Department of Chemistry and Pharmaceutical Sciences, University of Ferrara, via L. Borsari 46, Ferrara, 44121, Italy.
Department of Chemistry, Materials and Chemical Engineering "Giulio Natta,", Politecnico di Milano, via Mancinelli 7, Milano, 20131, Italy.
Biotechnol J. 2020 Aug;15(8):e1900226. doi: 10.1002/biot.201900226. Epub 2020 May 4.
Oligonucleotides (ONs) are gaining increasing importance as a promising novel class of biopharmaceuticals. Thanks to their fundamental role in gene regulation, they can be used to develop custom-made drugs (also called N-to-1) able to act on the gene expression at pre-translational level. With recent approvals of ON-based therapeutics by the Food and Drug Administration (FDA), a growing demand for high-quality chemically modified ONs is emerging and their market is expected to impressively prosper in the near future. To satisfy this growing market demand, a scalable and economically sustainable ON production is needed. In this paper, the state of the art of the whole ON production process is illustrated with the aim of highlighting the most promising routes toward the auspicated market-size production. In particular, the most recent advancements in both the upstream stage, mainly based on solid-phase synthesis and recombinant technology, and the downstream one, focusing on chromatographic techniques, are reviewed. Since ON production is projected to expand to the large scale, automatized multicolumn countercurrent technologies will reasonably be required soon to replace the current ones based on batch single-column operations. This consideration is supported by a recent cutting-edge application of continuous chromatography for the ON purification.
寡核苷酸（ONs）作为一类有前途的新型生物制药，其重要性日益增加。由于它们在基因调控中的基本作用，ONs 可用于开发定制药物（也称为 N-to-1），能够在翻译前水平上作用于基因表达。随着食品和药物管理局 (FDA) 最近批准了基于 ON 的治疗药物，对高质量化学修饰的 ON 的需求不断增长，预计其市场在不久的将来将显著繁荣。为了满足这一不断增长的市场需求，需要能够规模化且经济可持续的 ON 生产。本文展示了整个 ON 生产过程的最新技术，旨在突出最有前途的生产路线，以达到预期的市场规模。特别是，本文综述了在上游阶段（主要基于固相合成和重组技术）和下游阶段（主要集中在色谱技术）的最新进展。由于 ON 的生产预计将扩大到大规模，自动化多柱逆流技术将很快取代基于批量单柱操作的现有技术。这种考虑得到了连续色谱法在 ON 纯化中的最新前沿应用的支持。
