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

描述（由申请人提供）：单克隆抗体（mab）是治疗癌症和其他疾病的重要且快速增长的一类治疗药物，它们的成功导致了广泛的重新设计努力，以改善和扩展其功能。最近，我们发现了一种全新的、高度特异性的治疗性抗体和一个小肽（中间质）之间的相互作用。我们假设，与目前的单克隆抗体联合治疗相比，这种相互作用可以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。为了实现这些目标，我们已经证明了我们可以将这种介质偶联到抗原结合支架和靶向细胞上，这些细胞过表达肿瘤抗原EGFR，这些细胞已经用抗EGFR的治疗性单克隆抗体（西妥昔单抗）进行预处理。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质体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结合是高度创新的，其成功的演示将为开发和优化新的多价配体来治疗多种癌症类型奠定基础。

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.