Therapeutic Targeting Agents for Bladder Cancer

项目描述（由申请人提供）：本项目旨在开发用于治疗膀胱癌的新型细胞选择性靶向药物。利用已经开发的两种非重叠噬菌体展示衍生的膀胱癌特异性结合肽（BCSBPs），将在这些BCSBPs与活性化疗药物（表柔比星）和两种生物蛋白（细胞因子IL-2和IL-12）之间建立偶联物。这些bcsbp的结合和功能活性将针对小鼠膀胱癌细胞系进行优化，该细胞系先前显示与多种人类膀胱癌细胞系具有相同的bcsbp结合特性。长期目标是开发必要的方法，将这些靶向基序转化为临床使用的免疫治疗人类膀胱癌。为实现这些目标，将采取两项具体目标：

DESCRIPTION (provided by applicant): The purpose of this project is to develop novel cell-selective therapeutic targeting agents for treating bladder cancer. Making use of two non-overlapping phage-display derived bladder cancer-specific binding peptides (BCSBPs) already developed, conjugates will be created between these BCSBPs and both an active chemotherapeutic drug (Epirubicin) and two biologic proteins (cytokines IL-2 and IL-12). Binding and functional activity of these BCSBPs will be optimized against a mouse bladder cancer cell line previously shown to share the same binding characteristics for these BCSBPs as multiple human bladder cancer cell lines. The long-term goal is to develop the necessary methodology for translating these targeting motifs into clinical use immunotherapeutic against human bladder cancer. Towards achieving these goals, two specific aims will be undertaken: Specific Aim 1: To chemically conjugate BCSBPs with the chemotherapeutic drug Epirubicin, and to assess cytotoxicity of the conjugates in targeting bladder cancer cells. The conjugates will be made through a chemical coupling process that explores positional effects, number of targeting motifs and use of spacers to achieve maximal binding specificity, affinity, and functional cytotoxic activity. Specific aim 2: To genetically conjugate BCSBPs with Thl cytokines IL-2 and IL-12, and to assess the binding and biological activities of these fusion proteins upon targeted bladder cancer cells. These fusion proteins will be made using prokaryotic or insect expression systems. Binding specificity will be optimized using a GFP-conjugate prototype. Biological activity for IL-2 and IL-12, alone and as synergistic agents will be tested using well-established bioassays. Successful completion of this study will result in future pre-clinical studies using these novel therapeutic conjugates in animal bladder cancer models that may further lead to a quick translation of this strategy into a clinically useful treatment modality for human bladder cancer.