| Autor: |
Jha R; Autolus Therapeutics, London W12 7FP, U.K.; Research Department of Haematology, UCL Cancer Institute, University College London, London WC1E 6DD, U.K., Kinna A; Autolus Therapeutics, London W12 7FP, U.K., Hotblack A; Research Department of Haematology, UCL Cancer Institute, University College London, London WC1E 6DD, U.K., Bughda R; Autolus Therapeutics, London W12 7FP, U.K., Bulek A; Autolus Therapeutics, London W12 7FP, U.K., Gannon I; Autolus Therapeutics, London W12 7FP, U.K., Ilca T; Autolus Therapeutics, London W12 7FP, U.K., Allen C; Autolus Therapeutics, London W12 7FP, U.K., Lamb K; Autolus Therapeutics, London W12 7FP, U.K., Dolor A; Autolus Therapeutics, London W12 7FP, U.K., Scott I; Autolus Therapeutics, London W12 7FP, U.K., Parekh F; Autolus Therapeutics, London W12 7FP, U.K., Sillibourne J; Autolus Therapeutics, London W12 7FP, U.K., Cordoba S; Autolus Therapeutics, London W12 7FP, U.K., Onuoha S; Autolus Therapeutics, London W12 7FP, U.K., Thomas S; Autolus Therapeutics, London W12 7FP, U.K., Ferrari M; Autolus Therapeutics, London W12 7FP, U.K., Pule M; Autolus Therapeutics, London W12 7FP, U.K.; Research Department of Haematology, UCL Cancer Institute, University College London, London WC1E 6DD, U.K. |
| Abstrakt: |
A versatile, safe, and effective small-molecule control system is highly desirable for clinical cell therapy applications. Therefore, we developed a two-component small-molecule control system based on the disruption of protein-protein interactions using minocycline, an FDA-approved antibiotic with wide availability, excellent biodistribution, and low toxicity. The system comprises an anti-minocycline single-domain antibody (sdAb) and a minocycline-displaceable cyclic peptide. Here, we show how this versatile system can be applied to OFF-switch split CAR systems (MinoCAR) and universal CAR adaptors (MinoUniCAR) with reversible, transient, and dose-dependent suppression; to a tunable T cell activation module based on MyD88/CD40 signaling; to a controllable cellular payload secretion system based on IL12 KDEL retention; and as a cell/cell inducible junction. This work represents an important step forward in the development of a remote-controlled system to precisely control the timing, intensity, and safety of therapeutic interventions. |
