Systemic Delivery of CpG Oligonucleotides

CpG 寡核苷酸的全身递送

基本信息

批准号：
7524167
负责人：
MOO J CHO
金额：
$ 30.15万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-16 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7524167
关键词：
2,4-Dinitrophenol A Mouse Abbreviations Animal Model Animals Antibodies Antigen-Antibody Complex Antigens Antithymoglobulin Appendix Arecaceae Asthma Avidity Azides Bacterial DNA Binding Biodistribution Blood Blood Circulation Bone Marrow Cancer Patient Carbohydrates Cells Cercopithecidae Chemistry Clinical Trials Communicable Diseases Complex Custom Cytidine DNA Dendritic Cells Dendritic cell activation Development Dinitrophenols Dinucleoside Phosphates Disaccharides Disease Dissociation Dose Drug Formulations Drug Kinetics Endocytosis Epitopes Erythrocytes Fc Receptor Flow Cytometry Fluorescein Fluoresceins Genomics Grant Guanidines Half-Life Haptens Host Defense Human Hypersensitivity Ice Immune response Immunization Immunoglobulins Immunotherapy In Situ In Vitro Inbred BALB C Mice Incubated Intravenous Knock-out Knockout Mice Label Licensing Light Lipids Liquid substance Malignant Neoplasms Measures Mediating Minor Modeling Monitor Mouse Strains Mus Natural Immunity Natural Killer Cells Nucleic Acids Oligonucleotides Organ Oryctolagus cuniculus Outcome Permeability Personal Satisfaction Pharmacodynamics Phase Pongidae Preparation Process Proteins Public Health Route Signal Transduction Solid Neoplasm Solutions Structure Study models Suspension substance Suspensions System T-Lymphocyte Testing Time Tissues Tumor Antigens Tumor Tissue Wild Type Mouse Work base cancer immunotherapy cancer therapy chemical conjugate crosslink day design fight against guanidinium human disease human study improved in vivo intravenous administration killings knockout gene macrophage monocyte neoplastic cell neutrophil polypeptide prevent research study size stoichiometry subcutaneous targeted delivery tumor tumor growth uptake

项目摘要

DESCRIPTION (provided by applicant): Bacterial extracts often show anti-tumor effect. It was only recently discovered that the active component in the ill-defined cancer treatment is bacterial DNA, not protein, carbohydrate, or lipid. In contrast to human genomic DNA, bacterial DNA shows unmethylated cytidine-guanidine dinucleotide sequences, commonly referred to as CpG. Our own body's host defense system has evolved such a way that whenever CpG is found in the body, it serves as a "danger" signal. Resulting innate immunity can be harnessed to fight against tumor growth. Most attractively, once tumor-associated antigens are shed from the tumor, dendritic cells activated by CpG can process them and present to T lymphocytes that can kill the tumor cells. In short, CpG-based immunotherapy can exploit not only its innate immune response but also subsequent adaptive immune response. Thus CpG has become one of the most exciting immunotherapies in recent years. However, the approach works only with intra-tumoral or peri-tumoral route of administration in animal models. In Phase II human studies, intravenous route was ineffective while subcutaneous administration produced only minor effects. Taken together these rather disappointing outcomes can be attributed to poor delivery of the CpG in vivo. Recently we were able to demonstrate a way to circumvent this critical problem in delivery. Our approach was based on the fact that immune complexes can circulate in the blood for a long time so long as they do not trigger antigen crosslinking. In tumor-bearing mice our formulation showed a half-life of several days in the blood and as much as 20% of the dose accumulated in tumor tissue. In accordance with this favorable pharmacokinetic, intravenously administered CpG successfully retarded solid tumor growth. More recently we also discovered that a subcutaneous route was as effective. We have our own explanations of these exciting results and this proposal is designed to test these hypotheses. This portion constitutes one aspect of the proposal. The other portion of the proposal is concerned with development of two new systems that will not require a step that may be acceptable in animal studies but may not be in humans. Successful outcome of the proposed studies will undoubtedly accelerate CpG-based immunocancer therapy and will provide another viable option in treating cancer along with other existing treatments. Public Health Relevance: It has been known for many years that bacterial DNA fragments exert anti-tumor effect. To be effective, they must be introduced where tumor is growing. This proposal deals with strategies for developing a convenient intravenous or subcutaneous route of administration that will deliver the agents to the tumor tissue.

描述（申请人提供）：细菌提取物通常表现出抗肿瘤作用。最近才发现，这种不明确的癌症治疗中的活性成分是细菌 DNA，而不是蛋白质、碳水化合物或脂质。与人类基因组 DNA 不同，细菌 DNA 显示未甲基化的胞苷-胍二核苷酸序列，通常称为 CpG。我们身体的宿主防御系统已经进化到这样的方式：每当体内发现 CpG 时，它就会作为“危险”信号。由此产生的先天免疫可以用来对抗肿瘤的生长。最吸引人的是，一旦肿瘤相关抗原从肿瘤中脱落，被 CpG 激活的树突状细胞就可以处理它们并将其呈递给 T 淋巴细胞，从而杀死肿瘤细胞。简而言之，基于 CpG 的免疫疗法不仅可以利用其先天免疫反应，还可以利用随后的适应性免疫反应。因此，CpG 已成为近年来最令人兴奋的免疫疗法之一。然而，该方法仅适用于动物模型中的瘤内或瘤周给药途径。在II期人体研究中，静脉注射途径无效，而皮下注射仅产生轻微效果。总而言之，这些相当令人失望的结果可归因于 CpG 体内递送不良。最近，我们能够展示一种规避交付中这一关键问题的方法。我们的方法基于这样一个事实：只要免疫复合物不触发抗原交联，它们就可以在血液中长时间循环。在荷瘤小鼠中，我们的制剂在血液中的半衰期为几天，并且在肿瘤组织中累积的剂量高达 20%。根据这种有利的药代动力学，静脉注射 CpG 成功地延缓了实体瘤的生长。最近我们还发现皮下途径同样有效。我们对这些令人兴奋的结果有自己的解释，该提案旨在测试这些假设。这部分构成该提案的一方面。该提案的另一部分涉及两个新系统的开发，这两个系统不需要动物研究中可能可接受但人类可能无法接受的步骤。拟议研究的成功结果无疑将加速基于 CpG 的免疫癌症治疗，并将与其他现有疗法一起提供另一种治疗癌症的可行选择。公共健康相关性：多年来人们都知道细菌 DNA 片段具有抗肿瘤作用。为了有效，必须将它们引入肿瘤生长的地方。该提案涉及开发一种方便的静脉内或皮下给药途径的策略，将药物递送至肿瘤组织。