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Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity

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Abstract

4-1BB (CD137, TNFRSF9) is a costimulatory receptor expressed on several subsets of activated immune cells. Numerous studies of mouse and human T cells indicate that 4-1BB promotes cellular proliferation, survival, and cytokine production. 4-1BB agonist mAbs have demonstrated efficacy in prophylactic and therapeutic settings in both monotherapy and combination therapy tumor models and have established durable anti-tumor protective T-cell memory responses. PF-05082566 is a fully human IgG2 that binds to the extracellular domain of human 4-1BB with high affinity and specificity. In preclinical studies, this agonist antibody demonstrated its ability to activate NF-κB and induce downstream cytokine production, promote leukocyte proliferation, and inhibit tumor growth in a human PBMC xenograft tumor model. The mechanism of action and robust anti-tumor efficacy of PF-05082566 support its clinical development for the treatment of a broad spectrum of human malignancies.

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Acknowledgments

We thank Pfizer La Jolla Comparative Medicine for animal support; Jerry Casperson, James Christensen and Steve Bender for project support; Bart Jessen, Robert Arch, Tim Paradis, Craig Davis, Karin Jooss and Mike Primiano for discussion of the manuscript.

Conflicts of interest

All authors are current or former employees of Pfizer Inc.

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Authors and Affiliations

  1. Oncology Research Unit, Pfizer Inc., 10724 Science Center Drive, San Diego, CA, 92121, USA

    Timothy S. Fisher, Victoria A. Love, Paul D. Lira, Simon Bergqvist, Sangita M. Baxi, Allison Rohner & Leslie L. Sharp

  2. Immunotoxicology Center of Emphasis, Drug Safety Research and Development, Pfizer Inc., Groton, CT, USA

    Cris Kamperschroer

  3. Biomarkers Flow Cytometry Core Facility, Drug Safety Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT, 06340, USA

    Amy C. Shen, Chunli Huang & Sharon A. Sokolowski

  4. Genetically Engineered Models Center of Emphasis, Pfizer Inc., Eastern Point Road, Groton, CT, 06340, USA

    Regis Doyonnas

  5. Protein Therapeutics Center of Emphasis, Pfizer Inc., 700 Chesterfield Parkway West, Chesterfield, MO, 63017, USA

    Theodore Oliphant

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  1. Timothy S. Fisher
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Fisher, T.S., Kamperschroer, C., Oliphant, T. et al. Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity. Cancer Immunol Immunother 61, 1721–1733 (2012). https://doi.org/10.1007/s00262-012-1237-1

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