A TPO Receptor Agonist, ALXN4100TPO, Mitigates Radiation-Induced Lethality and Stimulates Hematopoiesis in CD2F1 Mice
A TPO Receptor Agonist, ALXN4100TPO, Mitigates Radiation-Induced Lethality and Stimulates Hematopoiesis in CD2F1 Mice
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DOI：
10.1667/rr2462.1
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发表时间：
2011-06-01
影响因子：
3.4
通讯作者：
Srinivasan, Venkataraman
中科院分区：
文献类型：
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作者：
Satyamitra, Merriline;Lombardini, Eric;Srinivasan, Venkataraman
通过将已知的肽序列移植到人抗炭疽抗体的铰链和/或κ恒定区中，设计了与血小板生成素（TPO）缺乏序列同源性的TPO受体激动剂。这些蛋白质中的一些在体外刺激cMpl-r活性和在体内增加血小板水平方面与TPO等效。ALXN 4100 TPO（4100 TPo）是该系列中最好的激动剂，对cMpl-r的K（d）为30 nM，在暴露于来自钴-60 γ射线源的致死全身辐射的CD 2F 1小鼠中表现出作为辐射对抗剂的有效活性。4100 TPO（2 mg/kg，s.c.）在TBI前24小时或TBI后6小时给药一次显示出优于在TBI前或TBI后每天给药5次的上级保护作用。预防性给药（69 - 94%的存活率）上级治疗性给药（60%的存活率）。当在暴露前4天或甚至暴露后12小时给药时，在0.1至8 mg/kg的剂量范围内，4100 TPO赋予显著的生存益处（P < 0.01）。4100 TPo 1 mg/kg剂量组的剂量减少因子（DRF）分别为1.32和1.11（P < 0.0001）。此外，4100 TPO增加了骨髓细胞和巨核细胞的发育，并加速了受辐射小鼠的多系造血恢复，证明了4100 TPO在发生放射性事件时作为保护剂和缓解剂的潜力。(C)2011年，辐射研究学会
Thrombopoietin (TPO) receptor agonists lacking sequence homology to TPO were designed by grafting a known peptide sequence into the hinge and/or kappa constant regions of a human anti-anthrax antibody. Some of these proteins were equipotent to TPO in stimulating cMpl-r activity in vitro and in increasing platelet levels in vivo. ALXN4100TPO (4100TPo), the best agonist in this series with a K(d) of 30 nM for cMpl-r, exhibited potent activity as a radiation countermeasure in CD2F1 mice exposed to lethal total-body radiation from a cobalt-60 gamma-ray source. 4100TPO (2 mg/kg, s.c.) administered once either 24 h before or 6 h after TBI showed superior protection to five daily doses given before or after TBI. Prophylactic administration (69 to 94% survival) was superior to therapeutic schedules (60% survival). 4100TPO conferred a significant survival benefit (P < 0.01) when administered 4 days before or even 12 h after exposure and across a dose range of 0.1 to 8 mg/kg. The dose reduction factors (DRFs) with a single dose of 1 mg/kg 4100TPo 24 h before or 12 h after TBI were 1.32 and 1.11, respectively (P < 0.0001). Furthermore, 4100TPO increased bone marrow cellularity and megakaryocytic development and accelerated multilineage hematopoietic recovery in irradiated mice, demonstrating the potential of 4100TPO as both a protector and a mitigator in the event of a radiological incident. (C) 2011 by Radiation Research Society