T cell Immunoreceptor with Ig and ITIM domains (TIGIT) is a co-inhibitory receptor expressed by lymphocytes, preferentially CD8+ T cells, NK, as well as by regulatory T cells (Treg). TIGIT ligands belong to the PVR/nectin family, among which PVR (CD155) shows the highest affinity and is commonly expressed on myeloid and tumor cells. CD226 (DNAM-1), a co-stimulatory receptor also expressed on NK and T cells competes with TIGIT for PVR binding but with a lower affinity. Co-expression of TIGIT and CD226 receptors on T and NK effector cells suggests a role in the fine control of their activation. In cancer, TIGIT is frequently co-expressed with exhaustion markers such as PD-1 and represents an attracting target for combination therapies to reverse T or NK cell dysfunction linked with cancer progression. Antagonist anti-TIGIT antibodies were selected using a synthetic yeast display library of fully human antibodies. EOS884448 anti-TIGIT mAb displays a strong affinity to recombinant human TIGIT and to native TIGIT expressed on human primary T cells. It competes with CD155 binding and shows potency to restore cytokine production when human primary T cells are suppressed in presence of CD155. A surrogate mouse anti-TIGIT mAb was used to evaluate the anti-tumor efficacy in the CT26 syngeneic model. In monotherapy on established mouse tumors, anti-TIGIT delays CT26 tumor growth, and some mice achieve complete response. In combination with anti PD-1 mAb, complete tumor regression occurs in most of the animals treated with the anti-TiGIT mAb combined with anti-PD-1 mAb. Anti-tumor efficacy was associated with an increased CD8+: Treg ratio, upregulation of TH1 cytokines and an increased expression of cytolytic T cell markers. Confident in the potential of EOS884448 to promote antitumor immunity as monotherapy or in combination with anti PD-1 in human, we explore combinations with other promising immune modulators from our pipeline.
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