CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies.

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.

• Authors: 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
• Journal: Blood (Blood) Vol. 117 Issue 8 Pg. 2423-32 (Feb 24 2011) ISSN: 1528-0020 [Electronic] United States
• PMID: 21193697 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Murine-Derived
• Antigens, CD20
• Tumor Necrosis Factor Receptor Superfamily, Member 9
• Rituximab

Topics

• Animals
• Antibodies, Monoclonal (pharmacology, therapeutic use)
• Antibodies, Monoclonal, Murine-Derived (pharmacology)
• Antibody-Dependent Cell Cytotoxicity
• Antigens, CD20 (immunology)
• Drug Synergism
• Humans
• Rituximab
• Tumor Cells, Cultured
• Tumor Necrosis Factor Receptor Superfamily, Member 9 (genetics, immunology)
• Xenograft Model Antitumor Assays