MOLECULAR ENGINEERING OF MONOCLONAL ANTIBODIES FOR THE MANAGEMENT OF CANCER

用于癌症治疗的单克隆抗体分子工程

• 批准号: 6269481
• 负责人: SHUI-ON LEUNG
• 金额: $ 28.13万
• 依托单位: CTR FOR MOLECULAR MEDICINE/IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-16 至 1999-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6269481
• 关键词: antitumor antibody; chimeric proteins; colorectal neoplasms; human genetic material tag; immunoconjugates; immunoglobulin G; molecular cloning; monoclonal antibody; nucleic acid sequence; pancreas neoplasms; pharmacokinetics; protein engineering; radiotracer; transfection

Several problems limiting the use of monoclonal antibodies (MAbs) for the diagnosis and therapy of diseases are addressed using the techniques of molecular biology. The approaches of humanization will be undertaken in an attempt to reduce the immunogenicities elicited by multiple injections of rodent antibodies. The MAbs used for this research include PAM4 (anti-pancreatic cancer), MN-14 (anti-colorectal cancer) and Mu-9 (anti-colorectal cancer), which have been demonstrated to have significant clinical utilities. Favorable pharmacokinetic and biodistribution characteristics, such as faster blood clearance, lower liver and kidney uptake, etc., will be engineered in MAbs. This can be achieved by the deletion of the CH2 domain from the whole IgG molecule. Humanized MN-14 antibody will be used as the prototype for the initial construction and evaluation of this new form of MAb. Moreover, to facilitate and increase the loading capacity for radiolabeling, whole IgG or F(ab')2 fragments containing an IgG3 hinge region, instead of that of IgG1, will be constructed. The improvement in the ease of labeling and radioisotope loading capacity of the IgG3 hinge-containing molecules will be compared to those carrying the IgG1 hinge regions. Hopefully, a humanized, CH2-deleted antibody with a long IgG3 hinge region will serve as a non-immunogenic, highly radioactive biopharmaceutical that can be used repeatedly for the treatment for diseases, without undesirable accumulations in normal tissues and organs. Large quantities of these recombinant MAbs are required for their clinical efficacy assessment; however, the current system for production of MAbs is inadequate. New DNA vectors and transfection protocols will be developed to allow for high level of expression of the recombinant MAbs in a bioreactor.

限制使用单抗(MAb)治疗的几个问题 疾病的诊断和治疗是使用这些技术 分子生物学的研究。将采取人性化的方法 在试图降低由多个 注射啮齿动物抗体。用于这项研究的单抗 包括PAM4(抗胰腺癌)、MN-14(抗结直肠癌) 和Mu-9(抗结直肠癌)，已被证明具有 具有重要的临床实用价值。良好的药代动力学和 生物分布特点，如血液清除较快，较低 肝脏和肾脏的摄取等将在单抗中进行工程设计。这可以是 通过从整个免疫球蛋白分子中删除CH2结构域来实现。 人源化的MN-14抗体将作为初步的原型 这一新形式的单抗的构建和评价。此外，为了 促进和提高放射性标记的承载能力，整体 含有IgG3铰链区的Ig G或F(ab‘)2片段，而不是 将被构建为免疫球蛋白G_1。易用性的提高 含IgG3铰链的标记和放射性同位素载量 分子将被与那些携带IgG1铰链区的分子进行比较。 希望一种人源化的、CH2缺失的抗体带有长的IgG3铰链 区域将作为非免疫原性的、高放射性的 可重复使用的生物制药治疗 疾病，在正常组织中没有不必要的积聚 器官。需要大量的这些重组单抗 他们的临床疗效评估；然而，目前的系统 单抗生产不足。新型DNA载体及其转染法 将开发协议以允许高水平地表达 生物反应器中的重组单抗。