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

单克隆抗体（mab）已被证明在癌症治疗中具有相当大的效用。目前有许多未经修饰的单克隆抗体可用于患者治疗。然而，为了提高单克隆抗体的治疗价值，人们正在努力通过将细胞毒性药物附着在生物分子上来增强其活性。这种小分子药物和抗原特异性生物分子的结合产生了一种靶向药物递送系统，即抗体-药物偶联物（ADC）。然而，许多正在开发的adc存在效力和毒性变化的问题。创建成功的修饰ADC治疗药物的一个重大障碍是需要以均匀形式生产具有确定和控制的毒性有效载荷的共轭产物。然而，现有的化学蛋白修饰方法导致产物的混合物，在许多位置结合了不同数量的毒素。我们已经开发了一种技术平台，能够以可控的、特定位点的方式对蛋白质进行化学修饰。利用这项技术，我们可以产生一组修饰的重组igg，它们具有均匀的附着位点，并且很容易用有毒的有效载荷进行化学修饰。所得的均质adc在蛋白质上的指定位置装载一定量的药物。如果成功，我们相信这项工作将改变ADC的效用

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.