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Optimization of multivalent ligands by super-resolution microscopy to treat cance

通过超分辨率显微镜优化多价配体治疗癌症

基本信息

批准号：
8837581
负责人：
Tijana Talisman
金额：
$ 20.68万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-16 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8837581
关键词：
Accounting Address Adverse effects Affect Affinity Animals Antibodies Antigen Targeting Antigens Avidity Binding Binding Sites Biological Assay Cancer Patient Cell Proliferation Cell membrane Cells Cetuximab Clinic Colorectal Cancer Cyclic Peptides Data Detection Development Diagnostic Disease Engineering Epidermal Growth Factor Receptor Epitopes Geometry Goals Growth Health Human Image Immunoglobulin G Individual Investigation Kinetics Knowledge Lead Length Ligands Malignant Neoplasms Methods Microscopy Monoclonal Antibodies Monoclonal Antibody Therapy Mus Peptides Pertuzumab Property Protein Engineering Proteins Protocols documentation Reagent Research Personnel Resolution Signal Transduction Site Specificity Staging System Techniques Technology Testing Therapeutic Therapeutic Monoclonal Antibodies Therapeutic antibodies Tissues Translating Trastuzumab Tumor Antigens Work analog antigen binding base cancer imaging cancer therapy cancer type cost density design high throughput screening improved innovation insight killings malignant breast neoplasm neoplastic cell novel overexpression preclinical study receptor receptor density scaffold single molecule success tool tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Monoclonal antibodies (mAbs) represent an important and rapidly growing class of therapeutics to treat cancer and other diseases, and their success has lead to extensive re-engineering efforts to improve and extend their functionality. Recently, we have uncovered a completely novel and highly specific interaction between a therapeutic antibody and a small peptide (a meditope). We hypothesize that this interaction can be exploited to more effectively target diseased tissue, potentially reduce adverse side effects, and lower the cost compared to current treatments involving combination of monoclonal antibodies. Towards these goals, we have demonstrated that we can couple this meditope to an antigen binding scaffold and target cells overexpressing the tumor antigen EGFR that have been pre-treated with the therapeutic monoclonal antibody against EGFR (cetuximab). This application leverages a new super-resolution protocol we recently developed which allows for quantitative investigation of single-molecule distribution on the plasma membrane. We will use super-resolution microscopy to systematically optimize multivalent meditopes as leads for cancer therapy and imaging. This combination of unique reagents and single molecule detection is highly innovative, and its successful demonstration will set the stage to develop and optimize new multivalent ligands to treat multiple cancer types.

描述（由申请人提供）：单克隆抗体（mAb）代表了治疗癌症和其他疾病的一类重要且快速增长的治疗剂，其成功导致了广泛的再工程努力，以改善和扩展其功能。最近，我们发现了治疗性抗体与小肽（中间位）之间的一种全新的高度特异性相互作用。我们假设，这种相互作用可以被利用来更有效地靶向病变组织，潜在地减少不良副作用，并降低成本相比，目前的治疗涉及单克隆抗体的组合。为了实现这些目标，我们已经证明，我们可以将该中间位偶联至抗原结合支架和过表达肿瘤抗原EGFR的靶细胞，所述靶细胞已经用针对EGFR的治疗性单克隆抗体（西妥昔单抗）预处理。该应用程序利用了我们最近开发的一种新的超分辨率协议，该协议允许对质膜上的单分子分布进行定量研究。我们将使用超分辨率显微镜系统地优化多价中间表位作为癌症治疗和成像的线索。这种独特试剂和单分子检测的组合具有高度创新性，其成功演示将为开发和优化新的多价配体以治疗多种癌症类型奠定基础。