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

使用醛标签生成位点特异性修饰的抗体药物偶联物

• 批准号: 8521563
• 负责人: David Ian Rabuka
• 金额: $ 53.03万
• 依托单位: REDWOOD BIOSCIENCE, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-10 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8521563
• 关键词: Affect; Aldehydes; Antibodies; Antigens; Avastin; Biological Assay; Biological Response Modifier Therapy; CD22 gene; Cell Line; Characteristics; Chemicals; Chinese Hamster Ovary Cell; Chronic Lymphocytic Leukemia; Clinical; Clinical Research; Colorectal Cancer; Coupled; Cytotoxic agent; Data; Data Set; Development; Drug Delivery Systems; Enzymes; Erbitux; Immunoglobulin G; In Vitro; Kinetics; Large Intestine Carcinoma; Lead; Light; Location; Malignant Neoplasms; Methods; Monoclonal Antibodies; Non-Hodgkin' s Lymphoma; Patients; Peptides; Pharmaceutical Preparations; Positioning Attribute; Post-Translational Protein Processing; Production; Proteins; Protocols documentation; Recombinants; Redwood; Relative (related person); Roche brand of rituximab; Roche brand of trastuzumab; Safety; Series; Site; Solutions; Suspension substance; Suspensions; Technology; Therapeutic; Toxic effect; Toxicology; Toxin; Toxin Conjugates; Vertebral column; Work; antibody conjugate; antigen binding; cancer therapy; catalyst; chemical stability; cytotoxicity; design; fluorophore; formylglycine; improved; in vivo; leukemia/lymphoma; malignant breast neoplasm; novel; pre-clinical; public health relevance; scale up; small molecule; tool

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.

描述：单克隆抗体（mAb）在癌症治疗中表现出相当大的效用。目前有许多未修饰的单克隆抗体可用于患者治疗。但是，为了提高mAb的治疗价值，大量精力的重点是通过将细胞毒性药物附着在生物分子上来增强其活性。小分子药物和抗原特异性生物分子的这种组合导致了靶向递送的靶向系统，一种抗体 - 药物结合物（ADC）。但是，许多正在开发的ADC都有效力和毒性可变的问题。创建成功修改的ADC治疗性的一个重要障碍是需要以均质形式生产具有定义和控制的有毒有效载荷的共轭产品。但是，现有的化学蛋白质修饰方法导致产物混合物，毒素在许多位置均与抗体偶联。我们已经开发了一个技术平台，该平台能够以受控的，特定地点的方式对蛋白质进行化学修饰。使用此技术，我们可以生成一组具有同质附件位点的改良重组IgG，并且可以通过有毒有效载荷在化学上精心制作。所得的同质ADC装有定义量的药物，放置在蛋白质上的定义位置。如果成功，我们相信这项工作将改变ADC的效用 疗法，将导致较强的类药物管道。我们提出的第一个ADC产品是一种与Maytansine偶联的抗CD22 IgG位点，用于治疗B细胞白血病和淋巴瘤。我们将生成一组抗CD22 ADC，并选择铅候选者作为临床研究的潜在生物治疗。