XPAT® proteins, conditionally activated T-cell engagers engineered to mitigate on-target, off-tumor toxicity for immunotherapy of solid tumors
Year: 2022
Type: preprint
Abstract: 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.
Source: Research Square
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4298121561