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Investigation of process conditions and chemical modulators on CHO-cell based trastuzumab production
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Chaturvedi, Antash. Investigation of process conditions and chemical modulators on CHO-cell based trastuzumab production. Retrieved from https://doi.org/doi:10.7282/t3-r4fh-fd45

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TitleInvestigation of process conditions and chemical modulators on CHO-cell based trastuzumab production
NameChaturvedi, Antash (author); Chundawat, Shishir (chair); Zhang, Haoran (member); Singh, Ravendra (member); Rutgers University; School of Graduate Studies
Date Created2022
Other Date2022-05 (degree)
SubjectChemical engineering, Bioengineering, Bioprocess, CHO cells, Glycans, Glycoproteins, MAbs
Extent80 pages : illustrations
DescriptionOver the past few decades several technological and manufacturing advancements have led to the cost-effective production of biotherapeutic drugs. These advancements have opened the horizon for production of complex drug biomolecules like monoclonal antibodies (mAbs) and fusion proteins that have better specificity and efficacy compared to traditional small molecule drugs. However, there are numerous biomanufacturing challenges that still need to be addressed. Production of biologics like mAbs requires mammalian cellular machinery that is extremely sensitive to changes in the cellular environment such as cell culture duration, process conditions (e.g., pH, Temperature), nutrient feed addition etc. Deviations in the process due to various reasons can modify cellular metabolism and in conjunction protein quality attributes (e.g., post-translational protein modifications like N-linked glycosylation). These challenges complicate optimization of the design space for production of such biomolecules. Hence, there is a critical need for improved understanding of process parameters on drug critical quality attributes. Trastuzumab is one such therapeutic glycoprotein, a humanized antibody developed to target overexpressed HER2 receptor in cancer cells. The most common expression system for glycoproteins like trastuzumab are Chinese Hamster Ovary (CHO) cells. CHO cells can produce glycoproteins with humanized N-glycans. However, CHO cells are notoriously known to give poor protein yields and cell-specific productivity when compared to some prokaryotic expression systems. To overcome this challenge this thesis focuses on using process condition and chemical modulators to influence the cell specific productivity of CHOK1GS cell (CHO cell clone) and to understand its impact on trastuzumab critical quality attributes such as glycosylation.This thesis is divided in two research objectives. Objective-1 is focused in understanding the influence of process modulations such as temperature and pH shift during CHO cell culture operating in a fed-batch bioreactor mode. Step change in these process conditions were introduced at the end of exponential growth phase to study the impact on CHOGSK1 cells metabolic state and drug product formation. Objective-2 studies the impact of four exogenous chemical modulators: suramin, dextran sulfate, valeric acid and sodium butyrate in a dose dependent manner to increase the cell specific productivity while maintaining the desired glycosylation states for drug manufacturing. Overall, this work highlights rational bioprocess engineering techniques for late-phase process development to improve the CHO cell specific productivity for glycoproteins without compromising on the mature glycoforms necessary for biological activity and help in developing more optimal process design space.
NoteM.E.
NoteIncludes bibliographical references
Genretheses
Persistent URLhttps://doi.org/doi:10.7282/t3-r4fh-fd45
LanguageEnglish
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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