Selection of an anti-ceramide mitigator of acute radiation toxicity of the GI tra

描述（由申请人提供）：胃肠道（GI）综合征是癌症治疗的主要并发症，与治疗剂量的化疗和放疗相关，也是意外电离辐射（IR）暴露的潜在致死结果。该综合征由胃肠道干细胞区室的耗竭引起，导致胃肠道上皮剥脱，以及由于缺乏营养吸收、腹泻和脱水、电解质失衡和肠细菌性脓毒症而导致的死亡。没有有效的方法来减轻胃肠道综合征的基本病理。《生物防护法》项目是保护美国土地免受有限核攻击或核事故威胁的战略的一部分，强调需要研究制定有效的对策，以减轻一般人群在辐射暴露后至少24小时的胃肠道致死率。隐窝-绒毛单位内的微血管功能障碍调节胃肠道致死性的证据确定了减轻胃肠道综合征的新靶点。这种血管功能障碍是由内皮细胞质膜外叶上促凋亡鞘脂神经酰胺的产生以及随后神经酰胺驱动的膜重组为富含神经酰胺的平台（CRP）介导的，可进行药理学灭活。基于这些发现，开发了小鼠2A 2（m2 A2）抗神经酰胺IgM抗体以结合和中和神经酰胺，并抑制体内IR诱导的组织损伤。m2 A2显著改善胃肠道干细胞存活并促进组织恢复，两者都是在致死辐射暴露之前或之后长达24小时施用时。重要的是，2A 2减轻了亚致死和致死胃肠道损伤。这些数据表明，抗神经酰胺抗体代表了一类新的药理学药物，用于缓解胃肠道综合征，并作为放射性对策。人源化2A 2已经产生，并被证实是隐窝致死性的有效缓解剂。在本申请中，我们建议从一组人源化抗神经酰胺试剂（包括抗神经酰胺Ab和抗体片段）中鉴定最有前途的放射缓解治疗剂，以推进临床前开发。 公共卫生相关性：卫生与公众服务部强调，需要开展辐射生物学研究，以制定有效的对策，减轻一般人群在辐射照射后至少24小时的胃肠道致死率。最近的证据表明，用神经酰胺特异性单克隆抗体中和膜脂质神经酰胺可保护GI干细胞免于死亡，并促进高剂量辐射暴露后的器官再生，即使在暴露后24小时给药。这项研究计划旨在从一组人源化抗神经酰胺试剂中确定最有效的辐射缓解剂，以推进临床前开发。

DESCRIPTION (provided by applicant): The Gastrointestinal (GI) Syndrome is a primary complication of cancer treatments, associated with delivery of therapeutic doses of chemotherapy and radiation, and also constitutes a potentially lethal result of accidental ionizing radiation (IR) exposure. The syndrome results from depletion of the stem cell compartment of the GI tract, resulting in denudation of the GI epithelium, and death due to lack of nutrient adsorption, diarrhea and dehydration, electrolyte imbalance and enterobacterial sepsis. There is no effective approach to mitigate the basic underlying pathology of the GI Syndrome. The Project BioShield Act, part of a strategy to defend American soil from threat of a limited nuclear attack or nuclear accident, emphasizes the need for research towards development of effective countermeasures to mitigate GI tract lethality in the general population at least 24 h after radiation exposure. Evidence that microvascular dysfunction within the crypt-villus unit regulates GI tract lethality identified a novel target for mitigation of the GI Syndrome. This vascular dysfunction, mediated by generation of the pro-apoptotic sphingolipid ceramide on the outer leaflet of the endothelial plasma membrane and subsequent ceramide-driven membrane reorganization into ceramide-rich platforms (CRPs), is amenable to pharmacologic inactivation. Based upon these discoveries, mouse 2A2 (m2A2) anti- ceramide IgM antibody was developed to bind and neutralize ceramide, and inhibit IR-induced tissue damage in vivo. m2A2 significantly improved GI tract stem cell survival and promoted tissue recovery, both when administered prior to or up to 24 hours following lethal radiation exposure. Critically, 2A2 mitigated both sublethal and lethal GI tract damage. These data indicate that anti-ceramide Abs represent a novel class of pharmacologic agents for mitigation of the GI Syndrome, and for use as radiological countermeasures. Humanized 2A2 has since been generated, and confirmed to be an effective mitigator of crypt lethality. In the current application, we propose to identify the most promising radiation mitigating therapeutic from a panel of humanized anti-ceramide reagents, including anti-ceramide Abs and antibody fragments, for advancement into preclinical development. PUBLIC HEALTH RELEVANCE: The Department of Health and Human Services has emphasized the need for radiation biology research towards development of effective countermeasures to mitigate gastrointestinal (GI) tract lethality in the general population at least 24 h after radiation exposure. Recent evidence demonstrates that neutralization of the membrane lipid ceramide with a monoclonal antibody specific for ceramide protects GI stem cells from death and promotes organ regeneration following high-dose radiation exposure, even when administered 24 hours following exposure. This research proposal aims to identify the most effective radiation mitigator from a panel of humanized anti-ceramide reagents for advancement into preclinical development.