Mechanisms of mitigation of radiation damage of GI tract by Protectan CBLB502

描述（由申请人提供）：人体辐射损伤的严重程度在很大程度上取决于胃肠道（GI）的高敏感性，但没有药物被批准用于这一适应症。该提案的重点是一种新的临床阶段候选药物Protectan CBLB502，这是一种toll样受体5 （TLR5）激动剂，能够有效减轻小鼠和非人灵长类动物（NHPs）致命的辐射诱导的GI损伤。根据FDA动物功效规则，药物开发需要对作用机制有全面的了解。因此，本提案的主要目的是使用小鼠和NHP模型来详细表征CBLB502对胃肠道系统各种元素的缓解作用，并确定这种作用的细胞和分子介质。具体来说，我们的多机构合作团队将：(i)创建一个全面的“组织学图谱”，说明CBLB502对受辐射损害的胃肠道基础设施的各种要素的缓解作用；（ii）确定有助于CBLB502减轻胃肠道辐射活性的目标器官，特别关注骨髓和肝脏；以及（iii）确定CBLB502的初级和次级细胞和分子应答者，期望确定药物辐射缓解功能的分子导体以及新的功效生物标志物。该项目的完成将为将动物数据转化为合理的预计人体有效剂量建立坚实的机制基础，并将对FDA批准CBLB502作为减轻胃肠道辐射损伤的医疗对策至关重要。

DESCRIPTION (provided by applicant): The severity of radiation injury in humans is largely determined by high sensitivity of the gastrointestinal (GI) tract, yet no drugs are approved for this indication. This proposal is focused on a novel clinical-stage drug candidate, Protectan CBLB502, a toll-like receptor 5 (TLR5) agonist capable of effective mitigation of otherwise lethal radiation-induced GI injury in mice and non-human primates (NHPs). A comprehensive understanding of mechanisms of action is required for drug development under the FDA Animal Efficacy Rule. Accordingly, the main objective of this proposal is to use mouse and NHP models to characterize in detail the mitigating effect of CBLB502 on various elements of the GI system and to identify cellular and molecular mediators of this effect. Specifically, our multi-institutional collaborative team will: (i) create a comprehensive "histological atlas" illustrating the mitigating effects of CBLB502 on various elements of GI infrastructure damaged by radiation, (ii) define the target organs that contribute to the GI radiomitigation activity of CBLB502 with specific focus on bone marrow and liver, and (iii) identify primary and secondary cellular and molecular responders to CBLB502 with the expectation of defining molecular conductors of the radiomitigating function of the drug as well as novel efficacy biomarkers. Completion of this program should create a solid mechanistic base for translation of animal data into a well-justified projected human efficacious dose and will be critical for FDA approval of CBLB502 as a medical countermeasure to mitigate GI radiation damage.