Neutralization of ceramide as a novel approach to specifically inhibit acute GvHD

描述（由申请人提供）：急性移植物抗宿主病（GvHD）是同种异体干细胞移植的主要并发症，与消耗、免疫抑制和对肠道、肝脏和皮肤的特异性损伤有关。GvHD是由人类白细胞抗原（HLA）相同或相关的供体T细胞对宿主组织的激活引起的。目前缓解急性GvHD基本潜在病理的治疗方法包括免疫抑制药物或从移植物中消耗T细胞，然而这些选择使严重免疫功能低下的患者容易感染或肿瘤复发。因此，减弱GvHD相关病理同时保持免疫功能抵抗残余恶性肿瘤或感染是HCST辅助治疗的“圣杯”。神经酰胺治疗提出了抗神经酰胺单克隆IgG抗体的产生和发展，作为一种基于机制的方法来保护宿主组织和预防或治疗急性GvHD。神经酰胺调节急性GvhD期间组织病理生理的证据是用缺乏酸性鞘磷脂酶（ASMase）介导的神经酰胺生成的小鼠作为次要抗原错配的骨髓和T细胞宿主获得的。宿主ASMase的失活消除了GvHD期间的组织损伤，减轻了负责传播宿主组织CTL攻击的炎症反应，从而显著提高了小鼠模型的存活率。对GvHD期间肝细胞凋亡作用机制的研究表明，ctl诱导靶肝细胞表面产生神经酰胺，推动外质膜的生物物理重组，形成称为神经酰胺富平台（CRPs）的结构。CRPs是发生跨膜凋亡信号转导的位点，可发生药理学失活。在目前的应用中，我们建议产生一种高亲和力中和抗神经酰胺IgG，以推进临床前开发。

DESCRIPTION (provided by applicant): Acute graft-versus-host disease (GvHD) is a primary complication of allogeneic stem cell transplantation, associated with wasting, immunosuppression and specific damage to the intestines, liver and skin. GvHD results from activation of donor T cells from human leukocyte antigen (HLA)-identical or related donors against host tissues. Current therapeutic approaches to mitigate the basic underlying pathology of acute GvHD include immune-suppressive drugs or depletion of T cells from the graft, however these options render severely immunocompromised patients susceptible to infection or neoplastic relapse. As such, attenuation of GvHD- associated pathology while maintaining immune function against residual malignancy or infection is the 'holy grail' of HCST adjuvant therapies. Ceramide Therapeutics proposes the generation and development of anti- ceramide monoclonal IgG antibody as a mechanism-based approach to protect host tissue and prevent or treat acute GvHD. Evidence that ceramide regulates tissue pathophysiology during acute GvhD was obtained using mice deficient in acid sphingomyelinase (ASMase)-mediated ceramide generation as hosts for minor antigen mismatched bone marrow and T cells. Inactivation of host ASMase abrogated tissue damage during GvHD and attenuated the inflammatory response responsible for propagating CTL attack of host tissue, thereby significantly improving survival in mouse models. Investigation into the mechanism of action of hepatocyte apoptosis during GvHD revealed that CTLs induce ceramide generation on the target hepatocyte surface, driving the biophysical reorganization of the exoplasmic membrane into structures called ceramide-rich platforms (CRPs). CRPs are sites where transmembrane apoptotic signal transduction takes place, and are amenable to pharmacologic inactivation. In the current application, we propose to generate a high-affinity neutralizing anti-ceramide IgG for advancement into preclinical development.