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Assessing agonistic potential of a candidate therapeutic anti-IL21R antibody

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Author(s): Guo Yongjing | Hill Andrew | Ramsey Renee | Immermann Frederick | Corcoran Christopher | Young Deborah | LaVallie Edward | Ryan Mark | Bechard Theresa | Pfeifer Richard | Warner Garvin | Bologna Marcia | Bloom Laird | O'Toole Margot

Journal: Journal of Translational Medicine
ISSN 1479-5876

Volume: 8;
Issue: 1;
Start page: 50;
Date: 2010;
Original page

ABSTRACT
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.
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