Gene transfer of antibodies targeting tumor angiogenesis

描述(申请人提供)：肿瘤的新兴分子图景 血管生成激发了癌症治疗的新策略，这些策略包括 目前处于临床前和临床发展的不同阶段。其中 这些是针对单个分子成分的单抗。 参与了病理过程。在提议的项目中，我们假设 更具体的战略是瞄准两个人而不是一个人 分子成分。特别是，我们正在检验这样一种假设： 血管内皮细胞生长因子在肿瘤血管生成部位的选择性中和作用 不加选择地进行中和。为此，我们将开发双功能抗体。 将血管内皮生长因子中和活性与靶向装置相结合的构建物 并将它们与相应的单功能抗体构建物进行比较。我们的 抗体构建体旨在促进(I)选择性的血管内皮生长因子 通过Tie-2或Tie-2/Ang-2复合体靶向中和，(Ii)全身 通过使用重组腺病毒的基因转移来传递，以及(Iii)临床前 同基因小鼠肿瘤模型的评价。与现有的单抗相比 靶向肿瘤血管生成的抗体，我们预期我们的抗体 构造在功效方面更优越。此外，它们还被设计成 促进从临床前开发到临床开发的更快过渡 基于(I)与人和鼠抗原的交叉反应和(Ii)建立 抗体人源化策略。

DESCRIPTION (PROVIDED BY APPLICANT): The emerging molecular picture of tumor angiogenesis has inspired new strategies for cancer therapy, which are currently in various stages of preclinical and clinical development. Among these are monoclonal antibodies that target individual molecular components involved in the pathologic process. In the proposed project, we hypothesize that a more specific strategy would result from targeting two rather than one molecular component. In particular, we are testing the hypothesis that selective neutralization of VEGF at the site of tumor angiogenesis is superior to unselective neutralization. For this, we will develop bifunctional antibody constructs that combine a VEGF neutralization activity with a targeting device and compare them to the corresponding monofunctional antibody constructs. Our antibody constructs are designed to facilitate (i) selective VEGF neutralization through Tie-2 or Tie-2/ang-2 complex targeting, (ii) systemic delivery by gene transfer using recombinant adenoviruses, and (iii) preclinical evaluation in syngeneic mouse tumor models. Compared to existing monoclonal antibodies that target tumor angiogenesis, we anticipate our antibody constructs to be superior in terms of efficacy. In addition, they are designed to facilitate a faster transition from preclinical to clinical development based on (i) cross-reactivity with human and mouse antigen and (ii) established antibody humanization strategies.