Impact of IgG Fc‐Oligosaccharides on Recombinant Monoclonal Antibody Structure, Stability, Safety, and Efficacy

Abstract

Glycosylation of the conserved asparagine residue in the CH2 domain is the most common posttranslational modification of recombinant monoclonal antibodies. Ideally, a consistent oligosaccharide profile should be maintained from early clinical material to commercial material for the development of recombinant monoclonal therapeutics, though variation in the profile is a typical result of process changes. The risk of oligosaccharide variation posed to further development is required to be thoroughly evaluated based on its impact on antibody structure, stability, efficacy and safety. The variation should be controlled within a range so that there is no detrimental impact on safety and efficacy and thus allowing the use of early phase safety and efficacy data to support project advancement to later phase. This review article focuses on the current scientific understanding of the commonly observed oligosaccharides found in recombinant monoclonal antibodies and their impact on structure, stability and biological functions, which are the basis to evaluate safety and efficacy. It also provides a brief discussion on critical quality attribute (CQA) assessment with regard to oligosaccharides based on the mechanism of action (MOA). © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1173-1181, 2017.

Engineering of Fc Fragments with Optimized Physicochemical Properties Implying Improvement of Clinical Potentials for Fc-Based Therapeutics

“…The primary sequence of IgG CH2 has a glycosylation motif N297–S298–T299 that results in N-linked glycosylation ( 48 ). The oligosaccharides are important for the stability, aggregation propensity, and effector functions of Fc fragment ( 49 ). For example, removal of the oligosaccharides results in reduction of aggregation resistance in IgG1 under acidic conditions ( 50 ).…”

“…According to the difference of oligosaccharides on the outer arms, N-glycan can be classified into three categories including high mannose (Man), complex, and hybrid ( 49 ). All of these classes share an invariable core structure containing two copies of primary N -acetylglucosamine (GlcNAc), one primary Man and the two secondary Man residues.…”

Monoclonal Antibodies as an Antibacterial Approach Against Bacterial Pathogens

“…More recent advances also include the development of phage display libraries of engineered Hu-mAbs that can dramatically increase the total number of human antibodies for testing to increase the likelihood of finding a unique antibody to interfere with or delay a disease-state [12]. Molecular biology and recombinant DNA techniques have also allowed researchers to modify different amino acids of the antibody's structure to improve stability and utility in the host [13]. On the whole, the state of the science has advanced to where three major approaches are typically used to isolate/generate Hu-mAbs for therapeutic use: combinatorial display libraries, humanized mice, or single B cell cloning, and each of these strategies are Until the Golden Age of Antibiotics began in the 1940s with the advent of penicillin, delivering passive immunity via horse serum or using bacteriophage therapy were the standards to treat bacterial infection [4,5], and the epic story of the birth of the Iditarod indicates how important serum was at limiting the spread of a bacterial infection outbreak.…”

Identification and Characterization of a Residual Host Cell Protein Hexosaminidase B Associated with N-glycan Degradation During the Stability Study of a Therapeutic Recombinant Monoclonal Antibody Product

“…Glycosylation is a critical posttranslational modification (PTM) in biologics that affects several relevant functions, such as pharmacokinetics, pharmacodynamics, and immunogenicity. [9][10][11] For instance, sialic acid is present on N-linked or O-linked glycans. Both variants can extend biologics half-life, while high mannose glycosylation is known to reduce half-life.…”