Chemically Programmed Antibodies for Cancer Therapy

这里提出的研究旨在开发有效的治疗癌症的新药物。我们假设，通过化学和免疫效应剂的结合，我们可以制备一种多功能和有效的新型免疫治疗药物，化学编程抗体或cabs。在该基金的第一个资助期内，我们证明了小分子配体可以有效地编程催化抗体38C2，以靶向肿瘤及其支持血管系统。在异种移植的人类黑色素瘤和乳腺癌模型以及同基因小鼠黑色素瘤和结肠癌模型中，cabs被证明是有效的治疗药物。在这里，我们的目标是显著增加化学编程抗体方法的范围。我们将开发多功能和有效的连接化学物质，使cabs适应于几乎任何小分子、肽、核酸配体和shrna的组合。我们假设cpAb方法可以赋予每一类分子特征，使它们成为更有效的癌症治疗药物。我们将利用这些连接体制备多功能cabs，这些cabs可以通过多种作用模式攻击癌症，如参与肿瘤相关抗原和中和促血管生成细胞因子，以选择性地杀死肿瘤。我们假设，如果抗血管生成治疗能够定位于肿瘤部位，可能会更有效，副作用更少。我们进一步假设，同时处理肿瘤相关受体和血管生成因子的多功能cabs将是更有效和广泛适用的治疗药物。考虑到我们的靶点与黑色素瘤、乳腺癌、结肠癌、卵巢癌、头颈癌和血管生成的相关性，这种方法的成功发展可能会带来很多好处。利用多功能cabs，我们将在动物模型中研究单个cabs靶向两个或多个受体并中和促血管生成细胞因子治疗癌症的治疗潜力和机制，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。

The study proposed here seeks to develop efficacious new therapeutic agents for the treatment of cancer. We hypothesize that through the combination of chemistry and an immune effector we can prepare a versatile and effective new class of immunotherapeutics, chemically programmed antibodies or cpAbs. During the first funding period of this grant, we demonstrated that small molecule ligands could be used to effectively program the catalytic antibody 38C2 to target tumors and their supporting vasculature. cpAbs were shown to be effective therapeutics in xenografted human melanoma and breast cancer models as well as syngeneic murine melanoma and colon cancer models. Here we aim to significantly increase the scope of the chemically programmed antibody approach. We will develop versatile and effective linker chemistries that will allow cpAbs to be adapted to work with virtually any combinations of small molecules, peptides, nucleic acids ligands and shRNAs. We hypothesize that the cpAb approach can endow each of these classes of molecules with characteristics that make them more effective cancer therapeutics. We will use these linkers to prepare multifunctional cpAbs that can attack cancers through multiple modes of action such as engaging tumor associated antigens and neutralizing proangiogenic cytokines to selectively kill tumors. We hypothesize that antiangiogenic therapy might be more effective and engender fewer side effects if it can be localized to the tumor site. We further hypothesize that multifunctional cpAbs that simultaneously address tumor associated receptors as well as angiogenic factors will be more potent and broadly applicable therapeutic agents. Given the relevance of our targets in melanoma, breast, colon, ovarian, and head and neck cancers and in angiogenesis in general, successful development of this approach may have many benefits. With multifunctional cpAbs, we will address the therapeutic potential and mechanism of treating cancer in animal models with single cpAbs that target two or more receptors and neutralize proangiogenic cytokines 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.