TY - JOUR
T1 - Fc-dependent expression of CD137 on human NK cells
T2 - Insights into "agonistic" effects of anti-CD137 monoclonal antibodies
AU - Lin, Wei
AU - Voskens, Caroline J.
AU - Zhang, Xiaoyu
AU - Schindler, Daniel G.
AU - Wood, Aaron
AU - Burch, Erin
AU - Wei, Yadong
AU - Chen, Lieping
AU - Tian, Guoliang
AU - Tamada, Koji
AU - Wang, Lai Xi
AU - Schulze, Dan H.
AU - Mann, Dean
AU - Strome, Scott E.
PY - 2008/8/1
Y1 - 2008/8/1
N2 - CD137 (4-1 BB) is a costimulatory molecule that can be manipulated for the treatment of cancer and autoimmune disease. Although it is known that agonistic antibodies (mAbs) against CD137 enhance the rejection of murine tumors in a natural killer (NK) cell- and T cell-dependent fashion, the mechanism for NK dependence is poorly understood. In this study, we evaluated the ability of 2 different glycoforms of a chimerized antihuman CD137 mAb, an aglycosylated (GA) and a low fucose form (GG), to react with human NK cells. Both mAbs bound similarly to CD137 and partially blocked the interaction between CD137 and CD137 ligand. However, unlike GA mAb, immobilized GG mAb activated NK cells and enhanced CD137 expression. These effects were seemingly dependent on Fc interaction with putative Fc receptors on the NK-cell surface, as only the immobilized Fc-fragment of GG was required for CD137 expression. Furthermore, CD137 expression could be enhanced with antibodies directed against non-CD137 epitopes, and the expression levels directly correlated with patterns of Fc-glycosylation recognized to improve Fc interaction with Fcγ receptors. Our data suggest that CD137 can be enhanced on NK cells in an Fc-dependent fashion and that expression correlates with phenotypic and functional parameters of activation.
AB - CD137 (4-1 BB) is a costimulatory molecule that can be manipulated for the treatment of cancer and autoimmune disease. Although it is known that agonistic antibodies (mAbs) against CD137 enhance the rejection of murine tumors in a natural killer (NK) cell- and T cell-dependent fashion, the mechanism for NK dependence is poorly understood. In this study, we evaluated the ability of 2 different glycoforms of a chimerized antihuman CD137 mAb, an aglycosylated (GA) and a low fucose form (GG), to react with human NK cells. Both mAbs bound similarly to CD137 and partially blocked the interaction between CD137 and CD137 ligand. However, unlike GA mAb, immobilized GG mAb activated NK cells and enhanced CD137 expression. These effects were seemingly dependent on Fc interaction with putative Fc receptors on the NK-cell surface, as only the immobilized Fc-fragment of GG was required for CD137 expression. Furthermore, CD137 expression could be enhanced with antibodies directed against non-CD137 epitopes, and the expression levels directly correlated with patterns of Fc-glycosylation recognized to improve Fc interaction with Fcγ receptors. Our data suggest that CD137 can be enhanced on NK cells in an Fc-dependent fashion and that expression correlates with phenotypic and functional parameters of activation.
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U2 - 10.1182/blood-2007-11-122465
DO - 10.1182/blood-2007-11-122465
M3 - Article
C2 - 18519814
AN - SCOPUS:50949132226
SN - 0006-4971
VL - 112
SP - 699
EP - 707
JO - Blood
JF - Blood
IS - 3
ER -