| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T32578 | ||||
| Target Name | Interleukin-6 | ||||
| Target Type | Successful |
||||
| Drug Potency against Target | C326 | Drug Info | IC50 = 0.253 nM | [552565] | |
| Action against Disease Model | Tocilizumab | ELISA assay demonstrated that tociliz uMab bound to sIL-6R and inhibited IL-6 binding to sIL-6R in a dose-dependent manner. The dissociation constant (Kd value) for IL-6R was determined to be 2.54+/-0.12 nmol/L by Scatchard analysis. In addition, tociliz uMab had the ability to dissociate IL-6 and sIL-6R from their preformed complex. The immune complex of tociliz uMab and sIL-6R did not transmit signaling. Moreover, tociliz uMab suppressed the IL-6/sIL-6R complex-induced proliferation of h uMan gp130-transfected cell, BAF-h130. In addition, tociliz uMab had the ability to bind to h uMan IL-6R expressing COS-7 cells and to suppress the growth of the IL-6-dependent myeloma cell line. Tociliz uMab inhibited the proliferation of BaF/IL-6R induced by IL-6, but did not inhibit the proliferation of BaF/IL-11R, BaF/OSMR, BaF/LIFR and BaF/CNTFR cells induced by their corresponding cytokines. These lines of evidence indicate that tociliz uMab is able to bind to both sIL-6Rand mIL-6R and to inhibit IL-6 binding to its receptors, leading to the blockade of the IL-6 signaling through both sIL-6R and mIL-6R, but not block the signaling of other IL-6 family cytokines. | [552541] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | We examined the effect of the source of IL-6 by analyzing the role IL-6 deficiency in donor T cells, donor bone marrow or in host tissues. We confirmed and extended the relevance of IL-6 deficiency on graft-versus-host disease and graft-versus-t uMor by treating BMT recipients with anti-mouse IL-6 receptor (IL-6R), MR16-1.Deficiency of IL-6 in donor T cells led to prolongation of survival. Total inhibition of IL-6 with MR16-1 caused an even greater reduction in GVHD-induced mortality. The reduction in GVHD was independent of the direct effects on T effector cell expansion or donor regulatory T cells. GVT responses were preserved after treatment with MR16-1. | [552565] | |||
| References | |||||
| Ref 552565 | Multivalent avimer proteins evolved by exon shuffling of a family of human receptor domains. Nat Biotechnol. 2005 Dec;23(12):1556-61. Epub 2005 Nov 20. | ||||
| Ref 552541 | Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine family. Int Immunopharmacol. 2005 Nov;5(12):1731-40. | ||||
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