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| Status |
Public on Nov 14, 2014 |
| Title |
3 Week IV Study of RGMC Ab in Female Sprague Dawley Rats |
| Organism |
Rattus norvegicus |
| Experiment type |
Expression profiling by array
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| Summary |
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.
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| Overall design |
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
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| Contributor(s) |
Michael L, Rita C |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Nov 12, 2014 |
| Last update date |
Jul 31, 2017 |
| Contact name |
Rita Ciurlionis |
| E-mail(s) |
rita.ciurlionis@abbvie.com
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| Phone |
(847)935-6258
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| Organization name |
Abbvie
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| Street address |
1 North Waukegan Road
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| City |
North Chicago |
| State/province |
IL |
| ZIP/Postal code |
60064 |
| Country |
USA |
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| Platforms (1) |
| GPL1355 |
[Rat230_2] Affymetrix Rat Genome 230 2.0 Array |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA267073 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE63200_RAW.tar |
32.4 Mb |
(http)(custom) |
TAR (of CEL) |
| GSE63200_fold_change.txt.gz |
90.0 Kb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
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