Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Cell Physiol Biochem. 2024 Aug 21;58(4):418-430. doi: 10.33594/000000721.
BACKGROUND/AIMS: 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.
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.
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.
While CX-01 prevents GI-ARS lethality, structural modification to extend half-life may be necessary to optimize first responder prophylaxis.
背景/目的：9/11 事件后，多个政府机构制定了计划，旨在针对两种综合征开发医学放射性对策（MRCs），这两种综合征在有限核攻击后的数周内致命；造血急性辐射综合征（H-ARS）和更高剂量的胃肠道急性辐射综合征（GI-ARS）。虽然重新利用增强骨髓再生的药物可以治疗 H-ARS，但没有缓解剂可以保护胃肠道。
我们最近报道，抗神经酰胺 6B5 单链可变片段（scFv）预处理可消除正在进行的小肠内皮细胞凋亡，从而挽救 Lgr5 干细胞，防止 C57B/L6J 小鼠发生 GI-ARS 致死。在这里，在美国国防部的支持下，我们提供了证据表明，人源化抗神经酰胺 scFv（CX-01）是一种有前途的一线救援人员预防性 MRC，他们在进入放射性污染区域时面临暴露风险。
CX-01 可在照射前 90 分钟内给药，可高度有效地预防小鼠小肠内皮细胞凋亡和两性的致死性。出乎意料的是，雌性需要比雄性高出约 2 倍的 CX-01 剂量才能完全保护。CX-01 皮下和肌肉内给药均有效，这是战场使用的关键特性。将最大有效剂量增加 5 倍不会延长生物效应的持续时间。
虽然 CX-01 可预防 GI-ARS 致死性，但可能需要进行结构修饰以延长半衰期，从而优化一线救援人员的预防措施。
