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

• 批准号: 8722066
• 负责人: JULIA Y LJUBIMOVA
• 金额: $ 14.09万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 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/8722066
• 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); receptor; receptor binding; receptor mediated endocytosis; therapeutic target; transcytosis; transferrin receptor 2; tumor; tumor growth; tumor microenvironment; uptake

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治疗乳腺癌的新型无生物偶联物。纳米生物偶联物基于可生物降解的无毒聚苹果酸纳米平台，具有共价附着的抗转铁蛋白受体（TfR）单克隆抗体，可通过肿瘤血管内皮系统递送，反义寡核苷酸（AON）可抑制血管生成，和/或针对乳腺癌抗原HER2/neu的强效免疫刺激抗体-细胞因子融合蛋白。我们假设，新的纳米生物聚合物单独使用或联合使用时，将能够通过抑制肿瘤血管生成，随后诱导细胞凋亡，激活先天和适应性免疫反应，导致长期抗肿瘤免疫，不仅针对HER2/neu，而且针对其他肿瘤抗原，对癌细胞进行多管齐下的攻击。此外，纳米生物偶联物由于结合了肿瘤新生血管内皮细胞上过表达的TfR介导的胞吞作用，靶向肿瘤过表达的HER2/neu或TfR，以及纳米聚合物所表现出的增强的渗透性和滞留性（EPR）效应，将表现出优越的肿瘤靶向性。通过AON抑制血管蛋白laminin-411和/或血管内皮生长因子（VEGF）的表达，可以达到抗血管生成的效果。VEGF是癌细胞产生的关键因子，需要形成支持肿瘤的新血管系统。此外，为了实现HER2/neu靶向和免疫激活，我们将使用有效的免疫刺激细胞因子白介素-2 （IL-2）或白介素-12 (IL-12)，这些细胞因子将通过抗HER2/neu igg3细胞因子融合蛋白作为纳米生物聚合物的一部分传递到肿瘤中。我们还将探索将游离抗体-细胞因子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的细胞因子，增加了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和独特的分子。据我们所知，所提出的治疗或其他具有类似作用机制的分子既没有被描述也没有在开发中。该项目的具体目标是：目标1。纳米生物聚合物的合成及体外表征，目的2。纳米生物聚合物的初始药代动力学和毒理学研究，以及Aim 3。研究纳米生物聚合物抑制肿瘤生长的能力，探讨其抗肿瘤保护和免疫记忆的机制。所提出的纳米生物聚合物代表了新一代癌症治疗的起点，并有望有效治疗侵袭性乳腺癌肿瘤，如过表达HER2/neu的肿瘤。一种新的基于纳米生物聚合物的治疗HER2/neu表达癌细胞的方法，具有抑制血管生成和协调抗肿瘤免疫反应的能力，应该会产生重大的临床影响。