Chemically Programmed Antibodies for Cancer Therapy

描述（由申请人提供）：本文提出的研究旨在开发用于治疗癌症的有效新治疗剂。对与支持癌症生长的肿瘤血管生成相关的分子靶点、参与癌症转移的受体以及与肿瘤细胞本身相关的分子靶点的理解增加，为在多个水平上有效靶向癌症提供了新的机会。将抗体靶向肿瘤血管和肿瘤本身的前景是用于多种癌症的新的有效疗法。我们假设整合素avb3和avb5可能满足这些标准中的一些。在初步研究中，我们已经制备了一种新的化学程序化抗体，其靶向整合素avb3和avb5，并在卡波西肉瘤、黑色素瘤和结肠癌的动物模型中证明了这种免疫抑制剂的功效。此外，我们已经鉴定了靶向几种其他肿瘤相关标志物的配体，这些标志物可以补充整合素标志物，为癌症提供协同的分子治疗。我们假设靶向肿瘤相关抗原以及血管生成受体的抗体将是更有效和广泛适用的治疗剂。我们将尝试进一步验证我们的化学程序化抗体方法和双室靶向假说在癌症动物模型中的实用性。考虑到整联蛋白avb3和avb5在黑素瘤、卵巢癌和宫颈癌中的相关性以及一般在血管生成中的相关性，使用这些分子靶标和本文提出的化学程序化抗体方法的成功可能具有许多益处。利用化学程序化抗体，我们将探讨在动物模型中用靶向1、2或3种确定受体的单一抗体治疗黑色素瘤、乳腺癌和卵巢癌的治疗潜力和机制，同时探讨在癌症中结合抗血管生成和肿瘤靶向免疫疗法是否具有协同或相加优势的问题。预计这项工作的结果将为癌症的治疗提供一种有前途的新方法。

DESCRIPTION (provided by applicant): The study proposed here seeks to develop efficacious new therapeutic agents for the treatment of cancer. An increased understanding of molecular targets associated with tumor angiogenesis that supports cancer growth, receptors involved in cancer metastasis, and molecular targets associated with tumor cells themselves, provide novel opportunities for effective targeting of cancer at multiple levels. The promise of targeting antibodies to both the tumors vasculature and the tumor itself is a new and effective therapy for a variety of cancers. We hypothesize that the integrins avb3 and avb5 might fulfill some of these criteria. In preliminary studies, we have prepared a novel chemically programmed antibody that targets the integrins avb3 and avb5 and demonstrated the efficacy of this immunotherapeutic in animal models of Kaposi's sarcoma, melanoma, and colon cancer. Additionally, we have identified ligands that target several other tumor associated markers that can complement the integrin markers in providing a concerted molecular therapy for cancer. We hypothesize that antibodies that target tumor associated antigens as well as angiogenic receptors wilt be more potent and broadly applicable therapeutic agents. We will attempt to further validate the utility of our chemically programmed antibody approach and the dual compartment targeting hypothesis in animal models of cancer. Given the relevance of integrins avb3 and avb5 in melanoma, ovarian, and cervical cancers and in angiogenesis in general, success using these molecular targets and the chemically programmed antibody approach proposed herein may have many benefits. With chemically-programmed antibodies, we will address the therapeutic potential and mechanism of treating melanoma, breast, and ovarian cancer in animal models with single antibodies that target 1,2, or 3 defined receptors while addressing the question of whether there is a synergistic or additive advantage of combining anti-angiogenic and tumor targeted immunotherapies in cancer. It is anticipated that the results of this work will provide a promising new approach to the treatment of cancer.