Protectan CBLB502

说明(申请人提供)：核战争和恐怖主义的威胁日益增长，突显了开发有效和无毒的辐射对策的必要性，这种对策可以提高急性呼吸综合征患者的存活率，并在核事件发生后至少12-24小时给予治疗，以缓解辐射后的血小板减少症。CBLB502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大的抗辐射药物。CBLB502可显著缩短非人类灵长类动物辐射引起的血小板减少症的持续时间和严重程度，并降低小鼠和非人类灵长类动物的死亡率，即使在致死照射后16-48小时注射也是如此。CBLB502可诱导多种细胞因子的产生，可能与其抗辐射和抗血小板减少作用有关。CBLB502毒性低(治疗剂量比NOAEL低100倍)，免疫原性降低。目前这项提案的目标是研究CBLB502抗血小板减少活性的潜在机制，并优化缓解方案，目的是在受到致命辐射12小时后拯救灵长类动物。我们将(1)在体外测试CBLB502对巨核祖细胞的直接影响；(2)评估CBLB502在体内有无辐射对小鼠血小板生成的影响；(3)优化CBLB502在高度致死(LD70)照射16小时后在非人类灵长类动物中给予的抗血小板减少和挽救生命的治疗。核战争和恐怖主义的威胁日益增加，突显出需要开发有效和无毒的辐射对策，以提高急性呼吸综合征患者的存活率，并在核事件发生后至少12-24小时给药，缓解辐射后的血小板减少症。CBLB502是一种新型重组蛋白抗辐射药物候选药物，即使在致死照射后16-48小时注射，也能显著缩短非人类灵长类动物辐射诱导的血小板减少症的持续时间和严重程度，并降低小鼠和非人类灵长类动物的死亡率。目前这项提案的目标是研究CBLB502抗血小板减少活性的潜在机制，并优化缓解方案，目的是在受到致命辐射12小时后拯救灵长类动物。

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.