Abstract
The emerging field of biotherapeutics provides successful treatments for various diseases, yet immunogenicity and limited efficacy remain major concerns for many products. Glycosylation is a key factor determining the pharmacological properties of biotherapeutics, including their stability, solubility, bioavailability, pharmacokinetics, and immunogenicity. Hence, an increased attention is directed at optimizing the glycosylation properties of biotherapeutics. Currently, most biotherapeutics are produced in non-human mammalian cells in light of their ability to produce human-like glycosylation. However, most mammals produce the sialic acid N-glycolylneuraminic acid (Neu5Gc), while humans cannot due to a specific genetic defect. Humans consume Neu5Gc in their diet from mammalian derived foods (red meat and dairy) and produce polyclonal antibodies against diverse Neu5Gc-glycans. Moreover, Neu5Gc can metabolically incorporate into human cells and become presented on surface or secreted glycans, glycoproteins, and glycolipids. Several studies in mice suggested that the combination of Neu5Gc-containing epitopes and anti-Neu5Gc antibodies could contribute to exacerbation of chronic inflammation-mediated diseases (e.g., cancer, cardiovascular diseases, and autoimmunity). This could potentially become complicated with exposure to Neu5Gc-containing biotherapeutics, bio-devices or xenografts. Indeed, Neu5Gc can be found on various approved and marketed biotherapeutics. Here, we provide a perspective review on the possible consequences of Neu5Gc glycosylation of therapeutic protein drugs due to the limited published evidence of Neu5Gc glycosylation on marketed biotherapeutics and studies on their putative effects on immunogenicity, drug efficacy, and safety.
Highlights
Biotherapeutics are a rapidly increasing portion of the pharmaceutical market, with over a 100 new products approved and marketed in the U.S and the European Union over the past decade [1]
The variety of possible monosaccharide compositions and modifications, linkage configurations and branching points gives rise to a tremendous diversity of glycan structures (Varki et al, 2015). Since this is not a template-driven process, proteins with identical amino acid sequences would typically differ in the degree of occupancy of their glycosylation sites, and would carry different glycans in a specific glycosylation site [5]
Production of many biotherapeutics involves non-human mammalian cells, serum or serum-derived substances, are likely to contain some levels of Neu5Gc
Summary
Biotherapeutics are a rapidly increasing portion of the pharmaceutical market, with over a 100 new products approved and marketed in the U.S and the European Union over the past decade [1]. While yeast cells contain mostly high-mannose structures, mammalian-derived systems carry more complex glycans that include galactose, fucose and sialic acids (Figure 1)—all dramatically affecting the pharmacodynamics and pharmokinetics of the drugs, most notable in glycosylated-antibodies [11,12,13]. In a human-like mouse model (Cmah-KO) high consumption of Neu5Gc resulted in an inflammatory phenotype, and together with circulating anti-Neu5Gc antibodies (in Cmah/Ldlr-DKO mouse model) resulted in increased atherosclerosis [52, 86, 90] These findings in mice fit the reported high risk of cardiovascular disease that is associated with consumption of red meat and processed meat [91, 92], clear evidence in humans is still controversial, at least through in vitro studies on effects of anti-Neu5Gc antibodies on human endothelial cells that express authentic Neu5Gc levels [65]. The consequences of Neu5Gc/anti-Neu5Gc responses in humans could potentially be further exacerbated by exposure to Neu5Gccontaining biotherapeutics, bio-devices, or xenografts
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