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An IMiD-inducible degron provides reversible regulation for chimeric antigen receptor expression and activity

Carbonneau, Seth and Sharma, Sujata and Peng, Liaomin and Rajan, Vaisakh and Hainzl, Dominik and Henault, Martin and Yang, Chian and Hale, Jacob and Shulok, Janine and Tallarico, John and Porter, Jeffrey and Brogdon, Jennifer and Dranoff, Glenn and Bradner, Jay and Hild, Marc and Guimaraes, Carla (2021) An IMiD-inducible degron provides reversible regulation for chimeric antigen receptor expression and activity. Cell Chemical Biology. ISSN 24519448

Abstract

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.

Item Type: Article
Keywords: chimeric antigen receptor (CART) CRBN degron IMiD protein regulation
Date Deposited: 23 Feb 2021 00:45
Last Modified: 23 Feb 2021 00:45
URI: https://oak.novartis.com/id/eprint/42557

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