Small-Molecule Antibody Recruiting Therapeutics for Treating Human Disease

用于治疗人类疾病的小分子抗体招募疗法

• 批准号: 7431968
• 负责人: David A Spiegel
• 金额: $ 248.13万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7431968
• 关键词: Adverse effects; Affinity; Antibodies; Antiviral Agents; B lymphoid malignancy; Binding; Biological; Biological Availability; Blood Circulation; Cell surface; Cells; Chemicals; Complement-Dependent Cytotoxicity; Complex; Evaluation; HIV; HIV Envelope Protein gp120; Human; In Vitro; Interleukin 6 Receptor; Lead; Ligands; Malignant Neoplasms; Methods; Modeling; Molecular; Multiple Myeloma; Oral; Range; Reagent; Recruitment Activity; Reporting; Rheumatoid Arthritis; Surface; Therapeutic; antibody-dependent cell cytotoxicity; base; cell type; chemical synthesis; cost; cytotoxicity; dinitrophenyl; high throughput screening; human disease; in vivo; instrument; mathematical model; novel therapeutics; small molecule; therapeutic target; tissue culture

In recent years, antibody-based therapeutics have become important instruments in treating human diseases ranging from rheumatoid arthritis to cancer. However, these approaches suffer from certain limitations including severe (often fatal) side-effects, lack of oral bioavailability, and high cost. Here, we propose an alternative method that exploits the powerful cytolytic potential of antibodies already present in the human bloodstream. We will synthesize small-molecules capable of redirecting endogenous anti-2,4-dinitrophenyl (anti-DNP) antibodies to the surfaces of various pathogenic cell-types (Figure). As shown, bifunctional molecular constructs will be composed of a bivalent antibody-binding terminus (ABT), a cell surfacebinding terminus (CBT), and a linker region. Formation of a ternary complex between these agents, anti-DNP antibodies, and target cells, will lead to targeted cytotoxicity through various mechanisms including antibody-dependent cellular cytotoxicity (ADCC), or complement-dependent cytotoxicity (CDC). Applications of this approach to cancer and HIV treatment are described, along with more general directions. The proposed studies involve three aims: (1) to synthesize and evaluate an ABT capable of binding endogenous anti-DNP antibodies with high affinity, (2) to synthesize and evaluate a bifunctional small-molecule antiviral reagent targeting HIV gp120, and (3) to identify a small-molecule ligand for the interleukin-6 (IL-6) receptor for incorporation into bifunctional therapeutics targeting the B-cell malignancy multiple myeloma. Concise chemical syntheses of these agents are set forth, and encompass no more than six chemical transformations each. Biological evaluation will employ well established in vitro, and tissue culture models. Mathematical modeling studies are also reported that demonstrate numerically the feasibility of this approach for in vivo applications. Since high-throughput screening methods are ideally suited to identifying cell surface binding small-molecules, this general strategy is not limited to any particular type of target cell. If successful, the proposed method would represent a novel therapeutic approach to a variety of human diseases.

近年来，基于抗体的疗法已成为治疗从类风湿关节炎到癌症等人类疾病的重要工具。然而，这些方法存在一定的局限性，包括严重（通常是致命的）副作用、缺乏口服生物利用度和高成本。 在这里，我们提出了一种替代方法，利用人类血液中已有抗体的强大细胞溶解潜力。 我们将合成能够将内源性抗 2,4-二硝基苯基（抗 DNP）抗体重定向至各种致病细胞类型表面的小分子（图）。如图所示，双功能分子构建体将由二价抗体结合末端（ABT）、细胞表面结合末端（CBT）和接头区域组成。这些药物、抗 DNP 抗体和靶细胞之间形成三元复合物，将通过各种机制产生靶向细胞毒性，包括抗体依赖性细胞毒性 (ADCC) 或补体依赖性细胞毒性 (CDC)。 描述了这种方法在癌症和艾滋病毒治疗中的应用，以及更一般的方法 方向。 拟议的研究涉及三个目标：（1）合成和评估能够以高亲和力结合内源性抗DNP抗体的ABT，（2）合成和评估针对HIV gp120的双功能小分子抗病毒试剂，以及（3）鉴定白细胞介素6（IL-6）受体的小分子配体以掺入 针对 B 细胞恶性肿瘤多发性骨髓瘤的双功能疗法。阐述了这些试剂的简明化学合成，并且每种试剂包含不超过六种化学转化。生物学评估将采用成熟的体外和组织培养模型。还报道了数学模型研究，以数字方式证明了这种方法在体内应用的可行性。由于高通量筛选方法非常适合鉴定细胞表面结合小分子，因此这种一般策略不限于任何 特定类型的靶细胞。如果成功，所提出的方法将代表一种治疗多种人类疾病的新方法。