Targeting Siglec-8/-F to treat eosinophil and mast cell related disorders

靶向 Siglec-8/-F 治疗嗜酸性粒细胞和肥大细胞相关疾病

• 批准号: 8804904
• 负责人: Bruce S Bochner
• 金额: $ 38.63万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-15 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8804904
• 关键词: Acute; Adrenal Cortex Hormones; Adverse effects; Allergic; Allergic Disease; Anaphylaxis; Antibodies; Apoptosis; Applications Grants; Asthma; Avidity; Award; Binding; Biological Assay; Biology; Biopsy; Cell Degranulation; Cell Surface Proteins; Cells; Cessation of life; Chronic; Chronic Disease; Chronic eosinophilic leukemia; Classification; Contrast Media; Cytoplasmic Granules; Data; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Dose; Drug toxicity; Effector Cell; Endoscopy; Eosinophilia; Eosinophilic Esophagitis; Extrinsic asthma; Family; Funding; Gastrointestinal Diseases; Goals; Growth; Health; Human; IgE; Image; Immunoglobulins; Immunotoxins; In Vitro; Indolent Systemic Mastocytosis; Inflammatory; Inflammatory Response; Knock-in Mouse; Lectin; Legal patent; Leukocytes; Life Expectancy; Ligands; Liposomes; Location; Lung; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Mast-Cell Leukemia; Mediator of activation protein; Modeling; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Mus; Myelogenous; Oligosaccharides; Organ; Paper; Pathogenesis; Patients; Pharmaceutical Preparations; Polysaccharides; Proteins; Publishing; Safety; Sialic Acids; Signal Transduction; Specific qualifier value; Specificity; Systemic Mastocytosis; Testing; Therapeutic; Tissues; Toxic effect; Transgenic Mice; Transgenic Organisms; Urticaria Pigmentosa; World Health Organization; allergic response; base; cell type; chemotherapy; cost; cytokine; design; effective therapy; eosinophil; eosinophilic inflammation; human SIGLEC8 protein; human tissue; imaging agent; in vitro Assay; in vivo; inhibitor/antagonist; innovation; iron oxide; mast cell; mastocytosis; mouse model; nanoparticle; novel; outcome forecast; paralogous gene; pre-clinical; prevent; research study; response; selective expression; sialic acid binding Ig-like lectin; sialyl-2-3-(6' -sulfo)galactosyl-1-4-(fucopyranosyl-1-3)-N-acetylglucosamine; therapeutic target; tumor growth

DESCRIPTION (provided by applicant): In anaphylaxis, asthma and other forms of acute and chronic allergic diseases, eosinophils and mast cells, through release of preformed and newly generated mediators, granule proteins, and cytokines, are felt to be key effector cells. For allergic diseases, drugs that inhibit mast cell degranulation, reduce eosinophil numbers, or counteract their released mediators are useful therapies, but all remain incompletely effective. Eosinophils and mast cells are implicated in other chronic diseases including eosinophilic esophagitis. Systemic Mastocytosis, a malignant disease, presents with varying prognoses depending on the extent of involvement, but Aggressive Systemic Mastocytosis and Mast Cell Leukemia are always fatal due to the lack of effective treatments. For eosinophil-related malignancies, the revised 2008 WHO classification recognizes both molecularly defined and undefined myeloid disorders, and there remains an unmet need for treatment of unexplained eosinophilia and "chronic eosinophilic leukemia, not otherwise specified". Siglecs (sialic acid-binding, immunoglobulin-like lectins) are cell surface proteins found predominantly on leukocytes. Siglec-8 was discovered by us about a decade ago and is selectively expressed on eosinophils and mast cells. Its closest functional paralog in the mouse is Siglec-F, which is also selectively expressed by eosinophils but unfortunately not on mast cells. Both Siglec-8 and Siglec-F preferentially and uniquely recognize the glycan 6'-sulfo-sialyl Lewis X (6'-sulfo-sLeX) and its non-fucosylated form. Engagement of Siglec- 8/-F with antibodies (Abs) and/or artificial ligands causes eosinophil death. Administration of Siglec-F Abs in mouse models of chronic allergic asthma and eosinophilia normalizes eosinophilic inflammatory responses and abrogates lung remodeling. This application is a competitive renewal of R01 AI72265 entitled "Targeting Siglec-8/Siglec-F to Reduce Allergic Responses in vitro and in vivo", funded from 07/01/07 with an ARRA supplement from 07/01/10-06/30/11. The overarching goals were to explore ligands for Siglec-8/-F, their functions, and the mechanisms by which they regulate eosinophilic and allergic responses. Since 2007, we have published 22 papers related to this award and have received six patents related to Siglec-8. The goal of the present application is to employ monoclonal antibodies (mAbs) and glycan ligands for Siglec-8 in highly translational, preclinical in vitro and murine studies (including Siglec-8 transgenics) to define their utility as therapeutic targets. Innovations include liposomal targeting to reduce systemic toxicity of drugs by selectively targeting Siglec-8/-F bearing cells, thus reducing total dose of drug delivered. Approaches proposed involve use of nanoparticles for imaging of eosinophilic inflammation (Aim 1), liposomal delivery of inhibitory drugs selectively to eosinophils or mast cells by targeting Siglec-8/-F and its ligands to treat allergic and inflammatory diseases involving these cells (Aim 2), and use of Siglec-8/-F targeting liposomes carrying chemotherapies or our Siglec-8 mAb to treat malignant diseases involving eosinophils and mast cells (Aim 3).

