Novel Nanopolymers to Inhibit Angiogenesis and Increase the Anti-tumor Immunity

新型纳米聚合物抑制血管生成并增加抗肿瘤免疫力

基本信息

批准号：
8477146
负责人：
JULIA Y LJUBIMOVA
金额：
$ 45.49万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-05 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8477146
关键词：
Acids Adverse effects Affect Affinity Angiogenesis Inducing Agents Angiogenesis Inhibition Antibodies Antibody Affinity Antigen-Presenting Cells Antigens Antineoplastic Agents Antisense Oligonucleotides Avidity Binding Biochemical Biodistribution Biopolymers Blood Blood Vessels Breast Cancer Cell Breast Cancer Treatment Cancer Etiology Cancer Prognosis Cell Death Cells Cessation of life Chemicals Chimeric Proteins Cleaved cell Clinical Complex Cytokine Receptors Cytotoxic T-Lymphocytes Dendritic Cells Development Disadvantaged Disease Dose Drug Delivery Systems Drug Kinetics ERBB2 gene Endocytosis Endosomes Endothelial Cells Evaluation Exhibits Family Generations Glutathione Goals Growth Growth Factor Inhibition Half-Life Human IgG3 Immune response Immune system Immunity Immunocompetent Immunologic Memory In Vitro Induction of Apoptosis Interleukin-12 Interleukin-2 Laminin Link Malignant Neoplasms Mammary Neoplasms Mediating Methods Modeling Molecular Monoclonal Antibodies Mus Nanoconjugate Natural Killer Cells Nude Mice Organ Permeability Pharmaceutical Preparations Polymers Probability Process Proteins Relapse Reproducibility Specificity Structure Surface System Testing Therapeutic Transferrin Receptor Tumor Angiogenesis Tumor Antigens Tumor Immunity Vascular Endothelial Growth Factors Woman Xenograft Model Xenograft procedure angiogenesis antiangiogenesis therapy base cancer cell cancer therapy cytokine economic cost innovation malignant breast neoplasm nanopolymer neoplastic cell neovasculature novel overexpression poly(malic acid)public health relevance receptor receptor binding receptor mediated endocytosis therapeutic target transcytosis transferrin receptor 2 tumor tumor growth tumor microenvironment uptake

项目摘要

DESCRIPTION (provided by applicant): We propose to develop novel anobioconjugates for the treatment of breast cancer by inhibiting angiogenesis and stimulating the host immune system simultaneously. The nanobioconjugates are based on a biodegradable and non-toxic polymalic acid nanoplatform with covalently attached anti-transferrin receptor (TfR) monoclonal antibody for delivery through the endothelial system of the tumor vasculature, antisense oligonucleotides (AON) to inhibit angiogenesis, and/or potent immunostimulatory antibody-cytokine fusion proteins specific for the breast cancer antigen HER2/neu. We hypothesize that the new nanobiopolymers when used alone or in combination would be capable of a multi-pronged attack against cancer cells by inhibiting tumor angiogenesis with the subsequent induction of apoptosis and by activating innate and adaptive immune responses resulting in long-term anti-tumor immunity not only against HER2/neu but also against other tumor antigens. In addition, the nanobioconjugates would exhibit superior tumor targeting as a consequence of the combination of transcytosis mediated by TfR overexpressed on the endothelial cells of the tumor neovasculature, targeting of HER2/neu or TfR overexpressed by the tumor, and the enhanced permeability and retention (EPR) effect exhibited by nanopolymers. The anti-angiogenic effect would be achieved using AON to inhibit the expression of vascular protein laminin-411 and/or vascular endothelial growth factor (VEGF), critical factors produced by the cancer cells needed to develop new vasculature that supports the tumor. In addition, to achieve HER2/neu targeting and immunoactivation we will use the potent immunostimulatory cytokines interleukin-2 (IL-2) or interleukin-12 (IL-12) that would be delivered into the tumor by an anti-HER2/neu IgG3-cytokine fusion protein as part of the nanobiopolymer. We will also explore the effect of combining free antibody-cytokine fusion proteins with the anti-angiogenic nanopolymer. Importantly, IL-12 is also an anti-angiogenic cytokine increasing the anti-angiogenic effect of AON. The proposed nanobiopolymers represent novel and unique molecules in terms of structure and mechanisms of action. To the best of our knowledge, neither the proposed therapeutic nor other molecules with similar mechanisms of action have either been described or are under development. The specific aims of this project are: Aim 1. Synthesis and in vitro characterization of nanobiopolymers, Aim 2. Initial pharmacokinetic and toxicological studies of the nanobiopolymers, and Aim 3. Examine the ability of nanobiopolymers to inhibit tumor growth and investigate the mechanism responsible for anti-tumor protection and immunological memory. The proposed nanobiopolymers represent the starting point for a new generation of cancer therapeutics and are expected to be effective against aggressive breast cancer tumors such as those overexpressing HER2/neu. A novel nanobiopolymer-based therapy against HER2/neu expressing cancer cells with sufficient capacity to inhibit angiogenesis and orchestrate an anti-tumor immune response should make a significant clinical impact.

