Post-translational covalent assembly of CAR and synNotch receptors for programmable antigen targeting

Elisa Ruffo, Adam A. Butchy, Yaniv Tivon, Victor So, Michael Kvorjak, Avani Parikh, Eric L. Adams, Natasa Miskov-Zivanov, Olivera J. Finn, Alexander Deiters and Jason Lohmueller ()
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Elisa Ruffo: University of Pittsburgh
Adam A. Butchy: University of Pittsburgh
Yaniv Tivon: University of Pittsburgh
Victor So: University of Pittsburgh
Michael Kvorjak: University of Pittsburgh
Avani Parikh: University of Pittsburgh
Eric L. Adams: University of Pittsburgh
Natasa Miskov-Zivanov: University of Pittsburgh
Olivera J. Finn: University of Pittsburgh
Alexander Deiters: University of Pittsburgh
Jason Lohmueller: University of Pittsburgh

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37863-5

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