Chemically Programmed Antibodies for Cancer Therapy

本文提出的研究旨在开发用于治疗癌症的有效的新治疗剂。我们假设，通过化学和免疫效应物的组合，我们可以制备通用且有效的新型免疫治疗剂，化学程序化抗体或cpAb。在该资助的第一个资助期内，我们证明了小分子配体可用于有效地编程催化抗体38C2以靶向肿瘤及其支持血管系统。cpAb在异种移植的人黑素瘤和乳腺癌模型以及同基因鼠黑素瘤和结肠癌模型中显示出有效的治疗剂。在这里，我们的目标是显着增加化学程序化抗体方法的范围。我们将开发多功能和有效的接头化学，使cpAb能够适应小分子，肽，核酸配体和shRNA的几乎任何组合。我们假设cpAb方法可以赋予这些类别的分子中的每一种特征，使它们成为更有效的癌症治疗剂。我们将使用这些接头来制备多功能cpAb，这些cpAb可以通过多种作用模式来攻击癌症，例如接合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。我们推测，如果抗血管生成治疗能定位于肿瘤部位，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以及血管生成因子的多功能cpAb将是更有效和广泛适用的治疗剂。鉴于我们的靶点在黑色素瘤、乳腺癌、结肠癌、卵巢癌和头颈癌以及一般血管生成中的相关性，这种方法的成功开发可能具有许多益处。利用多功能cpAb，我们将解决用靶向两种或更多种受体并中和促血管生成细胞因子的单一cpAb治疗动物模型中的癌症的治疗潜力和机制，同时解决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。

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.