TIGIT (T-Cell Immunoreceptor With Ig and ITIM Domains) is a co-inhibitory receptor expressed on all T-cell subtypes and NK cells. It is expressed on immune cells normally during an immune response to dampen it, to protect the body from an overreactive immune system. Binding of TIGIT ligands triggers a negative signal in T cells and NK cells, inhibiting their activation. It also competes for binding of shared ligands to co-activator receptor DNAM, that is needed for full NK and T cell activation. Tumor cells have co-opted this regulatory mechanism to prevent immune cells from recognizing and attacking them. Cancer cells express TIGIT ligands that bind to TIGIT expressed on effector and regulatory T cells. In this way, cancer cells prevent immune cell attack and support the inhibitory activity of suppressive Treg cells. TIGIT-mediated immune suppression is markedly enhanced in the tumor microenvironment.
Administration of TIGIT blocking antibodies prevents cancer-mediated immune suppression and provides a therapeutic benefit in several murine models in monotherapy and in combination with other checkpoint modulators. Altogether, these data give a strong rationale for the development of antibody targeting TIGIT for immuno-oncology.
iTeos has selected a clinical candidate antibody, which will enter a Phase I clinical trial in the second half of 2019.