TY - JOUR
T1 - Functional attributes of antibodies, effector cells, and target cells affecting nk cell-mediated antibody-dependent cellular cytotoxicity
AU - Temming, A. Robin
AU - de Taeye, Steven W.
AU - de Graaf, Erik L.
AU - de Neef, Louise A.
AU - Dekkers, Gillian
AU - Bruggeman, Christine W.
AU - Koers, Jana
AU - Ligthart, Peter
AU - Nagelkerke, Sietse Q.
AU - Zimring, James C.
AU - Kuijpers, Taco W.
AU - Wuhrer, Manfred
AU - Rispens, Theo
AU - Vidarsson, Gestur
PY - 2019
Y1 - 2019
N2 - Ab-dependent cellular cytotoxicity (ADCC) is one of the most important effector mechanisms of tumor-targeting Abs in current immunotherapies. In ADCC and other Ab-dependent activation of myeloid effector cells, close cell-cell contact (between effector and target cell) and formation of immunological synapses are required. However, we still lack basic knowledge on the principal factors influencing ADCC potential by therapeutic Abs. In this study we investigated the combined roles of five factors affecting human NK cell-mediated ADCC, namely: 1) Ag density, 2) target cell membrane composition, 3) IgG FcgR polymorphism, 4) FcgR-blocking cytophilic Abs, and 5) Ab fucosylation.We demonstrate that the magnitude of NK cell-mediated ADCC responses is predominantly influenced by Ag density and Ab fucosylation. Afucosylation consistently induced efficient ADCC, even at very low Ag density, where fucosylated target Abs did not elicit ADCC. On the side of the effector cell, the FcgRIIIa-Val/Phe158 polymorphism influenced ADCC potency, with NK cells expressing the Val158 variant showing more potent ADCC. In addition, we identified the sialic acid content of the target cell membrane as an important inhibitory factor for ADCC. Furthermore, we found that the presence and glycosylation status of aspecific endogenous Abs bound to NK cell FcgRIIIa (cytophilic Abs) determine the blocking effect on ADCC. These five parameters affect the potency of Abs in vitro and should be further tested as predictors of in vivo capacity.
AB - Ab-dependent cellular cytotoxicity (ADCC) is one of the most important effector mechanisms of tumor-targeting Abs in current immunotherapies. In ADCC and other Ab-dependent activation of myeloid effector cells, close cell-cell contact (between effector and target cell) and formation of immunological synapses are required. However, we still lack basic knowledge on the principal factors influencing ADCC potential by therapeutic Abs. In this study we investigated the combined roles of five factors affecting human NK cell-mediated ADCC, namely: 1) Ag density, 2) target cell membrane composition, 3) IgG FcgR polymorphism, 4) FcgR-blocking cytophilic Abs, and 5) Ab fucosylation.We demonstrate that the magnitude of NK cell-mediated ADCC responses is predominantly influenced by Ag density and Ab fucosylation. Afucosylation consistently induced efficient ADCC, even at very low Ag density, where fucosylated target Abs did not elicit ADCC. On the side of the effector cell, the FcgRIIIa-Val/Phe158 polymorphism influenced ADCC potency, with NK cells expressing the Val158 variant showing more potent ADCC. In addition, we identified the sialic acid content of the target cell membrane as an important inhibitory factor for ADCC. Furthermore, we found that the presence and glycosylation status of aspecific endogenous Abs bound to NK cell FcgRIIIa (cytophilic Abs) determine the blocking effect on ADCC. These five parameters affect the potency of Abs in vitro and should be further tested as predictors of in vivo capacity.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85076326933&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31748349
U2 - https://doi.org/10.4049/jimmunol.1900985
DO - https://doi.org/10.4049/jimmunol.1900985
M3 - Article
C2 - 31748349
SN - 0022-1767
VL - 203
SP - 3126
EP - 3135
JO - Journal of immunology (Baltimore, Md.
JF - Journal of immunology (Baltimore, Md.
IS - 12
ER -