TY - JOUR
T1 - CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies
AU - Kohrt, Holbrook E.
AU - Houot, Roch
AU - Goldstein, Matthew J.
AU - Weiskopf, Kipp
AU - Alizadeh, Ash A.
AU - Brody, Josh
AU - Müller, Antonia
AU - Pachynski, Russell
AU - Czerwinski, Debra
AU - Coutre, Steven
AU - Chao, Mark P.
AU - Chen, Lieping
AU - Tedder, Thomas F.
AU - Levy, Ronald
PY - 2011/2/24
Y1 - 2011/2/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79952124960&partnerID=8YFLogxK
U2 - 10.1182/blood-2010-08-301945
DO - 10.1182/blood-2010-08-301945
M3 - Article
C2 - 21193697
AN - SCOPUS:79952124960
SN - 0006-4971
VL - 117
SP - 2423
EP - 2432
JO - Blood
JF - Blood
IS - 8
ER -