Using Aldehyde Tags to Generate Site-Specifically Modified Antibody Drug Conjugat

描述：单克隆抗体（mAb）已被证明在癌症治疗中具有相当大的实用性。目前有许多未修饰的mAb可用于患者治疗。然而，为了提高单克隆抗体的治疗价值，相当大的努力集中在通过将细胞毒性药物连接到生物分子来增强其活性。小分子药物和抗原特异性生物分子的这种组合产生了药物递送的靶向系统，即抗体-药物缀合物（ADC）。然而，许多开发中的ADC具有可变效力以及毒性的问题。产生成功的经修饰的ADC治疗剂的显著障碍是需要产生具有限定和受控的毒性有效负载的均质形式的缀合产物。然而，用于化学蛋白质修饰的现有方法导致产物的混合物，其中不同量的毒素在许多位置与抗体缀合。我们开发了一个技术平台，可以以可控的、位点特异性的方式对蛋白质进行化学修饰。使用这种技术，我们可以产生一组修饰的重组IgG，其具有同质的附着位点，并且易于用有毒的有效载荷进行化学加工。所得的均质ADC负载有置于蛋白质上的限定位置处的限定量的药物。如果成功，我们相信这项工作将改变ADC的效用 治疗，并将导致最好的同类药物的强大管道。我们提出的第一个ADC产品是与美登素位点特异性缀合的抗CD 22 IgG，用于治疗B细胞白血病和淋巴瘤。我们将产生一组抗CD 22 ADC，并选择一种主要候选药物，作为临床研究的潜在生物制剂。

DESCRIPTION: Monoclonal antibodies (mAbs) have demonstrated considerable utility in cancer treatment. There are a number of unmodified mAbs currently available for patient treatment. However, in order to improve the therapeutic value of mAbs considerable effort is being focused on enhancing their activity by attaching cytotoxic drugs to the biomolecules. This combination of small molecule drugs and antigen specific biomolecules results in a targeted system for drug delivery, an antibody-drug conjugate (ADC). However, many ADCs in development have had issues with variable potency as well as toxicity. A significant obstacle to the creation of a successful modified ADC therapeutic is the need to produce the conjugated product in a homogenous form with a defined and controlled toxic payload. However, the existing methods for chemical protein modification result in mixtures of product, with varying amounts of toxin conjugated to the antibody in numerous locations. We have developed a technology platform that enables the chemical modification of proteins in a controlled, site-specific manner. Using this technology we can generate a panel of modified recombinant IgGs that have homogenous attachment sites and are easy to chemically elaborate with a toxic payload. The resulting homogenous ADCs are loaded with a defined amount of drug placed at a defined position on the protein. If successful, we believe this work will change the utility of ADC therapeutics and will result in a robust pipeline of best in class drugs. Our first proposed ADC product is an anti-CD22 IgG site-specifically conjugated with maytansine to be used for the treatment of B-cell leukemia and lymphomas. We will generate a panel of anti-CD22 ADCs and select a lead candidate to be developed as a potential biotherapeutic for clinical studies.