EMD SERONO | TIGIT

TIGIT is upregulated on T cells, Tregs and NK cells in the tumor microenvironment (TME) of some tumor types. It inhibits their activity and prohibits CD226-mediated immune activation. TIGIT expression is a marker of exhausted T cells and immunosuppressive Tregs in the TME.^1-9

M6223 – anti-TIGIT mAb

Description and Potential Mechanism of Action:

M6223 is an investigational fully human IgG1 anti-TIGIT antibody with Fc effector function. By blocking the interaction between TIGIT and its ligand, CD155, M6223 is thought to reduce TIGIT-mediated T cell immunosuppression.^10,11

M6223 is thought to restore T cell and NK cell activity, enable CD226-mediated immune activation, and is designed to deplete exhausted T cells and suppressive Tregs in the TME via the Fc-mediated effector function.^5-9,11,12

Areas of Interest:

Solid tumors

TARGETS UNDER INVESTIGATION

PD-L1

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A2A/A2B

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EMD Serono is the healthcare business of Merck KGaA, Darmstadt, Germany in the U.S. and Canada.

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Investigational compounds are not approved by any health authority. Safety and efficacy have not been established.

Abbreviations:
A2A/A2B, A_2A and A_2B receptors; CD, cluster of differentiation; Fc, fragment crystallizable; FcyR, Fc gamma receptor; IgG1, immunoglobulin G1; IFNγ, interferon gamma; mAb, monoclonal antibody; NK, natural killer; PD-L1, programmed death-ligand 1; TIGIT, T-cell immunoglobulin and ITIM domain; TNF, tumor necrosis factor; Treg, regulatory T cell.

References:

Harjunpää H, Guillerey C. TIGIT as an emerging immune checkpoint. Clin Exp Immunol. 2019;200(2):108-119.
Johnston RJ, Comps-Agrar L, Hackney J, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell. 2014;26(6):923-937.
Wang F, Hou H, Wu S, et al. TIGIT expression levels on human NK cells correlate with functional heterogeneity among healthy individuals. Eur J Immunol. 2015;45(10):2886-2897.
Chauvin J-M, Pagliano O, Fourcade J, et al. TIGIT and PD-1 impact tumor antigen-specific CD8+ T cells in melanoma patients. J Clin Invest. 2015;125(5):2046-2058.
Kurtulus S, Sakuishi K, Ngiow S-F, et al. TIGIT predominantly regulates the immune response via regulatory T cells. J Clin Invest. 2015;125(11):4053-4062.
Kim HR, Park HJ, Son J, et al. Tumor microenvironment dictates regulatory T cell phenotype: unregulated immune checkpoints reinforce suppressive function. J Immunother Cancer. 2019;7(1):339. doi:10.1186/s40425-019-0785-8.
Fuhrman CA, Yeh W-I, Seay HR, et al. Divergent phenotypes of human regulatory T cells expressing the receptors TIGIT and CD226. J Immunol. 2015;195(1):145-155.
Joller N, Lozano E, Burkett PR, et al. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity. 2014;40(4):569-581.
Fourcade J, Sun Z, Chauvin J-M, et al. CD226 opposes TIGIT to disrupt Tregs in melanoma. JCI Insight. 2018;3(14):e121157. doi:10.1172/jci.insight.121157.
Merck KGaA, Darmstadt, Germany pipeline. Biopharma-pipeline. Accessed April 28, 2023. https://www.emdgroup.com/en/research/biopharma-pipeline.html
TIGIT Inhibitor M6223 (Code C173891). Accessed April 28, 2023. https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI%20Thesaurus&code=C173891
Yeo J, Ko M, Lee D-H, Park Y, Jin H-S. TIGIT/CD226 axis regulates anti-tumor immunity. Pharmaceuticals (Basel). 2021;14(3):200. doi:10.3390/ph14030200.