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

神经酰胺中和作为特异性抑制急性 GvHD 的新方法

基本信息

批准号：
8395366
负责人：
Jim Rotolo
金额：
$ 28.48万
依托单位：
CERAMIDE THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8395366
关键词：
Acute Acute Graft Versus Host Disease Adjuvant Adjuvant Therapy Affinity Allogenic Allografting Animals Antibodies Antigens Apoptosis Apoptotic Attenuated Automobile Driving Binding Biological Assay Bone Marrow Bovine Serum Albumin Cell physiology Cells Ceramides Chemotherapy-Oncologic Procedure Chronic Clinical Coculture Techniques Colony-forming units Complex Complication Cytotoxic T-Lymphocytes Development Dose Effector Cell Engraftment Enzyme-Linked Immunosorbent Assay Event Failure Functional disorder Funding Generations Genetic Genus Mycobacterium Graft-Versus-Tumor Induction HLA Antigens Half-Life Hematopoietic Hematopoietic Stem Cell Transplantation Hepatocyte Immune Immune system Immunization Immunocompromised Host Immunoglobulin Class Switching Immunoglobulin G Immunoglobulin M Immunologics Immunosuppression In Vitro Infection Infection Control Inflammatory Inflammatory Response Intestines Investigation Ligands Liver Malignant Neoplasms Mammals Mediating Membrane Minor Modeling Molecular Monoclonal Antibodies Morbidity - disease rate Mus N-palmitoylsphingosine National Institute of Allergy and Infectious Disease Oligodeoxyribonucleotides Organ Pathology Penetration Pharmaceutical Preparations Phase Plasma Cells Prevention Process Radiation Reading Refractory Disease Relapse Residual state Risk Screening procedure Serum Signal Transduction Site Skin Small Business Innovation Research Grant Sphingolipids Stem cell transplant Stem cells Stress Structure Surface Syndrome T-Cell Depletion T-Lymphocyte Testing Therapeutic Tissues Toxicology acid sphingomyelinase attenuation base chemokine conditioning cytokine efficacy testing graft vs host disease human disease humanized monoclonal antibodies immune function improved in vivo mortality mouse model neoplastic novel novel strategies pre-clinical prevent research study response tumor wasting

项目摘要

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.

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，与肠道、肝脏和皮肤的消耗、免疫抑制和特异性损伤有关。 GvHD 是来自人类白细胞抗原 (HLA) 相同或相关供体的供体 T 细胞针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清除移植物中的 T 细胞，但这些选择使严重免疫功能低下的患者容易受到感染或肿瘤复发。因此，减轻 GvHD 相关病理，同时维持针对残留恶性肿瘤或感染的免疫功能，是 HCST 辅助疗法的“圣杯”。 Ceramide Therapeutics 提出抗神经酰胺单克隆 IgG 抗体的产生和开发，作为保护宿主组织和预防或治疗急性 GvHD 的基于机制的方法。使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 期间的组织损伤，并减弱了负责传播宿主组织的 CTL 攻击的炎症反应，从而显着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 诱导靶肝细胞表面生成神经酰胺，驱动外质膜生物物理重组为富含神经酰胺平台 (CRP) 的结构。 CRP 是跨膜细胞凋亡信号转导发生的位点，并且易于药物失活。在当前的应用中，我们建议生成高亲和力中和性抗神经酰胺 IgG，以推进临床前开发。公共卫生相关性：抑制急性 GvHD 相关病理生理学，同时维持针对残留恶性肿瘤和感染的整体免疫功能，是 HCST 辅助疗法的“圣杯”。神经酰胺在急性 GvhD 期间调节组织病理生理学，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 期间的组织损伤，减弱了传播宿主组织 CTL 攻击的炎症反应，并显着提高了小鼠模型的存活率。在这里，我们建议生成一种高亲和力中和性抗神经酰胺 IgG，以特异性抑制 GvHD 病理生理学，同时不影响整体 T 细胞功能，以推进临床前开发。