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

描述（由申请人提供）：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，包括Rituxan（非霍奇金淋巴瘤）、Erbitux（结直肠癌）、Herceptin（转移性乳腺癌）和Avastin（结直肠癌）。为了提高单克隆抗体的治疗价值，目前人们正致力于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具有不同的效力和毒性问题，特别是肝毒性。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，现有的化学蛋白质修饰方法导致产物的混合物，不同量的毒素结合到肽主链上。我们已经开发了一个技术平台，以一种可控的、特定位点的方式修饰蛋白质。该技术可以产生修饰的重组IgG，具有均匀的附着位点，并且易于化学修饰，从而产生偶联抗体，偶联到指定数量的药物。如果成功，我们相信这项工作将改变ADC治疗的效用，并将导致一流生物治疗药物的强大管道。

DESCRIPTION (provided by applicant): Monoclonal antibodies (mAbs) have demonstrated considerable utility in cancer treatment. There are a number of unmodified mAbs currently available for patient treatment, including Rituxan (non-Hodgkin's lymphoma), Erbitux (colorectal carcinoma), Herceptin (metastatic breast cancer), and Avastin (colorectal cancer). In order to improve the therapeutic value of mAbs, considerable effort is now 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, in particular, hepatotoxicity. 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 peptide backbone. We have developed a technology platform that modifies proteins in a controlled, site-specific manner. This technology can generate a modified recombinant IgG that has homogenous attachment sites and is easy to chemically elaborate, resulting in a conjugated antibody coupled to a defined amount of drug. If successful, we believe this work will change the utility of ADC therapeutics and will result in a robust pipeline of best in class biotherapeutics. PUBLIC HEALTH RELEVANCE: The combination of small molecule drugs and antigen specific biomolecules results in a targeted system for drug delivery, an antibody-drug conjugate (ADC). Redwood Bioscience's aldehyde-tagged technology can generate a novel, modified recombinant ADC. We believe this work will change the utility of ADC therapeutics and will result in a robust pipeline of best in class biotherapeutics.