In:
The Journal of Immunology, The American Association of Immunologists, Vol. 186, No. 1_Supplement ( 2011-04-01), p. 164.3-164.3
Abstract:
Since therapeutic blockade of the cellular proteasome has previously demonstrated preclinical efficacy against inflammatory diseases, the evaluation of a novel, orally active proteosome inhibitor, CEP-18770, was tested in models of systemic lupus erythematosus (SLE). Age matched, 8-week old (MRL/lpr) or 8 months old (NZM) mice with established SLE or lupus nephritis (LN), respectively, were treated with CEP-18770 either 3mg/kg 1-2x/wk, iv, or orally at 10mg/kg. Reference agent, bortezomib, was provided at 0.5mg/kg, 1x/wk, or 0.3mg/kg 1-2x/wk. Standard of care agents included dexamethasone or cyclophosphamide. Mice were monitored for clinical, pathological and immunological changes. Reductions in the frequencies of specific anti-chromatin, smith and dsDNA antibody secreting cells (ASC) and levels of the corresponding antinuclear antibodies (ANA), followed CEP-18770 treatment and were accompanied by decreases in spleen ASCs, plasma cells, and serum cytokines (IL-12, IL-17A, IL-1β, TNFα). CEP-18770-treatment also mitigated the incidence of renal histopathology, and subsequently, proteinuria, in both models. CEP-18770 treatment also extended survival for both models over bortezomib. Proteasome inhibition and IκBα accumulation in target tissues followed administration of CEP-18770 and bortezomib. CEP-18770 was equivalent to treatment with bortezomib; however, CEP-18770 resulted in greater tolerability and rate of response resulting in greater SLE disease stability overtime.
Type of Medium:
Online Resource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.186.Supp.164.3
Language:
English
Publisher:
The American Association of Immunologists
Publication Date:
2011
detail.hit.zdb_id:
1475085-5
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