CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies

February 26, 2011

BlankBlood, 24 February 2011, Vol. 117, No. 8, pp. 2423-2432.

Holbrook E. Kohrt1,*, Roch Houot13,*, J. Goldstein1, Kipp Weiskopf1, Ash

A. Alizadeh1, Josh Brody1, Antonia Müller1, Pachynski1, Debra

Czerwinski1, Coutre4, Mark P. Chao5, Lieping Chen6, F. Tedder7,

and Levy1

1 Department of Medicine, Division of Oncology, Stanford University, Stanford,

CA; 2 Service d'Hématologie Clinique, Centre Hospitalier Universitaire de

Rennes, Rennes, France; 3 Inserm U917, Université de Rennes 1, Rennes, France; 4

Department of Medicine, Division of Hematology and 5 Institute for Stem Cell

Biology and Regenerative Medicine, Stanford University, Stanford CA; 6

Department of Oncology, s Hopkins University School of Medicine, Baltimore,

MD; and 7 Department of Immunology, Duke University Medical Center, Durham, NC

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.

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