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Molecular Cancer Therapeutics
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Cancer Biology and Translational Studies

TSR-033, a Novel Therapeutic Antibody Targeting LAG-3, Enhances T-Cell Function and the Activity of PD-1 Blockade In Vitro and In Vivo

Srimoyee Ghosh, Geeta Sharma, Jon Travers, Sujatha Kumar, Justin Choi, H. Toni Jun, Marilyn Kehry, Sridhar Ramaswamy and David Jenkins
Srimoyee Ghosh
1TESARO, Inc., Waltham, Massachusetts.
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  • For correspondence: sghosh@tesarobio.com
Geeta Sharma
1TESARO, Inc., Waltham, Massachusetts.
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Jon Travers
1TESARO, Inc., Waltham, Massachusetts.
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Sujatha Kumar
1TESARO, Inc., Waltham, Massachusetts.
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Justin Choi
2AnaptysBio, San Diego, California.
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H. Toni Jun
2AnaptysBio, San Diego, California.
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Marilyn Kehry
2AnaptysBio, San Diego, California.
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Sridhar Ramaswamy
1TESARO, Inc., Waltham, Massachusetts.
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David Jenkins
1TESARO, Inc., Waltham, Massachusetts.
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DOI: 10.1158/1535-7163.MCT-18-0836
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Abstract

Progressive upregulation of checkpoints on tumor-infiltrating lymphocytes promotes an immunosuppressive tumor microenvironment, severely compromising tumor immunity. Lymphocyte activation gene-3 (LAG-3) is a coinhibitory receptor associated with impaired T-cell function and is frequently coexpressed with programmed cell death protein-1 (PD-1) in the context of human cancers. Targeting LAG-3 in conjunction with PD-1 thus represents a strategy to amplify and broaden the therapeutic impact of PD-1 blockade alone. We have generated a high affinity and selective humanized monoclonal IgG4 antibody, TSR-033, which binds human LAG-3 and serves as a functional antagonist, enhancing in vitro T-cell activation both in mixed lymphocyte reactions and staphylococcal enterotoxin B-driven stimulation assays. In a humanized mouse non–small cell lung carcinoma model, TSR-033 boosted the antitumor efficacy of PD-1 monotherapy, with a concomitant increase in immune activation. Analogous studies in a murine syngeneic tumor model using surrogate antibodies demonstrated significant synergy between LAG-3 and PD-1 blockade—combination treatment led to a marked improvement in therapeutic efficacy, increased T-cell proliferation, IFNγ production, and elicited durable immunologic memory upon tumor rechallenge. Taken together, the pharmacologic activity of TSR-033 demonstrates that it is a potent anti-LAG-3 therapeutic antibody and supports its clinical investigation in cancer patients.

Footnotes

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

  • Received July 30, 2018.
  • Revision received September 25, 2018.
  • Accepted December 18, 2018.
  • Published first December 26, 2018.
  • ©2018 American Association for Cancer Research.
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This OnlineFirst version was published on February 20, 2019
doi: 10.1158/1535-7163.MCT-18-0836

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TSR-033, a Novel Therapeutic Antibody Targeting LAG-3, Enhances T-Cell Function and the Activity of PD-1 Blockade In Vitro and In Vivo
Srimoyee Ghosh, Geeta Sharma, Jon Travers, Sujatha Kumar, Justin Choi, H. Toni Jun, Marilyn Kehry, Sridhar Ramaswamy and David Jenkins
Mol Cancer Ther February 20 2019 DOI: 10.1158/1535-7163.MCT-18-0836

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TSR-033, a Novel Therapeutic Antibody Targeting LAG-3, Enhances T-Cell Function and the Activity of PD-1 Blockade In Vitro and In Vivo
Srimoyee Ghosh, Geeta Sharma, Jon Travers, Sujatha Kumar, Justin Choi, H. Toni Jun, Marilyn Kehry, Sridhar Ramaswamy and David Jenkins
Mol Cancer Ther February 20 2019 DOI: 10.1158/1535-7163.MCT-18-0836
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Molecular Cancer Therapeutics
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