TY - JOUR
T1 - Targeting natural killer cells to acute myeloid leukemia in vitro with a CD16×33 bispecific killer cell engager and ADAM17 inhibition
AU - Wiernik, Andres
AU - Foley, Bree
AU - Zhang, Bin
AU - Verneris, Michael R.
AU - Warlick, Erica
AU - Gleason, Michelle K.
AU - Ross, Julie A.
AU - Luo, Xianghua
AU - Weisdorf, Daniel J.
AU - Walcheck, Bruce
AU - Vallera, Daniel A.
AU - Miller, Jeffrey S.
PY - 2013/7/15
Y1 - 2013/7/15
N2 - Purpose: The graft versus leukemia effect by natural killer (NK) cells prevents relapse following hematopoietic stem cell transplantation. We determined whether a novel bispecific killer cell engager (BiKE) signaling through CD16 and targeting CD33 could activate NK cells at high potency against acute myelogenous leukemia (AML) targets. Experimental Design: We investigated the ability of our fully humanized CD16 × CD33 (CD16×33) BiKE to trigger in vitro NK cell activation against HL60 (CD33+ ), RAJI (CD33-), and primary AML targets (de novo and refractory) to determine whether treatment with CD16×33 BiKE in combination with an ADAM17 inhibitor could prevent CD16 shedding (a novel inhibitory mechanism induced by NK cell activation) and overcome inhibition of class I MHC recognizing inhibitory receptors. Results: NK cell cytotoxicity and cytokine release were specifically triggered by the CD16×33 BiKE when cells were cultured with HL60 targets, CD33+ de novo and refractory AML targets. Combination treatment with CD16×33 BiKE and ADAM17 inhibitor resulted in inhibition of CD16 shedding in NK cells, and enhanced NK cell activation. Treatment of NK cells from double umbilical cord blood transplant (UCBT) recipients with the CD16×33 BiKE resulted in activation, especially in those recipients with cytomegalovirus reactivation. Conclusion: CD16×33 BiKE can overcome self-inhibitory signals and effectively elicit NK cell effector activity against AML. These in vitro studies highlight the potential of CD16×33 BiKE ± ADAM17 inhibition to enhance NK cell activation and specificity against CD33+ AML, which optimally could be applied in patients with relapsed AML or for adjuvant antileukemic therapy posttransplantation.
AB - Purpose: The graft versus leukemia effect by natural killer (NK) cells prevents relapse following hematopoietic stem cell transplantation. We determined whether a novel bispecific killer cell engager (BiKE) signaling through CD16 and targeting CD33 could activate NK cells at high potency against acute myelogenous leukemia (AML) targets. Experimental Design: We investigated the ability of our fully humanized CD16 × CD33 (CD16×33) BiKE to trigger in vitro NK cell activation against HL60 (CD33+ ), RAJI (CD33-), and primary AML targets (de novo and refractory) to determine whether treatment with CD16×33 BiKE in combination with an ADAM17 inhibitor could prevent CD16 shedding (a novel inhibitory mechanism induced by NK cell activation) and overcome inhibition of class I MHC recognizing inhibitory receptors. Results: NK cell cytotoxicity and cytokine release were specifically triggered by the CD16×33 BiKE when cells were cultured with HL60 targets, CD33+ de novo and refractory AML targets. Combination treatment with CD16×33 BiKE and ADAM17 inhibitor resulted in inhibition of CD16 shedding in NK cells, and enhanced NK cell activation. Treatment of NK cells from double umbilical cord blood transplant (UCBT) recipients with the CD16×33 BiKE resulted in activation, especially in those recipients with cytomegalovirus reactivation. Conclusion: CD16×33 BiKE can overcome self-inhibitory signals and effectively elicit NK cell effector activity against AML. These in vitro studies highlight the potential of CD16×33 BiKE ± ADAM17 inhibition to enhance NK cell activation and specificity against CD33+ AML, which optimally could be applied in patients with relapsed AML or for adjuvant antileukemic therapy posttransplantation.
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U2 - 10.1158/1078-0432.CCR-13-0505
DO - 10.1158/1078-0432.CCR-13-0505
M3 - Article
C2 - 23690482
AN - SCOPUS:84881169028
SN - 1078-0432
VL - 19
SP - 3844
EP - 3855
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 14
ER -