Impact of cell culture on recombinant monoclonal antibody product heterogeneity

Liu, Hongcheng; Nowak, Christine; Shao, Mingwang; Ponniah, Gomathinayagam; Neill, Alyssa

doi:10.1002/btpr.2327

Cited by 33 publications

(35 citation statements)

References 128 publications

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“…Although many protein modifications may cause charge heterogeneity, only the most commonly occurring modifications and their associated impacts are covered here (Figure ). In addition, sialic acid post‐translational modifications (PTMs) are a significant source of acidic species that have been well summarized by other reviews that focus solely on the impact of glycosylation (Gramer, ; Hossler, Khattak, & Li, ; Liu, Nowak, Shao, Ponniah, & Neill, ; Sha, Agarabi, Brorson, Lee, & Yoon, ; Wang, Yin, Chung, & Betenbaugh, ) and are beyond the scope of this review.…”

Section: Commonly Occurring Charge Variants and Their Cqa Managementmentioning

confidence: 99%

“…The many factors influencing charge heterogeneity are broadly grouped here into four categories: cell line development, process conditions, cell culture media, and post‐culture handling. Previous reviews have examined the impact of cell culture medium factors (Liu et al, ) on overall cell culture performance, but none have attempted to provide a comprehensive summary of all relevant methods for controlling charge variants and their mechanism of action. This section will highlight successful control strategies and discuss any known mechanisms of these strategies.…”

Section: Upstream Process Strategies For Charge Variants Controlmentioning

confidence: 99%

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Industrial bioprocessing perspectives on managing therapeutic protein charge variant profiles

Chung

Tian

Tan

et al. 2018

Biotech & Bioengineering

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Controlling the charge profile of therapeutic protein is a critical challenge in the current quality-by-design (QbD) paradigm, throughout all phases of biologics process development (PD): cell line development, upstream cell culture, recovery process, downstream purification, and analytical characterization. Charge variant profiles may influence efficacy and/or lead to unintended side-effects. Thus, maintaining a consistent charge profile is of tremendous importance, and increasingly, researchers have focused efforts toward developing strategies to mitigate variability during cell culture and to improve separation and detection of charge variants. Current understanding of factors affecting charge variant formation during manufacturing remains inadequate, and sometimes, even substantial commitment of resources may still not fully achieve the desired or consistent profiles. As such, this review attempts to provide a comprehensive resource for the biologics community by summarizing the impact of charge variants and CQA management, analytical methods for charge variant detection, as well as strategies in downstream and upstream PD for controlling charge variant profiles.

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Section: Commonly Occurring Charge Variants and Their Cqa Managementmentioning

confidence: 99%

Section: Upstream Process Strategies For Charge Variants Controlmentioning

confidence: 99%

Industrial bioprocessing perspectives on managing therapeutic protein charge variant profiles

Chung

Tian

Tan

et al. 2018

Biotech & Bioengineering

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“…The presence or absence of fucose on the first core GlucNAc dramatically impacts antibody-dependent cell-mediated cytotoxicity (ADCC). 1,[3][4][5][6][7][8] Similarly, the level of terminal galactosylation affects complement-dependent cytotoxicity (CDC). 3,6,[9][10][11] Antibodies with high mannose-containing glycosylation structures (Man5 and higher) are cleared from the bloodstream at a faster rate than those with mature, complex type oligosaccharides, which has direct implications for drug efficacy.…”

Section: Introductionmentioning

confidence: 99%

“…Numerous media additives have been used to modulate glycosylation structures [15][16][17][18][19][20][21][22][23] (reviewed in ref. 8). Similarly, a variety of selective inhibitors have been exploited, blocking either glycosidase, 24,25 mannosidase, 25,26 or sialyl-or fucosyltransferase activities.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive manipulation of glycosylation profiles across development scales

Loebrich

Clark

Ladd

et al. 2018

mAbs

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The extent and pattern of glycosylation on therapeutic antibodies can influence their circulatory halflife, engagement of effector functions, and immunogenicity, with direct consequences to efficacy and patient safety. Hence, controlling glycosylation patterns is central to any drug development program, yet poses a formidable challenge to the bio-manufacturing industry. Process changes, which can affect glycosylation patterns, range from manufacturing at different scales or sites, to switching production process mode, all the way to using alternative host cell lines. In the emerging space of biosimilars development, often times all of these aspects apply. Gaining a deep understanding of the direction and extent to which glycosylation quality attributes can be modulated is key for efficient fine-tuning of glycan profiles in a stage appropriate manner, but establishment of such platform knowledge is time consuming and resource intensive. Here we report an inexpensive and highly adaptable screening system for comprehensive modulation of glycans on antibodies expressed in CHO cells. We characterize 10 media additives in univariable studies and in combination, using a design of experiments approach to map the design space for tuning glycosylation profile attributes. We introduce a robust workflow that does not require automation, yet enables rapid process optimization. We demonstrate scalability across deep wells, shake flasks, AMBR-15 cell culture system, and 2 L singleuse bioreactors. Further, we show that it is broadly applicable to different molecules and host cell lineages. This universal approach permits fine-tuned modulation of glycan product quality, reduces development costs, and enables agile implementation of process changes throughout the product lifecycle. ARTICLE HISTORY

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“…Variation of oligosaccharides is a major topic of discussion for recombinant monoclonal antibody development. Process changes including the use of different cell lines, clones, media type, cell culture conditions, scale, sites and raw materials can all potentially impact the oligosaccharide profiles . The impacts on the product quality, safety and efficacy are required to be thoroughly evaluated.…”

Section: Introductionmentioning

confidence: 99%

Impact of IgG Fc‐Oligosaccharides on Recombinant Monoclonal Antibody Structure, Stability, Safety, and Efficacy

Liu

Nowak

Andrien

et al. 2017

Biotechnology Progress

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Glycosylation of the conserved asparagine residue in the CH2 domain is the most common posttranslational modification of recombinant monoclonal antibodies. Ideally, a consistent oligosaccharide profile should be maintained from early clinical material to commercial material for the development of recombinant monoclonal therapeutics, though variation in the profile is a typical result of process changes. The risk of oligosaccharide variation posed to further development is required to be thoroughly evaluated based on its impact on antibody structure, stability, efficacy and safety. The variation should be controlled within a range so that there is no detrimental impact on safety and efficacy and thus allowing the use of early phase safety and efficacy data to support project advancement to later phase. This review article focuses on the current scientific understanding of the commonly observed oligosaccharides found in recombinant monoclonal antibodies and their impact on structure, stability and biological functions, which are the basis to evaluate safety and efficacy. It also provides a brief discussion on critical quality attribute (CQA) assessment with regard to oligosaccharides based on the mechanism of action (MOA). © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1173-1181, 2017.

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Impact of cell culture on recombinant monoclonal antibody product heterogeneity

Cited by 33 publications

References 128 publications

Industrial bioprocessing perspectives on managing therapeutic protein charge variant profiles

Industrial bioprocessing perspectives on managing therapeutic protein charge variant profiles

Comprehensive manipulation of glycosylation profiles across development scales

Impact of IgG Fc‐Oligosaccharides on Recombinant Monoclonal Antibody Structure, Stability, Safety, and Efficacy

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