Polarizing Macrophages to Tumor Suppressors by Blocking Multiple CCR2 Chemokine Receptor Epitopes

通过阻断多个 CCR2 趋化因子受体表位将巨噬细胞极化为肿瘤抑制因子

• 批准号: 10380283
• 负责人: Juliane Nguyen
• 金额: $ 5.06万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380283
• 关键词: Acute; Antibodies; Antibody Specificity; Antineoplastic Agents; Binding; Breast Cancer Patient; CCL2 gene; CD8-Positive T-Lymphocytes; Cancer Patient; Cells; Chronic; Clinical; Clinical Trials; Communicable Diseases; Data; Disease; Dose; Drug Delivery Systems; Epitopes; FDA approved; FOXP3 gene; Immune System Diseases; Immunoglobulin Fragments; Immunosuppression; Inflammation; Inflammatory; Legal patent; Leucine Zippers; Ligands; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Mediating; Myelogenous; Myeloid-derived suppressor cells; Myocardial Infarction; N-terminal; Neoplasm Metastasis; Outcome; PD-1 blockade; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Proteins; Publishing; Regulatory T-Lymphocyte; Role; Schedule; Signal Transduction; Specificity; System; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Treatment Efficacy; Tumor Suppressor Proteins; Tumor-associated macrophages; Work; anti-PD-1; anti-PD1 therapy; base; cancer cell; cancer therapy; cancer type; chemokine; chemokine receptor; chemotherapy; clinical care; cytotoxic; design; effector T cell; extracellular; improved; in vivo; macrophage; malignant breast neoplasm; migration; monocyte; monocyte chemoattractant protein 1 receptor; mouse model; neglect; neoplastic cell; novel therapeutic intervention; novel therapeutics; pathogen; prevent; receptor structure function; recruit; response; small molecule; targeted cancer therapy; therapy outcome; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis; wound healing

Project Summary Despite the important role of the tumor stroma in cancer progression, the vast majority of anticancer therapies target cancer cells and not the tumor microenvironment. A novel drug delivery approach that not only target tumor cells but also the inflammatory cells would be highly desirable. Here we propose to develop a delivery platform that builds on our recent work designing single chain variable fragment antibodies that both inhibit inflammatory monocyte migration to tumors and polarize macrophages towards the tumoricidal M1 phenotype by hijacking the CCL2/CCR2 pathway. This approach capitalizes on antibody binding specificity but exploits CCR2 receptor structure and function to improve therapeutic efficacy. We hypothesize that simultaneous targeting of multiple CCR2 epitopes will mediate a synergistic drug effect and inhibit tumor growth and metastasis by inducing M1 macrophage polarization and reducing macrophage migration. Our protein delivery approach capitalizes on both the targeting specificity of antibody fragments and also their ability to induce or modify downstream signaling. Thus, the antibody fragments will serve both as a delivery vehicle and therapeutic drug and have the potential to minimize carrier-induced toxicity. The specific aims of this proposal are to (1) synthesize a modular CCR2-targeting zip-ligand system for macrophage polarization and establish its mechanism of action; (2) assess the effects of multi-epitope CCR2-targeting constructs on macrophage polarization, tumor growth, and metastasis in a triple-negative breast cancer (TNBC) mouse model; and (3) evaluate the therapeutic effects of multi-epitope CCR2 targeting in combination with (a) anti-PD-1 blockade and (b) other therapeutics in a mouse model of TNBC, a subtype with particularly poor clinical outcomes and limited treatment options. Upon successful completion, this project will establish a new delivery concept to modify downstream signaling and modulate cellular phenotypes.

项目摘要 尽管肿瘤间质在癌症进展中起着重要作用，但绝大多数抗癌治疗 以癌细胞为目标，而不是肿瘤微环境。一种新的药物输送方法，不仅针对 肿瘤细胞和炎性细胞也是非常可取的。在这里，我们建议开发一种交付 该平台建立在我们最近的工作基础上，设计了既能抑制 炎性单核细胞向肿瘤迁移并使巨噬细胞偏向杀瘤M1表型 通过劫持CCL2/CCR2途径。这种方法利用了抗体结合的特异性，但利用了 CCR2受体的结构和功能有助于提高治疗效果。我们假设同时 靶向多个CCR2表位将介导协同药物效应并抑制肿瘤生长和转移 通过诱导M1巨噬细胞极化，减少巨噬细胞迁移。我们的蛋白质输送方法 利用抗体片段的靶向性和诱导或修饰的能力 下行信令。因此，抗体片段既可以作为载体，也可以作为治疗药物。 并有可能将载体诱导的毒性降至最低。这项建议的具体目的是：(1)综合 以CCR2为靶点的模块化Zip-配体巨噬细胞极化系统及其作用机制； (2)评价多表位CCR2靶向构建体对巨噬细胞极化、肿瘤生长、 在三阴性乳腺癌(TNBC)小鼠模型中的作用和转移；以及(3)评估治疗效果 多表位CCR2靶向联合(A)抗PD-1阻断和(B)其他疗法在小鼠中的应用 TNBC的模型，这是一种临床结果特别差、治疗选择有限的亚型。成功后 完成后，该项目将建立一种新的交付理念，以修改下行信令和调制 细胞表型。