Increased serum clearance of oligomannose species present on a human IgG1 molecule
| Autor: | Taro Fujimori, Aima Acquah, Leslie Alessandri, David Ouellette, Czeslaw Radziejewski, Mathew Rieser, Ivan Correia, Mary Saltarelli, David LeBlond |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
glycoprotein
Glycan Time Factors Metabolic Clearance Rate Immunology Mannose Oligosaccharides oligomannose Immunoglobulin G law.invention Sepharose chemistry.chemical_compound Pharmacokinetics law Report serum clearance Immunology and Allergy Humans ortho-Aminobenzoates Glucans Chromatography High Pressure Liquid Chromatography biology Molecular Structure Chemistry Antibodies Monoclonal Ligand (biochemistry) Immunoglobulin Fc Fragments Biochemistry Monoclonal biology.protein Recombinant DNA pharmacokinetics Monte Carlo Method glycan clearance |
| Zdroj: | mAbs |
| ISSN: | 1942-0870 1942-0862 |
| Popis: | The role of Fc glycans on clearance of IgG molecule has been examined by various groups in experiments where specific glycans have been enriched or the entire spectrum of glycans was studied after administration in pre-clinical or clinical pharmacokinetic (PK) studies. The overall conclusions from these studies are inconsistent, which may result from differences in antibody structure or experimental design. In the present study a well-characterized recombinant monoclonal IgG1 molecule (mAb-1) was analyzed from serum samples obtained from a human PK study. mAb-1 was recovered from serum using its ligand cross-linked to Sepharose beads. The overall purity and recovery of all isoforms were carefully evaluated using a variety of methods. Glycans were then enzymatically cleaved, labeled using 2-aminobenzamide and analyzed by normal phase high performance liquid chromatography. The assays for recovering mAb-1 from serum and subsequent glycan analysis were rigorously qualified at a lower limit of quantitation of 15 μg/mL, thus permitting analysis to day 14 of the clinical PK study. Eight glycans were monitored and classified into two groups: (1) the oligomannose type structures (M5, M6 and M7) and (2) fucosylated biantennary oligosaccharides (FBO) structures (NGA2F, NA1F, NA2F, NA1F-GlcNAc and NGA2F-GlcNAc). We observed that the oligomannose species were cleared at a much faster rate (40%) than FBOs and conclude that high mannose species should be carefully monitored and controlled as they may affect PK of the therapeutic; they should thus be considered an important quality attribute. These observations were only possible through the application of rigorous analytical methods that we believe will need to be employed when comparing innovator and biosimilar molecules. |
| Databáze: | OpenAIRE |
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