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

• 批准号: 8662733
• 负责人: Tijana Talisman
• 金额: $ 20.76万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-16 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8662733
• 关键词: Adverse effects; Affect; Affinity; Antibodies; Antigen Targeting; Antigens; Binding; Binding Sites; Biological Assay; Cell Proliferation; Cell membrane; Cells; Cetuximab; Clinic; Colorectal Cancer; Cyclic Peptides; Data; Detection; Disease; Disorder by Site; Engineering; Epidermal Growth Factor Receptor; Epitopes; Geometry; Goals; Growth; Health; Human; Image; Immunoglobulin G; Individual; Investigation; Knowledge; Lead; Length; Ligands; Malignant Neoplasms; Methods; Microscopy; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; Peptides; Pertuzumab; Proteins; Protocols documentation; Reagent; Research Personnel; Resolution; Signal Transduction; Site; Specificity; Staging; Technology; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Therapeutic antibodies; Tissues; Translating; Trastuzumab; Tumor Antigens; Work; antigen binding; base; cancer imaging; cancer therapy; cancer type; cost; design; high throughput screening; improved; innovation; killings; malignant breast neoplasm; neoplastic cell; novel; overexpression; receptor; receptor density; scaffold; single molecule; success; tool; tumor; tumor growth

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(申请人提供)：单抗代表了一种重要且迅速增长的治疗癌症和其他疾病的疗法，它们的成功导致了广泛的重组努力，以改进和扩展它们的功能。最近，我们发现了治疗性抗体和小肽(冥想体)之间的一种全新的、高度特异的相互作用。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，潜在地减少副作用，并与目前涉及单抗组合的治疗方法相比，降低成本。为了达到这些目标，我们已经证明了我们可以将这种抗体偶联到抗原结合支架和过表达肿瘤抗原EGFR的靶细胞上，这些细胞已经用治疗性的抗EGFR单抗(西妥昔单抗)进行了预处理。这一应用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药物作为癌症治疗和成像的先导。这种独特的试剂和单分子检测的组合具有很高的创新性，它的成功示范将为开发和优化治疗多种癌症类型的新的多价配体奠定基础。