Post-translational covalent assembly of CAR and synNotch receptors for programmable antigen targeting
| Autor: | Natasa Miskov-Zivanov, Olivera J. Finn, Alexander Deiters, Jason Lohmueller, Michael Kvorjak, Yaniv Tivon, Adam A. Butchy |
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| Rok vydání: | 2020 |
| Předmět: |
chemistry.chemical_classification
0303 health sciences Antigen Targeting biology Chemistry Chimeric antigen receptor 3. Good health Cell biology 03 medical and health sciences 0302 clinical medicine Enzyme Antigen 030220 oncology & carcinogenesis Sense (molecular biology) biology.protein Antibody Receptor Gene 030304 developmental biology |
| Popis: | 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. To expand the targeting capabilities of these receptors, we have developed switchable adaptor receptor systems for which receptor specificity can be directed post-translationally via covalent attachment of a co-administered antibody. Instead of directly targeting an antigen, our receptors contain the SNAPtag self-labeling enzyme, which reacts with benzylguanine (BG)-conjugated antibodies to assemble covalently-associated antigen receptors. We demonstrate that activation of SNAP-CAR and SNAP-synNotch receptors and their downstream effector functions can be successfully targeted by several clinically-relevant BG-conjugated antibodies in an antigen-specific and antibody dose-dependent manner. To better define parameters affecting receptor signaling, we developed a mathematical model of switchable receptor systems. SNAP receptors provide a powerful new strategy to post-translationally reprogram the targeting specificity of engineered cells. |
| Databáze: | OpenAIRE |
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