Assessing agonistic potential of a candidate therapeutic anti-IL21R antibody.

Guo, Y., Hill, A.A., Ramsey, R.C., Immermann, F.W., Corcoran, C., Young, D., Lavallie, E.R., Ryan, M., Bouchard, T., Pfeifer, R., Warner, G., Bologna, M., Bloom, L., O'Toole, M.
Journal   J Transl Med.
Species  
Analytes Measured   IL-10 , IL-12 p70 , IL-13 , IL-2 , IL-4 , IL-5 , IL-6 , IL-8 , MCP-1
Matrix Tested   Peripheral blood mononuclear cell (PBMC) culture supernatants
Year   2010
Volume   8
Page Numbers  
Application   Cytokines and Chemokines
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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