Abstract 1062P
Background
TCEs can overcome common immunotherapy obstacles by activating T-cells regardless of specificity, thereby having the potential to work in immunologically cold tumors. Further, cold tumors like EGFR+ KRAS/BRAF CRC, NSCLC, pancreas have few options for immunotherapy survival benefits. TCEs have been challenging due to on-target, off-tumor toxicity. To address this challenge, Amunix has developed a pro-drug TCE, the XPAT or XTENylated Protease-Activated bispecific T Cell Engager, that exploits the tumor protease activity vs. healthy tissue, enabling expansion of the therapeutic index (TI). The core of EGFR-XPAT (XPAT) consists of 2 tandem scFVs targeting CD3 and EGFR. Attached to the core, two unstructured polypeptide masks (XTEN) sterically reduce target engagement and extend T1/2. Protease cleavage sites encoded at the base of XTEN enable proteolytic activation of XPATs in the tumor microenvironment, unleashing a highly potent TCE with a short T1/2, further improving the TI.
Methods
The efficacy of XPAT and PAT (cleaved XPAT) were characterized for cytotoxicity in vitro and in huPBMC/tumor-bearing mice. Toxicology studies were conducted in NHP.
Results
Cleaved PAT demonstrated potent in vitro T cell cytotoxicity against KRAS/BRAF tumor cells (EC50 1-2pM), while XPAT provided up to 5-13,000-fold protection. XPAT demonstrated CRs in HT-29 BRAF tumors. In NHP, XPAT has been dose escalated up to 1.5mg/kg, with 1mg/kg as the MTD. The NOAEL for PAT by continuous infusion was 33μg/kg/d. XPAT demonstrated T-cell margination at 0.46mg/kg, and mild elevations of cytokines that were well tolerated, whereas 1mg/kg demonstrated more significant elevations of CRS and minimal sequelae on histopathology. XPAT has demonstrated >100-fold protection over PAT with little evidence of CRS up to 1mg/kg.
Conclusions
EGFR-XPAT is a novel T cell engager pro-drug with promising evidence of a TI in NHP with the potential for immunotherapy in EGFR KRAS/BRAF tumors. With the prior XTEN clinical data demonstrating low immunogenicity, XPATs provide a promising solution to overcome On-target, Off-tumor toxicity. Additional PK, PD, cytokines, safety, and efficacy data will be presented.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Amunix Pharmaceuticals.
Funding
Amunix Pharmaceuticals.
Disclosure
B. Irving: Leadership role, Shareholder/Stockholder/Stock options: Amunix Pharmaceuticals. A. Nazeer, F. Cattaruzza, Z. Lange, C. Koski, M. Hammond, A. Henkensiefken: Shareholder/Stockholder/Stock options, Full/Part-time employment: Amunix Pharmaceuticals. B-C. Sim: Shareholder/Stockholder/Stock options, Full/Part-time employment: Exelixis. M. Derynck: Leadership role, Shareholder/Stockholder/Stock options: Amunix Pharmaceuticals; Shareholder/Stockholder/Stock options: Roche; Shareholder/Stockholder/Stock options: Pliant Therapeutics. V. Schellenberger: Leadership role, Shareholder/Stockholder/Stock options: Amunix Pharmaceuticals; Shareholder/Stockholder/Stock options: Teneo Bio.