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.

摘要： 癌症免疫疗法已经成为对抗癌症的中心舞台。mAb及其 相关的同行仍然处于癌症免疫治疗应用的最前沿。但新 以及可以克服其产生的改进的治疗剂和/或治疗方法， 给药和药理学局限性，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， 克服这些限制的是具有靶向和效应物的小到中等大小的分子 抗体的功能。为此，我们的研究目标是模拟抗体 半合成肽-蛋白质生物缀合物的靶向和效应器功能。在这 在本申请中，肽序列Pep 42已被选择用于靶向葡萄糖调节蛋白。 78千道尔顿的蛋白质（GRP 78）存在于肿瘤表面，但不存在于健康组织。所选 肿瘤抗原B7-H6表现出NK细胞上的NKp 30受体结合和免疫刺激性， 通过释放最终触发肿瘤溶解和死亡的炎性细胞因子来激活肿瘤。 然而，B7-H6从肿瘤的下调或脱落减少了NK细胞的NKp 30活化。 细胞，最终降低其抗肿瘤免疫反应。因此，我们建议 开发新的Pep 42-B7-H6缀合物，其提供有效的NK细胞靶向， 杀死缺乏细胞表面B7-H6的过表达GRP 78的肿瘤。拟建项目 1）Pep 42-B7-H6缀合物的制备和 2)评价其抗癌作用。值得注意的是，Pep 42-B7-H6缀合物是 预计将加强对逃避NK细胞依赖性肿瘤的癌症免疫治疗， 免疫，同时提供对半合成抗体模拟物的生产的见解。