LBPO.CH01 · 化学 · Late-Breaking
KH617原料药生产：一种合成生物学方法
KH617 API manufacturing: A synthetic biology approach
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
KH617是一种首创（first-in-class）的抗肿瘤候选药物，用于治疗胶质瘤，已获FDA和NMPA批准。可持续地获取高质量、高纯度的关键活性成分（-）-β-榄香烯具有挑战性。为克服这些局限，我们采用合成生物学方法，在酵母中高滴度地生产大牻牛儿烯A（germacrene A），即（-）-β-榄香烯的直接前体。通过引入异源大牻牛儿烯合酶并对内源性甲羟戊酸途径进行迭代重构，获得了一株产大牻牛儿烯A的酵母菌株。使用3升生物反应器对发酵参数进行了广泛优化。最终的生物工艺实现了31 g/L的滴度，这是在不进行原位有机溶剂萃取的情况下酵母中报告的最高值。最后，在GMP条件下使用立方米级工业发酵罐验证了该生物工艺。所得产品质量高、纯度高，符合临床使用要求。近期在中国完成的I期研究显示出令人鼓舞的数据，复发性胶质母细胞瘤患者的预期中位总生存期（mOS）超过18个月。这项工作支持KH617的未来临床研究，KH617是唯一一款由合成生物学赋能、处于II期临床试验的植物来源在研药物。
查看英文原文 English abstract
KH617 is a first-in-class anti-tumor drug candidate for the treatment of glioma approved by FDA and NMPA. Sustainable sourcing of the key active ingredient (-)-beta-elemene of high quality and purity was challenging. To overcome these limitations, we employed a synthetic biology approach to manufacture germacrene A, an immediate precursor of (-)-beta-elemene, at high titers in yeast. By introducing heterologous germacrene synthase and iterative rewiring of indigenous mevalonate pathway, a germacrene A-producing yeast strain was obtained. Extensive optimization of fermentation parameters was performed using 3-L bioreactors. The final bioprocess resulted in a titer of 31 g/L,the highest reported value in yeast in the absence of in situ organic solvent extraction. Lastly, this bioprocess was validated using a cubic-meter industrial fermentor under GMP settings. The resulting products was of high quality and purity and met the requirements for clinical use. Recent completion of Phase I study in China demonstrated encouraging data of an expected mOS over 18 months in patients with recurrent glioblastoma. This work supports future clinical research of KH617 which is the only investigational plant derived drug under Phase II clinical trial empowered by synthetic biology.
利益披露 Disclosure
Y. Zhou,
Sichuan Honghe Biotechnology Co., Ltd. No. 108, Shuxi East Road, Jinniu District, Chengdu, Sichuan, China Employment.
J. Liu,
Sichuan Honghe Biotechnology Co., Ltd. No. 108, Shuxi East Road, Jinniu District, Chengdu, Sichuan, China Employment.
Biotechnology Innovation Drug Application and Transformation Key Laboratory of Sichuan Province, Chengdu, China ).
C. Gao,
Sichuan Honghe Biotechnology Co., Ltd. No. 108, Shuxi East Road, Jinniu District, Chengdu, Sichuan, China Employment.
H. Luo,
Sichuan Honghe Biotechnology Co., Ltd. No. 108, Shuxi East Road, Jinniu District, Chengdu, Sichuan, China Employment.
Biotechnology Innovation Drug Application and Transformation Key Laboratory of Sichuan Province, Chengdu, China ).
M. Zhao,
Sichuan Honghe Biotechnology Co., Ltd. No. 108, Shuxi East Road, Jinniu District, Chengdu, Sichuan, China Employment.
Therapeutic Proteins Key Laboratory of Sichuan Province, Chengdu, China ).
Chengdu Kanghong Pharmaceuticals Group Co. Ltd, Chengdu, China Employment.
X. Ke,
Sichuan Honghe Biotechnology Co., Ltd. No. 108, Shuxi East Road, Jinniu District, Chengdu, Sichuan, China Employment.
Therapeutic Proteins Key Laboratory of Sichuan Province, Chengdu, China ).
Chengdu Kanghong Pharmaceuticals Group Co. Ltd, Chengdu, China Employment.