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.

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