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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Large Molecule Therapeutics

Restoration of T-cell Effector Function, Depletion of Tregs, and Direct Killing of Tumor Cells: The Multiple Mechanisms of Action of a-TIGIT Antagonist Antibodies

Julie Preillon, Julia Cuende, Virginie Rabolli, Lucile Garnero, Marjorie Mercier, Noémie Wald, Angela Pappalardo, Sofie Denies, Diane Jamart, Anne-Catherine Michaux, Romain Pirson, Vincent Pitard, Martine Bagot, Shruthi Prasad, Erica Houthuys, Margreet Brouwer, Reece Marillier, Florence Lambolez, Joäo R. Marchante, Florence Nyawouame, Mathew J. Carter, Véronique Baron-Bodo, Anne Marie-Cardine, Mark Cragg, Julie Déchanet-Merville, Gregory Driessens and Catherine Hoofd
Julie Preillon
1iTeos Therapeutics, Gosselies, Belgium and Cambridge, Massachusetts.
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Julia Cuende
1iTeos Therapeutics, Gosselies, Belgium and Cambridge, Massachusetts.
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Virginie Rabolli
1iTeos Therapeutics, Gosselies, Belgium and Cambridge, Massachusetts.
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Lucile Garnero
1iTeos Therapeutics, Gosselies, Belgium and Cambridge, Massachusetts.
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Marjorie Mercier
1iTeos Therapeutics, Gosselies, Belgium and Cambridge, Massachusetts.
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  • ORCID record for Marjorie Mercier
Noémie Wald
1iTeos Therapeutics, Gosselies, Belgium and Cambridge, Massachusetts.
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  • ORCID record for Noémie Wald
Angela Pappalardo
2ImmunoConcEpT, UMR 5164, Bordeaux University, CNRS, Bordeaux, France.
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Sofie Denies
1iTeos Therapeutics, Gosselies, Belgium and Cambridge, Massachusetts.
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Diane Jamart
1iTeos Therapeutics, Gosselies, Belgium and Cambridge, Massachusetts.
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Anne-Catherine Michaux
1iTeos Therapeutics, Gosselies, Belgium and Cambridge, Massachusetts.
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Romain Pirson
1iTeos Therapeutics, Gosselies, Belgium and Cambridge, Massachusetts.
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Vincent Pitard
2ImmunoConcEpT, UMR 5164, Bordeaux University, CNRS, Bordeaux, France.
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Martine Bagot
3INSERM U976, Université de Paris, Hôpital Saint Louis, Paris, France.
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Shruthi Prasad
1iTeos Therapeutics, Gosselies, Belgium and Cambridge, Massachusetts.
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Erica Houthuys
1iTeos Therapeutics, Gosselies, Belgium and Cambridge, Massachusetts.
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Margreet Brouwer
1iTeos Therapeutics, Gosselies, Belgium and Cambridge, Massachusetts.
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Reece Marillier
1iTeos Therapeutics, Gosselies, Belgium and Cambridge, Massachusetts.
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Florence Lambolez
1iTeos Therapeutics, Gosselies, Belgium and Cambridge, Massachusetts.
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Joäo R. Marchante
1iTeos Therapeutics, Gosselies, Belgium and Cambridge, Massachusetts.
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Florence Nyawouame
1iTeos Therapeutics, Gosselies, Belgium and Cambridge, Massachusetts.
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Mathew J. Carter
4Antibody & Vaccine Group, Centre for Cancer Immunology, Cancer Sciences Unit, Southampton University Faculty of Medicine, Southampton, United Kingdom.
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Véronique Baron-Bodo
1iTeos Therapeutics, Gosselies, Belgium and Cambridge, Massachusetts.
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Anne Marie-Cardine
3INSERM U976, Université de Paris, Hôpital Saint Louis, Paris, France.
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Mark Cragg
4Antibody & Vaccine Group, Centre for Cancer Immunology, Cancer Sciences Unit, Southampton University Faculty of Medicine, Southampton, United Kingdom.
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Julie Déchanet-Merville
2ImmunoConcEpT, UMR 5164, Bordeaux University, CNRS, Bordeaux, France.
5Team labeled LIGUE 2017.
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Gregory Driessens
1iTeos Therapeutics, Gosselies, Belgium and Cambridge, Massachusetts.
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  • For correspondence: gregory.driessens@iteostherapeutics.com
Catherine Hoofd
1iTeos Therapeutics, Gosselies, Belgium and Cambridge, Massachusetts.
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DOI: 10.1158/1535-7163.MCT-20-0464 Published January 2021
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Abstract

