Peptide conjugated liposomes activate anti-tumor immunity

肽缀合脂质体激活抗肿瘤免疫

• 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
• 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

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.

项目摘要 研究目标是设计一种纳米颗粒平台来结合细胞受体并抑制细胞信号传导 比抗体更有效。迄今为止，抗体由于其高结合性而被普遍用作拮抗剂 对靶细胞受体的亲和力。然而，它们的大尺寸可能在阻止多个小区中不太有效， 在脂筏内组织为同源二聚体或共定位的表面受体。我们认为肽- 结合脂质体（PCL）-在最佳肽密度-可能比FDA批准的更有效 由于它们能够通过最佳的肽间间隔结合和抑制受体同型二聚体， 受体单体由于合作结合。本建议将评估脂质体肽密度的作用 和细胞受体组织对PCL体外结合和抑制以及药代动力学的影响， 体内药效学。与封装和释放药物的其他脂质体递送系统相比， PCL的生物活性是由于脂质双层的肽密度和扩散性。我们先前已经 表明优化的PCL结合并抑制CXCR 4同源二聚体，减少三阴性乳腺癌。 癌症（TNBC）原发性肿瘤生长和转移。在本建议书中，我们会把专业牌照应用于三地广播公司 免疫疗法免疫检查点抑制剂（ICI）疗法基于抗体之间的强结合 及其靶受体，诱导抗肿瘤活性。Atezolizumab被FDA批准用于TNBC， 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 化疗和ICI治疗。需要进一步研究以提高抗肿瘤免疫活性 在TNBC。细胞毒性T淋巴细胞相关蛋白4（CTLA-4）主要以同源二聚体形式存在于细胞表面， 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-PD 1）、PD-L1（L-PDL 1）和 CTLA-4（L-CTLA 4），肽密度增加（9 k/µ m2、24 k/µm2、39 k/µm2、53 k/µm2和74 k/µm2）。TNBC 并测量活化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PCL在免疫活性TNBC肿瘤小鼠模型中的生物分布和PCL耗尽的小鼠中的生物分布。 淋巴细胞、嗜中性粒细胞或巨噬细胞来评估免疫细胞如何影响PCL肿瘤积聚。PCL 抗肿瘤活性将通过细胞因子表达（aim 1）和肿瘤免疫细胞浸润的变化来测量 (aim 2）相对于FDA批准的ICI疗法（抗PD-1（派姆单抗）、抗PD-L1（阿特珠单抗）、抗PD-L2（阿替珠单抗）、抗PD-L3（阿替珠单抗）和抗PD-L4（阿替珠单抗））， CTLA-4（伊匹单抗））。我们团队在药物递送、TNBC小鼠模型和肿瘤治疗方面的综合专业知识 免疫学足以成功完成这项研究。拟议研究的成果包括 鉴定PCL肽相对于靶受体同源二聚体（CTLA-4）和单体（PD-1、PD-L1）的密度，以及 由于强协同结合和抑制而在体内诱导抗肿瘤活性。