Sialix, Inc. 1396 Poinsettia Ave. Vista, CA 92081-8504, USA.
Biotechnol Genet Eng Rev. 2012;28:147-75. doi: 10.5661/bger-28-147.
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.
制药行业发展最快的领域之一是治疗性糖蛋白市场。如今，这些分子在治疗各种疾病方面发挥着重要作用，包括几类蛋白质，即凝血因子、激素、细胞因子、抗血清、酶、酶抑制剂、Ig-Fc 融合蛋白和单克隆抗体。糖基化是治疗性糖蛋白的关键，因为聚糖可以影响它们的产量、免疫原性和功效，从而影响这些治疗的成本和效果。虽然目前使用的几种哺乳动物细胞表达系统可以产生主要被人源化聚糖修饰的治疗性糖蛋白，但它们在最暴露的末端位置可以呈现两种结构，与人类糖链不同。首先，天然的人 N-聚糖缺乏末端 Gal 1-3Gal（α-Gal）修饰；其次，它们不含有非人类唾液酸 N-糖基化神经氨酸（Neu5Gc）。所有人类都会自发产生针对这两种聚糖结构的抗体，从而增加携带这些非人类糖基表位的生物治疗药物的免疫原性。然而，与α-Gal 表位形成鲜明对比的是，外源性 Neu5Gc 可以代谢性地整合到人类细胞中，并以几种可能的表位出现在表达的糖蛋白上。最近的研究表明，这种非人类唾液酸在批准用于治疗各种医疗条件的生物治疗性糖蛋白中以不同的量存在。这些药物糖基上的 Neu5Gc 可能来源于涉及非人类哺乳动物细胞系的生产过程和/或添加动物源性组织培养补充剂。需要进一步研究以充分了解 Neu5Gc 在生物治疗剂中的影响。类似的问题也适用于在动物源性组织培养补充剂中生长的用于同种异体或自体移植的人类细胞。
