Improving Downstream Process Related Manufacturability Based on Protein Engineering—A Feasibility Study

IF 3.9 4区 生物学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Engineering in Life Sciences Pub Date : 2024-06-28 DOI:10.1002/elsc.202400019
Florian Capito, Ting Hin Wong, Christine Faust, Kilian Brand, Werner Dittrich, Mark Sommerfeld, Garima Tiwari, Thomas Langer
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Abstract

While bioactivity and a favorable safety profile for biotherapeutics is of utmost importance, manufacturability is also worth of consideration to ease the manufacturing process. Manufacturability in the scientific literature is mostly related to stability of formulated drug substances, with limited focus on downstream process-related manufacturability, that is, how easily can a protein be purified. Process-related impurities or biological impurities like viruses and host cell proteins (HCP) are present in the harvest which have mostly acid isoelectric points and need to be removed to ensure patient safety. Therefore, during molecule design, the surface charge of the target molecule should preferably differ sufficiently from the surface charge of the impurities to enable an efficient purification strategy. In this feasibility study, we evaluated the possibility of improving manufacturability by adapting the surface charge of the target protein. We generated several variants of a GLP1-receptor-agonist-Fc-domain-FGF21-fusion protein and demonstrated proof of concept exemplarily for an anion exchange chromatography step which then can be operated at high pH values with maximal product recovery allowing removal of HCP and viruses. Altering the surface charge distribution of biotherapeutic proteins can thus be useful allowing for an efficient manufacturing process for removing HCP and viruses, thereby reducing manufacturing costs.

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基于蛋白质工程改善下游工艺的可制造性--可行性研究
生物治疗药物的生物活性和良好的安全性是最重要的,但为了简化生产流程,可制造性也值得考虑。科学文献中的可制造性大多与配制药物的稳定性有关,对下游工艺相关的可制造性(即蛋白质的纯化难易程度)关注有限。收获物中存在与工艺相关的杂质或生物杂质,如病毒和宿主细胞蛋白(HCP),它们大多具有酸等电点,需要去除以确保患者安全。因此,在分子设计过程中,目标分子的表面电荷最好与杂质的表面电荷有足够大的差异,以便采用高效的纯化策略。在这项可行性研究中,我们评估了通过调整目标蛋白质的表面电荷来提高可制造性的可能性。我们生成了几种 GLP1 受体拮抗剂-Fc-结构域-FGF21 融合蛋白的变体,并示范了阴离子交换色谱步骤的概念验证,该步骤可在高 pH 值下操作,并能最大限度地回收产品,从而去除 HCP 和病毒。因此,改变生物治疗蛋白的表面电荷分布有助于实现去除 HCP 和病毒的高效生产工艺,从而降低生产成本。
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来源期刊
Engineering in Life Sciences
Engineering in Life Sciences 工程技术-生物工程与应用微生物
CiteScore
6.40
自引率
3.70%
发文量
81
审稿时长
3 months
期刊介绍: Engineering in Life Sciences (ELS) focuses on engineering principles and innovations in life sciences and biotechnology. Life sciences and biotechnology covered in ELS encompass the use of biomolecules (e.g. proteins/enzymes), cells (microbial, plant and mammalian origins) and biomaterials for biosynthesis, biotransformation, cell-based treatment and bio-based solutions in industrial and pharmaceutical biotechnologies as well as in biomedicine. ELS especially aims to promote interdisciplinary collaborations among biologists, biotechnologists and engineers for quantitative understanding and holistic engineering (design-built-test) of biological parts and processes in the different application areas.
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