TIGIT is an immune checkpoint inhibitor expressed by effector CD4+ and CD8+ T cells, NK cells, and regulatory T cells (Tregs). Inhibition of TIGIT-ligand binding using antagonistic anti-TIGIT mAbs has shown in vitro potential to restore T-cell function and therapeutic efficacy in murine tumor models when combined with an anti–PD(L)-1 antibody. In the current work, we demonstrate broader TIGIT expression than previously reported in healthy donors and patients with cancer with expression on γδ T cells, particularly in CMV-seropositive donors, and on tumor cells from hematologic malignancies. Quantification of TIGIT density revealed tumor-infiltrating Tregs as the population expressing the highest receptor density. Consequently, the therapeutic potential of anti-TIGIT mAbs might be wider than the previously described anti–PD(L)-1-like restoration of αβ T-cell function. CD155 also mediated inhibition of γδ T cells, an immune population not previously described to be sensitive to TIGIT inhibition, which could be fully prevented via use of an antagonistic anti-TIGIT mAb (EOS-448). In PBMCs from patients with cancer, as well as in tumor-infiltrating lymphocytes from mice, the higher TIGIT expression in Tregs correlated with strong antibody-dependent killing and preferential depletion of this highly immunosuppressive population. Accordingly, the ADCC/ADCP–enabling format of the anti-TIGIT mAb had superior antitumor activity, which was dependent upon Fcγ receptor engagement. In addition, the anti-TIGIT mAb was able to induce direct killing of TIGIT-expressing tumor cells both in human patient material and in animal models, providing strong rationale for therapeutic intervention in hematologic malignancies. These findings reveal multiple therapeutic opportunities for anti-TIGIT mAbs in cancer therapeutics.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2021;20:121–31

  • Received June 5, 2020.
  • Revision received August 24, 2020.
  • Accepted November 3, 2020.
  • Published first December 4, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 20 (1)
January 2021
Volume 20, Issue 1
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Restoration of T-cell Effector Function, Depletion of Tregs, and Direct Killing of Tumor Cells: The Multiple Mechanisms of Action of a-TIGIT Antagonist Antibodies
Julie Preillon, Julia Cuende, Virginie Rabolli, Lucile Garnero, Marjorie Mercier, Noémie Wald, Angela Pappalardo, Sofie Denies, Diane Jamart, Anne-Catherine Michaux, Romain Pirson, Vincent Pitard, Martine Bagot, Shruthi Prasad, Erica Houthuys, Margreet Brouwer, Reece Marillier, Florence Lambolez, Joäo R. Marchante, Florence Nyawouame, Mathew J. Carter, Véronique Baron-Bodo, Anne Marie-Cardine, Mark Cragg, Julie Déchanet-Merville, Gregory Driessens and Catherine Hoofd
Mol Cancer Ther January 1 2021 (20) (1) 121-131; DOI: 10.1158/1535-7163.MCT-20-0464

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Restoration of T-cell Effector Function, Depletion of Tregs, and Direct Killing of Tumor Cells: The Multiple Mechanisms of Action of a-TIGIT Antagonist Antibodies
Julie Preillon, Julia Cuende, Virginie Rabolli, Lucile Garnero, Marjorie Mercier, Noémie Wald, Angela Pappalardo, Sofie Denies, Diane Jamart, Anne-Catherine Michaux, Romain Pirson, Vincent Pitard, Martine Bagot, Shruthi Prasad, Erica Houthuys, Margreet Brouwer, Reece Marillier, Florence Lambolez, Joäo R. Marchante, Florence Nyawouame, Mathew J. Carter, Véronique Baron-Bodo, Anne Marie-Cardine, Mark Cragg, Julie Déchanet-Merville, Gregory Driessens and Catherine Hoofd
Mol Cancer Ther January 1 2021 (20) (1) 121-131; DOI: 10.1158/1535-7163.MCT-20-0464
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Molecular Cancer Therapeutics
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