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Research Articles

Bispecific Targeting of PD-1 and PD-L1 Enhances T-cell Activation and Antitumor Immunity

Helen Kotanides, Yiwen Li, Maria Malabunga, Carmine Carpenito, Scott W. Eastman, Yang Shen, George Wang, Ivan Inigo, David Surguladze, Anthony L. Pennello, Krishnadatt Persaud, Sagit Hindi, Michael Topper, Xinlei Chen, Yiwei Zhang, Danielle K. Bulaon, Tim Bailey, Yanbin Lao, Bing Han, Stacy Torgerson, Darin Chin, Andreas Sonyi, Jaafar N. Haidar, Ruslan D. Novosiadly, Christopher M. Moxham, Gregory D. Plowman, Dale L. Ludwig and Michael Kalos
Helen Kotanides
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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  • For correspondence: helen.kotanides@lilly.com mkalos@arsenalbio.com
Yiwen Li
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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Maria Malabunga
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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Carmine Carpenito
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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Scott W. Eastman
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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Yang Shen
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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George Wang
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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Ivan Inigo
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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David Surguladze
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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Anthony L. Pennello
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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Krishnadatt Persaud
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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Sagit Hindi
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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Michael Topper
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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Xinlei Chen
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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Yiwei Zhang
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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Danielle K. Bulaon
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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Tim Bailey
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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Yanbin Lao
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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Bing Han
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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Stacy Torgerson
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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Darin Chin
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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Andreas Sonyi
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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Jaafar N. Haidar
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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Ruslan D. Novosiadly
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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Christopher M. Moxham
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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Gregory D. Plowman
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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Dale L. Ludwig
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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Michael Kalos
Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
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  • For correspondence: helen.kotanides@lilly.com mkalos@arsenalbio.com
DOI: 10.1158/2326-6066.CIR-20-0304 Published October 2020
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Abstract

The programmed cell death protein 1 receptor (PD-1) and programmed death ligand 1 (PD-L1) coinhibitory pathway suppresses T-cell–mediated immunity. We hypothesized that cotargeting of PD-1 and PD-L1 with a bispecific antibody molecule could provide an alternative therapeutic approach, with enhanced antitumor activity, compared with monospecific PD-1 and PD-L1 antibodies. Here, we describe LY3434172, a bispecific IgG1 mAb with ablated Fc immune effector function that targets both human PD-1 and PD-L1. LY3434172 fully inhibited the major inhibitory receptor–ligand interactions in the PD-1 pathway. LY3434172 enhanced functional activation of T cells in vitro compared with the parent anti–PD-1 and anti–PD-L1 antibody combination or respective monotherapies. In mouse tumor models reconstituted with human immune cells, LY3434172 therapy induced dramatic and potent antitumor activity compared with each parent antibody or their combination. Collectively, these results demonstrated the enhanced immunomodulatory (immune blockade) properties of LY3434172, which improved antitumor immune response in preclinical studies, thus supporting its evaluation as a novel bispecific cancer immunotherapy.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Cancer Immunol Res 2020;8:1300–10

  • Received April 17, 2020.
  • Revision received June 3, 2020.
  • Accepted July 24, 2020.
  • Published first July 27, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Immunology Research: 8 (10)
October 2020
Volume 8, Issue 10
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Bispecific Targeting of PD-1 and PD-L1 Enhances T-cell Activation and Antitumor Immunity
Helen Kotanides, Yiwen Li, Maria Malabunga, Carmine Carpenito, Scott W. Eastman, Yang Shen, George Wang, Ivan Inigo, David Surguladze, Anthony L. Pennello, Krishnadatt Persaud, Sagit Hindi, Michael Topper, Xinlei Chen, Yiwei Zhang, Danielle K. Bulaon, Tim Bailey, Yanbin Lao, Bing Han, Stacy Torgerson, Darin Chin, Andreas Sonyi, Jaafar N. Haidar, Ruslan D. Novosiadly, Christopher M. Moxham, Gregory D. Plowman, Dale L. Ludwig and Michael Kalos
Cancer Immunol Res October 1 2020 (8) (10) 1300-1310; DOI: 10.1158/2326-6066.CIR-20-0304

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Bispecific Targeting of PD-1 and PD-L1 Enhances T-cell Activation and Antitumor Immunity
Helen Kotanides, Yiwen Li, Maria Malabunga, Carmine Carpenito, Scott W. Eastman, Yang Shen, George Wang, Ivan Inigo, David Surguladze, Anthony L. Pennello, Krishnadatt Persaud, Sagit Hindi, Michael Topper, Xinlei Chen, Yiwei Zhang, Danielle K. Bulaon, Tim Bailey, Yanbin Lao, Bing Han, Stacy Torgerson, Darin Chin, Andreas Sonyi, Jaafar N. Haidar, Ruslan D. Novosiadly, Christopher M. Moxham, Gregory D. Plowman, Dale L. Ludwig and Michael Kalos
Cancer Immunol Res October 1 2020 (8) (10) 1300-1310; DOI: 10.1158/2326-6066.CIR-20-0304
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