Chemically Programmed Antibodies for Cancer Therapy

描述（由申请人提供）：本研究旨在开发有效的治疗癌症的新药物。对支持肿瘤生长的与肿瘤血管生成相关的分子靶标、参与肿瘤转移的受体以及与肿瘤细胞本身相关的分子靶标的进一步了解，为在多个水平上有效靶向癌症提供了新的机会。针对肿瘤血管和肿瘤本身的抗体是一种新的有效治疗多种癌症的方法。我们假设整合蛋白avb3和avb5可能满足这些标准。在初步研究中，我们制备了一种新的靶向整合素avb3和avb5的化学编程抗体，并在卡波西氏肉瘤、黑色素瘤和结肠癌的动物模型中证明了这种免疫治疗的有效性。此外，我们已经确定了靶向几种其他肿瘤相关标记的配体，这些配体可以补充整合素标记，为癌症提供协调的分子治疗。我们假设针对肿瘤相关抗原和血管生成受体的抗体将是更有效和广泛适用的治疗药物。我们将尝试进一步验证我们的化学编程抗体方法和双室靶向假设在癌症动物模型中的效用。考虑到整合素avb3和avb5在黑色素瘤、卵巢癌和宫颈癌以及血管生成中的相关性，成功使用这些分子靶点和本文提出的化学编程抗体方法可能有许多好处。通过化学编程抗体，我们将在动物模型中研究针对1、2或3个特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，同时解决联合抗血管生成和肿瘤靶向免疫治疗癌症是否有协同或附加优势的问题。预计这项工作的结果将为治疗癌症提供一种有希望的新方法。

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.