| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T13251 | ||||
| Target Name | Interleukin-12 | ||||
| Target Type | Successful |
||||
| Drug Potency against Target | STA-5326 | Drug Info | IC50 = 1 nM | [536292] | |
| Action against Disease Model | ABT-874 | ABT-874 inhibited the binding of radiolabeled IL-12 to the IL-12R on phytohemagglutinin (PHA)-activated lymphoblasts with an IC50 value of approximately 11 pM, and inhibited IL-12-stimulated PHA-activated lymphoblast proliferation with an IC50 value of approximately 10 pM. ABT-874 also suppressed h uMan IFN|??production from IL-12-stimulated, PHA-activated lymphoblasts with an IC50 value of approximately 5 pM. In a mouse model, ABT-874 (16 ng/kg to 50 |?g/kg ip, on days 0, 2 and 4) dose-dependently inhibited IFN|??production induced by injection of a chimeric IL-12 protein | [536708] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | Bronchial-alveolar eosinophilic inflammation is among the characteristic pathological changes in asthma, which has been shown to be correlated with type 2 cytokine and chemokineproduction. Exogenous IL-12 has been found to be inhibitory for pulmonary eosinophilia in reported studies. Using a murine asthma-like model induced by OVA, we found in the present study that IL-12 gene knockout (KO) mice showed substantially reduced airway recruitment of eosinophils compared with wild-type control mice following OVA sensitization/challenge, although the levels of circulating eosinophils were comparable in these two groups of mice. Cytokine analysis showed Ag-driven Th1 (IFN-gamma) and Th2 (IL-4, IL-5, IL-10, and IL-13) cytokine production by CD4 T cells from local draining lymph nodes and spleen. Similarly, local eotaxin production was comparable in wild-type and IL-12 KO mice. In contrast, immunohistochemical analysis showed that the expression of VCAM-1 on the lung endotheli uM of IL-12 KO mice was dramatically less than that in wild-type mice. Furthermore, administration of rIL-12 at the stage of sensitization and challenge with OVA restored airway eosinophilia and VCAM-1 expression in IL-12 KO mice. The results suggest that endogenous IL-12 contributes to the recruitment of eosinophils into airways observed in asthma, possibly via enhancement of the expression of VCAM-1 on local vascular endothelial cells. | [536708] | |||
| References | |||||
| Ref 536708 | ABT-874, a fully human monoclonal anti-IL-12/IL-23 antibody for the potential treatment of autoimmune diseases. Curr Opin Investig Drugs. 2008 May;9(5):515-22. | ||||
| Ref 536292 | Selective abrogation of Th1 response by STA-5326, a potent IL-12/IL-23 inhibitor. Blood. 2007 Feb 1;109(3):1156-64. Epub 2006 Oct 19. | ||||
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