Peptide conjugated liposomes activate anti-tumor immunity

肽缀合脂质体激活抗肿瘤免疫

基本信息

批准号：
10371286
负责人：
Debra Auguste
金额：
$ 20万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10371286
关键词：
Active Sites Affect Affinity Amphotericin B Antibodies Antitumor Response Binding Biodistribution Biological Breast Cancer Cell Breast Cancer Model CTLA4 gene CXCR4 gene Cell Surface Receptors Cell surface Cells Chemoresistance Diffuse Doxorubicin Hydrochloride Liposome Drug Delivery Systems Encapsulated Engineering Epidermal Growth Factor Receptor Estrogen Receptors Exhibits FDA approved Future Human Immune Immune checkpoint inhibitor Immunocompetent In Vitro Infiltration Interleukin-2 Lipid Bilayers Liposomes Lymphocyte Malignant Neoplasms Measures Membrane Microdomains Mus Neoplasm Metastasis Outcome Peptides Pharmaceutical Preparations Primary Neoplasm Progesterone Receptors Progression-Free Survivals Receptor Cell Receptor Inhibition Recurrence Research Research Project Summaries Role Series Signal Transduction System T-Lymphocyte Therapeutic Studies Tumor Immunity Tumor-infiltrating immune cells antagonist anti-PD-1 anti-PD-L1 base cancer immunotherapy checkpoint therapy chemotherapy cytokine density drug biological activity immune activation immune checkpoint improved in vivo ipilimumab liposomal delivery macrophage monomer mouse model nanoparticle neutrophil pembrolizumab pharmacokinetics and pharmacodynamics programmed cell death ligand 1 programmed cell death protein 1 protein expression receptor receptor binding response triple-negative invasive breast carcinoma tumor tumor growth tumor immunology

项目摘要

PROJECT SUMMARY The research objective is to engineer a nanoparticle platform to bind cell receptors and inhibit cell signaling more effectively than an antibody. To date, antibodies are universally employed as antagonists due to their high binding affinity for their target cell receptor. However, their large size may be less effective in blocking multiple cell surface receptors that organize as homodimers or colocalize within lipid rafts. We propose that peptide- conjugated liposomes (PCLs) - at an optimal peptide density - may be more effective than FDA-approved antibodies due to their ability to bind and inhibit receptor homodimers via optimal interpeptide spacings and receptor monomers due to cooperative binding. This proposal will evaluate the role of liposome peptide density and cell receptor organization on PCL binding and inhibition in vitro and pharmacokinetics and pharmacodynamics in vivo. In contrast to other liposomal delivery systems that encapsulate and release drugs, the biological activity of PCLs is due to the peptide density and diffusivity of the lipid bilayer. We have previously demonstrated that an optimized PCL bound and inhibited the CXCR4 homodimer, reducing triple negative breast cancer (TNBC) primary tumor growth and metastasis. In this proposal, we will apply PCLs to TNBC immunotherapy. Immune checkpoint inhibitor (ICI) therapy is predicated on strong binding between antibodies and their target receptor, inducing anti-tumor activity. Atezolizumab is FDA approved for use in TNBC to activate the anti-tumor response but only extends progression free survival from 5.5 months with chemotherapy to 7.2 months with chemotherapy and ICI therapy. Further research is needed to improve anti-tumor immune activity in TNBC. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), is present primarily as a homodimer on cell surfaces whereas programmed cell death ligand 1 (PD-L1) and programmed cell death 1 (PD-1) are monomeric, which suggests that different peptide spacings may be necessary to achieve maximal binding and inhibition. Thus, we will synthesize and characterize a series of PCLs that target PD-1 (L-PD1), PD-L1 (L-PDL1), and CTLA-4 (L-CTLA4) with increasing peptide density (9k/µm2, 24k/µm2, 39k/µm2, 53k/µm2, and 74k/µm2). TNBC and activated T cells will be measured for PD-1, PD-L1 or CTLA-4 expression, PCL-cell binding, and inhibition. We will compare PCL biodistribution in an immune competent TNBC tumor mice model and mice depleted of lymphocytes, neutrophils, or macrophages to assess how immune cells affect PCL tumor accumulation. PCL anti-tumor activity will be measured by cytokine expression (aim 1) and changes in tumor immune cell infiltration (aim 2) relative to the FDA-approved, ICI therapy (anti-PD-1 (pembrolizumab), anti-PD-L1 (atezolizumab), anti- CTLA-4 (ipilimumab)). Our team’s combined expertise in drug delivery, TNBC mouse models, and tumor immunology is sufficient to successfully complete this research. The outcomes of the proposed research include identifying PCL peptide densities to target receptor homodimers (CTLA-4) and monomers (PD-1, PD-L1) and induce anti-tumor activity in vivo due to strong, cooperative binding and inhibition.

