| Autor: |
Fiore Cattaruzza, Ayesha Nazeer, Milton To, Mikhail Hammond, Caitlin Koski, Lucas Liu, V. Pete Yeung, Deena Rennerfeldt, Angela Henkensiefken, Michael Fox, Sharon Lam, Kari Morrissey, Zachary Lange, Vladimir Podust, Mika Derynck, Bryan Irving, Volker Schellenberger |
| Rok vydání: |
2022 |
| Popis: |
To enhance the therapeutic index of T-cell engagers (TCE), we engineered masked, conditionally active TCEs (XPAT proteins), targeting a tumor antigen (human epidermal growth factor receptor 2 [HER2] or epidermal growth factor receptor 2 [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 induces protease-dependent anti-tumor activity and is proteolytically stable in healthy tissues. In non-human primates (NHPs), HER2-XPAT demonstrates a strong safety margin (> 400-fold increase in tolerated maximum concentration versus uTCE). HER2-XPAT cleavage is low and similar in plasma samples from healthy and diseased humans and NHPs, supporting translatability of stability to human patients. The EGFR-XPAT confirmed the utility of XPAT technology for tumor targets more widely expressed in healthy tissues. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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