title: Impact of glycation on antibody clearance.
abstract: Glycation of therapeutic proteins occurs during mammalian cell culture expression and upon administration to patients. Since the chemical attachment of mannose or other sugars via a chemical linker has been shown to increase a protein's clearance rate in mice through the mannose receptor, we explored the effect of mannose glycation on the clearance of an IgG in mice. An IgG decorated with high levels of mannose (~18 mol/mol protein) through glycation did not clear faster in mice than the underivatized protein, whereas the same IgG decorated with mannose attached in a way to maintain the normal glycosidic bond (2-imino-2-methoxyethyl-1-thiomannoside, or IMT-mannose) at similar derivatization levels cleared significantly faster. Surface plasmon resonance studies revealed that the IgG derivatized with IMT-mannose bound tightly to the mannose receptor (KD = 20 nM) but the IgG glycated with mannose did not bind. These results indicate that glycation, even at unnaturally elevated levels, does not appear to be a clearance concern for therapeutic proteins.
authors.affiliation: Departments of Product Attribute Sciences, Thousand Oaks, California, 91320, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Yang
authors.forename: Ronya
authors.initials: R
authors.lastname: Primack
authors.forename: Mike
authors.initials: M
authors.lastname: Frohn
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Peng
authors.initials: P
authors.lastname: Luan
authors.forename: Marc W
authors.initials: MW
authors.lastname: Retter
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Flynn
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism*; D006031:Glycosylation; D007074:Immunoglobulin G / Q000737:chemistry / Q000378:metabolism*; D037181:Lectins, C-Type / Q000378:metabolism*; D008297:Male; D008358:Mannose / Q000737:chemistry / Q000378:metabolism*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism*; D051379:Mice; D011956:Receptors, Cell Surface / Q000378:metabolism*; D020349:Surface Plasmon Resonance
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D008358:Mannose