Additional file 3: of CDP7657, an anti-CD40L antibody lacking an Fc domain, inhibits CD40L-dependent immune responses without thrombotic complications: an in vivo study

CDP7657 immune complex ( IC ) and aglycosyl hu5c8 IC do not induce platelet aggregation in rhesus monkey platelets both in the absence of presence of sub-aggregatory amounts of the platelet agonist (ADP). In vitro aggregation assay of rhesus monkey washed platelets. A CDP7657 IC did not aggregate rhesus monkey washed platelets in the absence (blue and red), or presence (black and green) of ADP. B Similarly, aglycosyl hu5c8 IC did not aggregate rhesus monkey washed platelets in the absence (blue and red), or presence (black and green) of ADP. (PDF 171 kb

Additional file 1: of CDP7657, an anti-CD40L antibody lacking an Fc domain, inhibits CD40L-dependent immune responses without thrombotic complications: an in vivo study

Inhibition of secondary immune response in Cynomolgus monkeys. CDP7657 at 5 or 20 mg/kg (60 mg/kg was not evaluated in this study) was compared with hu5c8 at 20 mg/kg. Animals were administered a single dose of antibody or i.v saline. and challenged with tetanus toxoid (TT) on day 1; they then received a second dose of antibody and TT on day 30. Data are expressed as the mean anti-TT IgG titer ± standard deviation; approximately 50 % inhibition was observed at 20 mg/kg CDP7657, although this was not statistically significant. ***P <0.001 (one-way analysis of variance) compared with control; NS not significant. (PDF 66 kb

Discovery of a Potent, Orally Bioavailable PI4KIIIβ Inhibitor (UCB9608) Able To Significantly Prolong Allogeneic Organ Engraftment <i>in Vivo</i>

The primary target of a novel series of immuno­suppressive 7-piperazin-1-yl­thiazolo­[5,4-<i>d</i>]­pyrimidin-5-amines was identified as the lipid kinase, PI4KIIIβ. Evaluation of the series highlighted their poor solubility and unwanted off-target activities. A medicinal chemistry strategy was put in place to optimize physico­chemical properties within the series, while maintaining potency and improving selectivity over other lipid kinases. Compound <b>22</b> was initially identified and profiled <i>in vivo</i>, before further modifications led to the discovery of <b>44</b> (UCB9608), a vastly more soluble, selective compound with improved metabolic stability and excellent pharmaco­kinetic profile. A co-crystal structure of <b>44</b> with PI4KIIIβ was solved, confirming the binding mode of this class of inhibitor. The much-improved <i>in vivo</i> profile of <b>44</b> positions it as an ideal tool compound to further establish the link between PI4KIIIβ inhibition and prolonged allogeneic organ engraftment, and suppression of immune responses <i>in vivo</i>

Discovery of a Potent, Orally Bioavailable PI4KIIIβ Inhibitor (UCB9608) Able To Significantly Prolong Allogeneic Organ Engraftment <i>in Vivo</i>

The primary target of a novel series of immuno­suppressive 7-piperazin-1-yl­thiazolo­[5,4-<i>d</i>]­pyrimidin-5-amines was identified as the lipid kinase, PI4KIIIβ. Evaluation of the series highlighted their poor solubility and unwanted off-target activities. A medicinal chemistry strategy was put in place to optimize physico­chemical properties within the series, while maintaining potency and improving selectivity over other lipid kinases. Compound <b>22</b> was initially identified and profiled <i>in vivo</i>, before further modifications led to the discovery of <b>44</b> (UCB9608), a vastly more soluble, selective compound with improved metabolic stability and excellent pharmaco­kinetic profile. A co-crystal structure of <b>44</b> with PI4KIIIβ was solved, confirming the binding mode of this class of inhibitor. The much-improved <i>in vivo</i> profile of <b>44</b> positions it as an ideal tool compound to further establish the link between PI4KIIIβ inhibition and prolonged allogeneic organ engraftment, and suppression of immune responses <i>in vivo</i>