Description
AX-024 is an inhibitor of the CD3ε-Nck interaction. It binds to the SH3.1 N-terminal domain of Nck1, preventing its binding to the proline-rich sequence of the CD3ε subunit of T cells. AX-024 inhibits T cell receptor-triggered T cell activation (IC
50 = 1 nM for human T cells) and selectively decreases proliferation of T cells over B cells. It prevents CD4
+ T cell and macrophage infiltration to the cerebellum and spinal cord and improves neurological impairments in a MOG
35-55 mouse model of experimental autoimmune encephalomyelitis (EAE) when administered at a dose of 10 mg/kg per day for ten days starting on the day of immunization. AX-024 (50 mg/kg) prevents the infiltration of eosinophils, macrophages, and neutrophils into the airway, as well as prevents an increase in IL-4 levels in bronchoalveolar lavage fluid (BALF), in an ovalbumin-sensitized mouse model of allergic airway disease. It does not prevent the memory T cell response to an immunodominant B8R poxvirus antigen peptide or to infection by ectromelia virus (mousepox).
References
1) Borroto et al. (2016), First-in-class inhibitor of the T cell receptor for the treatment of autoimmune diseases; Sci. Transl. Med., 8 370ra184
