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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）是异基因干细胞移植的主要并发症，与消耗、免疫抑制和肠道、肝脏和皮肤的特异性损伤有关。GvHD由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活化引起。目前缓解急性GvHD的基本潜在病理学的治疗方法包括免疫抑制药物或从移植物中耗尽T细胞，然而这些选择使严重免疫功能低下的患者易于感染或肿瘤复发。因此，GvHD相关病理的减弱同时维持针对残余恶性肿瘤或感染的免疫功能是HCST辅助疗法的“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。神经酰胺在急性GvhD期间调节组织病理生理学的证据是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细胞的宿主获得的。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期间肝细胞凋亡的作用机制的研究表明，CTL诱导靶肝细胞表面上的神经酰胺产生，驱动外质膜的生物物理重组为称为富含神经酰胺的平台（CRP）的结构。CRP是跨膜凋亡信号转导发生的位点，并且适合于药理学失活。在本申请中，我们提出产生高亲和力中和抗神经酰胺IgG，以推进临床前开发。公共卫生相关性：抑制急性GvHD相关的病理生理学，同时保持针对残留恶性肿瘤和感染的整体免疫功能是HCST辅助治疗的“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，减弱了负责传播宿主组织的CTL攻击的炎症反应，并且显著改善了小鼠模型中的存活率。在这里，我们提出产生高亲和力中和抗神经酰胺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。