Jefferis Roy
Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
Adv Biochem Eng Biotechnol. 2021;175:281-318. doi: 10.1007/10_2017_32.
The human genome has become a subject of public interest, whilst the proteome remains the province of specialists. Less appreciated is the human glycoprotein (GP) repertoire (proteoglycome!); however, some 50% of open reading frame genes encode for proteins (P) that may accept the addition of N-linked and/or O-linked sugar chains (oligosaccharides). It is established that the attachment of defined oligosaccharide structures impacts mechanisms of action (MoAs), pharmacokinetics, pharmacodynamics, etc., and is a critical quality attribute (CQA) for recombinant GP therapeutics. The oligosaccharide structure attached at a given site may exhibit structural heterogeneity, and individual structures (glycoforms) may modulate MoAs. The biopharmaceutical industry is challenged, therefore, to produce recombinant GP therapeutics that have structural fidelity to the natural (endogenous) molecule, in non-human cells. Multiple production platforms have been developed that, in addition to the natural glycoform, may produce unnatural glycoforms, including sugar residues that can be immunogenic in human subjects. Following a general introduction to the field, this review discusses glycosylation of recombinant monoclonal antibodies (mAbs), the contribution of glycoforms to MoAs and the development of customised mAb therapeutic glycoforms to optimise MoAs for individual disease indications.
人类基因组已成为公众关注的话题，而蛋白质组仍然是专家们研究的领域。人们对人类糖蛋白（GP）库（蛋白聚糖组！）的了解较少；然而，约50%的开放阅读框基因编码的蛋白质（P）可能会接受N-连接和/或O-连接糖链（寡糖）的添加。已确定特定寡糖结构的附着会影响作用机制（MoA）、药代动力学、药效学等，并且是重组GP治疗药物的关键质量属性（CQA）。在给定位点附着的寡糖结构可能表现出结构异质性，并且单个结构（糖型）可能会调节作用机制。因此，生物制药行业面临的挑战是在非人类细胞中生产与天然（内源性）分子具有结构保真度的重组GP治疗药物。已经开发了多种生产平台，除了天然糖型外，这些平台还可能产生非天然糖型，包括在人类受试者中可能具有免疫原性的糖残基。在对该领域进行一般性介绍之后本文献综述讨论了重组单克隆抗体（mAb）的糖基化、糖型对作用机制的贡献以及定制mAb治疗性糖型的开发，以针对个体疾病适应症优化作用机制。
