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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：
8893025
负责人：
BIN LIU
金额：
$ 32.89万
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 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8893025
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 Patients Penetration Pharmaceutical Preparations Positioning Attribute Primary Neoplasm Property Prostatic Neoplasms RNA Binding Recurrent disease Reporter Genes Research Resistance Resources 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 castration resistant prostate cancer human monoclonal antibodies improved in vivo innovation laser capture microdissection men nanoparticle nanosized neoplastic cell novel novel therapeutics pre-clinical prostate cancer cell prostate cancer cell line screening 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.

描述（由申请人提供）：本项目的目标是开发一种新型的人单克隆抗体靶向小干扰RNA（siRNA）治疗药物，该药物有可能成为治疗肿瘤和转移的首个同类药物。我们之前已经确定了一组快速内化靶向临床代表的肿瘤细胞表面抗原的人单链抗体（scFv）。使用激光捕获显微切割从噬菌体抗体展示文库中选择这些scFv，因为它们能够原位结合驻留在其组织微环境中的肿瘤细胞，并介导有效的细胞内有效载荷递送至肿瘤细胞。我们还鉴定了新的siRNA结合基序，其可以与我们的内化scFv连接并作为融合蛋白产生，其获得肿瘤靶向的细胞内siRNA递送功能。我们建议开发一类新的scFv靶向siRNA治疗剂，其基于我们通过新的siRNA结合基序与靶向对肿瘤细胞存活至关重要的基因的siRNA连接的快速内化的人scFv。