Protectan CBLB502

描述（由申请人提供）：核战争和恐怖主义的威胁日益增长，突出了开发有效和无毒辐射对策的必要性，这些对策在核事件后至少12-24小时施用时可以增加ARS受害者的存活率并减轻辐射后血小板减少症。CBLB 502是一种来源于沙门氏菌鞭毛蛋白的新型重组蛋白，是一种符合这些要求的强效抗辐射药物。CBLB 502强烈降低非人灵长类动物中辐射诱导的血小板减少症的持续时间和严重程度，并降低小鼠和非人灵长类动物的死亡率，即使在致死辐射后16-48小时注射。CBLB 502诱导多种细胞因子，可能有助于其抗辐射和抗血小板减少症活性。CBLB 502显示出低毒性（在小鼠中治疗剂量比NOAEL低>100倍）和降低的免疫原性。本提案的目标是研究CBLB 502抗血小板减少活性的机制，并优化缓解方案，旨在拯救暴露于致死辐射后>12小时的灵长类动物。我们将（1）测试CBLB 502给药对体外巨核细胞祖细胞的直接影响;（2）评估CBLB 502在有和没有辐射的情况下对小鼠体内血小板生成的影响，以及（3）优化在非人灵长类动物中高致死（LD 70）辐射后>16小时给予的抗血小板减少和拯救生命的CBLB 502治疗。日益增长的核战争和恐怖主义的威胁突出了需要开发有效和无毒的辐射对策，当在核事件后至少12-24小时施用时，可以增加ARS受害者的存活率并减轻照射后血小板减少症。CBLB 502是一种新型重组蛋白抗辐射候选药物，即使在致死辐射暴露后16-48小时注射，也能显著降低非人灵长类动物中辐射诱导的血小板减少症的持续时间和严重程度，并降低小鼠和非人灵长类动物的死亡率。本提案的目标是研究CBLB 502抗血小板减少活性的机制，并优化缓解方案，旨在拯救暴露于致死辐射后>12小时的灵长类动物。

DESCRIPTION (provided by applicant): The growing threats of nuclear warfare and terrorism highlight the need to develop effective and non-toxic radiation countermeasures that can increase survival of ARS victims and alleviate post-irradiation thrombocytopenia when administered at least 12-24 hours after a nuclear event. CBLB502, a novel recombinant protein derived from Salmonella FliC flagellin, is a powerful anti- radiation drug that fits those requirements. CBLB502 strongly reduces the duration and severity of radiation-induced thrombocytopenia in non-human primates and reduces mortality of mice and non-human primates even if injected 16-48 hours after lethal irradiation. Multiple cytokines are induced by CBLB502, possibly contributing to its anti-radiation and anti-thrombocytopenia activities. CBLB502 displays low toxicity (with therapeutic doses >100 times lower than NOAEL in mice) and reduced immunogenicity. The goals of the current proposal are investigating the mechanism underlying the anti-thrombocytopenia activity of CBLB502 and optimization of mitigation regimens aimed at rescuing primates >12 hours after exposure to lethal irradiation. We will (1) test the direct influence of CBLB502 administration on megakaryocyte progenitors in vitro; (2) evaluate the effect of CBLB502, with and without radiation, on mouse thrombopoiesis in vivo, and (3) optimize anti-thrombocytopenia and life rescuing CBLB502 treatment given >16 hours after highly lethal (LD70) irradiation in non-human primates. The growing threats of nuclear warfare and terrorism highlight the need to develop effective and non-toxic radiation countermeasures that can increase survival of ARS victims and alleviate post-irradiation thrombocytopenia when administered at least 12-24 hours after a nuclear event. CBLB502 a novel recombinant protein anti-radiation drug candidate, strongly reduces the duration and severity of radiation-induced thrombocytopenia in non-human primates and reduces mortality of mice and non-human primates even if injected 16-48 hours after lethal irradiation exposure. The goals of the current proposal are investigating the mechanism underlying the anti-thrombocytopenia activity of CBLB502 and optimization of mitigation regimens aimed at rescuing primates >12 hours after exposure to lethal irradiation.