title: Assessing agonistic potential of a candidate therapeutic anti-IL21R antibody.
abstract: BACKGROUND
  Selective neutralization of the IL21/IL21R signaling pathway is a promising approach for the treatment of a variety of autoimmune diseases. Ab-01 is a human neutralizing anti-IL21R antibody. In order to ensure that the activities of Ab-01 are restricted to neutralization even under in vitro cross-linking and in vivo conditions, a comprehensive assessment of agonistic potential of Ab-01 was undertaken.
  
  
  METHODS
  In vitro antibody cross-linking and cell culture protocols reported for studies with a human agonistic antibody, TGN1412, were followed for Ab-01. rhIL21, the agonist ligand of the targeted receptor, and cross-linked anti-CD28 were used as positive controls for signal transduction. In vivo agonistic potential of Ab-01 was assessed by measuring expression levels of cytokine storm-associated and IL21 pathway genes in blood of cynomolgus monkeys before and after IV administration of Ab-01.
  
  
  RESULTS
  Using a comprehensive set of assays that detected multiple activation signals in the presence of the positive control agonists, in vitro Ab-01-dependent activation was not detected in either PBMCs or the rhIL21-responsive cell line Daudi. Furthermore, no difference in gene expression levels was detected in blood before and after in vivo Ab-01 dosing of cynomolgus monkeys.
  
  
  CONCLUSIONS
  Despite efforts to intentionally force an agonistic signal from Ab-01, none could be detected.
authors.affiliation: Pfizer, BioTherapeutics Clinical Translational Medicine, Cambridge, MA, USA. margot.otoole@pfizer.com.
authors.forename: Yongjing
authors.initials: Y
authors.lastname: Guo
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Hill
authors.forename: Renee C
authors.initials: RC
authors.lastname: Ramsey
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Immermann
authors.forename: Christopher
authors.initials: C
authors.lastname: Corcoran
authors.forename: Deborah
authors.initials: D
authors.lastname: Young
authors.forename: Edward R
authors.initials: ER
authors.lastname: Lavallie
authors.forename: Mark
authors.initials: M
authors.lastname: Ryan
authors.forename: Theresa
authors.initials: T
authors.lastname: Bechard
authors.forename: Richard
authors.initials: R
authors.lastname: Pfeifer
authors.forename: Garvin
authors.initials: G
authors.lastname: Warner
authors.forename: Marcia
authors.initials: M
authors.lastname: Bologna
authors.forename: Laird
authors.initials: L
authors.lastname: Bloom
authors.forename: Margot
authors.initials: M
authors.lastname: O'Toole