Adenoviral delivery of protein-based therapeutics to the tumor microenvironment

腺病毒将基于蛋白质的治疗药物递送至肿瘤微环境

基本信息

批准号：
9247907
负责人：
Sheena N Smith
金额：
$ 0.89万
依托单位：
UNIVERSITY OF ZURICH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247907
关键词：
Adaptor Signaling Protein Adenoviruses Adverse effects Affinity Ankyrin Repeat Antigen Targeting Binding Binding Proteins Biological Markers Blood Circulation Bolus Infusion Bystander Effect Cell Line Cells Chimeric Proteins Clinical Development Dissociation Dose Drug resistance ERBB2 gene Engineering Epidermal Growth Factor Receptor Family Gene Delivery Generic Drugs Genes Goals Growth Growth Factor Gene Growth Factor Overexpression HGF gene Half-Life Health Histology Hormones Injection of therapeutic agent Insulin-Like Growth Factor I Interleukin-6 Ligands Literature Luciferases Malignant Neoplasms Monoclonal Antibodies Patients Pharmaceutical Preparations Production Proliferating Proteins Reporter Genes Resistance development Risk SCID Mice Safety Series Serotyping Signal Transduction Signaling Molecule Somatomedins Source System Technology Testing Therapeutic Therapeutic Agents Therapeutic Monoclonal Antibodies Time Treatment Efficacy Tumor Cell Line Tumor Escape Tumor Markers Viral Virus abstracting base cancer cell cancer therapy combat design improved in vivo interest malignant breast neoplasm monoclonal antibody production mouse model neoplastic cell novel strategies overexpression paracrine particle receptor targeted agent targeted treatment treatment strategy tumor tumor microenvironment tumor progression

项目摘要

DESCRIPTION (provided by applicant): Abstract A major limitation of current strategies targeting growth factors in cancer is achieving a high local concentration of therapeutics to keep growth factors at very low levels for extended periods of time. In vivo production of monoclonal antibody (mAb)-based therapeutics in tumor cells provides an attractive alternative to treatment with repeated high bolus injections, as expression of the secreted therapeutic in tumor cells could provide high local concentrations that could act in a paracrine fashion to quench growth factors in the tumor microenvironment with minimal side effects. In contrast to "tumorlytic" viral approaches, this strategy does not require that all tumor cells be infected, as uninfected cells are still subject to bystander effects of the secreted therapeutic. My project focuses on the use of an adenoviral delivery system to transduce tumor cells with genes encoding secreted payloads for the paracrine delivery of protein-based therapeutics to the tumor microenvironment. These payloads consist of growth factor neutralizing agents that target a series of growth factors overexpressed in cancer (i.e. IL-6, HGF, IGF-1, and EGFR-family associated ligands). My project accomplishes this objective through two specific aims. Aim 1: To develop an adenoviral delivery system for tumor production of payloads in HER-2 expressing tumor lines. Using an adaptor system that utilizes a specific target module for the delivery of an adenovirus to HER2-overexpressing tumors, I will test a series of growth factor neutralizing agents for delivery and secretion efficiency in HER2 tumor cell lines. Aim 2: To evaluate efficacy and safety of adenoviral treatment in HER2-expressing tumors in a murine model. Using SCID mice harboring HER2-positive tumors, the delivery system described will be use to transduce tumor cells with genes encoding these therapeutic agents.

描述（由适用提供）：摘要靶向癌症生长因子的当前策略的主要局限性是达到局部较高的治疗，以使生长因子长时间保持非常低的水平。肿瘤细胞中基于单克隆抗体（MAB）的疗法的体内产生提供了一种有吸引力的替代方法，可以重复进行高注射剂注射，因为肿瘤细胞中分泌的疗法的表达可以提供高局部浓度，可以提供高旁分泌的方式，可在微小副作用中以较小的肿瘤微观效应来抛光肿瘤生长因子。与“肿瘤”病毒方法相比，该策略不需要感染所有肿瘤细胞，因为未感染的细胞仍受到分泌疗法的旁观者的影响。我的项目着重于使用腺病毒递送系统用编码分泌有效载荷的基因转导肿瘤细胞，以将基于蛋白质的疗法递送到肿瘤微环境中。这些有效载荷包括生长因子中和剂，这些因子靶向一系列癌症中过表达的生长因子（即IL-6，HGF，IGF-1和EGFR与家庭相关的配体）。我的项目通过两个具体目标实现了这一目标。目标1：开发一种腺病毒输送系统，用于在HER-2表达肿瘤线中产生有效载荷的肿瘤。使用适配系统，该适配器系统利用特定的目标模块将腺病毒递送到HER2过表达的肿瘤中，我将测试一系列的生长因子中和剂中和剂中和HER2肿瘤细胞系中的分泌效率和分泌效率。目标2：评估鼠模型中腺病毒治疗在表达HER2的肿瘤中的有效性和安全性。使用带有HER2阳性肿瘤的SCID小鼠，描述的递送系统将用于用编码这些治疗剂的基因翻译肿瘤细胞。