Assessing agonistic potential of a candidate therapeutic anti-IL21R antibody.
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.
Guo
Yongjing
Y
Pfizer, BioTherapeutics Clinical Translational Medicine, Cambridge, MA, USA. margot.otoole@pfizer.com.
Hill
Andrew A
AA
Ramsey
Renee C
RC
Immermann
Frederick W
FW
Corcoran
Christopher
C
Young
Deborah
D
Lavallie
Edward R
ER
Ryan
Mark
M
Bechard
Theresa
T
Pfeifer
Richard
R
Warner
Garvin
G
Bologna
Marcia
M
Bloom
Laird
L
O'Toole
Margot
M