Cell Culture and Bioprocess Operations, Genentech, South San Francisco, California, USA.
Biotechnol Prog. 2024 Jan-Feb;40(1):e3399. doi: 10.1002/btpr.3399. Epub 2023 Oct 24.
Monoclonal antibodies (mAbs) are effective therapeutic agents against many acute infectious diseases including COVID-19, Ebola, RSV, Clostridium difficile, and Anthrax. mAbs can therefore help combat a future pandemic. Unfortunately, mAb development typically takes years, limiting its potential to save lives during a pandemic. Therefore "pandemic mAb" timelines need to be shortened. One acceleration tool is "deferred cloning" and leverages new Chinese hamster ovary (CHO) technology based on targeted gene integration (TI). CHO pools, instead of CHO clones, can be used for Phase I/II clinical material production. A final CHO clone (producing the mAb with a similar product quality profile and preferably with a higher titer) can then be used for Phase III trials and commercial manufacturing. This substitution reduces timelines by ~3 months. We evaluated our novel CHO TI platform to enable deferred cloning. We created four unique CHO pools expressing three unique mAbs (mAb1, mAb2, and mAb3), and a bispecific mAb (BsAb1). We then performed single-cell cloning for mAb1 and mAb2, identifying three high-expressing clones from each pool. CHO pools and clones were inoculated side-by-side in ambr15 bioreactors. CHO pools yielded mAb titers as high as 10.4 g/L (mAb3) and 7.1 g/L (BsAb1). Subcloning yielded CHO clones expressing higher titers relative to the CHO pools while yielding similar product quality profiles. Finally, we showed that CHO TI pools were stable by performing a 3-month cell aging study. In summary, our CHO TI platform can increase the speed to clinic for a future "pandemic mAb."
单克隆抗体（mAbs）是对抗许多急性传染病的有效治疗药物，包括 COVID-19、埃博拉、RSV、艰难梭菌和炭疽。因此，mAbs 有助于应对未来的大流行。不幸的是，mAb 的开发通常需要数年时间，限制了其在大流行期间拯救生命的潜力。因此，“大流行 mAb”的时间线需要缩短。一种加速工具是“延迟克隆”，并利用基于靶向基因整合（TI）的新型中国仓鼠卵巢（CHO）技术。CHO 池，而不是 CHO 克隆，可以用于 I/II 期临床材料生产。然后可以使用最终的 CHO 克隆（产生具有相似产品质量特征的 mAb，最好具有更高的滴度）用于 III 期试验和商业制造。这种替代可以将时间线缩短约 3 个月。我们评估了我们的新型 CHO TI 平台以实现延迟克隆。我们创建了四个表达三种独特 mAb（mAb1、mAb2 和 mAb3）和一种双特异性 mAb（BsAb1）的独特 CHO 池。然后，我们对 mAb1 和 mAb2 进行单细胞克隆，从每个池鉴定出三个高表达的克隆。CHO 池和克隆并排接种在 ambr15 生物反应器中。CHO 池产生的 mAb 滴度高达 10.4 g/L（mAb3）和 7.1 g/L（BsAb1）。亚克隆产生的 CHO 克隆相对于 CHO 池表达更高的滴度，同时产生相似的产品质量特征。最后，我们通过进行 3 个月的细胞老化研究表明 CHO TI 池是稳定的。总之，我们的 CHO TI 平台可以加快未来“大流行 mAb”的临床速度。
