Molecular switch-mediated control of engineered cells

US12049482B2 · kind B2 · utility

Assignees

• The Brigham and Women's Hospital, Inc. · US
• The General Hospital Corporation · US
• President and Fellows of Harvard College · US

Inventors

• Max Jan · Boston, US
• Quinlan L. Sievers · Boston, US
• Benjamin Ebert · Brookline, US
• Marcela Maus · Lansdowne, US

Key dates

• Filing date: Oct 30, 2018
• Grant date: Jul 30, 2024
• Expiry date: Aug 24, 2040

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C07K2319/03
• WIPO field: Pharmaceuticals
• WIPO sector: Chemistry

Abstract

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.