An IMiD-inducible degron provides reversible regulation for chimeric antigen receptor expression and activity
| Autor: | Carla Guimaraes, Jennifer Brogdon, Janine Shulok, Marc Hild, Liaomin Peng, Jacob Hale, Chian Yang, John A. Tallarico, Vaisakh Rajan, Martin Henault, James E. Bradner, Sujata Sharma, Seth Carbonneau, Jeffrey A. Porter, Glenn Dranoff, Dominik Hainzl |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Drug Adolescent T-Lymphocytes Xenotransplantation medicine.medical_treatment media_common.quotation_subject Lymphoblastic Leukemia Clinical Biochemistry Mice SCID Biology 01 natural sciences Biochemistry Cell Line Ikaros Transcription Factor Mice Mice Congenic Young Adult Mice Inbred NOD Drug Discovery medicine Animals Humans Immunologic Factors Molecular Biology Cell Proliferation Lenalidomide media_common Pharmacology Receptors Chimeric Antigen Molecular Structure 010405 organic chemistry Neoplasms Experimental Middle Aged IKZF3 Chimeric antigen receptor 0104 chemical sciences Membrane protein Cancer research Molecular Medicine Female Degron medicine.drug |
| Zdroj: | Cell Chemical Biology. 28:802-812.e6 |
| ISSN: | 2451-9456 |
| Popis: | Summary The recent development of successful CAR (chimeric antigen receptor) T cell therapies has been accompanied by a need to better control potentially fatal toxicities that can arise from adverse immune reactions. Here we present a ligand-controlled CAR system, based on the IKZF3 ZF2 β-hairpin IMiD-inducible degron, which allows for the reversible control of expression levels of type I membrane proteins, including CARs. Testing this system in an established mouse xenotransplantation model for acute lymphoblastic leukemia, we validate the ability of the CAR19-degron to target and kill CD19-positive cells displaying complete control/clearance of the tumor. We also demonstrate that the activity of CAR19-degron can be regulated in vivo when dosing a US Food and Drug Administration-approved drug, lenalidomide. |
| Databáze: | OpenAIRE |
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