Abstract
The neonatal Fc receptor (FcRn) is a key determinant of IgG homeostasis. It binds to the Fc domain of IgG in a strictly pH-dependent manner and protects IgG from lysosomal degradation. The impact of FcRn salvage pathway on IgG monoclonal antibody (mAb) pharmacokinetics (PK) has been well established. In this report, a set of mAbs with wild-type human Fc sequences but different Fab domains were used to examine the potential impact of Fab domain on in vitro FcRn binding and in vivo PK. We were surprised to find that mAbs with the same wild-type human Fc sequences but different Fab domains were shown to bind FcRn with considerable differences in both the binding at acidic pH and the dissociation at neutral pH, suggesting that the Fab domain may also have an impact on FcRn interaction. For these mAbs, no relationship between the FcRn binding affinity at acidic pH and in vivo PK was found. Instead, an apparent correlation between the in vitro FcRn dissociation at neutral pH and the in vivo PK in human FcRn mice, nonhuman primates and humans was observed. Our results suggested that the Fab domain of mAbs can affect their interaction with FcRn and thus their pharmacokinetic properties and that in vitro FcRn binding/dissociation assays can be a useful screening tool for pharmacokinetic assessment of mAbs with wild-type Fc sequences.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.039453.
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ABBREVIATIONS:
- mAb
- monoclonal antibody
- Fc
- fragment crystallizable
- FcRn
- neonatal Fc receptor
- β2m
- β2-microglobulin
- Fab
- fragment of antigen binding
- PK
- pharmacokinetic(s)
- IVIVC
- in vitro-in vivo correlation
- NHP
- nonhuman primate
- SPR
- surface plasmon resonance
- RU
- response unit
- %bound
- percentage bound
- hFcRn
- human FcRn.
- Received March 11, 2011.
- Accepted May 16, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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