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

小分子抗体模拟物：迈向癌症靶向治疗的新范式

• 批准号: 8663289
• 负责人: David A Spiegel
• 金额: $ 32.83万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8663289
• 关键词: Active Sites; Affinity; Antibodies; Binding; Binding Sites; Bispecific Monoclonal Antibodies; Cell Death; Cell surface; Cells; Colon Adenocarcinoma; Complex; Cryopreservation; Cytolysis; Data; Dendritic Cells; Development; Disease; Enzymes; Exhibits; Fc Receptor; Fc domain; Foundations; Glioblastoma; Glutamate Carboxypeptidase II; Goals; HIV; Human; IgG Receptors; Immune; Immune Cell Activation; Immune Targeting; Immune response; Immune system; Immunity; Immunoglobulin G; Immunology; In Vitro; Killer Cells; Laboratories; Lead; Ligands; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mole the mammal; Molecular; Natural Killer Cells; Non-Small-Cell Lung Carcinoma; Pancreatic Ductal Carcinoma; Patients; Performance; Phagocytes; Pharmaceutical Preparations; Physiological; Play; Positioning Attribute; Property; Proteins; Recruitment Activity; Relative (related person); Research; Role; Series; Surface; Therapeutic; Therapeutic Agents; Tissues; antigen binding; base; cancer cell; cancer therapy; cell type; crosslink; cytotoxic; design; human disease; improved; in vivo; inhibitor/antagonist; innovation; insight; killings; macrophage; neovasculature; novel; overexpression; peptidomimetics; programs; prostate cancer cell; receptor; receptor function; research study; scaffold; small molecule; therapeutic protein; tumor

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.

描述（由申请人提供）：拟定研究的重点是开发一种新的靶向癌症治疗模式。我们的方法是基于开发具有抗体功能特性的小分子;这些功能包括以下能力： 以高亲和力和选择性结合抗原，以及触发专职吞噬细胞和杀伤细胞作用的能力（例如，自然杀伤细胞、巨噬细胞和树突细胞）。这种材料将结合联合收割机的抗体为基础的治疗与传统的小分子为基础的方法的许多优点。在这里，我们建议开发小分子抗体模拟物（SAM），选择性结合过表达前列腺特异性膜抗原（PSMA）的癌细胞，并诱导免疫介导的细胞溶解通过Fc-γ受体1型（Fc？RI）。FC？RI触发免疫细胞仅在多价结合到适当的细胞表面固定化配体时释放细胞毒性内容物。PSMA是一种细胞表面酶，其在前列腺癌细胞和多种癌症（包括胰腺导管癌、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，在小分子、癌细胞和免疫细胞之间形成复合物将导致高度选择性的免疫介导的癌细胞破坏。这里提出的策略不限于任何一种特定的疾病-治疗作用简单地由抗体模拟物靶向哪种细胞类型来确定。因此，我们认为这项研究非常重要，是改善癌症和其他疾病患者生活的关键一步。