Impact of methionine oxidation in human IgG1 Fc on serum half-life of monoclonal antibodies

Combined glyco- and protein-Fc engineering simultaneously enhance cytotoxicity and half-life of a therapeutic antibody

“…In addition, other factors than FcRn binding have been shown to influence PK of natural mAbs: overall protein structure, glycosylation status, isoelectric point, 45 methionine oxidation, 59 interaction with the target but also specificity. Indeed, mAbs with the same wild-type human Fc sequences but different Fv domains were shown to bind FcRn with considerable differences.…”

Neonatal Fc receptor and IgG-based therapeutics

“…[12][13][14] Amino acid residues near the Fc hinge region mutated to increase binding to FcRn are grouped in colors according to the various combination listed in Table 1. decreased binding to FcRn and subsequent loss of protection from catabolism. 60,61 To improve the circulating half-life of Fc-fusion protein, Fc-fusion "monomers" were created where single rather than dimeric therapeutic protein was fused to the dimeric Fc domain. 62 Fc-fusion monomer of erythropoietin, interferon (IFN)α, IFNβ and Factor IX have all been shown to have longer circulating half-lives in mouse or cynomolgus monkey than its dimeric counterpart and administration by pulmonary or oral route also resulted in enhanced bioavailability of the agents.…”

Investigating the Interaction between the Neonatal Fc Receptor and Monoclonal Antibody Variants by Hydrogen/Deuterium Exchange Mass Spectrometry

“…Interestingly, posttranslational modifications such as oxidation of conserved methionines in the C H 2 and C H 3 domains of IgG 1 and IgG 2 have been shown to affect FcRn affinity negatively. Antibody oxidation that can occur during production or storage significantly reduces FcRn binding in vitro (20,21), which also translates to a reduced in vivo half-life in human FcRn transgenic mice models (22). The molecular origins of the effect of post-translational modifications on the IgG-FcRn interaction are, however, unclear.…”