Abstract LB189: Pharmacodynamic assessment of a-TIGIT mAb EOS-448 highlights multiple FcγR-mediated mode-of-actions in blood and tumor of patients with advanced solid tumors
Authors: Cuende Julia , Preillon Julie , Wald Noemie , Mercier Marjorie , Tieppo Paola , Welsby Iain , Bodo Veronique , McGrath Yvonne , Van Den Mooter Tom F. , Machiels Jean-Pascal , Truong Clarisse , De Henau Olivier , Driessens Gregory , Libouban Marion 
Published: June 2022

Abstract
T cell immunoglobulin and ITIM domain (TIGIT) is an immune checkpoint inhibitor expressed mainly on NK and T cell populations which has demonstrated clinical proof of concept in NSCLC for its inhibition in combination with a-PD(L)-1 agents1. EOS-448 (also named GSK4428859A) is an antagonistic anti-TIGIT human immunoglobulin G1 (hIgG1) antibody showing picomolar activity both to prevent ligand binding and to engage Fc gamma receptors (FcγR).
EOS-448 was selected based on its potent affinity to TIGIT, translating into strong antagonist and functional activity to restore T cell functions and potent antitumor activity in murine models2. Building EOS-448 on an isotype allowing to engage FcγR added potential additional mechanisms of action (MoAs), including the FcγR-induced activation of myeloid/NK populations and antibody-mediated depletion of TIGIT high cells.
To characterize and experimentally validate the multiple MoA triggered by EOS-448, we tested, both in preclinical and clinical settings, its potential to (i) activate effector T cells (ii) modulate antigen-presenting through FcγR engagement, and (iii) deplete suppressive regulatory T cells and terminally exhausted CD8 T cells that express the highest levels of TIGIT.
Our results obtained in murine models confirm the strong potential for the a-TIGIT + a-PD1 combination as well as major differences in activity depending on isotype, with only the Fc-engaging format inducing strong antitumor effect correlating with Treg depletion and CD8 T cell activation within the tumor. Similarly, activation markers on DC and antigen-mediated activation were only observed with the Fc-engaging version but totally absent with the Fc-dead format. In addition, we demonstrated, ex-vivo on human samples, that EOS-448 could preferentially deplete Tregs over effector CD8 T cells and progenitor-like exhausted T cells (Tpex) with low effector function over stem-like memory T cells (Tstem) with stronger effector potential3.
In a first-in-human trial, EOS-448 demonstrated a good tolerability profile with early signs of efficacy4. Pharmacodynamic assessment made by flow cytometry in the blood of patients treated across multiple dose levels of EOS-448 confirmed the multiple MoAs triggered by the drug with (i) increased Ki67 expression in memory CD8 T cells during the first treatment cycle, (ii) sustained depletion of suppressive Tregs, and (iii) of TIGIT high CD8+ T cells, known to be terminally exhausted5, overall resulting in an increased effector CD8/Treg ratio. This activity also translated into a significant decrease in the detection of TIGIT+ cells by immunohistochemistry (IHC), including FoxP3+ double stained cells, in 21 out of 22 tested paired biopsies, with EOS-448 being the first reported a-TIGIT mAb to engage TIGIT within patient tumor.
Overall, the preclinical and clinical evaluation demonstrate the multiple MoAs of EOS-448 supporting its clinical development as a differentiated a-TIGIT mAb to restore anti-tumor immune response. Multiple randomized studies are planned to be initiated in 2022.
1.Cho BC, et al. Abstract #LBA2 ESMO-IO; 2021 2.Preillon J, et al. Mol Cancer Ther ; 2021. 3.Galletti G, et al. Nat Immunol ; 2020. 4.Van den Mooter TF et al. Abstract #CT118 AACR; 2021. 5.Guo X et al. Nat Medicine ; 2018.
Citation Format: Julia Cuende, Julie Preillon, Noemie Wald, Marjorie Mercier, Paola Tieppo, Iain Welsby, Veronique Bodo, Yvonne McGrath, Tom F. Van Den Mooter, Jean-Pascal Machiels, Clarisse Truong, Olivier De Henau, Gregory Driessens, Marion Libouban. Pharmacodynamic assessment of a-TIGIT mAb EOS-448 highlights multiple FcγR-mediated mode-of-actions in blood and tumor of patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB189.