title: Novel, orally active, proteasome inhibitor, delanzomib (CEP-18770), ameliorates disease symptoms and glomerulonephritis in two preclinical mouse models of SLE.
abstract: Current therapies for late-stage systemic lupus erythematosus (SLE) are limited to cytotoxic agents. Delanzomib (CEP-18770) is an orally active, reversible P2 threonine boronic acid inhibitor of the 26S mammalian proteasome. Delanzomib was tested in a head-to-head comparison against bortezomib to protect and treat mice with fatal lupus nephritis (LN). Age matched MRL/lpr or NZBWF1 mice with established SLE or LN, respectively, were treated with delanzomib either 3 mg/kg once or twice weekly intravenously or orally at 10 mg/kg. Mice were also treated with reference agent bortezomib at 0.5 mg/kg, intraperitoneally, once a week or 0.3 mg/kg once or twice a week. Reductions in the frequencies of specific anti-chromatin, smith and dsDNA antibody secreting cells and levels of the corresponding circulating antinuclear antibodies, were observed following delanzomib treatment. Reductions in several serum pro-inflammatory cytokines were observed in delanzomib-treated animals. Delanzomib treatment suppressed the development and progression of renal tissue damage and extended the survival of ill mice. Proteinuria was significantly decreased and severity of various renal histopathologies reduced relative to vehicle-treated nephritic mice. Treatment of lupus in these models demonstrated that delanzomib treatment lead to greater tolerability and rate of response resulting in improved stabilization of disease.
authors.affiliation: Cephalon, Inc., Worldwide Discovery Research, 145 Brandywine Parkway, West Chester, PA 19380-4249, United States. mseavey@cephalon.com
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Seavey
authors.forename: Lily D
authors.initials: LD
authors.lastname: Lu
authors.forename: Kristine L
authors.initials: KL
authors.lastname: Stump
authors.forename: Nate H
authors.initials: NH
authors.lastname: Wallace
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Ruggeri
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D001897:Boronic Acids / Q000008:administration & dosage / Q000627:therapeutic use*; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D005260:Female; D007668:Kidney / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008181:Lupus Nephritis / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D013154:Spleen / Q000378:metabolism; D013912:Threonine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000974:Antibodies, Antinuclear; D001897:Boronic Acids; D016207:Cytokines; D061988:Proteasome Inhibitors; D013912:Threonine; C527966:delanzomib; D046988:Proteasome Endopeptidase Complex