The Brigham and Women's Hospital, Inc.

Harvard College

The General Hospital Corporation

The Broad Institute, Inc.

Quinlan Sievers

Benjamin L Ebert

Marcela V Maus

Tarjei Mikkelsen

Max Jan

Benjamin Levine Ebert

The present disclosure relates to therapeutic methods and clinically useful molecular switches, for which activity or degradation of a switch-presenting polypeptide can be precisely induced via administration or withdrawal of an FDA-approved drug. Certain aspects of the disclosure relate to an engineered drug-inducible heterodimeric system including a first polypeptide presenting a CRBN polypeptide disrupted for or lacking a DDB 1-interacting domain and a second polypeptide presenting a CRBN polypeptide substrate, where binding between the CRBN polypeptide and the CRBN polypeptide substrate are inducible via administration of an CFDA-approved thalidomide analog immunomodulatory drug (IMiD). Another aspect of the disclosure relates to a chimeric antigen receptor (CAR) that presents a minimal fragment of the CRBN polypeptide substrate IKZF3 capable of triggering proteasomal degradation of CAR upon administration of an FDA-approved IMiD.

Molecular switch-mediated control of engineered cells

In one aspect, the present invention features method of identifying a cell resistant to a modulator of Cereblon (CRBN). In another aspect, the present invention features a method of characterizing sensitivity of a subject to a modulator of CRBN. In yet another aspect, the present invention features a method of monitoring sensitivity of a subject to a modulator of CRBN.

Methods of characterizing resistance to modulators of Cereblon

In one aspect, the invention features a method for identifying a drug-modulated polypeptide substrate of cereblon (CRBN). In another aspect, the invention features a method of identifying a polypeptide target of a modulator of CRBN. In yet another aspect, the invention provides methods of monitoring or characterizing the sensitivity of a subject to a modulator of CRBN.

Methods of identifying a polypeptide target for degradation by a modulator of CRBN

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Quinlan Sievers