项目概要研究目标是设计一个纳米颗粒平台来结合细胞受体并更多地抑制细胞信号传导迄今为止，抗体由于其高结合力而被普遍用作拮抗剂。然而，它们的大尺寸在阻断多个细胞方面可能效果较差。表面受体组织为同二聚体或共定位于脂筏内。缀合脂质体 (PCL) - 在最佳肽密度下 - 可能比 FDA 批准的更有效抗体，因为它们能够通过最佳肽间间距结合和抑制受体同二聚体，该提案将评估脂质体肽密度的作用。和细胞受体组织对 PCL 结合和体外抑制以及药代动力学的影响与其他封装和释放药物的脂质体递送系统相比， PCL 的生物活性取决于脂质双层的肽密度和扩散性。证明优化的 PCL 结合并抑制 CXCR4 同二聚体，减少三阴性乳腺癌癌症（TNBC）原发性肿瘤生长和转移在本提案中，我们将 PCL 应用于 TNBC。免疫检查点抑制剂（ICI）疗法基于抗体之间的强结合。及其靶标受体，诱导抗肿瘤活性 Atezolizumab 已被 FDA 批准用于 TNBC 的激活。抗肿瘤反应，但仅将无进展生存期从化疗的 5.5 个月延长至 7.2 个月需要进一步研究几个月的化疗和 ICI 治疗来提高抗肿瘤免疫活性。在 TNBC 中，细胞毒性 T 淋巴细胞相关蛋白 4 (CTLA-4) 主要以同型二聚体形式存在于细胞上。表面，而程序性细胞死亡配体 1 (PD-L1) 和程序性细胞死亡 1 (PD-1) 是单体，这表明不同的肽间距可能是实现最大结合和抑制所必需的。因此，我们将合成并表征一系列靶向 PD-1 (L-PD1)、PD-L1 (L-PDL1) 和 CTLA-4 (L-CTLA4) 具有增加的肽密度（9k/μm2、24k/μm2、39k/μm2、53k/μm2 和 74k/μm2）。将测量激活的 T 细胞的 PD-1、PD-L1 或 CTLA-4 表达、PCL 细胞结合和抑制。我们将比较具有免疫能力的 TNBC 肿瘤小鼠模型和缺乏 PCL 的小鼠中的 PCL 生物分布。淋巴细胞、中性粒细胞或巨噬细胞来评估免疫细胞如何影响 PCL 肿瘤积累。抗肿瘤活性将通过细胞因子表达（目标 1）和肿瘤免疫细胞浸润的变化来衡量（目标 2）相对于 FDA 批准的 ICI 疗法（抗 PD-1（pembrolizumab）、抗 PD-L1（atezolizumab）、抗 CTLA-4（伊匹单抗））我们团队在药物输送、TNBC 小鼠模型和肿瘤方面的综合专业知识。免疫学足以成功完成这项研究。拟议研究的结果包括：识别目标受体同二聚体 (CTLA-4) 和单体（PD-1、PD-L1）的 PCL 肽密度，由于强烈的协同结合和抑制作用，在体内诱导抗肿瘤活性。