Small-Molecule Antibody Recruiting Therapeutics for Treating Human Disease

近年来，基于抗体的疗法已经成为治疗从类风湿性关节炎到癌症的人类疾病的重要工具。然而，这些方法受到某些限制，包括严重（通常致命）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，利用强大的细胞溶解潜力的抗体已经存在于人体血流。 我们将合成能够将内源性抗2，4-二硝基苯基（抗DNP）抗体重定向到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）和接头区组成。这些试剂、抗DNP抗体和靶细胞之间的三元复合物的形成将通过包括抗体依赖性细胞毒性（ADCC）或补体依赖性细胞毒性（CDC）的各种机制导致靶向细胞毒性。 这种方法在癌症和HIV治疗中的应用被描述，沿着更一般的 方向 拟议的研究涉及三个目标：（1）合成和评价能够以高亲和力结合内源性抗DNP抗体的ABT，（2）合成和评价靶向HIV gp 120的双功能小分子抗病毒试剂，和（3）鉴定用于掺入靶向B-受体的双功能治疗剂的白介素-6（IL-6）受体的小分子配体。多发性骨髓瘤阐述了这些试剂的简明化学合成，并且每种试剂包括不超过六种化学转化。生物学评价将采用完善的体外和组织培养模型。数学建模研究也报道，数值证明这种方法在体内应用的可行性。由于高通量筛选方法理想地适合于鉴定细胞表面结合小分子，因此该一般策略不限于任何方法。 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各种人类疾病的新方法。

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.