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.

项目总结 研究的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 比抗体更有效。迄今为止，抗体因其高结合性而被广泛用作拮抗剂。 对其靶细胞受体的亲和力。然而，它们较大尺寸在阻止多个细胞方面可能不太有效 表面受体以同源二聚体的形式组织或在脂筏内共定位。我们建议多肽- 结合脂质体(PCL)--在最佳多肽密度下--可能比FDA批准的更有效 抗体由于其通过最佳的肽间间隔结合和抑制受体同源二聚体的能力以及 由于协同结合导致的受体单体。这项建议将评估脂质体多肽密度的作用 和细胞受体组织在体外对PCL的结合和抑制以及药代动力学 体内药效学。与包裹和释放药物的其他脂质体递送系统相比， PCLS的生物学活性与脂双层的多肽密度和扩散性有关。我们之前已经 证明了优化的PCL结合并抑制了CXCR4同源二聚体，减少了三重负面乳房 癌症(TNBC)原发肿瘤的生长和转移。在本提案中，我们将对TNBC应用PCL 免疫疗法。免疫检查点抑制物(ICI)的治疗是基于抗体之间的强结合 和它们的靶受体，诱导抗肿瘤活性。FDA批准在TNBC中使用atezolizumab激活 抗肿瘤反应，但仅将无进展生存期从化疗的5.5个月延长到7.2个月 接受化疗和脑梗塞治疗。提高抗肿瘤免疫活性尚需进一步研究 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，我们将合成和表征一系列针对PD-1(L-PD1)、PD-L1(L-PDL1)和 CTLA-4(L-CTLA 4)，随着多肽密度的增加(9k/µm2、24k/µm2、39k/µm2、53k/µm2和74k/µm2)。TNBC 并将检测激活的T细胞的PD-1、PD-L1或CTLA-4的表达、PCL细胞的结合和抑制情况。 我们将比较PCL在免疫活性TNBC肿瘤模型小鼠和缺乏PCL的小鼠中的生物分布 淋巴细胞、中性粒细胞或巨噬细胞，以评估免疫细胞如何影响PCL肿瘤聚集。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衡量 (目的2)相对于FDA批准的ICI疗法(抗PD-1(Pembrolizumab)，抗PD-L1(Atezolizumab)，抗- CTLA-4(Ipilimumab))。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。拟议研究的成果包括 识别靶向受体同源二聚体(CTLA-4)和单体(PD-1，PD-L1)的PCL肽密度和 由于具有较强的协同结合和抑制作用，可在体内诱导抗肿瘤活性。