Designer Small-Molecule Control System Based on Minocycline-Induced Disruption of Protein-Protein Interaction

被引：4

作者：

Jha, Ram ^{[1
,2
]}

Kinna, Alexander ^{[1
]}

Hotblack, Alastair ^{[2
]}

Bughda, Reyisa ^{[1
]}

Bulek, Anna ^{[1
]}

Gannon, Isaac ^{[1
]}

Ilca, Tudor ^{[1
]}

Allen, Christopher ^{[1
]}

Lamb, Katarina ^{[1
]}

Dolor, Abigail ^{[1
]}

Scott, Ian ^{[1
]}

Parekh, Farhaan ^{[1
]}

Sillibourne, James ^{[1
]}

Cordoba, Shaun ^{[1
]}

Onuoha, Shimobi ^{[1
]}

Thomas, Simon ^{[1
]}

Ferrari, Mathieu ^{[1
]}

Pule, Martin ^{[1
,2
]}

机构：

[1] Autolus Therapeut, London W12 7FP, England

[2] UCL, UCL Canc Inst, Res Dept Haematol, London WC1E 6DD, England

来源：

ACS CHEMICAL BIOLOGY | 2024年 / 19卷 / 02期

关键词：

SINGLE-DOMAIN ANTIBODIES; CAR T-CELLS; TET REPRESSOR; RAPAMYCIN; SELECTION; AFFINITY; BINDING; SAFETY; LIBRARIES; DISPLAY;

D O I：

10.1021/acschembio.3c00521

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：308 / 324

页数：17

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