Kinetic modeling as a tool to understand the influence of cell culture process parameters on the glycation of monoclonal antibody biotherapeutics

Agarwal Nitin; Mason Alison; Pradhan Rahul; Kemper Jan; Bosley Allen; Serfiotis‐Mitsa Dimitra; Wang Jihong; Lindo Viv; Ahuja Sanjeev; Hatton Diane; Savery James; Miro‐Quesada Guillermo

摘要

Abstract >Glycation, the nonenzymatic reaction between the reducing sugar glucose and the primary amine residues on amino acid side chains, commonly occurs in the cell culture supernatant during production of therapeutic monoclonal antibodies (mAbs). While glycation has the potential to impact efficacy and pharmacokinetic properties for mAbs, the most common undesirable impact of glycation is on the distribution of charged species, often a release specification for commercial processes. Existing empirical approaches are usually insufficient to rationalize the effects of cell line and process changes on glycation. To address this gap, we developed a kinetic model for estimating mAb glycation levels during the cell culture process. The rate constant for glycation, including temperature and pH dependence, was estimated by fitting the kinetic model to time‐course glycation data from bioreactors operated at different process settings that yielded a wide range of glycation values. The parameter values were further validated by independently estimating glycation rate constants using cell‐free incubation studies at various temperatures. The model was applied to another mAb, by re‐estimating the activation energy to account for effect of a glycation “hotspot”. The model was further utilized to study the role of temperature shift as an approach to reduce glycation levels in the manufacturing process for mAb2. While a downshift in temperature resulted in lowering of glycation levels for mAb2, the model helped elucidate that this effect was caused due to contribution from changes in glucose consumption, mAb secretion and temperature, instead of a direct impact of temperature alone on the kinetic rate of glycation. </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 Type =“Main”XML：Lang =“en”> <标题类型=“main”>抽象</ title> <P>糖化，还原糖葡萄糖与氨基酸侧链上的伯胺残基之间的非酶反应，通常发生在治疗单克隆抗体（MAB）的生产过程中的细胞培养上清液中。虽然甘露解金有可能影响MAB的疗效和药代动力学性质，但糖化的最常见的不良影响是对带电物种的分布，通常是商业过程的释放规范。现有的经验方法通常不足以合理化细胞系和过程变化对糖化的影响。为了解决这种差距，我们开发了一种用于估算细胞培养过程中MAB糖化水平的动力学模型。通过将动力学模型与在不同工艺设置的生物反应器中，通过将动力学模型与在不同的工艺设置中运行的生物反应器的时间过程糖糖数据，估计糖化术，包括温度和pH依赖性的速率常数估计。通过在各种温度下使用无细胞孵育研究独立地估计糖化速率常数，进一步验证参数值。通过重新估算激活能量来估算糖化“热点”的影响，将该模型应用于另一种MAB。进一步利用该模型研究温度变化作为降低MAB2制造过程中糖化水平的方法的作用。虽然温度的降档导致MAB2的甘露糖水平降低，但该模型有助于阐明由于葡萄糖消耗，MAB分泌和温度的变化而不是单独对动力学率直接影响温度的贡献导致这种效果糖化。</ p> </摘要> </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-15005/'>《Biotechnology Progress》</a> <b style="margin: 0 2px;">|</b><span>2019年第5期</span><b style="margin: 0 2px;">|</b><span>共10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=Agarwal Nitin&option=202" target="_blank" rel="nofollow">Agarwal Nitin;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Mason Alison&option=202" target="_blank" rel="nofollow">Mason Alison;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Pradhan Rahul&option=202" target="_blank" rel="nofollow">Pradhan Rahul;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Kemper Jan&option=202" target="_blank" rel="nofollow">Kemper Jan;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Bosley Allen&option=202" target="_blank" rel="nofollow">Bosley Allen;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Serfiotis‐Mitsa Dimitra&option=202" target="_blank" rel="nofollow">Serfiotis‐Mitsa Dimitra;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Wang Jihong&option=202" target="_blank" rel="nofollow">Wang Jihong;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Lindo Viv&option=202" target="_blank" rel="nofollow">Lindo Viv;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Ahuja Sanjeev&option=202" target="_blank" rel="nofollow">Ahuja Sanjeev;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Hatton Diane&option=202" target="_blank" rel="nofollow">Hatton Diane;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Savery James&option=202" target="_blank" rel="nofollow">Savery James;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Miro‐Quesada Guillermo&option=202" target="_blank" rel="nofollow">Miro‐Quesada Guillermo;</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>Cell Culture &</p> <p>Fermentation SciencesMedImmuneGaithersburg Maryland;</p> <p>Cell Culture &</p> <p>Fermentation SciencesMedImmuneCambridge UK;</p> <p>Cell Culture &</p> <p>Fermentation SciencesMedImmuneCambridge UK;</p> <p>Cell Culture &</p> <p>Fermentation SciencesMedImmuneGaithersburg Maryland;</p> <p>Purification Process SciencesMedImmuneGaithersburg Maryland;</p> <p>Analytical SciencesMedImmuneCambridge UK;</p> <p>Analytical SciencesMedImmuneGaithersburg Maryland;</p> <p>Analytical SciencesMedImmuneCambridge UK;</p> <p>Cell Culture &</p> <p>Fermentation SciencesMedImmuneGaithersburg Maryland;</p> <p>Cell Culture &</p> <p>Fermentation SciencesMedImmuneCambridge UK;</p> <p>Quantitative SciencesMedImmuneGaithersburg Maryland;</p> <p>Quantitative SciencesMedImmuneGaithersburg Maryland;</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/15.html" title="生物科学">生物科学;</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=bioreactor&option=203" rel="nofollow">bioreactor;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=glucose&option=203" rel="nofollow">glucose;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=glycation&option=203" rel="nofollow">glycation;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=kinetic model&option=203" rel="nofollow">kinetic model;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=monoclonal antibody&option=203" rel="nofollow">monoclonal antibody;</a> </p> <div class="translation"> 机译：生物反应器;葡萄糖;糖化;动力学模型;单克隆抗体; </div> </li> </ul> </div> </div> <div class="literature cardcommon"> <div class="similarity "> <h3 class="all_title" id="enpatent66">相似文献</h3> <div class="similaritytab clearfix"> <ul> <li class="active" >外文文献</li> <li >中文文献</li> <li >专利</li> </ul> </div> <div class="similarity_details"> <ul > <li> <div> <b>1. </b><a class="enjiyixqcontent" href="/academic-journal-cn_chinese-journal-chemical-engineering_thesis/0201272602148.html">Chemometric identification of canonical metabolites linking critical process parameters to monoclonal antibody production during bioprocess development</a> <b>[J]</b> . <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Lijuan Shen&option=202" target="_blank" rel="nofollow" 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Vincent Price&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">J. Vincent Price,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Robert J. Lovelett&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Robert J. Lovelett,</a> <a href="/conference-foreign-59943/" target="_blank" rel="nofollow" class="tuijian_authcolor">Cell culture engineering conference .</a> <span>2018</span> </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：CHO细胞培养过程中单克隆抗体（MAB）产生和糖基化的建模</span> </p> </li> <li> <div> <b>8. </b><a class="enjiyixqcontent" href="/academic-degree-foreign_mphd_thesis/02061706761.html">Monoclonal antibody aggregation in cell culture: Aggregate characterization and protein stability analysis</a> <b>[D] </b> . <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Russell, Elisabeth Emily&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Russell, Elisabeth Emily </a> <span>2015</span> </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：细胞培养中的单克隆抗体聚集：聚集特征和蛋白质稳定性分析</span> </p> </li> <li> <div> <b>9. </b><a class="enjiyixqcontent" href="/academic-journal-foreign-pmc_detail_thesis/040005568302.html">Mammalian Cell Culture Process for Monoclonal Antibody Production: Nonlinear Modelling and Parameter Estimation</a> <b>[O] </b> . <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Dan Selişteanu&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Dan Selişteanu,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Dorin Șendrescu&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Dorin Șendrescu,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Vlad Georgeanu&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Vlad Georgeanu,</a> <span>-1</span> </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：单克隆抗体生产的哺乳动物细胞培养过程：非线性建模和参数估计。</span> </p> </li> <li> <div> <b>10. </b><a class="enjiyixqcontent" href="/open-access_resources_thesis/0100076295433.html ">Isolation and Characterization of Monoclonal Antibodies Directed Against Plant Plasma Membrane and Cell Wall Epitopes: Identification of a Monoclonal Antibody that Recognizes Extensin and Analysis of the Process of Epitope Biosynthesis in Plant Tissues and Cell Cultures</a> <b>[O] </b> . <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Meyer, David J.&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Meyer, David J.,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Alfonso, Claudio L.&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Alfonso, Claudio L.,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Galbraith, David W.&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Galbraith, David W. </a> <span>1988</span> </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：针对植物质膜和细胞壁表位的单克隆抗体的分离和鉴定：识别扩增素的单克隆抗体的鉴定和植物组织和细胞培养物中表位生物合成过程的分析</span> </p> </li> <li> <div> <b>11. </b><a class="enjiyixqcontent" href="/ntis-science-report_ad_thesis/020711470814.html">Model System for Removing Neuroblastoma Cells from Bone Marrow Using Monoclonal Antibodies and Magnetic Immunobeads</a> <b>[R] </b> . <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Reynolds, C. P.&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Reynolds, C. P.,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Seeger, R. C.