Chemically Programmed Antibodies for Cancer Therapy

这项研究旨在开发治疗癌症的有效的新的治疗剂。我们假设，通过化学和免疫效应器的结合，我们可以制备一种多功能和有效的新型免疫疗法，即化学程序化抗体或CPAB。在这笔赠款的第一个资助期，我们证明了小分子配体可以用于有效地编程催化抗体38C2，以靶向肿瘤及其支持的血管系统。CPAB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程序抗体方法的范围。我们将开发通用和有效的连接物化学，使CPAB能够与几乎任何小分子、肽、核酸配体和shRNA的组合一起工作。我们假设，cpAb方法可以赋予这类分子中的每一类使它们在癌症治疗中更有效的特征。我们将利用这些接头来制备多功能CPAB，它可以通过多种作用模式攻击癌症，如结合肿瘤相关抗原，中和促血管生成细胞因子，选择性地杀伤肿瘤。我们假设，如果抗血管生成治疗能够局限于肿瘤部位，可能会更有效，并产生更少的副作用。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CPAB将是更有效和更广泛适用的治疗剂。考虑到我们的靶点在黑色素瘤、乳腺癌、结肠癌、卵巢癌、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会有很多好处。通过多功能CPAB，我们将在单个CPAB靶向两个或更多受体并中和促血管生成细胞因子的动物模型中探讨治疗癌症的潜力和机制，同时解决联合抗血管生成和肿瘤靶向免疫治疗在癌症中是否存在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.