Abstract
The success of recombinant monoclonal immunoglobulins (IgG) is rooted in their ability to target distinct antigens with high affinity combined with an extraordinarily long serum half-life, typically around 3 weeks. The pharmacokinetics of IgGs is intimately linked to the recycling mechanism of the neonatal Fc receptor (FcRn). For long serum half-life of therapeutic IgGs, the highly pH-dependent interaction with FcRn needs to be balanced to allow efficient FcRn binding and release at slightly acidic pH and physiological pH, respectively. Some IgGs, like the antibody briakinumab has an unusually short half-life of ∼8 days. Here we dissect the molecular origins of excessive FcRn binding in therapeutic IgGs using a combination of hydrogen/deuterium exchange mass spectrometry and FcRn affinity chromatography. We provide experimental evidence for a two-pronged IgG-FcRn binding mechanism involving direct FcRn interactions with both the Fc region and the Fab regions of briakinumab, and correlate the occurrence of excessive FcRn binding to an unusually strong Fab-FcRn interaction.
Highlights
A Two-pronged Binding Mechanism of IgG to the Neonatal Fc Receptor Controls Complex Stability and IgG Serum Half-life Jensen, Pernille Foged; Schoch, Angela; Larraillet, Vincent; Hilger, Maximiliane; Schlothauer, Tilman; Emrich, Thomas; Rand, Kasper Dyrberg
Our analyses have revealed that several segments of the Fab regions of briakinumab and its variant, the light chain (LC) complementarity determining region (CDR), are stabilized upon FcRn binding (Fig. 1)
We observe that the conformation of the Fab of briakinumab variant is destabilized by mutation
Summary
IL-23 show remarkable differences in terminal half-life with about 20 days for the former and only 8 –9 days for the latter [16]. Recent studies by Schoch et al [17] indicates this difference in the elimination phase is FcRn-mediated as briakinumab showed excessive FcRn binding mediated by positively charged amino acids in the variable domain. While the antibodies had similar binding affinity at pH 5.5 [17], they showed large differences in FcRn dissociation pH when analyzed by FcRn affinity chromatography [17] (described in detail in [6]). Ustekinumab dissociated at a pH of ϳ7.45 whereas the dissociation pH of briakinumab was 7.85. Mutation of three residues in the light chain (LC) complementarity determining region (CDR) of briakinumab (R27A, R57A and R97A) had a dramatic impact in dissociation pH changing the elution pH to 7.5. The isolated Fc fragments of the antibodies showed identical FcRn dissociation at a pH of about 7.45 [17] indicating a clear role of the briakinumab Fab region in differential FcRn dissociation of the intact IgGs
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