posted on 2024-01-20, 14:06authored byRam Jha, Alexander Kinna, Alastair Hotblack, Reyisa Bughda, Anna Bulek, Isaac Gannon, Tudor Ilca, Christopher Allen, Katarina Lamb, Abigail Dolor, Ian Scott, Farhaan Parekh, James Sillibourne, Shaun Cordoba, Shimobi Onuoha, Simon Thomas, Mathieu Ferrari, Martin Pule
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.