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: Yongjing Guo, Andrew A Hill, Renee C Ramsey, Frederick W Immermann, Christopher Corcoran, Deborah Young, Edward R Lavallie, Mark Ryan, Theresa Bechard, Richard Pfeifer, Garvin Warner, Marcia Bologna, Laird Bloom, Margot O'Toole
• Journal: Journal of translational medicine (J Transl Med) Vol. 8 Pg. 50 (May 26 2010) ISSN: 1479-5876 [Electronic] England
• PMID: 20504348 (Publication Type: Journal Article)