title: CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells against primary MDS and MDSC CD33+ targets.
abstract: Myelodysplastic syndromes (MDS) are stem cell disorders that can progress to acute myeloid leukemia. Although hematopoietic cell transplantation can be curative, additional therapies are needed for a disease that disproportionally afflicts the elderly. We tested the ability of a CD16xCD33 BiKE to induce natural killer (NK) cell function in 67 MDS patients. Compared with age-matched normal controls, CD7(+) lymphocytes, NK cells, and CD16 expression were markedly decreased in MDS patients. Despite this, reverse antibody-dependent cell-mediated cytotoxicity assays showed potent degranulation and cytokine production when resting MDS-NK cells were triggered with an agonistic CD16 monoclonal antibody. Blood and marrow MDS-NK cells treated with bispecific killer cell engager (BiKE) significantly enhanced degranulation and tumor necrosis factor-α and interferon-γ production against HL-60 and endogenous CD33(+) MDS targets. MDS patients had a significantly increased proportion of immunosuppressive CD33(+) myeloid-derived suppressor cells (MDSCs) that negatively correlated with MDS lymphocyte populations and CD16 loss on NK cells. Treatment with the CD16xCD33 BiKE successfully reversed MDSC immunosuppression of NK cells and induced MDSC target cell lysis. Lastly, the BiKE induced optimal MDS-NK cell function irrespective of disease stage. Our data suggest that the CD16xCD33 BiKE functions against both CD33(+) MDS and MDSC targets and may be therapeutically beneficial for MDS patients.
authors.affiliation: Division of Epidemiology and Clinical Research, Department of Pediatrics.
authors.forename: Michelle K
authors.initials: MK
authors.lastname: Gleason
authors.forename: Julie A
authors.initials: JA
authors.lastname: Ross
authors.forename: Erica D
authors.initials: ED
authors.lastname: Warlick
authors.forename: Troy C
authors.initials: TC
authors.lastname: Lund
authors.forename: Michael R
authors.initials: MR
authors.lastname: Verneris
authors.forename: Andres
authors.initials: A
authors.lastname: Wiernik
authors.forename: Stephen
authors.initials: S
authors.lastname: Spellman
authors.forename: Michael D
authors.initials: MD
authors.lastname: Haagenson
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lenvik
authors.forename: Mark R
authors.initials: MR
authors.lastname: Litzow
authors.forename: Pearlie K
authors.initials: PK
authors.lastname: Epling-Burnette
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Louis M
authors.initials: LM
authors.lastname: Weiner
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisdorf
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Vallera
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Miller
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018033:Antibodies, Bispecific / Q000276:immunology* / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000276:immunology / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017452:Receptors, IgG / Q000276:immunology*; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
chemical_list: D018033:Antibodies, Bispecific; C571163:CD33 protein, human; D007166:Immunosuppressive Agents; D017452:Receptors, IgG; D063268:Sialic Acid Binding Ig-like Lectin 3; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma