Signalling system

Abstract

The present invention provides a chimeric antigen receptor (CAR) signalling system comprising; (i) a receptor component comprising an antigen binding domain, a transmembrane domain and a first binding domain; and (ii) an intracellular signalling component comprising a signalling domain and a second binding domain which specifically binds the first binding domain of the receptor component; wherein, binding of the first and second binding domains is disrupted by the presence of an agent, such that in the absence of the agent the receptor component and the signalling component heterodimerize and binding of the antigen binding domain to antigen results in signalling through the signalling domain, whereas in the presence of the agent the receptor component and the signalling component do not heterodimerize and binding of the antigen binding domain to antigen does not result in signalling through the signalling domain.

Description

FIELD OF THE INVENTION[0001]The present invention relates to a chimeric antigen receptor signalling system.BACKGROUND TO THE INVENTION[0002]Traditionally, antigen-specific T-cells have been generated by selective expansion of peripheral blood T-cells natively specific for the target antigen. However, it is difficult and quite often impossible to select and expand large numbers of T-cells specific for most cancer antigens. Gene-therapy with integrating vectors affords a solution to this problem as transgenic expression of Chimeric Antigen Receptor (CAR) allows generation of large numbers of T cells specific to any surface antigen by ex vivo viral vector transduction of a bulk population of peripheral blood T-cells.[0003]Chimeric antigen receptors are proteins which graft the specificity of a monoclonal antibody (mAb) to the effector function of a T-cell. Their usual form is that of a type I transmembrane domain protein with an antigen recognizing amino terminus, a spacer, a transmemb...

AI Technical Summary

Benefits of technology

The present invention is about a system called CAR that can recognize and signal when it binds to an antigen on a cell. The inventors found a way to stop this signaling quickly, even when antigen keeps binding to the CAR system. They accomplished this using a small molecule that prevents the CAR components from getting too close to each other. This allows for the reversible and controlled inhibition of CAR signaling to avoid potential toxic effects and makes it possible to tune the potency of CAR cells for therapeutic purposes.

Problems solved by technology

However, it is difficult and quite often impossible to select and expand large numbers of T-cells specific for most cancer antigens.

Such toxicities include immunological toxicity caused by sustained intense activation of the CAR T-cells resulting in a macrophage activation syndrome (MAS) and “On-target off-tumour” toxicity i.e. recognition of the target antigen on normal tissues.

A large spike in serum IL-6 is characteristic and the syndrome can result in a severe systemic illness requiring ICU admission.

These toxicities are very difficult to predict even with detailed animal studies or non-human primate work.

This technology adds a certain amount of safety to CAR T-cell therapy, however there are limitations.

Secondly, it is not clear whether a suicide gene would help with some of the immune-toxicities described above: for instance by the time a macrophage activation syndrome had been triggered, it may well no longer need the CAR T-cells to perpetuate and the suicide gene would no longer be helpful.

The more acute cytokine release syndromes probably occur too quickly for the suicide gene to work.

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