Systemic Delivery of CpG Oligonucleotides

CpG 寡核苷酸的全身递送

• 批准号: 8074537
• 负责人: MOO J CHO
• 金额: $ 29.3万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 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/8074537
• 关键词: 2,4-Dinitrophenol; A Mouse; Abbreviations; Animal Model; Animals; Antibodies; Antigen-Antibody Complex; Antigens; Antithymoglobulin; 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; Genes; 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; 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; Pharmacodynamics; Phase; Pongidae; Preparation; Process; Proteins; Route; Signal Transduction; Solid Neoplasm; Solutions; Structure; Study models; Suspension substance; Suspensions; System; T-Lymphocyte; Testing; Time; Tissues; Tumor Antigens; Tumor Tissue; Ultraviolet Rays; Wild Type Mouse; Work; base; cancer immunotherapy; cancer therapy; chemical conjugate; crosslink; design; fight against; human disease; improved; in vivo; intravenous administration; killings; macrophage; monocyte; neoplastic cell; neutrophil; polypeptide; premature; prevent; public health relevance; research study; stoichiometry; subcutaneous; targeted delivery; tumor; tumor growth; uptake

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（由申请人提供）：细菌提取物通常显示抗肿瘤作用。直到最近才发现，不确定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。与人基因组DNA相反，细菌DNA表现出未甲基化的胞丁丁胺二核苷酸序列，通常称为CpG。我们自己的身体的宿主防御系统已经发展出一种方式，每当在体内发现CPG时，它都会成为“危险”信号。可以利用其先天免疫来抵抗肿瘤生长。最吸引人的是，一旦从肿瘤中脱离了肿瘤相关的抗原，CPG激活的树突状细胞可以处理它们并将其呈现给可以杀死肿瘤细胞的T淋巴细胞。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。但是，该方法仅适用于动物模型中的肿瘤内或肿瘤内给药途径。在II期人类研究中，静脉内途径无效，而皮下给药仅产生较小的作用。总之，这些相当令人失望的结果可以归因于CpG在体内的交付不佳。最近，我们能够展示一种解决这个关键问题的方法。我们的方法是基于这样一个事实，即免疫复合物可以在血液中长时间循环，只要它们不触发抗原交联。在肿瘤的小鼠中，我们的制剂显示血液中几天的半衰期，多达20％的剂量积聚在肿瘤组织中。根据这种有利的药代动力学，静脉注射的CPG成功延迟实体瘤生长。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，该建议旨在检验这些假设。这部分构成了提案的一方面。该提案的另一部分与开发两个新系统的发展，这些系统不需要在动物研究中可以接受的步骤，但可能不在人类中。拟议研究的成功结果无疑将加速基于CPG的免疫疗法，并将为治疗癌症以及其他现有疗法提供另一种可行的选择。 公共卫生相关性：多年来，细菌DNA碎片发挥了抗肿瘤作用。为了有效，必须在肿瘤生长的地方引入它们。该建议涉及开发方便的静脉或皮下途径的策略，该途径将把药物运送到肿瘤组织。