A fully human anti-hepcidin antibody modulates iron metabolism in both mice and nonhuman primates.
Iron maldistribution has been implicated in the etiology of many diseases including the anemia of inflammation (AI), atherosclerosis, diabetes, and neurodegenerative disorders. Iron metabolism is controlled by hepcidin, a 25-amino-acid peptide. Hepcidin is induced by inflammation and causes iron to be sequestered within cells of the reticuloendothelial system, suppressing erythropoiesis and blunting the activity of erythropoiesis stimulating agents (ESAs). For this reason, neutralization of hepcidin has been proposed as a therapeutic treatment of AI. The aim of the current work was to generate fully human anti-hepcidin antibodies (Abs) as a potential human therapeutic for the treatment of AI and other iron maldistribution disorders. An enzyme-linked immunosorbent assay was established using these Abs to identify patients likely to benefit from either ESAs or anti-hepcidin agents. Using human hepcidin knock-in mice, the mechanism of action of the Abs was shown to be due to an increase in available serum iron leading to enhanced red cell hemoglobinization. One of the Abs, 12B9m, was validated in a mouse model of AI and demonstrated to modulate serum iron in cynomolgus monkeys. The 12B9m Ab was deemed to be an appropriate candidate for use as a potential therapeutic to treat AI in patients with kidney disease or cancer.
Department of Oncology.
Keegan S
KS
Cooke
Beth
B
Hinkle
Hossein
H
Salimi-Moosavi
Ian
I
Foltz
Chadwick
C
King
Palaniswami
P
Rathanaswami
Aaron
A
Winters
Shirley
S
Steavenson
C Glenn
CG
Begley
Graham
G
Molineux
Barbra J
BJ
Sasu
D018798:Anemia, Iron-Deficiency / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000096:biosynthesis / Q000494:pharmacology*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004797:Enzyme-Linked Immunosorbent Assay; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004920:Erythropoiesis / Q000187:drug effects; D005260:Female; D006397:Hematinics / Q000494:pharmacology; D006454:Hemoglobins / Q000096:biosynthesis*; D006801:Humans; D007249:Inflammation / Q000517:prevention & control; D007501:Iron / Q000097:blood*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice
D057134:Antibodies, Neutralizing; D006397:Hematinics; D006454:Hemoglobins; D007501:Iron