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Title: 3 Week IV Study of RGMC Ab in Female Sprague Dawley Rats      
dateReleased:
11-14-2014
description:
High levels of hepcidin, the main regulator of systemic iron metabolism leads to various diseases. Targeting hepcidin and lowering its concentration is a possible form of intervention in order to treat these diseases. High turnover rate of hepcidin is a major drawback of therapies directly targeting this peptide. We developed two monoclonal antibodies (mAbs) ABT-207 and h5F9-AM8 which inhibit hemojuvelin also known as repulsive guidance molecule c (RGMc) and downregulate hepcidin. After a single application of these antibodies hepcidin expression in liver and its concentration in serum were reduced. Serum iron increased for several weeks. The RGMc antibodies show a pronounced dose response relationship in rats with h5F9-AM8 having an IC50 (UIBC) of ~80 fold higher than ABT-207. When hepcidin levels were downregulated iron deposition in the liver was visible histologically one week post application. The anitbody-mediated iron deposition was not associated with any toxicologically relevant effect at the doses and timepoints evaluate. Iron depositions seen after 14 weekly treatments with ABT-207 were partially reversible in rats and in cynomolgus monkeys. Due to their long-lasting effects and excellent safety profile, both RGMc-blocking antibodies ABT-207 and h5F9-AM8 are favorable clinical candidates for diseases characterized by high serum hepcidin levels like anemia of chronic disease. Female Sprague-Dawley rats [Crl:CD®(SD)IGS BR], weighing ~200 g at study initiation were obtained from Charles River Laboratories, Inc. Rats were housed singly in ventilated, stainless steel, wire-bottom hanging cages, fed non-certified Rodent Chow and water ad libitum and acclimated for at least 5 days after arrival. Rats were randomly assigned to various treatment groups (5 rats/group) and were dosed once weekly by IV injection via tail vein with vehicle (30mM Histidine, 8% w/v Sucrose, pH6.0, + 0.02% Tween 80) or with 0.02, 0.2, or 20 mg/kg of RGMc antibody for a total of 4 doses. All rats were sacrificed under isoflurane anesthesia 24 hours after final dose. Liver and spleen waere flash frozen in liquid nitrogen and stored at 80°C until processing for gene expression profiling on the Affymetrix platform. total of 12 samples, 3 biological replicates (rats) from each of 4 treatments groups 1. vehicle control (30mM Histidine, 8% w/v Sucrose, pH6.0, + 0.02% Tween 80) 2. 0.02 mg/kg RGMC Ab 3. 0.2 mg/kg RGMC Ab 4. 20 mg/kg RGMC Ab; rats were dosed by IV injection via tail vein once weekly for 4 total doses, dose volume 2mL/kg/week
privacy:
not applicable
aggregation:
instance of dataset
ID:
E-GEOD-63200
refinement:
raw
alternateIdentifiers:
63200
keywords:
functional genomics
dateModified:
11-28-2014
availability:
available
types:
gene expression
name:
Rattus norvegicus
ID:
A-AFFY-43
name:
Affymetrix GeneChip Rat Genome 230 2.0 [Rat230_2]
accessURL: https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-63200/E-GEOD-63200.raw.1.zip
storedIn:
ArrayExpress
qualifier:
gzip compressed
format:
TXT
accessType:
download
authentication:
none
authorization:
none
accessURL: https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-63200/E-GEOD-63200.processed.1.zip
storedIn:
ArrayExpress
qualifier:
gzip compressed
format:
TXT
accessType:
download
authentication:
none
authorization:
none
accessURL: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE63200
storedIn:
Gene Expression Omnibus
qualifier:
not compressed
format:
HTML
accessType:
landing page
primary:
true
authentication:
none
authorization:
none
abbreviation:
EBI
homePage: http://www.ebi.ac.uk/
ID:
SCR:004727
name:
European Bioinformatics Institute
homePage: https://www.ebi.ac.uk/arrayexpress/
ID:
SCR:002964
name:
ArrayExpress

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