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）：我们建议开发新型纳米生物缀合物，通过同时抑制血管生成和刺激宿主免疫系统来治疗乳腺癌。纳米生物缀合物基于可生物降解且无毒的聚苹果酸纳米平台，具有共价连接的抗转铁蛋白受体（TfR）单克隆抗体，可通过肿瘤脉管系统的内皮系统进行递送，反义寡核苷酸（AON）可抑制血管生成，和/或有效针对乳腺癌抗原 HER2/neu 的免疫刺激抗体-细胞因子融合蛋白。我们假设，新的纳米生物聚合物单独或组合使用时，能够通过抑制肿瘤血管生成并随后诱导细胞凋亡，并通过激活先天性和适应性免疫反应，从而产生长期抗肿瘤作用，从而对癌细胞进行多管齐下的攻击。不仅对 HER2/neu 具有免疫力，而且对其他肿瘤抗原也具有免疫力。此外，由于肿瘤新生血管内皮细胞上过表达的 TfR 介导的转胞吞作用、肿瘤过表达的 HER2/neu 或 TfR 的靶向性以及增强的渗透性和保留性，纳米生物缀合物将表现出优异的肿瘤靶向性。 EPR）纳米聚合物表现出的效应。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) 的表达来实现抗血管生成作用，这是癌细胞产生的关键因子，需要形成支持肿瘤的新脉管系统。此外，为了实现 HER2/neu 靶向和免疫激活，我们将使用强效免疫刺激细胞因子白细胞介素 2 (IL-2) 或白细胞介素 12 (IL-12)，它们将通过抗 HER2/neu IgG3 递送到肿瘤中-作为纳米生物聚合物一部分的细胞因子融合蛋白。我们还将探索游离抗体-细胞因子融合蛋白与抗血管生成纳米聚合物相结合的效果。重要的是，IL-12 也是一种抗血管生成细胞因子，可增强 AON 的抗血管生成作用。所提出的纳米生物聚合物在结构和作用机制方面代表了新颖且独特的分子。据我们所知，所提出的治疗方法或具有类似作用机制的其他分子都尚未被描述或正在开发中。该项目的具体目标是：目标 1. 纳米生物聚合物的合成和体外表征，目标 2. 纳米生物聚合物的初步药代动力学和毒理学研究，目标 3. 检查纳米生物聚合物抑制肿瘤生长的能力并研究其机制抗肿瘤保护和免疫记忆。所提出的纳米生物聚合物代表了新一代癌症治疗的起点，预计可有效对抗侵袭性乳腺癌肿瘤，例如过度表达 HER2/neu 的肿瘤。一种针对表达 HER2/neu 的癌细胞的新型纳米生物聚合物疗法，具有足够的能力抑制血管生成并协调抗肿瘤免疫反应，应该会产生重大的临床影响。