title: Intermediate-affinity interleukin-2 receptor expression predicts CD56(bright) natural killer cell expansion after daclizumab treatment in the CHOICE study of patients with multiple sclerosis.
abstract: OBJECTIVE
  The objective of this study was to evaluate whether interleukin-2 (IL-2) receptor expression on CD56(bright) natural killer (NK) cells predicted CD56(bright) NK cell expansion and therapeutic response to daclizumab (DAC) in multiple sclerosis (MS).
  
  
  METHODS
  DAC exposure, CD56(bright) NK cell counts, IL-2 receptor alpha (CD25) and beta (CD122) subunits, and new or enlarged lesions on brain MRI were measured in 64 subjects in a pharmacokinetic/pharmacodynamic substudy of the phase 2 CHOICE trial at multiple time points. Peripheral blood mononuclear cell (PBMC) samples were obtained from healthy subjects to assess the relationship among DAC treatment, intermediate affinity IL-2 signaling, and CD56(bright) NK cell expansion.
  
  
  RESULTS
  Increased CD56(bright) NK cell counts in DAC/interferon beta (IFNβ)-treated subjects were observed by day 14, the first post-dosing time point (mean [SD] ln{CD56(bright) NK cell count}: DAC high/IFNβ, 2.01 [1.25]; DAC low/IFNβ, 2.29 [1.06]; placebo/IFNβ, 1.01 [1.03]; adjusted p = 0.003), and persisted throughout the treatment period. Higher DAC dose predicted a faster rate of CD56(bright) NK cell expansion (p < 0.001), but individual subjects' increases in CD56(bright) NK cells from baseline levels were only weakly correlated with DAC exposure (r(2) = 0.167). Higher expression of the intermediate-affinity IL-2 receptor subunit (CD122) on CD56(bright) NK cells at baseline predicted fewer new gadolinium-enhanced (Gd+) lesions during the treatment period (1.77 vs. 0.62 adjusted mean new Gd+ lesions during weeks 8-24, lowest vs. highest quartile of percentage CD122(+) CD56(bright) NK cells; p = 0.033) and a greater increase in CD56(bright) NK cell counts at the end of DAC dosing (p = 0.029).
  
  
  CONCLUSIONS
  CD56(bright) NK cell expansion after DAC treatment appears to reflect individual differences in the capacity for intermediate-affinity IL-2 signaling and could provide a basis for predicting clinical response to DAC in MS.
authors.affiliation: Department of Translational Medicine, Abbott Biotherapeutics, Redwood City, California 94063, USA. james.sheridan@abbott.com
authors.forename: James P
authors.initials: JP
authors.lastname: Sheridan
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Katherine
authors.initials: K
authors.lastname: Riester
authors.forename: Meina T
authors.initials: MT
authors.lastname: Tang
authors.forename: Lyubov
authors.initials: L
authors.lastname: Efros
authors.forename: Jia
authors.initials: J
authors.lastname: Shi
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Harris
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vexler
authors.forename: Jacob S
authors.initials: JS
authors.lastname: Elkins
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D019002:CD56 Antigen / Q000032:analysis*; D049109:Cell Proliferation / Q000187:drug effects; D000077561:Daclizumab; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D053646:Interleukin-2 Receptor beta Subunit / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D019002:CD56 Antigen; D007074:Immunoglobulin G; D053645:Interleukin-2 Receptor alpha Subunit; D053646:Interleukin-2 Receptor beta Subunit; D000077561:Daclizumab