Challenges of glycosylation analysis and control: an integrated approach to producing optimal and consistent therapeutic drugs

Zhang, Peiqing; Woen, Susanto; Wang, Tianhua; Liau, Brian; Zhao, Sophie; Chen, Chen; Yang, Yuansheng; Song, Zhiwei; Wormald, Mark R.; Yu, Chuanfei; Rudd, Pauline M.

doi:10.1016/j.drudis.2016.01.006

Cited by 183 publications

(169 citation statements)

References 238 publications

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“…As for the sialylated oligosaccharides, there are two kinds of sialic acid, including the mouse-type N-glycolyneuraminic acid (NGNA) and the human-type N-acetylneuraminic acid (NANA). Previously study has demonstrated that NGNA has an immunogenic risk to patients, while NANA has low hypersensitivity reactions 45 . Our recombinant mAb contained only NANA glycan without NGNA, which is the normal human-type sialylation with low potential immunogenicity.…”

Section: Discussionmentioning

confidence: 98%

A novel glycosylated anti-CD20 monoclonal antibody from transgenic cattle

Zhang

Tang

Guo³

et al. 2018

Sci Rep

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The monoclonal antibody (mAb) against CD20 known as Rituxan is widely used to treat autoimmune diseases and lymphomas. However, further application of Rituxan faces challenges of high production cost, which limits its availability in developing countries. Here, we report a new approach for large production of a recombinant anti-CD20 mAb in the milk of transgenic cattle (at a yield of up to ~6.8 mg/mL), with ~80% recovery rate and >99% purity. Crystallography study showed that our recombinant mAb is structurally nearly identical to Rituxan with only minor differences in N-linked glycosylation pattern. Functional study showed that, while our mAb shared similar target-cell binding capacities and complement-dependent cytotoxicity with Rituxan, our product exhibited a higher binding affinity for FcγRIIIα and a greater antibody-dependent cellular cytotoxicity. Accordingly, our recombinant mAb demonstrated a superior efficacy over Rituxan against B-cell lymphomas in severe combined immunodeficiency mice. Taken together, our data supports transgenic cattle as a novel model for cost-competitive, large-scale production of therapeutic antibodies.

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Section: Discussionmentioning

confidence: 98%

A novel glycosylated anti-CD20 monoclonal antibody from transgenic cattle

Zhang

Tang

Guo³

et al. 2018

Sci Rep

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“…Non-fucosylated therapeutic antibodies exhibit 50 to 1,000-fold higher efficacy than their fucosylated counterparts 65 due, in most cases, to enhanced ADCC activity 68 . Given the abundance of research efforts in this area, it is no surprise that many have concluded that glycosylation is one of the main areas requiring development 69 to improve efficacy 70 and safety 10,70 of next generation therapeutics 61 . Hence, the control of glycosylation of recombinant therapeutic molecules expressed in non-human systems is decisive 71 .…”

Section: Glycosylationmentioning

confidence: 99%

Tailoring recombinant protein quality by rational media design

Brühlmann

Jordan

Hemberger³

et al. 2015

Biotechnology Progress

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Clinical efficacy and safety of recombinant proteins are closely associated with their structural characteristics. The major quality attributes comprise glycosylation, charge variants (oxidation, deamidation, and C‐ & N‐terminal modifications), aggregates, low‐molecular‐weight species (LMW), and misincorporation of amino acids in the protein backbone. Cell culture media design has a great potential to modulate these quality attributes due to the vital role of medium in mammalian cell culture. The purpose of this review is to provide an overview of the way both classical cell culture medium components and novel supplements affect the quality attributes of recombinant therapeutic proteins expressed in mammalian hosts, allowing rational and high‐throughput optimization of mammalian cell culture media. A selection of specific and/or potent inhibitors and activators of oligosaccharide processing as well as components affecting multiple quality attributes are presented. Extensive research efforts in this field show the feasibility of quality engineering through media design, allowing to significantly modulate the protein function. © 2015 American Institute of Chemical Engineers Biotechnol. Prog., 31:615–629, 2015

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“…There are several excellent reviews focusing on the glycosylation analysis of therapeutic glycoproteins in detail [58][59][60][61][62][63]. N-glycosylation analysis of therapeutic proteins can be performed at three different levels (intact protein, glycopeptide, and released glycans), as depicted in Figure 3 [64]. Intact glycoproteins can be analyzed by mass spectrometry (MS) via direct infusion or coupling with separation techniques, such as liquid chromatography (LC)-MS or capillary electrophoresis (CE)-MS [65,66].…”

Section: Analytical Methods To Track N-glycosylation Patternsmentioning

confidence: 99%

“…The bottom-level analysis supports the in-depth microheterogeneity characterization of glycans. Reproduced, with permission, from [64]. For each point of the GU range, the RMP mean and its standard deviation (SD) is calculated to determine the lower and upper tolerance limits.…”

Section: András Guttmanmentioning

confidence: 99%

The glycosylation aspects of biosimilarity

Guttman¹

2018

J Bioanal Biomed

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Teaser: This review summarizes the critical quality attributes of biosimilarity, also introducing the glycosimilarity index as an additional parameter to prove similarity between innovator and biosimilar products. Highlights The critical quality attributes of biosimilarity are reviewed  Regulatory and statistical considerations are summarized.  Importance of glycosylation analysis during biosimilar production is detailed.  Analytical methods to track N-glycosylation patterns are reviewed.  Glycosimilarity index is introduced.The recent expiration of several protein therapeutics opened the door for biosimilar development. Biosimilars are biologic medical products that are similar but not identical copies of already-authorized protein therapeutics. Critical quality attributes (CQA), such as post-translational modifications of recombinant biotherapeutics, are important for the clinical efficacy and safety of both the innovative biologics and their biosimilar counterparts. Here, we summarize biosimilarity CQAs, considering the regulatory guidelines and the statistical aspects (e.g., biosimilarity index) and then discuss glycosylation as one of the important attributes of biosimilarity. Finally, we introduced the 'Glycosimilarity Index', which is based on the averaged biosimilarity criterion.

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Challenges of glycosylation analysis and control: an integrated approach to producing optimal and consistent therapeutic drugs

Cited by 183 publications

References 238 publications

A novel glycosylated anti-CD20 monoclonal antibody from transgenic cattle

A novel glycosylated anti-CD20 monoclonal antibody from transgenic cattle

Tailoring recombinant protein quality by rational media design

The glycosylation aspects of biosimilarity

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