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

描述(申请人提供)：急性移植物抗宿主病(GvHD)是异基因干细胞移植的主要并发症，与虚弱、免疫抑制和对肠道、肝脏和皮肤的特定损害有关。移植物抗宿主病(GVHD)是由人类白细胞抗原(HL A)相合或相关供者的供者T细胞对宿主组织的激活所致。目前缓解急性GvHD基本病理的治疗方法包括免疫抑制药物或耗尽移植物中的T细胞，然而这些选择使免疫严重受损的患者容易感染或肿瘤复发。因此，减弱GvHD相关的病理，同时保持免疫功能以抵御残留的恶性肿瘤或感染是HCST辅助治疗的“圣杯”。神经酰胺治疗公司建议产生和发展抗神经酰胺单抗，作为一种基于机制的方法来保护宿主组织，预防或治疗急性移植物抗宿主病。利用酸性鞘磷脂酶(ASMase)介导的神经酰胺生成缺陷小鼠作为次要抗原不匹配的骨髓和T细胞的宿主，获得了神经酰胺在急性GVHD期间调节组织病理生理学的证据。宿主ASMase的失活消除了GvHD过程中的组织损伤，并减弱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中肝细胞凋亡作用机制的研究表明，CTL诱导靶细胞表面神经酰胺的生成，推动外质膜的生物物理重组，形成富含神经酰胺的平台(CRPS)结构。CRP是发生跨膜凋亡信号转导的部位，容易受到药物失活的影响。在目前的应用中，我们建议产生一种高亲和力的中和抗神经酰胺抗体，以促进临床前开发。 公共卫生相关性：抑制急性GvHD相关的病理生理学，同时保持全球免疫功能，对抗残留的恶性肿瘤和感染，是HCST辅助治疗的“圣杯”。神经酰胺调节急性移植物抗宿主病(GVHD)时的组织病理生理，因为酸性鞘磷脂酶(ASMase)介导的神经酰胺生成的基因缺失消除了GvHD中的组织损伤，减轻了导致宿主组织CTL攻击的炎症反应，并显著提高了小鼠模型的存活率。在这里，我们建议生产一种高亲和力中和抗神经酰胺抗体，以特异性地抑制GvHD的病理生理，同时不影响全球T细胞功能，以促进临床前开发。

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. PUBLIC HEALTH RELEVANCE: Inhibition of acute GvHD-associated pathophysiology while maintaining global immune functioning against residual malignancy and infection is the 'holy grail' of HCST adjuvant therapies. Ceramide regulates tissue pathophysiology during acute GvhD, as genetic deletion of acid sphingomyelinase (ASMase)-mediated ceramide generation abrogated tissue damage during GvHD, attenuated the inflammatory response responsible for propagating CTL attack of host tissue, and significantly improved survival in mouse models. Here we propose the generation of a high-affinity neutralizing anti-ceramide IgG to specifically inhibit GvHD pathophysiology while not impacting global T cell function, for advancement into preclinical development.