title: pSTAT3: a target biomarker to study the pharmacology of the anti-IL-21R antibody ATR-107 in human whole blood.
abstract: BACKGROUND
  IL-21 has been shown to play an important role in autoimmune diseases. ATR-107 is an antibody which directly targets the IL-21 receptor (IL-21R). To aid the clinical development of ATR-107, there is a need for understanding the mechanism of action (MOA) of this antibody when assessing target engagement in human subjects.
  
  
  METHODS
  To determine ATR-107 biological activity and potency in human blood, its inhibitory function against IL-21 induced STAT3 phosphorylation in human peripheral T and B cells was measured.
  
  
  RESULTS
  The data show that IL-21 induces STAT3 phosphorylation in a concentration-dependent manner, consistent with its migration to the nuclear. Using a flow cytometry based functional whole blood assay, ATR-107 is demonstrated to be a potent IL-21 pathway inhibitor. It competes with IL-21 for receptor binding in a competitive manner, but once it binds to the receptor it behaves like a non-competitive inhibitor, most probably due to the long observed k(off). The concentration-dependent inhibition observed with ATR-107 correlates inversely with the levels of receptor occupancy, both in ex vivo whole blood assays and directly in human blood when ATR-107 was given to healthy volunteers.
  
  
  CONCLUSIONS
  IL-21 induced phosphorylation of STAT3 in T and B cells can be used as a biomarker to evaluate the target engagement of ATR-107 in human whole blood. The antibody behaves like a potent non-competitive inhibitor blocking IL-21 induced STAT3 phosphorylation for a long period of time. These results may help with the translation of preclinical information and dose selection towards ATR-107 clinical efficacy.
authors.affiliation: Precision Medicine, Pfizer BioTx Clinical R&D, 200 Cambridge Park Drive, Cambridge, MA 02140, USA. ming.zhu1@pfizer.com
authors.forename: Ming
authors.initials: M
authors.lastname: Zhu
authors.forename: Susan
authors.initials: S
authors.lastname: Pleasic-Williams
authors.forename: Tsung H
authors.initials: TH
authors.lastname: Lin
authors.forename: David A
authors.initials: DA
authors.lastname: Wunderlich
authors.forename: John B
authors.initials: JB
authors.lastname: Cheng
authors.forename: Jaime L
authors.initials: JL
authors.lastname: Masferrer
mesh_terms: D001323:Autoantibodies / Q000097:blood* / Q000494:pharmacology; D015415:Biomarkers / Q000097:blood*; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D010766:Phosphorylation; D021381:Protein Transport; D053655:Receptors, Interleukin-21 / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000097:blood*
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D053655:Receptors, Interleukin-21; D050796:STAT3 Transcription Factor