High titer oncolytic measles virus production process by integration of dielectric spectroscopy as online monitoring system

Grein Tanja A.; Loewe Daniel; Dieken Hauke; Salzig Denise; Weidner Tobias; Czermak Peter

摘要

Abstract <section xml:id="bit26538-sec-0001" numbered="no"> > Oncolytic viruses offer new hope to millions of patients with incurable cancer. One promising class of oncolytic viruses is Measles virus, but its broad administration to cancer patients is currently hampered by the inability to produce the large amounts of virus needed for treatment (10 10 –10 12 virus particles per dose). Measles virus is unstable, leading to very low virus titers during production. The time of infection and time of harvest are therefore critical parameters in a Measles virus production process, and their optimization requires an accurate online monitoring system. We integrated a probe based on dielectric spectroscopy (DS) into a stirred tank reactor to characterize the Measles virus production process in adherent growing Vero cells. We found that DS could be used to monitor cell adhesion on the microcarrier and that the optimal virus harvest time correlated with the global maximum permittivity signal. In 16 independent bioreactor runs, the maximum Measles virus titer was achieved approximately 40?hr after the permittivity maximum. Compared to an uncontrolled Measles virus production process, the integration of DS increased the maximum virus concentration by more than three orders of magnitude. This was sufficient to achieve an active Measles virus concentration of ?10 10 TCID <sub>50</sub> ml ?1 . </section> </abstract> </span> <span class="z_kbtn z_kbtnclass hoverxs" style="display: none;">展开▼</span> </div> <div class="translation abstracttxt"> <span class="zhankaihshouqi fivelineshidden" id="abstract"> <span>机译：</span><Abstract XMLNS =“http://www.wiley.com/namespaces/wiley”type =“main”xml：lang =“en”> <title type =“main”>抽象</ title> <section XML：ID =“bit26538-sec-0001”编号=“no”> >氯粘性病毒为数百万患者提供新的希望，可治愈的癌症。一类承诺的肉瘤病毒是麻疹病毒，但它的广泛给予癌症患者的施用目前因无法生产治疗所需的大量病毒（10 10 -10 12 < / sup>每剂量病毒颗粒）。麻疹病毒是不稳定的，导致生产过程中的病毒滴度非常低。因此，感染时间和收获时间是麻疹病毒生产过程中的关键参数，它们的优化需要准确的在线监测系统。我们将基于介电光谱（DS）的探针整合到搅拌釜反应器中，以表征粘附的vero细胞中的麻疹病毒生产过程。我们发现DS可用于监测微载波的细胞粘附，并且与全局最大介电常数信号相关的最佳病毒收获时间。在16个独立的生物反应器中，最大麻疹病毒滴度在介电常数最大后约40℃。与不受控制的麻疹病毒生产过程相比，DS的整合增加了超过三个数量级的病毒浓度。这足以实现活性麻疹病毒浓度的＆ 10 10-sup> tcid <sub> 50 </ sub> ml 1 </ sup>。 </ p> </ section> </ abstract> </span> <span class="z_kbtn z_kbtnclass hoverxs" style="display: none;">展开▼</span> </div> </div> <div class="record"> <h2 class="all_title" id="enpatent33" >著录项</h2> <ul> <li> <span class="lefttit">来源</span> <div style="width: 86%;vertical-align: text-top;display: inline-block;"> <a href='/journal-foreign-15017/'>《Biotechnology and Bioengineering》</a> <b style="margin: 0 2px;">|</b><span>2018年第5期</span><b style="margin: 0 2px;">|</b><span>共9页</span> </div> </li> <li> <div class="author"> <span class="lefttit">作者</span> <p id="fAuthorthree" class="threelineshidden zhankaihshouqi"> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Grein Tanja A.&option=202" target="_blank" rel="nofollow">Grein Tanja A.;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Loewe Daniel&option=202" target="_blank" rel="nofollow">Loewe Daniel;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Dieken Hauke&option=202" target="_blank" rel="nofollow">Dieken Hauke;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Salzig Denise&option=202" target="_blank" rel="nofollow">Salzig Denise;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Weidner Tobias&option=202" target="_blank" rel="nofollow">Weidner Tobias;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Czermak Peter&option=202" target="_blank" rel="nofollow">Czermak Peter;</a> </p> <span class="z_kbtnclass z_kbtnclassall hoverxs" id="zkzz" style="display: none;">展开▼</span> </div> </li> <li> <div style="display: flex;"> <span class="lefttit">作者单位</span> <div style="position: relative;margin-left: 3px;max-width: 639px;"> <div class="threelineshidden zhankaihshouqi" id="fOrgthree"> <p>Institute of Bioprocess Engineering Pharmaceutical TechnologyUniversity of Applied Sciences MittelhessenGiessen Germany;</p> <p>Institute of Bioprocess Engineering Pharmaceutical TechnologyUniversity of Applied Sciences MittelhessenGiessen Germany;</p> <p>Institute of Bioprocess Engineering Pharmaceutical TechnologyUniversity