Post-translational covalent assembly of CAR and synNotch receptors for programmable antigen targeting
Abstract
Chimeric antigen receptors (CARs) and synthetic Notch (synNotch) receptors are engineered cell-surface receptors that sense a target antigen and respond by activating T cell receptor signaling or a customized gene program, respectively. Here, to expand the targeting capabilities of these receptors, we develop “universal” receptor systems for which receptor specificity can be directed post-translationally via covalent attachment of a co-administered antibody bearing a benzylguanine (BG) motif. A SNAPtag self-labeling enzyme is genetically fused to the receptor and reacts with BG-conjugated antibodies for covalent assembly, programming antigen recognition. We demonstrate that activation of SNAP-CAR and SNAP-synNotch receptors can be successfully targeted by clinically relevant BG-conjugated antibodies, including anti-tumor activity of SNAP-CAR T cells in vivo in a human tumor xenograft mouse model. Finally, we develop a mathematical model to better define the parameters affecting universal receptor signaling. SNAP receptors provide a powerful strategy to post-translationally reprogram the targeting specificity of engineered cells.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 09, 2023
- Source ID
- 10.1038/s41467-023-37863-5
Entities
People
- Adam A. Butchy
- Alexander Deiters
- Avani Parikh
- Elisa Ruffo
- Eric L. Adams
- Jason Lohmueller
- Michael Kvorjak
- Nataša Miškov-Živanov
- Olivera J. Finn
- Victor So
- Yaniv Tivon
Organizations
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- National Cancer Institute
- National Institute of General Medical Sciences
- United States Department of Defense
- United States Department of Health and Human Services