TIGIT checkpoint blockade by mAb EOS884448 restores T cell effector functions and displays anti-tumor efficacy

Identification: Hoofd, Catherine


Description

TIGIT checkpoint blockade by mAb EOS884448 restores T cell effector functions and displays anti-tumor efficacy
 
Catherine Hoofd1, Véronique Bodo1, Julia Cuende1, Sofie Denies1, Florence Lambolez1, Xavier Leroy1, Marjorie Mercier1, Florence Nyawame1, Shruthi Prassad1, Julie Preillon1, Virginie Rabolli1, Noémie Wald1 and Gregory Driessens1
1iTeos Therapeutics
 
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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