Assessing agonistic potential of a candidate therapeutic anti-IL21R antibody

<p>Abstract</p> <p>Background</p> <p>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 <it>in vitro </it>cross-linking and <it>in vivo </it>conditions, a comprehensive assessment of agonistic potential of Ab-01 was undertaken.</p> <p>Methods</p> <p><it>In vitro </it>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. <it>In vivo </it>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.</p> <p>Results</p> <p>Using a comprehensive set of assays that detected multiple activation signals in the presence of the positive control agonists, <it>in vitro </it>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 <it>in vivo </it>Ab-01 dosing of cynomolgus monkeys.</p> <p>Conclusions</p> <p>Despite efforts to intentionally force an agonistic signal from Ab-01, none could be detected.</p

Age-related preference for geometric spatial cues during real-world navigation

International audienceAgeing effects on spatial navigation are characterized mainly in terms of impaired allocentric strategies. However, an alternative hypothesis is that navigation difficulties in aged people are associated with deficits in processing and encoding spatial cues. We tested this hypothesis by studying how geometry and landmark cues control navigation in young and older adults in a real, ecological environment. Recordings of body and gaze dynamics revealed a preference for geometry-based navigation in older adults, and for landmark-based navigation in younger ones. While cue processing was associated with specific fixation patterns, advanced age manifested itself in a longer reorientation time, reflecting an unbalanced exploration-exploitation trade-off in scanning policies. Moreover, a battery of tests revealed a specific cognitive deficit in older adults with geometric preference. These results suggest that allocentric strategy deficits in ageing can result from difficulties related to landmark coding, and predict recovery of allocentric strategies in geometrically polarized environments