Internalizing human antibody-targeted nanosized siRNA therapeutics

内化人类抗体靶向纳米 siRNA 疗法

基本信息

批准号：
8391664
负责人：
BIN LIU
金额：
$ 32.48万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-06 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8391664
关键词：
Affinity Animal Model Animals Antibodies Bacteriophages Binding Cancer Patient Castration Cell Line Cell Survival Cell surface Cells Characteristics Chimeric Proteins Complementary DNA Cytosol Development Disease Effectiveness Epitopes Gene Silencing Gene Targeting Genes Goals Growth Human In Situ In Vitro Lead Libraries Life Link Location Malignant neoplasm of prostate Mammalian Cell Mediating Modeling Neoplasm Metastasis PC3 cell line Patients Penetration Pharmaceutical Preparations Positioning Attribute Primary Neoplasm Property Prostatic Neoplasms RNA Binding Recurrent disease Reporter Genes Research Resistance Resources Screening procedure Small Interfering RNA Structure of base of prostate Surface Surface Antigens Technology Therapeutic Tissues Toxic effect Tumor Cell Line Tumor-Derived Work Xenograft Model Xenograft procedure Yeasts advanced disease base cancer cell human monoclonal antibodies improved in vivo innovation laser capture microdissection men nanoparticle nanosized neoplastic cell novel novel therapeutics pre-clinical tool tumor tumor growth tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): The goal of this project is to develop a novel human monoclonal antibody-targeted small interfering RNA (siRNA) therapeutic that has the potential to be first-in-its-kind for treating tumor and metastasis. We have previously identified a panel of rapidly internalizing human single chain antibodies (scFvs) that target clinically represented tumor cell surface antigens. These scFvs were selected from phage antibody display libraries using laser capture microdissection for their ability to bind to tumor cells in situ residing in thir tissue microenvironment, and to mediate efficient intracellular payload delivery to tumor cells. We have in addition identified novel siRNA binding motifs that can be joined with our internalizing scFv and produced as a fusion protein that gains the tumor-targeted intracellular siRNA delivery functions. We propose to develop a novel class of scFv-targeted siRNA therapeutics based on our rapidly internalizing human scFv linked via the novel siRNA binding motif to siRNAs that target genes critical for tumor cell survival. PUBLIC HEALTH RELEVANCE: Small interfering RNA (siRNA) has the potential to be a novel class of therapeutics due to its potent and specific effects on target genes. While siRNA has become an effective research tool, its therapeutic application has been hindered by the lack of an effective technology for targeted systemic delivery in vivo. The goal of this project is to develop novel human antibody-targeted systemic siRNA delivery vehicle that could eventually lead to a new class of therapeutics for treating tumor and cancer metastases. We have previously identified a panel of rapidly internalizing human single chain antibodies (scFvs) that target clinically represented prostate cancer cell surface antigens. These scFvs were selected from phage antibody display libraries using laser capture microdissection for their ability to bind to tumor cells in situ residing in their tissue microenvironment, and to mediate efficient intracellular payload delivery to castration resistant prostate cancer cells. We have in addition identified novel siRNA binding motifs that can be joined with our internalizing scFv and produced as a fusion protein that retains tumor targeting and siRNA binding functions. We propose to develop tumor- targeted systemic siRNA delivery vehicles based on our rapidly internalizing human scFv to modulate genes critical for tumor growth and survival.

描述（由申请人提供）：该项目的目标是开发一种新型人单克隆抗体靶向小干扰RNA（siRNA）治疗药物，该治疗药物有可能成为同类首个治疗肿瘤和转移的药物。我们之前已经确定了一个小组快速内化针对临床代表肿瘤细胞表面抗原的人类单链抗体（scFv）。这些 scFv 是使用激光捕获显微切割从噬菌体抗体展示库中选出的，因为它们能够与组织微环境中的肿瘤细胞原位结合，并介导有效的细胞内有效负载递送至肿瘤细胞。我们还发现了新的 siRNA 结合基序，可以与我们的内化 scFv 结合并产生融合蛋白，从而获得肿瘤靶向的细胞内 siRNA 递送功能。我们建议开发一类新型的 scFv 靶向 siRNA 疗法，其基础是我们快速内化的人类 scFv，通过新型 siRNA 结合基序与针对肿瘤细胞存活关键基因的 siRNA 连接。公共健康相关性：小干扰 RNA (siRNA) 由于其对靶基因的有效和特异性作用，有可能成为一类新型疗法。虽然 siRNA 已成为一种有效的研究工具，但由于缺乏体内靶向全身递送的有效技术，其治疗应用受到阻碍。该项目的目标是开发新型人类抗体靶向系统 siRNA 递送载体，最终可能开发出治疗肿瘤和癌症转移的新型疗法。我们之前已经鉴定了一组快速内化的人类单链抗体（scFv），它们靶向临床上代表的前列腺癌细胞表面抗原。这些 scFv 是使用激光捕获显微切割从噬菌体抗体展示库中选择的，因为它们具有结合能力到驻留在其组织微环境中的原位肿瘤细胞，并介导有效的细胞内有效负载递送至去势抵抗性前列腺癌细胞。我们还发现了新的 siRNA 结合基序，可以与我们的内化 scFv 结合并产生融合蛋白，保留肿瘤靶向和 siRNA 结合功能。我们建议开发基于我们快速内化的人 scFv 的肿瘤靶向系统 siRNA 递送载体，以调节对肿瘤生长和存活至关重要的基因。