描述（由申请人提供）：在过敏反应、哮喘和其他形式的急性和慢性过敏性疾病中，嗜酸性粒细胞和肥大细胞通过释放预先形成的和新产生的介质、颗粒蛋白和细胞因子而被认为是关键效应细胞。对于过敏性疾病，抑制肥大细胞脱颗粒、减少嗜酸性粒细胞数量或抵消其释放的介质的药物是有用的治疗方法，但所有药物都不完全有效。嗜酸性粒细胞和肥大细胞与其他慢性疾病有关，包括嗜酸性粒细胞性食管炎。系统性肥大细胞增多症是一种恶性疾病，根据受累程度的不同表现出不同的症状，但由于缺乏有效的治疗，侵袭性系统性肥大细胞增多症和肥大细胞白血病总是致命的。对于嗜酸性粒细胞相关的恶性肿瘤，修订的2008年WHO分类承认分子定义和未定义的骨髓疾病，并且对于不明原因的嗜酸性粒细胞增多症和“慢性嗜酸性粒细胞白血病，未另行说明”的治疗仍然存在未满足的需求。 Siglecs（唾液酸结合免疫球蛋白样凝集素）是主要在白细胞上发现的细胞表面蛋白。Siglec-8是我们在大约十年前发现的，选择性地表达在嗜酸性粒细胞和肥大细胞上。其在小鼠中最接近的功能性蛋白是Siglec-F，其也由嗜酸性粒细胞选择性表达，但不幸的是不在肥大细胞上表达。Siglec-8和Siglec-F均优先且独特地识别聚糖6 '-磺基-唾液酸刘易斯X（6'-磺基-sLeX）及其非岩藻糖基化形式。Siglec- 8/-F与抗体（Ab）和/或人工配体的接合导致嗜酸性粒细胞死亡。在慢性过敏性哮喘和嗜酸性粒细胞增多症的小鼠模型中施用Siglec-F Ab使嗜酸性粒细胞炎症反应正常化并消除肺重塑。本申请是R 01 AI 72265的竞争性更新，标题为“靶向Siglec-8/Siglec-F以减少体外和体内过敏反应”，从2007年7月1日开始资助，并从2010年7月1日至2011年6月30日补充ARRA。总体目标是探索Siglec-8/-F的配体、它们的功能以及它们调节嗜酸性粒细胞和过敏反应的机制。自2007年以来，我们已经发表了22篇与该奖项相关的论文，并获得了6项与Siglec-8相关的专利。本申请的目标是在高度翻译、临床前体外和鼠研究（包括Siglec-8转基因）中使用Siglec-8的单克隆抗体（mAb）和聚糖配体，以定义它们作为治疗性免疫调节剂的效用。 目标的创新包括脂质体靶向，以通过选择性靶向携带Siglec-8/-F的细胞来减少药物的全身毒性，从而减少递送的药物的总剂量。提出的方法涉及使用纳米颗粒用于嗜酸性粒细胞炎症的成像（目的1），通过靶向Siglec-8/-F及其配体将抑制性药物选择性地脂质体递送至嗜酸性粒细胞或肥大细胞以治疗涉及这些细胞的过敏性和炎性疾病（目的2），以及携带化疗剂的Siglec-8/-F靶向脂质体或我们的Siglec-8 mAb治疗涉及嗜酸性粒细胞和肥大细胞的恶性疾病的用途（目标3）。