描述（由申请人提供）：我们建议通过同时抑制血管生成和刺激宿主免疫系统来开发新型的苯二甲基缀合物来治疗乳腺癌。纳米生物偶联物基于可生物降解和无毒的多氧多数酸纳米植物与共价附着的抗转移蛋白受体（TFR）单克隆抗体通过肿瘤内皮系统递送，可通过肿瘤的内皮系统递送，抗固定寡核苷酸（抗固定寡核）（Animiim inim inim angimimi and andimibits inibib and inibib and inibib）inimimimimibits insimibib and inibib insibib and inibib andimihib和inibib insibib和特异性抗体 - 淋巴结融合蛋白针对乳腺癌抗原HER2/NEU。我们假设，单独使用或组合使用新的纳米生物聚合物可以通过抑制肿瘤血管生成而对癌细胞发作，并通过随后诱导凋亡的诱导，并激活先天和适应性免疫反应，从而导致长期的反肿瘤免疫，而不仅仅是对Her2/Neu anneu and tumor Antigens的长期抗肿瘤免疫。此外，由于TFR介导的跨胞菌病的组合在肿瘤新生血管内的内皮细胞上过表达，纳米二偶联物将表现出优质的肿瘤靶向，其靶向HER2/NEU或TFR被肿瘤过度表达，并具有增强的允许性和耐药性和退休（Eprention（Epr）（Epr）（Epr）（Epr）效应。将使用AON抑制血管蛋白层粘连蛋白-411和/或血管内皮生长因子（VEGF）的表达，这是抗血管生成作用，这是由开发支持肿瘤的新血管所需的癌细胞产生的关键因子。此外，为了实现HER2/NEU靶向和免疫活化，我们将使用有效的免疫刺激性细胞因子介体介体-2（IL-2）或白介素12（IL-12）（IL-12），这些抗肿瘤将通过抗-HER2/neu2/neu igg3-cytokine融合蛋白作为Nananobiomerymerymerymerymerymerymerymerymerymersery。我们还将探讨将游离抗体 - 循环融合蛋白与抗血管生成纳米聚合物结合的效果。重要的是，IL-12也是一种抗血管生成细胞因子，可增加AON的抗血管生成作用。所提出的纳米聚合物在结构和作用机理方面代表了新颖和独特的分子。据我们所知，提出的治疗性和其他具有相似作用机理的分子都没有描述或正在开发中。该项目的具体目的是：目标1。纳米聚物聚合物的合成和体外表征，目标2。纳米聚物聚合物的初始药代动力学和毒理学研究，AIM 3。检查纳米聚聚物抑制肿瘤生长的能力并研究导致抗肿瘤保护和免疫学记忆的机制。拟议的纳米聚合物代表了新一代癌症治疗剂的起点，预计将有效地抵抗侵袭性的乳腺癌肿瘤，例如过表达HER2/NEU的肿瘤。一种针对HER2/NEU表达癌细胞的新型基于纳米生物聚合物的疗法，具有足够的能力抑制血管生成并策划抗肿瘤免疫反应，应产生重大的临床影响。