Background/Purpose: Loss of T-cell tolerance to self-antigens underlies the development of all autoimmune diseases, and despite progress, there remains a significant unmet need for patients. The most effective modern therapeutic approaches  focus on the suppression of key cytokines that are important for disease progression.  In contrast, modulation rather than suppression of T cell receptor (TCR) activation offers the potential to normalize the patient’s immune response to self, while preserving protection against pathogens. AX-158 is an Nck modulator currently in a Phase 2a trial for psoriasis. 

Methods: Here, we present mechanistic pharmacology that provides insights into how AX-158 modulates, but does not suppress, T cell activation.  In particular, AX-158 acts by specific Nck inhibition at the SH3.1 domain, lowering T cell activation in response to weak avidity antigens.  Consistent with this,  we observe dose dependent modulation, but not inhibition, of Akt phosphorylation (S473) and IL-2 responses after T cell stimulation.  We further extend these mechanistic studies by demonstrating differential effects of AX-158 in murine models, for example those of autoimmunity versus others focused on immune response to foreign antigens.

Results: In the self-antigen driven murine experimental autoimmune encephalomyelitis (EAE) model, AX-158 conferred long-lasting protection in a therapeutic and in a self-antigen rechallenge setting.  In contrast, AX-158 did not suppress the T cell response to a viral antigen (B8R of poxviruses) or the T-dependent humoral response to a model haptenated (NP-CGG) antigen.  Finally, we evaluated the activity of AX-158 on primary human T cells demonstrating the breadth of mechanism across effector T helper cell subtypes. 

Conclusion: These data suggest that selective TCR-Nck modulation represents a fundamental paradigm shift in the treatment of autoimmune diseases, one aligned with the restoration of self/non-self discrimination by the immune system.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tcr-nck-modulators-pioneering-oral-modulation-of-t-cell-receptor-activation-holding-the-promise-of-treating-autoimmune-diseases/