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Báo cáo hóa học: " Assessing agonistic potential of a candidate therapeutic anti-IL21R antibody"

Assessing agonistic potential of a candidate therapeutic anti-IL21R antibody | Guo et al. Journal of Translational Medicine 2010 8 50 http www.translational-medicine.eom content 8 1 50 RESEARCH JOURNAL OF TRANSLATIONAL MEDICINE Open Access Assessing agonistic potential of a candidate therapeutic anti-IL21R antibody Yongjing Guo1 Andrew A Hill1 Renee C Ramsey1 Frederick W Immermann2 Christopher Corcoran1 Deborah Young3 Edward R LaVallie1 Mark Ryan3 Theresa Bechard4 Richard Pfeifer5 Garvin Warner6 Marcia Bologna7 Laird Bloom1 and Margot O Toole 8 9 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. Background IL21 interleukin 21 is a type I cytokine produced by activated CD4 T cells and natural killer NK T cells 14