An Fcγ receptor-dependent mechanism drives antibody-mediated target-receptor signaling in cancer cells.
Antibodies to cell-surface antigens trigger activatory Fcγ receptor (FcγR)-mediated retrograde signals in leukocytes to control immune effector functions. Here, we uncover an FcγR mechanism that drives antibody-dependent forward signaling in target cells. Agonistic antibodies to death receptor 5 (DR5) induce cancer-cell apoptosis and are in clinical trials; however, their mechanism of action in vivo is not fully defined. Interaction of the DR5-agonistic antibody drozitumab with leukocyte FcγRs promoted DR5-mediated tumor-cell apoptosis. Whereas the anti-CD20 antibody rituximab required activatory FcγRs for tumoricidal function, drozitumab was effective in the context of either activatory or inhibitory FcγRs. A CD40-agonistic antibody required similar FcγR interactions to stimulate nuclear factor-κB activity in B cells. Thus, FcγRs can drive antibody-mediated receptor signaling in target cells.
Department of Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Nicholas S
NS
Wilson
Becky
B
Yang
Annie
A
Yang
Stefanie
S
Loeser
Scot
S
Marsters
David
D
Lawrence
Yun
Y
Li
Robert
R
Pitti
Klara
K
Totpal
Sharon
S
Yee
Sarajane
S
Ross
Jean-Michel
JM
Vernes
Yanmei
Y
Lu
Cam
C
Adams
Rienk
R
Offringa
Bob
B
Kelley
Sarah
S
Hymowitz
Dylan
D
Daniel
Gloria
G
Meng
Avi
A
Ashkenazi
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D019013:CD40 Antigens / Q000819:agonists / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics / Q000276:immunology; D022423:Myeloid Cells / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics / Q000276:immunology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011940:Receptor Aggregation / Q000276:immunology; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019013:CD40 Antigens; C499172:Fcgr2b protein, mouse; C485700:Fcgr3 protein, mouse; C522404:Fcgr4 protein, mouse; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D016328:NF-kappa B; D017452:Receptors, IgG; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C530969:apomab; C548876:drozitumab