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有关，也构成意外电离辐射（IR）暴露的潜在致命结果。该综合征是由于胃肠道干细胞隔室的耗竭，导致胃肠道上皮的剥落，并因缺乏营养吸附、腹泻和脱水、电解质失衡和肠杆菌败血症而死亡。没有有效的方法来减轻胃肠道综合征的基本潜在病理。作为保护美国国土免受有限核攻击或核事故威胁战略的一部分，《生物盾工程法案》强调有必要研究开发有效的对策，以减轻普通人群在辐射暴露后至少24小时的胃肠道致死率。有证据表明，隐窝绒毛单位内的微血管功能障碍调节胃肠道的致命性，这为缓解胃肠道综合征确定了一个新的靶点。这种血管功能障碍是由内皮质膜外小叶上促凋亡鞘脂神经酰胺的生成和随后神经酰胺驱动的膜重组成富含神经酰胺的平台（CRPs）介导的，可导致药物失活。基于这些发现，小鼠2A2 （m2A2）抗神经酰胺IgM抗体被开发出来，可以结合和中和神经酰胺，在体内抑制ir诱导的组织损伤。m2A2在致死性辐射暴露前或暴露后24小时内均可显著改善胃肠道干细胞存活并促进组织恢复。重要的是，2A2减轻了亚致命性和致命性胃肠道损伤。这些数据表明，抗神经酰胺抗体代表了一类新的药物缓解胃肠道综合征，并用于放射对策。人类化的2A2已经产生，并被证实是一种有效的隐窝致命性缓解剂。在目前的应用中，我们建议从一组人源化抗神经酰胺试剂（包括抗神经酰胺抗体和抗体片段）中确定最有希望的放射缓解治疗，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.