&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Seeger, R. C.,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Vo, D. D.&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Vo, D. D.,</a> <span>1986</span> </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：用单克隆抗体和磁性免疫珠去除骨髓神经母细胞瘤细胞的模型系统</span> </p> </li> </ul> <ul style="display: none;"> <li> <div> <b>1. </b><a class="enjiyixqcontent" href="/academic-journal-cn_academic-abstracts-chemical-engineering-chinese-colleges-universities_thesis/0201249274671.html">Real time monitoring of bioreactor mAb IgG3 cell culture process dynamics via Fourier transform infrared spectroscopy: Implications for enabling cell culture process analytical technology</a> <b>[J]</b> <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Huiquan Wu&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . Huiquan Wu</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Erik Read&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,Erik Read</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Maury White&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,Maury White</a> <span> <a href="/journal-cn-9263/" target="_blank" rel="nofollow" class="tuijian_authcolor"> . 中国高等学校学术文摘·化学工程 </a> </span> <span> . 2015</span><span>,第003期</span> </span> </div> </li> <li> <div> <b>2. </b><a class="enjiyixqcontent" href="/academic-journal-cn_detail_thesis/0201296718630.html">Application of Bayesian Approach in the Parameter Estimation of Continuous Lumping Kinetic Model of Hydrocracking Process</a> <b>[J]</b> <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=S. Sina Hosseini Boosari&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . S. Sina Hosseini Boosari</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Neda Makouei&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,Neda Makouei</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Philip Stewart&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,Philip Stewart</a> <span> <a href="/journal-cn-56376/" target="_blank" rel="nofollow" class="tuijian_authcolor"> . 化学工程与科学期刊（英文） </a> </span> <span> . 2017</span><span>,第3期</span> </span> </div> </li> <li> <div> <b>3. </b><a class="enjiyixqcontent" href="/academic-conference-cn_meeting-9642_thesis/020222339704.html">Prediction of Fiber Diameter of Melt Blown Nonwovens Produced by Dual Slot Annular Die from Process Parameters by Intelligent Techniques and Empirical Models</a> <b>[C]</b> <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Zhao Bo&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . Zhao Bo</a> <span> <a href="/conference-cn-9642/" target="_blank" rel="nofollow" class="tuijian_authcolor"> . 第三届全国社会计算会议、平行控制会议、平行管理会议 </a> <span> <span> . 2011</span> </span> </div> </li> </ul> <ul style="display: none;"> <li> <div> <b>1. </b><a class="enjiyixqcontent" href="/patent-detail/06130425478540.html">method for immortalizing a cell population, cell population, oligoclonal or monoclonal cell population, cell culture, cell culture supernatant, DNA library, use of a cell population, cell culture, DNA supernatant or library, kit to identify and produce a monoclonal antibody, method to produce a cell culture, and method to produce a monoclonal antibody</a> <b>[P]</b> . <span> 外国专利：  BRPI0619908A2 </span> <span> . 2011-10-25</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：永生化细胞群体，细胞群体，寡克隆或单克隆细胞群体的方法，细胞培养物，细胞培养上清液，DNA文库，细胞群体的用途，细胞培养物，DNA上清液或文库，用于鉴定和生产单克隆抗体的试剂盒，方法产生细胞培养物和产生单克隆抗体的方法 </span> </p> </li> <li> <div> <b>2. </b><a class="enjiyixqcontent" href="/patent-detail/06130430265786.html">method for immortalizing a cell population, cell population, oligoclonal or monoclonal cell population, cell culture, cell culture supernatant, DNA library, use of a cell population, cell culture, DNA supernatant or library, kit to identify and produce a monoclonal antibody, method to produce a cell culture, and method to produce a monoclonal antibody</a> <b>[P]</b> . <span> 外国专利：  NO20092671L </span> <span> . 2009-09-03</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：永生化细胞群体，细胞群体，寡克隆或单克隆细胞群体的方法，细胞培养物，细胞培养上清液，DNA文库，细胞群体的用途，细胞培养物，DNA上清液或文库，用于鉴定和生产单克隆抗体的试剂盒，方法产生细胞培养物和产生单克隆抗体的方法 </span> </p> </li> <li> <div> <b>3. </b><a class="enjiyixqcontent" href="/patent-detail/06130432713430.html">method for immortalizing a cell population, cell population, oligoclonal or monoclonal cell population, cell culture, cell culture supernatant, DNA library, use of a cell population, cell culture, DNA supernatant or library, kit to identify and produce a monoclonal antibody, method to produce a cell culture, and method to produce a monoclonal antibody</a> <b>[P]</b> . <span> 外国专利：  NO20083160L </span> <span> . 2008-09-10</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：永生化细胞群体，细胞群体，寡克隆或单克隆细胞群体的方法，细胞培养物，细胞培养上清液，DNA文库，细胞群体的用途，细胞培养物，DNA上清液或文库，用于鉴定和生产单克隆抗体的试剂盒，方法产生细胞培养物和产生单克隆抗体的方法 </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 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