Abstract 1060P
Background
TCEs are effective in creating remissions in hematologic cancers but have been challenging in solid tumors due to on-target, off-tumor toxicity. Attempts to circumvent CRS include 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, expanding the therapeutic index (TI). The core of the HER2-XPAT (XPAT) consists of 2 tandem scFVs targeting CD3 and HER2. Two unstructured polypeptide masks (XTEN) are attached to the core and sterically reduce target engagement and extend T1/2. Protease cleavage sites 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 activity of XPAT and PAT (cleaved XPAT) were characterized for cytotoxicity in vitro and in huPBMC/tumor-bearing mice. Stability for XPAT was studied ex-vivo from cancer pt plasma. Toxicology studies were conducted in NHPs.
Results
Cleaved PAT demonstrated potent in vitro T cell cytotoxicity against tumor cells (EC50 1-2pM), while XPAT had up to 14,000-fold protection against killing. XPAT demonstrated CRs in with both BT-474 and SK-OV-3 tumors. In NHP, XPAT has been dose escalated up to 50 mg/kg, with 42mg/kg as the MTD which was well tolerated. PAT given by continuous infusion was not tolerated due to CRS at 0.3mg/kg/d. XPAT demonstrated T-cell margination at 2mg/kg but absence of CRS up to 42mg/kg. XPAT was also stable with no evidence of cleavage in the plasma of cancer pts over 7 days. XPAT has demonstrated >1000x protection over PAT with little evidence of CRS, including a 20x margin of safety over dose needed for pharmacodynamic activity.
Conclusions
HER2-XPAT is a novel T cell engager pro-drug with promising evidence of a wide TI in NHP. With XTEN’s prior clinical data of low immunogenicity, the XPAT TCEs provide a promising solution and will enter phase I in the near future. 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
F. Cattaruzza, A. Nazeer, Z. Lange, C. Koski, M. Hammond, A. Henkensiefken: Shareholder/Stockholder/Stock options, Full/Part-time employment: Amunix Pharmaceuticals. D. Hostetter: Shareholder/Stockholder/Stock options, Full/Part-time employment: CRISPR Therapeutics; Shareholder/Stockholder/Stock options: Cytomx; Advisory/Consultancy: Alaunus Biosciences; Advisory/Consultancy: Dren Bio. 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. B. Irving: Leadership role, Shareholder/Stockholder/Stock options: Amunix Pharmaceuticals.