title: Correlation of pharmacodynamic activity, pharmacokinetics, and anti-product antibody responses to anti-IL-21R antibody therapeutics following IV administration to cynomolgus monkeys.
abstract: BACKGROUND
  Anti-IL-21R antibodies are potential therapeutics for the treatment of autoimmune diseases. This study evaluated correlations between the pharmacodynamic (PD) activity, pharmacokinetics, and anti-product antibody responses of human anti-IL-21R antibodies Ab-01 and Ab-02 following IV administration to cynomolgus monkeys.
  
  
  METHODS
  The PD assay was based on the ability of recombinant human IL-21 (rhuIL-21) to induce expression of the IL-2RA gene in cynomolgus monkey whole blood samples ex vivo. Monkeys screened for responsiveness to rhuIL-21 stimulation using the PD assay, were given a single 10 mg/kg IV dosage of Ab-01, Ab-02, or a control antibody (3/group), and blood samples were evaluated for PD activity (inhibition of IL-2RA expression) for up to 148 days. Anti-IL-21R antibody concentrations and anti-product antibody responses were measured in serum using immunoassays and flow cytometry.
  
  
  RESULTS
  Following IV administration of Ab-01 and Ab-02 to cynomolgus monkeys, PD activity was observed as early as 5 minutes (first time point sampled). This PD activity had good correlation with the serum concentrations and anti-product antibody responses throughout the study. The mean terminal half-life (t1/2) was approximately 10.6 and 2.3 days for Ab-01 and Ab-02, respectively. PD activity was lost at approximately 5-13 weeks for Ab-01 and at approximately 2 weeks for Ab-02, when serum concentrations were relatively low. The estimated minimum concentrations needed to maintain PD activity were approximately 4-6 nM for Ab-01 and approximately 2.5 nM for Ab-02, and were consistent with the respective KD values for binding to human IL-21R. For Ab-01, there was noticeable inter-animal variability in t1/2 values (approximately 6-14 days) and the resulting PD profiles, which correlated with the onset of anti-product antibody formation. While all three Ab-01-dosed animals were positive for anti-Ab-01 antibodies, only one monkey (with the shortest t1/2 and the earliest loss of PD activity) had evidence of neutralizing anti-Ab-01 antibodies. All three Ab-02-dosed monkeys developed neutralizing anti-Ab-02 antibodies.
  
  
  CONCLUSIONS
  For anti-IL-21R antibodies Ab-01 and Ab-02, there was good correlation between PD activity and PK profiles following IV administration to cynomolgus monkeys. Compared with Ab-01, Ab-02 was eliminated markedly faster from the circulation, which correlated with a shorter duration of PD activity.
authors.affiliation: Pfizer, Inc,, Andover, MA 01810, USA. yulia.vugmeyster@pfizer.com
authors.forename: Yulia
authors.initials: Y
authors.lastname: Vugmeyster
authors.forename: Scott
authors.initials: S
authors.lastname: Allen
authors.forename: Pamela
authors.initials: P
authors.lastname: Szklut
authors.forename: Andrea
authors.initials: A
authors.lastname: Bree
authors.forename: Mark
authors.initials: M
authors.lastname: Ryan
authors.forename: Margery
authors.initials: M
authors.lastname: Ma
authors.forename: Vikki
authors.initials: V
authors.lastname: Spaulding
authors.forename: Deborah
authors.initials: D
authors.lastname: Young
authors.forename: Heath
authors.initials: H
authors.lastname: Guay
authors.forename: Laird
authors.initials: L
authors.lastname: Bloom
authors.forename: Michael W
authors.initials: MW
authors.lastname: Leach
authors.forename: Margot
authors.initials: M
authors.lastname: O'Toole
authors.forename: Karissa
authors.initials: K
authors.lastname: Adkins
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000276:immunology; D000917:Antibody Formation / Q000187:drug effects / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007118:Immunoassay; D007275:Injections, Intravenous; D008252:Macaca fascicularis / Q000097:blood / Q000276:immunology*; D008297:Male; D053655:Receptors, Interleukin-21 / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D053655:Receptors, Interleukin-21; D011994:Recombinant Proteins