Protectan CBLB502

保护素CBLB502

• 批准号: 7555568
• 负责人: ANDREI V GUDKOV
• 金额: $ 77.42万
• 依托单位: CLEVELAND BIOLABS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7555568
• 关键词: Attenuated; Childhood; 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; Urination; Whole-Body Irradiation; biodefense; cytokine; design; immunogenicity; improved; in vivo; irradiation; liver transplantation; 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）：核战争和恐怖主义的威胁日益严重，凸显了开发有效且无毒的辐射对策的必要性，这些措施可以在核事件后至少 12-24 小时内实施，从而提高 ARS 受害者的生存率并减轻辐射后血小板减少症。 CBLB502 是一种源自沙门氏菌 FliC 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。即使在致死性辐射后 16-48 小时注射，CBLB502 也能显着降低非人类灵长类动物中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。 CBLB502 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 显示出低毒性（治疗剂量比小鼠 NOAEL 低 100 倍以上）和降低的免疫原性。当前提案的目标是研究 CBLB502 抗血小板减少症活性的潜在机制，并优化缓解方案，旨在拯救暴露于致命辐射后 12 小时以上的灵长类动物。我们将（1）测试CBLB502给药对体外巨核细胞祖细胞的直接影响； (2) 评估 CBLB502 在有或没有辐射的情况下对小鼠体内血小板生成的影响，以及 (3) 在非人类灵长类动物中，在高致死性 (LD70) 辐射 >16 小时后优化抗血小板减少症和挽救生命的 CBLB502 治疗。核战争和恐怖主义的威胁日益严重，凸显了开发有效且无毒的辐射对抗措施的必要性，这些措施可以提高 ARS 受害者的生存率，并在核事件后至少 12-24 小时内实施，缓解辐射后血小板减少症。 CBLB502是一种新型重组蛋白抗辐射候选药物，即使在致命辐射暴露后16-48小时注射，也能显着降低非人类灵长类动物中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。当前提案的目标是研究 CBLB502 抗血小板减少症活性的潜在机制，并优化缓解方案，旨在拯救暴露于致命辐射后 12 小时以上的灵长类动物。