Fang Jianmin, Qian Jing-Jing, Yi Saili, Harding Thomas C, Tu Guang Huan, VanRoey Melinda, Jooss Karin
Department of Preclinical Oncology and Immunology, Cell Genesys, Inc., 500 Forbes Blvd., S. San Francisco, California 94080, USA.
Nat Biotechnol. 2005 May;23(5):584-90. doi: 10.1038/nbt1087. Epub 2005 Apr 17.
Therapeutic monoclonal antibodies (mAbs) are currently being developed for the treatment of cancer and other diseases. Despite clinical success, widespread application of mAb therapies may be limited by manufacturing capabilities. In this paper, we describe a mAb delivery system that allows continuous production of a full-length antibody at high-concentrations in vivo after gene transfer. The mAb is expressed from a single open reading frame by linking the heavy and light chains with a 2A self-processing peptide derived from the foot-and-mouth disease virus. Using this expression system, we generated a recombinant adeno-associated virus vector encoding the VEGFR2-neutralizing mAb DC101 (rAAV8-DC101). A single dose of rAAV8-DC101 resulted in long-term expression of >1,000 microg/ml of DC101 in mice, demonstrating significant anti-tumor efficacy. This report describes the first feasible gene therapy approach for stable delivery of mAbs at therapeutic levels, which may serve as an attractive alternative to direct injection of mAbs.
治疗性单克隆抗体（mAb）目前正被开发用于治疗癌症和其他疾病。尽管在临床上取得了成功，但mAb疗法的广泛应用可能会受到生产能力的限制。在本文中，我们描述了一种mAb递送系统，该系统在基因转移后能够在体内以高浓度持续产生全长抗体。通过将重链和轻链与源自口蹄疫病毒的2A自切割肽连接，mAb由单个开放阅读框表达。使用这种表达系统，我们构建了一种编码VEGFR2中和性mAb DC101的重组腺相关病毒载体（rAAV8-DC101）。单剂量的rAAV8-DC101可使小鼠体内长期表达超过1000μg/ml的DC101，显示出显著的抗肿瘤疗效。本报告描述了第一种可行的基因治疗方法，可在治疗水平稳定递送mAb，这可能是直接注射mAb的一种有吸引力的替代方法。
