Fc-dependent expression of CD137 on human NK cells: insights into “agonistic” effects of anti-CD137 monoclonal antibodies

CD137 (4-1BB) is a costimulatory mol-ecule 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...

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Bibliographic Details
Published in:Blood 2008-08, Vol.112 (3), p.699-707
Main Authors: Lin, Wei, Voskens, Caroline J., Zhang, Xiaoyu, Schindler, Daniel G., Wood, Aaron, Burch, Erin, Wei, Yadong, Chen, Lieping, Tian, Guoliang, Tamada, Koji, Wang, Lai-Xi, Schulze, Dan H., Mann, Dean, Strome, Scott E.
Format: Article
Language:English
Subjects:
Analysis of the immune response. Humoral and cellular immunity
Antibodies, Monoclonal - pharmacology
Biological and medical sciences
Cells, Cultured
Fundamental and applied biological sciences. Psychology
Fundamental immunology
Gene Expression Regulation - drug effects
Glycosylation
Humans
Immunobiology
Immunoglobulin Fc Fragments - physiology
Killer Cells, Natural - metabolism
Organs and cells involved in the immune response
Receptors, Fc - metabolism
Recombinant Fusion Proteins
Tumor Necrosis Factor Receptor Superfamily, Member 9 - genetics
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Summary:CD137 (4-1BB) is a costimulatory mol-ecule 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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2007-11-122465