Autoimmune diseases

Inhibitor of adaptor protein shows self-antigen selectivity

Credit: Raki Halder/Alamy Stock Photo

Patients suffering from autoimmune diseases are usually treated with immunosuppressive drugs, leaving them prone to infection. Now, reporting in Science Translational Medicine, Alarcon and colleagues show that a small molecule inhibitor of the adaptor protein NCK, which acts downstream of the T cell receptor (TCR), is highly potent in different models of autoimmune conditions, without affecting immune responses to infectious agents.

NCK is a modular adaptor protein that connects different transmembrane receptors to multiple intracellular signalling pathways and is a crucial regulator of the actin cytoskeleton. In mature T cells, antigen stimulation triggers the recruitment of NCK to the TCR — an interaction that is particularly important for TCR signalling in response to weak antigens.

Using virtual screening and combinatorial chemistry, the authors developed AX-024, an orally available low-molecular weight compound that specifically inhibits the interaction of NCK with the cytoplasmic tail of the TCR subunit CD3ɛ. In vitro, AX-024 potently inhibited the release of cytokines by T cells in response to anti-CD3-mediated TCR stimulation, but did not seem to disrupt other cellular functions of NCK.

In vivo experiments in mice and rats demonstrated that AX-024, administered orally or by intraperitoneal injection, was well tolerated, even at high doses. In the mouse model of imiquimod-induced psoriasis, daily oral treatment with AX-024 significantly reduced skin thickening and attenuated psoriasis-like symptoms of inflammation. In the ovalbumin-antigen-induced asthma model, it prevented allergic airway sensitization, and in the experimental autoimmune encephalomyelitis model of multiple sclerosis (MS), treatment with AX-024 was more effective than current MS drugs such as glatiramer acetate and cladribine. Even when treatment was delayed until the onset of neurological symptoms, AX-024 had therapeutic efficacy. This was comparable to treatment with the MS drug fingolimod (albeit with slightly slower kinetics). However, in contrast to fingolimod, the therapeutic effect of AX-024 persisted even after the treatment was discontinued.

“AX-024... promotes differentiation of CD4+ effector cells towards anti-inflammatory CD4+ T cell subsets and FOXP3+CD4+ regulatory T cells”

Further ex vivo and in vivo experiments indicated that AX-024, by altering the quality and/or strength of the TCR signal, promotes differentiation of CD4+ effector cells towards anti-inflammatory CD4+ T cell subsets and FOXP3+CD4+ regulatory T cells — providing an explanation for the lasting effects of the drug. Surprisingly, treatment with AX-024 did not impair the generation of protective memory T cell responses after vaccination with a poxviral CD8+ T cell epitope, and it did not affect survival rates after viral challenge with ectromelia virus, which causes mousepox.

The authors point out that the mechanism of selectivity for self-antigens versus pathogen-derived antigens is not completely understood but may lie in the differential requirement for NCK recruitment to the TCR in response to weak versus strong antigens. As AX-024 directly interferes with TCR signalling, it is an attractive candidate as a broad-spectrum agent for autoimmune and inflammatory conditions. Phase Ia/Ib clinical trials have been completed in healthy volunteers.

This article is modified from the original in Nat. Rev. Drug Discov. (http://dx.doi.org/10.1038/nrd.2017.5)

References

  1. 1

    Borroto, A. et al. First-in-class inhibitor of the T cell receptor for the treatment of autoimmune disease. Sci. Transl. Med. 8, 370ra184 (2016)

    Article  PubMed  Google Scholar 

Download references

Authors

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Flemming, A. Inhibitor of adaptor protein shows self-antigen selectivity. Nat Rev Immunol 17, 81 (2017). https://doi.org/10.1038/nri.2017.5

Download citation

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing