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首页> 外文会议>Conference on vaccine technology VI >A TAILOR-MADE PURIFICATION STRATEGY FOR ONCOLYTIC MEASLES VIRUSES USING MEMBRANE-BASED PROCESSES
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A TAILOR-MADE PURIFICATION STRATEGY FOR ONCOLYTIC MEASLES VIRUSES USING MEMBRANE-BASED PROCESSES

机译：基于膜的过程针对麻疹病毒的量身定制纯化策略

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Cancer patients can benefit from the Measles virus, since in the early 70s a relation between cancer remission and an infection with Measles was first mentioned (Bluming, Ziegler 1971). Further studies confirmed this oncolytic activity and therefore, the Measles virus became highly interesting for the application in cancer treatment. However, for the widespread application as a therapeutic agent several bottlenecks have to be overcome in context of quantity and quality. For one therapeutic dose of oncolytic Measles viruses (OMV) at least 1011 infectious particles are needed (one vaccination contains ~10~3 TCID_(50)) (Russell et al. 2014). Besides that, the impurities, such as host cell proteins (HCP) and host cell DNA (hcDNA), must be reduced to appropriate limits set by regulatory authorities. The full recovery of OMV infectivity must also addressed. This underlines the need of a tailor-made downstream processing. After we established a high titer production process, achieving OMV titers of 10~(11) TCID_(50) mL~(-1) (Grein et al. 2017), we are now focused on the downstream processing of OMV. For this purpose we characterized the OMV regarding process parameters used in DSP, such as stability towards ionic strength, osmolality, agglomeration and shear stress. Based on this, a clarification step was conducted, followed by the further purification with tangential flow filtration (TFF). By using polyether sulfone flat sheet membranes in concentration mode, we were able to recover the infectious virus and lowered the impurities by ~70% for hcDNA and ~80% for protein content. In the next purification step, we applied a discontinuous diafiltration and could deplete the impurities by ~95% in total. These results showed that TFF is an appropriate tool for the purification and formulation of OMV.
机译：癌症患者可以从麻疹病毒中受益，因为在70年代初，人们首先提到了癌症缓解与麻疹感染之间的关系（Bluming，Ziegler 1971）。进一步的研究证实了这种溶瘤活性，因此，麻疹病毒对于在癌症治疗中的应用变得非常有趣。然而，对于作为治疗剂的广泛应用，必须在数量和质量上克服几个瓶颈。对于一剂治疗剂量的溶瘤性麻疹病毒（OMV），至少需要1011个感染性颗粒（一次疫苗接种含〜10〜3 TCID_（50））（Russell等人，2014）。除此之外，还必须将杂质（例如宿主细胞蛋白（HCP）和宿主细胞DNA（hcDNA））降低至监管机构设定的适当限值。还必须解决OMV感染性的完全恢复。这强调了需要量身定制的下游处理。建立高滴度的生产工艺后，达到10〜（11）TCID_（50）mL〜（-1）的OMV滴度（Grein等人2017），我们现在专注于OMV的下游加工。为此，我们对OMV进行了DSP中使用的工艺参数的表征，例如对离子强度，渗透压，结块和剪切应力的稳定性。基于此，进行了澄清步骤，然后通过切向流过滤（TFF）进一步纯化。通过在浓缩模式下使用聚醚砜平板膜，我们能够回收感染性病毒，并将hcDNA的杂质降低约70％，将蛋白质含量的杂质降低约80％。在接下来的纯化步骤中，我们进行了不连续的渗滤，可以使杂质总共减少约95％。这些结果表明，TFF是纯化和配制OMV的合适工具。

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