Fc-dependent expression of CD137 on human NK cells: insights into "agonistic" effects of anti-CD137 monoclonal antibodies.
CD137 (4-1BB) 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 Fc gamma 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.
Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland, Baltimore, MD 21201-168, USA.
Wei
W
Lin
Caroline J
CJ
Voskens
Xiaoyu
X
Zhang
Daniel G
DG
Schindler
Aaron
A
Wood
Erin
E
Burch
Yadong
Y
Wei
Lieping
L
Chen
Guoliang
G
Tian
Koji
K
Tamada
Lai-Xi
LX
Wang
Dan H
DH
Schulze
Dean
D
Mann
Scott E
SE
Strome
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects*; D006031:Glycosylation; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000502:physiology*; D007694:Killer Cells, Natural / Q000378:metabolism*; D011961:Receptors, Fc / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics*
D000911:Antibodies, Monoclonal; D007141:Immunoglobulin Fc Fragments; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9