Protectan CBLB502

保护素CBLB502

• 批准号: 7919056
• 负责人: ANDREI V GUDKOV
• 金额: $ 45.85万
• 依托单位: CLEVELAND BIOLABS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-22 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7919056
• 关键词: Attenuated; Dose; Evaluation; Event; Exposure to; Flagellin; Gastrointestinal tract structure; Goals; Hour; In Vitro; Investigation; Life; Mediating; Medical; Megakaryocytes; Modeling; Mus; No-Observed-Adverse-Effect Level; Nuclear; Nuclear Warfare; Pharmaceutical Preparations; Primates; Radiation; Recombinant Proteins; Salmonella; Severities; Staging; System; Terrorism; Testing; Therapeutic; Thrombocytopenia; Thrombopoiesis; Time; Toxic effect; Treatment Protocols; Whole-Body Irradiation; biodefense; cytokine; design; drug candidate; immunogenicity; improved; in vivo; irradiation; mortality; nonhuman primate; novel; progenitor

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.

描述（由申请人提供）：日益增长的核战争和恐怖主义威胁突出了开发有效和无毒辐射对策的必要性，这些对策可以在核事件发生后至少12-24小时内增加ARS受害者的存活率并减轻辐射后血小板减少症。CBLB502是一种从沙门氏菌flc鞭毛蛋白中提取的新型重组蛋白，是一种强大的抗辐射药物，符合这些要求。CBLB502在致死性辐照后16-48小时内注射，可显著减少非人类灵长类动物放射性血小板减少的持续时间和严重程度，降低小鼠和非人类灵长类动物的死亡率。CBLB502可诱导多种细胞因子，可能有助于其抗辐射和抗血小板减少活性。CBLB502表现出低毒性（小鼠治疗剂量比NOAEL低100倍）和低免疫原性。本研究的目标是研究CBLB502抗血小板减少活性的机制，并优化缓解方案，以拯救暴露于致死辐射后12小时的灵长类动物>。我们将在体外测试CBLB502给药对巨核细胞祖细胞的直接影响；(2)评估CBLB502在有和无辐射情况下对小鼠体内血小板生成的影响；(3)优化在非人类灵长类动物高致死（LD70）照射后>16小时给予CBLB502抗血小板减少和挽救生命的治疗。日益增长的核战争和恐怖主义威胁突出表明，需要制定有效和无毒的辐射对策，以便在核事件发生后至少12-24小时内，提高ARS受害者的存活率并减轻辐射后血小板减少症。CBLB502是一种新型的重组蛋白抗辐射候选药物，可显著降低非人类灵长类动物放射性血小板减少的持续时间和严重程度，即使在致死性辐射暴露后16-48小时注射，也能降低小鼠和非人类灵长类动物的死亡率。本研究的目标是研究CBLB502抗血小板减少活性的机制，并优化缓解方案，以拯救暴露于致死辐射后12小时的灵长类动物>。