目的:在9/11之后,多个政府机构制定了计划,旨在针对两种在有限核攻击后几周内致死的综合征:造血急性放射综合征(H-ARS)和高剂量胃肠道急性放射综合征(GI-ARS)。虽然重新使用增强骨髓再增殖的药物治疗H-ARS,没有缓解剂保护胃肠道。
方法:我们最近报道了抗神经酰胺6B5单链可变片段(scFv)预处理消除正在进行的小肠内皮凋亡以拯救Lgr5干细胞,在C57B/L6J小鼠中预防GI-ARS致死性。这里,在美国国防部的支持下,我们提供的证据表明,人源化抗神经酰胺scFv(CX-01)是一个有前途的预防MRC第一反应者,他们在进入受辐射污染的场所时面临暴露的风险。
结果:CX-01,在照射前90分钟交付时,在预防小鼠小肠内皮细胞凋亡和两性致死方面非常有效。出乎意料的是,女性需要比男性高2倍的CX-01剂量来获得完全保护。CX-01是有效的皮下和肌肉,对战场使用至关重要的属性。将最大有效剂量增加5倍不会延长生物有效性的持续时间。
结论:虽然CX-01可以防止GI-ARS致死性,可能需要进行结构修饰以延长半衰期,以优化第一反应者的预防。
OBJECTIVE: After 9/11, multiple government agencies instituted programs aimed at developing medical radiation countermeasures (MRCs) for two syndromes lethal within weeks of a limited nuclear attack; the hematopoietic-acute radiation syndrome (H-ARS) and the higher-dose gastrointestinal-acute radiation syndrome (GI-ARS). While re-purposing drugs that enhance marrow repopulation treats H-ARS, no mitigator protects GI tract.
METHODS: We recently reported anti-ceramide 6B5 single-chain variable fragment (scFv) pre-treatment abrogates ongoing small intestinal endothelial apoptosis to rescue Lgr5+ stem cells, preventing GI-ARS lethality in C57B/L6J mice. Here, with US Department of Defense support, we provide evidence that humanized anti-ceramide scFv (CX-01) is a promising prophylactic MRC for first responders, who risk exposure upon entering a radiation-contaminated site.
RESULTS: CX-01, when delivered up to 90 min before irradiation, is highly-effective in preventing small intestinal endothelial apoptosis in mice and lethality in both sexes. Unexpectedly, females require an ~2-fold higher CX-01 dose than males for full protection. CX-01 is effective subcutaneously and intramuscularly, a property critical for battlefield use. Increasing the maximally-effective dose 5-fold does not extend duration of bioeffectiveness.
CONCLUSIONS: While CX-01 prevents GI-ARS lethality, structural modification to extend half-life may be necessary to optimize first responder prophylaxis.