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

描述：单抗已在癌症治疗中显示出相当大的效用。目前有许多未经修饰的单抗可用于患者治疗。然而，为了提高单抗的治疗价值，人们正致力于通过将细胞毒药物附着在生物分子上来增强单抗的活性。这种小分子药物和抗原特异性生物分子的结合形成了靶向给药系统，即抗体-药物结合物(ADC)。然而，许多正在开发的ADC存在效力和毒性可变的问题。创造成功的改良ADC疗法的一个重要障碍是需要生产具有定义和控制的毒性有效载荷的同质形式的结合产品。然而，现有的蛋白质化学修饰方法导致产物的混合物，不同数量的毒素在许多位置与抗体结合。我们已经开发了一种技术平台，能够以受控的、特定于部位的方式对蛋白质进行化学修饰。使用这项技术，我们可以产生一组修饰的重组IgG，它们具有同质的附着位置，并且很容易用有毒的有效载荷进行化学加工。所产生的同质ADC被加载一定数量的药物，放置在蛋白质上的特定位置。如果成功，我们相信这项工作将改变ADC的实用价值 治疗，并将导致一流药物的强大流水线。我们的第一个建议的ADC产品是抗CD22免疫球蛋白G位点-与美坦辛特异性结合，用于治疗B细胞白血病和淋巴瘤。我们将生成一组抗CD22的ADC，并选择一种主要候选者作为潜在的生物治疗药物用于临床研究。

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.