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