NK Cell-Dependent Cancer Immunotherapy with Semi-Synthetic Peptide-Protein Bio-Conjugates

使用半合成肽-蛋白质生物缀合物进行 NK 细胞依赖性癌症免疫治疗

• 批准号: 9307136
• 负责人: David Sabatino
• 金额: $ 7.92万
• 依托单位: SETON HALL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-22 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9307136
• 关键词: Address; Affinity; American Cancer Society; Annual Reports; Antibodies; Applications Grants; Attenuated; Binding; Biological; Biological Availability; Biological Markers; Biology; Cause of Death; Cell Death; Cell secretion; Cell surface; Cells; Cessation of life; Coculture Techniques; Coupling; Cyclic Peptides; Cytolysis; Detection; Development; Down-Regulation; Dyes; Enzyme-Linked Immunosorbent Assay; Evaluation; Evolution; Exhibits; Flow Cytometry; Fluorescein-5-isothiocyanate; Fluorescence Microscopy; Goals; HepG2; High Pressure Liquid Chromatography; Immune response; Immunity; Immunologic Monitoring; Immunotherapy; In Vitro; Inflammatory; Interferons; Interleukin-6; Label; Lead; Length; Ligands; Ligation; Location; Malignant Neoplasms; Malignant neoplasm of liver; Mass Spectrum Analysis; Measurement; Methods; Migration Assay; Molecular Chaperones; Molecular Weight; NK Cell Activation; Natural Killer Cells; Neoplasm Metastasis; Peptide Synthesis; Peptides; Pharmacology; Phase; Preparation; Production; Propidium Diiodide; Proteins; Public Health; Recurrence; Renaissance; Research; Research Project Grants; Resistance; Signal Transduction; Solid; Specificity; Staining method; Stains; Surface; TNF gene; Therapeutic; Tissues; Treatment Efficacy; Tumor Antigens; Tumorigenicity; United States; anticancer research; base; cancer cell; cancer immunotherapy; cancer therapy; cell killing; cell type; cytokine; cytotoxic; design; fight against; fluorophore; glucose-regulated proteins; improved; in vivo; innovation; insight; killings; mortality; mouse model; neoplasm immunotherapy; neoplastic cell; novel; overexpression; protein aminoacid sequence; receptor; receptor binding; response; synthetic antibodies; synthetic biology; synthetic peptide; synthetic protein; technological innovation; therapy resistant; tumor; tumorigenic

Abstract: Cancer immunotherapy has taken center stage in the fight against cancer. The mAb and their related counterparts remain at the forefront of cancer immunotherapy applications. However, new and improved therapeutics and/or treatment methods that may overcome their production, administration, and pharmacological limitations, including the evolution of treatment resistance are still in widespread demand. Key to the development of technological innovations that may overcome these limitations are small to intermediate size molecules with the targeting and effector functions of antibodies. Towards this goal, our research objective is to mimic antibody targeting and effector functions with semi-synthetic peptide-protein bioconjugates. In this application, the peptide sequence, Pep42, has been selected to target the Glucose Regulated Protein of 78 kilodalton (GRP78) on the surface of tumors but not on healthy tissues. The selected tumor antigen, B7-H6, exhibits NKp30 receptor binding on NK cells and immunostimulatory activity by the release of inflammatory cytokines that ultimately trigger tumor lysis and death. However, the downregulation or shedding of B7-H6 from tumors reduces NKp30 activation of NK cells, ultimately diminishing their anti-tumor immune responses. Therefore, we propose the development of new Pep42-B7-H6 conjugates that provide effective NK cell targeting and killing of GRP78 overexpressing tumors that lack cell surface B7-H6. The proposed project will be addressed by two specific aims: 1) the preparation of the Pep42-B7-H6 conjugates and 2) evaluation of their anti-cancer effects. Significantly, the Pep42-B7-H6 conjugates are anticipated to potentiate cancer immunotherapy of resilient tumors that evade NK cell-dependent immunity while providing insights into the production of semi-synthetic antibody mimics.

抽象的： 癌症免疫疗法已成为与癌症斗争的中心阶段。 mab及其 相关的对应物仍然处于癌症免疫疗法应用的最前沿。但是，新的 并改善了可以克服其生产的治疗方法和/或治疗方法， 给药和药理局限性，包括治疗耐药性的演变 仍然有广泛的需求。发展技术创新的关键 克服这些局限性很小至中间大小的分子，靶向和效应子 抗体的功能。为了实现这一目标，我们的研究目标是模仿抗体 半合成肽蛋白生物缀合物的靶向和效应函数。在这个 已选择应用肽序列PEP42来靶向葡萄糖调节 肿瘤表面上的78千达顿（GRP78）的蛋白质，但不在健康组织上。选定的 肿瘤抗原B7-H6表现出NKP30受体在NK细胞和免疫刺激上的结合 通过释放炎症性细胞因子的活性，最终引发肿瘤裂解和死亡。 但是，肿瘤中B7-H6的下调或脱落会降低NK的NKP30激活 细胞，最终减少其抗肿瘤免疫反应。因此，我们提出了 开发新的PEP42-B7-H6共轭物，可提供有效的NK细胞靶向和 杀死缺乏细胞表面B7-H6的过表达肿瘤的GRP78。拟议的项目 将通过两个具体目的来解决：1）PEP42-B7-H6共轭物和 2）评估其抗癌作用。值得注意的是，PEP42-B7-H6偶联物是 预计会增强逃避NK细胞依赖性弹性肿瘤的癌症免疫疗法 免疫力在提供半合成抗体模仿的产生的同时。