https://www.cell.com/trends/molecular-medicine/pdf/S1471-4914(08)00133-0.pdf

Sialic acids in human health and disease

Biologics such as monoclonal antibodies are much more complex than small-molecule drugs, which raises challenging questions for the development and regulatory evaluation of follow-on versions of such biopharmaceutical products (also known as biosimilars) and their clinical use once patent protection for the pioneering biologic has expired. With the recent introduction of regulatory pathways for follow-on versions of complex biologics, the role of analytical technologies in comparing biosimilars with the corresponding reference product is attracting substantial interest in establishing the development requirements for biosimilars. Here, we discuss the current state of the art in analytical technologies to assess three characteristics of protein biopharmaceuticals that regulatory authorities have identified as being important in development strategies for biosimilars: post-translational modifications, three-dimensional structures and protein aggregation.

Analytical tools for characterizing biopharmaceuticals and the implications for biosimilars

Recombinant glycoproteins produced in animal cell lines often bear the nonhuman sialic acid N-glycolylneuraminic acid (Neu5Gc). Ghaderi et al. show that two monoclonal antibodies in clinical use differ with respect to addition of Neu5Gc and propose that drug developers should consider the consequences of the Neu5Gc modification.

/pdf/implications-of-the-presence-of-n-glycolylneuraminic-acid-in-4nscwnbsm5.pdf

Implications of the presence of N -glycolylneuraminic acid in recombinant therapeutic glycoproteins

One of the fastest growing fields in the pharmaceutical industry is the market for therapeutic glycoproteins. Today, these molecules play a major role in the treatment of various diseases, and include several protein classes, i.e., clotting factors, hormones, cytokines, antisera, enzymes, enzyme inhibitors, Ig-Fc-Fusion proteins, and monoclonal antibodies. Optimal glycosylation is critical for therapeutic glycoproteins, as glycans can influence their yield, immunogenicity and efficacy, which impact the costs and success of such treatments. While several mammalian cell expression systems currently used can produce therapeutic glycoproteins that are mostly decorated with human-like glycans, they can differ from human glycans by presenting two structures at the terminal and therefore most exposed position. First, natural human N-glycans are lacking the terminal Gal 1-3Gal (alpha-Gal) modification; and second, they do not contain the non-human sialic acid N-glycolylneuraminic acid (Neu5Gc). All humans spontaneously express antibodies against both of these glycan structures, risking increased immunogenicity of biotherapeutics carrying such non-human glycan epitopes. However, in striking contrast to the alpha-Gal epitope, exogenous Neu5Gc can be metabolically incorporated into human cells and presented on expressed glycoproteins in several possible epitopes. Recent work has demonstrated that this non-human sialic acid is found in widely varying amounts on biotherapeutic glycoproteins approved for treatment of various medical conditions. Neu5Gc on glycans of these medical agents likely originates from the production process involving the non-human mammalian cell lines and/or the addition of animal-derived tissue culture supplements. Further studies are needed to fully understand the impact of Neu5Gc in biotherapeutic agents. Similar concerns apply to human cells prepared for allo- or auto-transplantation, that have been grown in animal-derived tissue culture supplements.

https://www.tandfonline.com/doi/pdf/10.5661/bger-28-147

Production platforms for biotherapeutic glycoproteins. Occurrence, impact, and challenges of non-human sialylation

Critical quality attributes (CQA) are physical, chemical, biological or microbiological properties or characteristics that must be within an appropriate limit, range or distribution to ensure the desired product quality, safety and efficacy. For monoclonal antibody therapeutics that rely on fraction crystalizable (Fc)-mediated effector function for their clinical activity, the terminal sugars of Fc glycans have been shown to be critical for safety or efficacy. Different glycosylation variants have also been shown to influence the pharmacodynamic and pharmacokinetic behavior while other Fc glycan structural elements may be involved in adverse immune reactions. This review focuses on the role of Fc glycans as CQAs. Fc glycan information from the published literature is summarized and evaluated for impact on patient safety, immunogenicity, bioactivity and pharmacodynamics/pharmacokinetics.

/pdf/fc-glycans-of-therapeutic-antibodies-as-critical-quality-595ivs7azn.pdf

Fc glycans of therapeutic antibodies as critical quality attributes

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2890%2981427-P

Sialylated carbohydrate chains of recombinant human glycoproteins expressed in Chinese hamster ovary cells contain traces of N-glycolylneuraminic acid

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Sialylated carbohydrate chains of recombinant human glycoproteins expressed in Chinese hamster ovary cells contain traces of N-glycolylneuraminic acid