[PDF][PDF] An Fcγ receptor-dependent mechanism drives antibody-mediated target-receptor signaling in cancer cells

NS Wilson, B Yang, A Yang, S Loeser, S Marsters… - Cancer cell, 2011 - cell.com
NS Wilson, B Yang, A Yang, S Loeser, S Marsters, D Lawrence, Y Li, R Pitti, K Totpal, S Yee…
Cancer cell, 2011cell.com
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 …
Summary
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.
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