masks enable proteolytic activation of XPATs in the tumor microenvironment, unleashing a highly potent TCE with a short T1/ 2, and further improving the TI.