IMMUNO-ONCOLOGY

The TIGIT pathway

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 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

The TIGIT Pathway

Areas of Interest:

TRIALS

First-in-Human Study of M622313 (NCT04457778)

M6223 is being investigated in a first-in-human, Phase I, open-label, dose-escalation study as a monotherapy and in combination with bintrafusp alfa, in patients with metastatic or locally advanced solid unresectable tumors.

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Abbreviations:
Fc, fragment crystallizable; IgG1, immunoglobulin G1; mAb, monoclonal antibody; NK, natural killer; PD-L1, programmed death-ligand 1; TGF-β, transforming growth factor-β; TIGIT, T-cell immunoglobulin and ITIM domain; Treg, regulatory T cell.

References:

  1. Harjunpää H, Guillerey C. TIGIT as an emerging immune checkpoint. Clin Exp Immunol. 2019;200(2):108-119.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. Merck KGaA, Darmstadt, Germany pipeline. Biopharma-pipeline. Accessed November 4, 2021. https://www.emdgroup.com/en/research/biopharma-pipeline.html
  11. TIGIT Inhibitor M6223 (Code C173891). Accessed October 4, 2021. https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI%20Thesaurus&code=C173891
  12. 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.
  13. First in human study of M6223. ClinicalTrials.gov identifier: NCT04457778. Updated October 22, 2021. Accessed November 4, 2021. https://clinicaltrials.gov/ct2/show/NCT04457778

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