A fully human anti-hepcidin antibody modulates iron metabolism in both mice and nonhuman primates
A fully human anti-hepcidin antibody modulates iron metabolism in both mice and nonhuman primates
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DOI：
10.1182/blood-2013-06-505792
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发表时间：
2013-10-24
期刊：
影响因子：
20.3
通讯作者：
Sasu, Barbra J.
中科院分区：
文献类型：
--
作者：
Cooke, Keegan S.;Hinkle, Beth;Sasu, Barbra J.
铁分布不均与许多疾病的病因有关，包括炎症性贫血（AI）、动脉粥样硬化、糖尿病和神经退行性疾病。铁代谢由铁调素（hepcidin）控制，铁调素是一种25个氨基酸的肽。铁调素由炎症诱导，并导致铁被隔离在网状内皮系统的细胞内，抑制红细胞生成并减弱红细胞生成刺激剂（ESA）的活性。出于这个原因，已经提出中和铁调素作为AI的治疗性治疗。目前工作的目的是产生完全人源抗铁调素抗体（Abs），作为治疗AI和其他铁分布不良疾病的潜在人类治疗剂。酶联免疫吸附试验建立使用这些抗体，以确定患者可能受益于ESA或抗铁调素剂。使用人铁调素敲入小鼠，显示Ab的作用机制是由于可利用的血清铁增加导致红细胞血红蛋白化增强。其中一种抗体12B9m在AI小鼠模型中得到验证，并证明可调节食蟹猴的血清铁。12B9m Ab被认为是一种合适的候选药物，可用作治疗肾脏疾病或癌症患者AI的潜在治疗药物。
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.