title: 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.affiliation: Department of Medicine, Division of Oncology, Stanford University Medical Center, Stanford, CA 94305, USA.
authors.forename: Holbrook E
authors.initials: HE
authors.lastname: Kohrt
authors.forename: Roch
authors.initials: R
authors.lastname: Houot
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Goldstein
authors.forename: Kipp
authors.initials: K
authors.lastname: Weiskopf
authors.forename: Ash A
authors.initials: AA
authors.lastname: Alizadeh
authors.forename: Josh
authors.initials: J
authors.lastname: Brody
authors.forename: Antonia
authors.initials: A
authors.lastname: Müller
authors.forename: Russell
authors.initials: R
authors.lastname: Pachynski
authors.forename: Debra
authors.initials: D
authors.lastname: Czerwinski
authors.forename: Steven
authors.initials: S
authors.lastname: Coutre
authors.forename: Mark P
authors.initials: MP
authors.lastname: Chao
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Tedder
authors.forename: Ronald
authors.initials: R
authors.lastname: Levy
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity; D018951:Antigens, CD20 / Q000276:immunology*; D004357:Drug Synergism; D006801:Humans; D000069283:Rituximab; D014407:Tumor Cells, Cultured; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D000069283:Rituximab