Small Molecule Antibody Mimics: Toward a New Paradigm in Targeted Cancer Therapy

描述(由申请人提供)：拟议的研究重点是开发一种新的靶向癌症治疗范例。我们的方法是基于具有抗体功能特性的小分子的开发；这些功能包括 以高亲和力和选择性结合抗原，并能够触发专业吞噬细胞和杀伤细胞(如自然杀伤细胞、巨噬细胞和树突状细胞)的行动。这种材料将结合基于抗体的疗法和传统的基于小分子的方法的许多优点。在这里，我们建议开发小分子抗体模拟物(SAM)，它选择性地与过度表达前列腺特异性膜抗原(PSMA)的癌细胞结合，并通过Fc-Gamma 1型受体(Fc？RI)诱导免疫介导的细胞溶解。Fc？RI只有在与合适的细胞表面固定的配体多价结合时，才能触发免疫细胞释放细胞毒内容物。PSMA是一种细胞表面酶，在前列腺癌细胞和多种癌症(包括胰腺癌、结肠腺癌、多形性胶质母细胞瘤和非小细胞肺癌)的肿瘤新生血管中过表达。初步数据表明，小分子、癌细胞和免疫细胞之间形成的复合体将导致高度选择性的免疫介导的癌细胞破坏。这里提出的策略并不局限于任何一种特定的疾病--治疗行动只取决于抗体模拟物针对的细胞类型。因此，我们认为这项拟议的研究具有非常重要的意义，是改善癌症和其他疾病患者生活的关键一步。

DESCRIPTION (provided by applicant): The proposed studies focus on the development of a new paradigm for targeted cancer therapy. Our approach is based on the development of small molecules that possess the functional properties of antibodies; these functions include the ability to bind antigens with high affinity and selectivity, and the ability to trigger the action of professional phagocytic and killer cells (e.g., natural killer cells, macrophages, and dendritic cells). Such materials would combine the many advantages of antibody-based therapeutics with those of traditional small-molecule-based approaches. Here we propose to develop small molecule antibody mimics (SAMs) that bind selectively to cancer cells that overexpress the prostate-specific membrane antigen (PSMA), and induce immune-mediated cytolysis through the Fc-gamma receptor type 1 (Fc?RI). Fc?RI triggers immune cells to release cytotoxic contents only upon multivalent binding to an appropriate cell-surface-immobilized ligand. PSMA is a cell surface enzyme that is overexpressed both in prostate cancer cells and in tumor neovasculature for a wide variety of cancers (including pancreatic ductal carcinoma, colon adenocarcinoma, glioblastoma multiforme, and non-small cell lung carcinoma). Preliminary data suggests that formation of complexes between the small molecule, cancer cells, and immune cells will lead to highly selective immune-mediated cancer cell destruction. The strategy proposed here is not limited any one particular disease - the therapeutic action is determined simply by which cell type is targeted by antibody mimics. As such, we believe that the proposed research is highly significant, and constitutes a critical step toward improving the lives of patients suffering with cancer and other diseases.