In:
The Journal of Immunology, The American Association of Immunologists, Vol. 194, No. 1_Supplement ( 2015-05-01), p. 208.5-208.5|68.3
Abstract:
Increased production of the inflammatory cytokine IL-17A by Th17 cells is a driver of multiple autoimmune disorders, including psoriasis, ankylosing spondylitis (AS) and psoriatic arthritis (PsA). The nuclear receptor RORγt, IL-23 and TGFb are required for the differentiation of Th17 cells. RORγt stabilizes the Th17 phenotype by increasing the expression of IL-23R and inducing the synthesis of IL-17A in Th17 cells. Antibodies targeting IL-23 or IL-17A are highly effective in the treatment of psoriasis, AS and PsA, validating the RORγt /Th17 pathway in human disease. VTP-43742 is an orally active inhibitor of RORgt that is being pursued for the treatment of autoimmune disorders. VTP-43742 binds to RORγt with high affinity (Ki=3.5 nM) and exhibits & gt;1000-fold selectivity versus the RORa and RORβ isotypes. VTP-43742 inhibits Th17 differentiation and IL-17A secretion from mouse splenocytes (IC50=57 nM) without affecting Th1, Th2, or Treg cell differentiation. In the MOG35-55/CFA immunized mouse EAE model, orally dosed VTP-43742 significantly suppressed clinical symptoms, demyelination and mRNA expression of multiple inflammatory markers in the spinal cord. Importantly, VTP-43742 inhibits the secretion of IL-17A from activated hPBMCs (IC50=18 nM) and human whole blood (IC50=192 nM) from healthy and psoriatic donors. Further, VTP-43742 is well absorbed after oral administration in multiple animal species and has pharmacokinetics consistent with once-a-day dosing in humans.
Type of Medium:
Online Resource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.194.Supp.208.5
Language:
English
Publisher:
The American Association of Immunologists
Publication Date:
2015
detail.hit.zdb_id:
1475085-5
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