title: Targeting natural killer cells to acute myeloid leukemia in vitro with a CD16 x 33 bispecific killer cell engager and ADAM17 inhibition.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Hematology, Oncology, and Transplantation, Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Andres
authors.initials: A
authors.lastname: Wiernik
authors.forename: Bree
authors.initials: B
authors.lastname: Foley
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Michael R
authors.initials: MR
authors.lastname: Verneris
authors.forename: Erica
authors.initials: E
authors.lastname: Warlick
authors.forename: Michelle K
authors.initials: MK
authors.lastname: Gleason
authors.forename: Julie A
authors.initials: JA
authors.lastname: Ross
authors.forename: Xianghua
authors.initials: X
authors.lastname: Luo
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisdorf
authors.forename: Bruce
authors.initials: B
authors.lastname: Walcheck
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Vallera
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Miller
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072198:ADAM17 Protein; D036101:Cord Blood Stem Cell Transplantation; D003587:Cytomegalovirus / Q000502:physiology; D003602:Cytotoxicity, Immunologic; D058851:GPI-Linked Proteins / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000276:immunology*; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D008213:Lymphocyte Activation; D010880:Piperidines / Q000494:pharmacology; D017452:Receptors, IgG / Q000378:metabolism*; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000378:metabolism*; D013141:Spiro Compounds / Q000494:pharmacology; D014775:Virus Activation
chemical_list: C571163:CD33 protein, human; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; C513090:INCB3619; D010880:Piperidines; D017452:Receptors, IgG; D063268:Sialic Acid Binding Ig-like Lectin 3; D013141:Spiro Compounds; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human