The effects of the anti-hepcidin Spiegelmer NOX-H94 on inflammation-induced anemia in cynomolgus monkeys.
Anemia of chronic inflammation is the most prevalent form of anemia in hospitalized patients. A hallmark of this disease is the intracellular sequestration of iron. This is a consequence of hepcidin-induced internalization and subsequent degradation of ferroportin, the hepcidin receptor and only known iron-export protein. This study describes the characterization of novel anti-hepcidin compound NOX-H94, a structured L-oligoribonucleotide that binds human hepcidin with high affinity (Kd = 0.65 ± 0.06 nmol/L). In J774A.1 macrophages, NOX-H94 blocked hepcidin-induced ferroportin degradation and ferritin expression (half maximal inhibitory concentration = 19.8 ± 4.6 nmol/L). In an acute cynomolgus monkey model of interleukin 6 (IL-6)-induced hypoferremia, NOX-H94 inhibited serum iron reduction completely. In a subchronic model of IL-6-induced anemia, NOX-H94 inhibited the decrease in hemoglobin concentration. We conclude that NOX-H94 protects ferroportin from hepcidin-induced degradation. Therefore, this pharmacologic approach may represent an interesting treatment option for patients suffering from anemia of chronic inflammation.
NOXXON Pharma AG, Berlin, Germany. fschwoebel@noxxon.com
Frank
F
Schwoebel
Lucas T
LT
van Eijk
Dirk
D
Zboralski
Simone
S
Sell
Klaus
K
Buchner
Christian
C
Maasch
Werner G
WG
Purschke
Martin
M
Humphrey
Stefan
S
Zöllner
Dirk
D
Eulberg
Frank
F
Morich
Peter
P
Pickkers
Sven
S
Klussmann
D000740:Anemia / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D023181:Antimicrobial Cationic Peptides / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D006454:Hemoglobins / Q000032:analysis / Q000187:drug effects; D064451:Hepcidins; D007249:Inflammation / Q000150:complications* / Q000188:drug therapy*; D015850:Interleukin-6 / Q000008:administration & dosage / Q000009:adverse effects; D007501:Iron / Q000097:blood / Q000378:metabolism; D019189:Iron Metabolism Disorders / Q000139:chemically induced; D008252:Macaca fascicularis; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009843:Oligoribonucleotides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D000893:Anti-Inflammatory Agents; D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D006454:Hemoglobins; D064451:Hepcidins; D015850:Interleukin-6; D009843:Oligoribonucleotides; C581096:NOX-H94; D007501:Iron