Authors: Fiore Cattaruzza, Ayesha Nazeer, Milton To, Mikhail Hammond, Caitlin Koski, Lucas Y. Liu, V. Pete Yeung, Deena A. Rennerfeldt, Angela Henkensiefken, Michael Fox, Sharon Lam, Kari M. Morrissey, Zachary Lange, Vladimir N. Podust, Mika K. Derynck, Bryan A. Irving, Volker Schellenberger
Published: 2023-04-04
DOI: 10.1038/s43018-023-00536-9
Source: Full article
AbstractTo enhance the therapeutic index of T-cell engagers (TCEs), we engineered masked, precision-activated TCEs (XPAT proteins), targeting a tumor antigen (human epidermal growth factor receptor 2 (HER2) or epidermal growth factor receptor (EGFR)) and CD3. Unstructured XTEN polypeptide masks flank the N and C termini of the TCE and are designed to be released by proteases in the tumor microenvironment. In vitro, unmasked HER2-XPAT (uTCE) demonstrates potent cytotoxicity, with XTEN polypeptide masking providing up to 4-log-fold protection. In vivo, HER2-XPAT protein induces protease-dependent antitumor activity and is proteolytically stable in healthy tissues. In non-human primates, HER2-XPAT protein demonstrates a strong safety margin (>400-fold increase in tolerated maximum concentration versus uTCE). HER2-XPAT protein cleavage is low and similar in plasma samples from healthy and diseased humans and non-human primates, supporting translatability of stability to patients. EGFR-XPAT protein confirmed the utility of XPAT technology for tumor targets more widely expressed in healthy tissues.