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，但尚无药物获批用于该适应症。该提案的重点是一种新的临床阶段候选药物Protectan CBLB 502，一种能够有效减轻小鼠和非人灵长类动物（NHP）中致命辐射诱导的GI损伤的Toll样受体5（TLR5）激动剂。根据FDA动物疗效规则，药物开发需要全面了解作用机制。因此，本提案的主要目的是使用小鼠和NHP模型来详细表征CBLB 502对GI系统的各种元素的缓解作用，并鉴定该作用的细胞和分子介质。具体而言，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CBLB 502对辐射损伤的GI基础结构的各种元素的缓解作用，（ii）定义有助于CBLB 502的GI放射性激动活性的靶器官，特别关注骨髓和肝脏，和（iii）鉴定对CBLB 502的主要和次要细胞和分子应答者，期望定义药物的放射性激动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奠定坚实的机制基础，并将对FDA批准CBLB 502作为减轻GI辐射损伤的医学对策至关重要。

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.