of Applied Sciences MittelhessenGiessen Germany;</p> <p>Institute of Bioprocess Engineering Pharmaceutical TechnologyUniversity of Applied Sciences MittelhessenGiessen Germany;</p> <p>Institute of Bioprocess Engineering Pharmaceutical TechnologyUniversity of Applied Sciences MittelhessenGiessen Germany;</p> <p>Institute of Bioprocess Engineering Pharmaceutical TechnologyUniversity of Applied Sciences MittelhessenGiessen Germany;</p> </div> <span class="z_kbtnclass z_kbtnclassall hoverxs" id="zhdw" style="display: none;">展开▼</span> </div> </div> </li> <li > <span class="lefttit">收录信息</span> <span style="width: 86%;vertical-align: text-top;display: inline-block;"></span> </li> <li> <span class="lefttit">原文格式</span> <span>PDF</span> </li> <li> <span class="lefttit">正文语种</span> <span>eng</span> </li> <li> <span class="lefttit">中图分类</span> <span><a href="https://www.zhangqiaokeyan.com/clc/180.html" title="生物工程学（生物技术）">生物工程学（生物技术）;</a></span> </li> <li class="antistop"> <span class="lefttit">关键词</span> <p style="width: 86%;vertical-align: text-top;"> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=cell adhesion time&option=203" rel="nofollow">cell adhesion time;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=process analytical technology&option=203" rel="nofollow">process analytical technology;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=time of harvest&option=203" rel="nofollow">time of harvest;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=vero cells&option=203" rel="nofollow">vero cells;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=virus production&option=203" rel="nofollow">virus production;</a> </p> <div class="translation"> 机译：细胞粘附时间;过程分析技术;收获时间;Vero细胞;病毒生产; 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href="/patent-detail/06120111340515.html">一种石墨碳套在线除瘤装置和除瘤方法</a> <b>[P]</b> . <span> 中国专利： CN108857688A </span> <span> . 2018-11-23</span> </div> </li> <li> <div> <b>3. </b><a class="enjiyixqcontent" href="/patent-detail/06130449103874.html">Attenuated measles virus, recombinantly generated, isolated, measles virus, human respiratory syncytial virus (rsv), subgroup b, attenuated, recombinantly generated, isolated, rsv, subgroup b, vaccine process for immunizing an individual to induce protection against virus measles, process for immunizing an individual to induce protection against rsv, subgroup b, composition, process for producing attenuated infectious measles virus, process for producing attenuated infectious rsv subgroup b</a> <b>[P]</b> . <span> 外国专利：  BR9909076A </span> <span> . 2000-12-05</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：减毒的麻疹病毒，重组产生的，分离的，麻疹病毒，人呼吸道合胞病毒（rsv），b组，减毒，重组产生，分离的，rsv，b组，用于免疫接种以诱导针对病毒麻疹的保护的疫苗方法，免疫个体以诱导针对rsv的保护，b组，组成，减毒的传染性麻疹病毒的生产方法，减毒的rsv传染性亚组的生产方法 </span> </p> </li> <li> <div> <b>4. </b><a class="enjiyixqcontent" href="/patent-detail/06130457216935.html">PRODUCTION AND ADMINISTRATION OF HIGH TITER RECOMBPRODUCTION AND ADMINISTRATION OF HIGH TITER RECOMBINANT RETROVIRUSES INANT RETROVIRUSES</a> <b>[P]</b> . <span> 外国专利：  WO9621014A3 </span> <span> . 1996-09-26</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：高滴度重组的生产和管理以及高滴度重组反转录的管理 </span> </p> </li> <li> <div> <b>5. </b><a class="enjiyixqcontent" href="/patent-detail/06130409295107.html">ONCOLYTIC MEASLES VIRUS.</a> <b>[P]</b> . <span> 外国专利：  MX348369B </span> <span> . 2017-06-08</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：溶瘤性麻疹病毒。 </span> </p> </li> </ul> </div> </div> </div> <div class="theme cardcommon" style="overflow: auto;display:none"> <h3 class="all_title" id="enpatent55">相关主题</h3> <ul id="subject"> </ul> </div> </div> </div> </div> <div class="right rightcon"> <div class="details_img cardcommon clearfix" style="margin-bottom: 10px;display:none;" > </div> </div> </div> <div id="thesis_get_original1" class="downloadBth" style="bottom: 19px;z-index: 999;" onclick="ywcd('0704021882098','4',7,2,1,'',this,24)" class="delivery" prompt="010401" title="通过人工服务将文献原文发送至邮箱" >获取原文</div> <div class="journalsub-pop-up" style="display: none"> <div class="journal-sub"> <h2>期刊订阅</h2> <img src="https://cdn.zhangqiaokeyan.com/img/loginclose.png" alt="关闭" onclick="$('.journalsub-pop-up').hide()"> <p class="pardon">抱歉，该期刊暂不可订阅，敬请期待！</p> <p class="current">目前支持订阅全部北京大学中文核心（2020）期刊目录。</p> <div style="display: flex;margin-top: 69px;justify-content: 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