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

基本信息

批准号：
10737843
负责人：
Juliane Nguyen
金额：
$ 7.22万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737843
关键词：
Acute Antibodies Antibody Specificity Antineoplastic Agents Binding Breast Cancer Patient CCL2 gene CD8-Positive T-Lymphocytes Cancer Patient Cd68 Cell Count Cells Chronic Clinical Clinical Trials Communicable Diseases Data Disease Dose Drug Delivery Systems Epitopes FDA approved FOXP3 gene Immune System Diseases Immunoglobulin Fragments Immunosuppression Infiltration Inflammation Inflammatory Invaded Legal patent Leucine Zippers Ligands Link Macrophage Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of pancreas Mediating Metastasis Induction 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 Structure System Testing Therapeutic Therapeutic Effect Toxic effect Treatment Efficacy Tumor Promotion Tumor Suppressor Proteins Tumor-associated macrophages Work antagonist anti-PD-1 anti-PD1 therapy cancer cell cancer therapy cancer type chemokine chemokine receptor chemotherapy clinical care cytotoxic delivery vehicle design effector T cell extracellular improved in vivo malignant breast neoplasm migration monocyte monocyte chemoattractant protein 1 receptor mouse model neglect neoplastic cell novel therapeutic intervention novel therapeutics pathogen prevent recruit response small molecule targeted cancer therapy therapy outcome triple-negative invasive breast carcinoma tumor tumor growth tumor microenvironment tumor progression tumorigenesis wound healing

项目摘要

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.

项目摘要尽管肿瘤基质在癌症进展中起着重要作用，但绝大多数抗癌疗法靶向癌细胞，而不是肿瘤微环境。一种新型的药物输送方法，不仅针对肿瘤细胞和炎症细胞也是非常需要的。在这里，我们建议开发交货基于我们最近设计的单链可变片段抗体的平台，两者都抑制炎性单核细胞向肿瘤迁移，并使巨噬细胞朝向肿瘤M1表型通过劫持CCL2/CCR2途径。这种方法利用抗体结合特异性，但利用 CCR2受体结构和功能以提高治疗功效。我们假设同时靶向多个CCR2表位将介导协同的药物作用并抑制肿瘤的生长和转移通过诱导M1巨噬细胞极化并减少巨噬细胞的迁移。我们的蛋白质输送方法利用抗体片段的靶向特异性以及它们诱导或修改的能力下游信号传导。因此，抗体片段将既用作递送车和治疗药物并有可能最大程度地减少载体引起的毒性。该建议的具体目的是（1）合成用于巨噬细胞极化的模块化CCR2靶向拉链系统，并建立其作用机理；（2）评估多势CCR2靶向构建体对巨噬细胞极化，肿瘤生长，三阴性乳腺癌（TNBC）小鼠模型中的转移；（3）评估治疗效果与（a）抗PD-1封锁和（b）小鼠中的其他治疗剂结合使用的多角色CCR2靶向 TNBC的模型，一种亚型，具有临床结果特别差和有限的治疗选择。成功完成，该项目将建立一个新的交付概念，以修改下游信号和调节细胞表型。