研究动态
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杀手到救世:烟草植物制备肿瘤免疫检查点抑制剂的表达和生产成本计算。

Killer to cure: Expression and production costs calculation of tobacco plant-made cancer immune checkpoint inhibitors.

发表日期:2023 Feb 21
作者: Laura A Ridgley, Nicole Falci Finardi, Benjamin Gengenbach, Patrick Opdensteinen, Zack Croxford, Julian K-C Ma, Mark Bodman-Smith, Johannes F Buyel, Audrey Y-H Teh
来源: PLANT BIOTECHNOLOGY JOURNAL

摘要:

抗免疫检查点抑制剂(ICIs)在临床上取得了巨大的成功。然而,很多人仍然有限的反应率并且价格昂贵。需要有效而实惠的ICIs,以及本地制造能力来提高可达性,特别是向低收入和中等收入国家(LMIC)扩展。在这里,我们成功地在烟草和丝兰科植物中瞬时表达了三个关键的抗ICIs(anti-PD-1尼伏单抗,抗NKG2A Monalizumab和抗LAG-3 Relatimab)。这些ICIs与不同Fc区域和糖基化特征的组合表达。它们从蛋白质积累水平,靶细胞结合,结合到人类新生儿Fc受体(hFcRn),人类补体C1q(hC1q)和各种Fcγ受体等方面进行了表征,并在100毫克和千克级别的纯化过程中进行了蛋白质回收。发现所有的ICIs都能与目标细胞结合。此外,纯化过程中的回收以及Fcγ受体结合可以根据所使用的Fc区域和糖基化特性进行改变。这打开了使用这两个参数来微调ICIs的预期效果函数的可能性。还生成了一个基于两种生产情境的生产成本模型,即假想的高收入和低收入国家。我们已经证明,植物生产平台的产物积累和回收与哺乳动物细胞基础平台一样具有竞争力。这凸显了植物交付ICIs,可以使市场更加实惠和易于获取的潜力,包括LMIC。本文受版权保护。版权所有。
Immune checkpoint inhibitors (ICIs) have achieved huge clinical success. However, many still have limited response rates, and are prohibitively costly. There is a need for effective and affordable ICIs, as well as local manufacturing capacity to improve accessibility, especially to low-to-middle income countries (LMICs). Here, we have successfully expressed three key ICIs (anti-PD-1 Nivolumab, anti-NKG2A Monalizumab, and anti-LAG-3 Relatimab) transiently in Nicotiana benthamiana and Nicotiana tabacum plants. The ICIs were expressed with a combination of different Fc regions and glycosylation profiles. They were characterised in terms of protein accumulation levels, target cell binding, binding to human neonatal Fc receptors (hFcRn), human complement component C1q (hC1q) and various Fcγ receptors, as well as protein recovery during purification at 100 mg- and kg-scale. It was found that all ICIs bound to the expected target cells. Furthermore, the recovery during purification, as well as Fcγ receptor binding, can be altered depending on the Fc region used and the glycosylation profiles. This opens the possibility of using these two parameters to fine tune the ICIs for desired effector functions. A scenario-based production cost model was also generated based on two production scenarios in hypothetical high- and low-income countries. We have shown that the product accumulation and recovery of plant production platforms were as competitive as mammalian cell-based platforms. This highlights the potential of plants to deliver ICIs that are more affordable and accessible to a widespread market, including LMICs.This article is protected by copyright. All rights reserved.