PHAGE ANTIBODY BASED PROBES OF ERBB RECEPTOR FUNCTION

说明：（申请人提供） 针对受体酪氨酸的分子疗法的疗效 激酶（RTK）不仅依赖于结合，而且依赖于介导的生物学效应 通过直接或间接作用于受体FT 1受体。我们假设 同时分析受体功能以及受体 密度，将是必不可少的，以确定患者谁将响应新的 抗RTK疗法。对于这个项目，我们建议开发基于抗体的 允许在体外快速评估密度的工具和测定， 磷酸化状态和RTKs的内吞活性。磷酸化状态 很可能被证明是对抑制肿瘤生长的药物有反应的预测 通过抑制受体信号传导（例如赫赛汀和TK抑制剂）。 内吞活性的评估可能预测治疗反应， 利用受体结合作为细胞内给药手段的药物 (for例如免疫脂质体）。内吞作用也可以作为替代 在某些情况下是受体磷酸化状态的标志物。为 本提案的目的，我们将集中精力为 RTKs的ErbB家族的功能评估，包括EGF受体， ErbB 2、ErbB 3和ErbB 4。探针将用于基于机制的 评价新的基于分子的治疗策略， ErbB受体，一个重要的和不断扩大的治疗策略组， 剂.通过提供有关ErbB活性的功能信息， 工具将有助于早期的，基于机制的评估治疗 需要ErbB受体功能以获得抗肿瘤活性的策略（例如， 用于受体介导的内吞药物递送的抗ErbB 2免疫脂质体）作为 以及设计为ErbB功能拮抗剂的那些疗法（例如， 小分子TK抑制剂或ErbB下调调节剂）。这些工具和化验 将基于重组单克隆噬菌体抗体，其允许：1） 分析试剂的最佳工程化;以及2）可靠地生成分析试剂。 重现性试剂

Description: (provided by applicant) The efficacy of molecular based therapies directed at receptor tyrosine kinases (RTKs) depends not only on binding but on biologic effects mediated through direct or indirect effects on receptor ft1nction. We hypothesize that the ability to simultaneously profile receptor function, as well as receptor density, will be essential to identify patients who will respond to novel anti-RTK therapies. For this project, we propose to develop antibody based tools and assays that will permit rapid in vitro assessment of the density, phosphorylation state, and endocytic activity of RTKs. Phosphorylation state is likely to prove predictive of responders to drugs that inhibit tumor growth by inhibiting receptor signaling (for example Herceptin and TK inhibitors). Assessment of endocytic activity is likely to predict therapeutic response to drugs that use receptor binding as a means of delivering drugs intracellularly (for example immunoliposomes). Endocytosis may also serve as a surrogate marker for receptor phosphorylation status in some instances. For the purposes of this proposal, we will focus on generating probes for the functional assessment of the ErbB family of RTKs, including the EGF receptor, ErbB2, ErbB3, and ErbB4. The probes will be used for mechanism-based evaluation of novel molecular based therapeutic strategies directed against ErbB receptors, an important and expanding group of therapeutic strategies and agents. By providing functional information regarding ErbB activity, these tools will facilitate early, mechanism-based assessments of therapeutic strategies requiring ErbB receptor function for anti-tumor activity (e.g., anti-ErbB2 immunoliposomes for receptor-mediated endocytotic drug delivery) as well as those therapies designed to be antagonists of ErbB function (e.g., small molecule TK inhibitors or ErbB-down modulators). These tools and assays will be based on recombinant monoclonal phage antibodies which permit: 1) optimal engineering of the assay reagent; and 2) the reliable generation of a reproducible reagent.