CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies

Holbrook E. Kohrt, Roch Houot, Matthew J. Goldstein, Kipp Weiskopf, Ash A. Alizadeh, Josh Brody, Antonia Müller, Russell Pachynski, Debra Czerwinski, Steven Coutre, Mark P. Chao, Lieping Chen, Thomas F. Tedder, Ronald Levy

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161 Scopus citations

Abstract

Antibody-dependent cell-mediated cytotoxicity (ADCC), which is largely mediated by natural killer (NK) cells, is thought to play an important role in the efficacy of rituximab, an anti-CD20 monoclonal antibody (mAb) used to treat patients with B-cell lymphomas. CD137 is a costimulatory molecule expressed on a variety of immune cells after activation, including NK cells. In the present study, we show that an anti-CD137 agonistic mAb enhances the antilymphoma activity of rituximab by enhancing ADCC. Human NK cells up-regulate CD137 after encountering rituximab-coated tumor B cells, and subsequent stimulation of these NK cells with anti-CD137 mAb enhances rituximab-dependent cytotoxicity against the lymphoma cells. In a syngeneic murine lymphoma model and in a xenotransplanted human lymphoma model, sequential administration of anti-CD20 mAb followed by anti-CD137 mAb had potent antilymphoma activity in vivo. These results support a novel, sequential antibody approach against B-cell malignancies by targeting first the tumor and then the host immune system.

Original languageEnglish
Pages (from-to)2423-2432
Number of pages10
JournalBlood
Volume117
Issue number8
DOIs
StatePublished - Feb 24 2011
Externally publishedYes

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    Kohrt, H. E., Houot, R., Goldstein, M. J., Weiskopf, K., Alizadeh, A. A., Brody, J., Müller, A., Pachynski, R., Czerwinski, D., Coutre, S., Chao, M. P., Chen, L., Tedder, T. F., & Levy, R. (2011). CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies. Blood, 117(8), 2423-2432. https://doi.org/10.1182/blood-2010-08-301945