An Fc receptor structurally related to MHC class I antigens

Simister, Neil E.; Mostov, Keith E.

doi:10.1038/337184a0

Cited by 662 publications

(491 citation statements)

References 29 publications

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“…The NCBI protein accession numbers are: NM_004107 (human) [24], CAH91593 (orangutan), AF485818 (macaque), AF421499 (sheep) [25], AF221522 (cattle), NP_999362 (pig) [26], AY894681 (camel) [27], XM_533618 (dog), NM NM_033351 (rat) [28], Q61559 (mouse) [29] and AF191647 (possum) [30]. Fig.…”

Section: Fcrn Sequence Analysismentioning

confidence: 99%

The conserved histidine 166 residue of the human neonatal Fc receptor heavy chain is critical for the pH‐dependent binding to albumin

2006

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The MHC class I-related neonatal Fc receptor (FcRn) serves in the homeostatic regulation of IgG and albumin by increasing their half-lives. FcRn may bind IgG and albumin simultaneously, and in a pH-dependent manner, with ligand binding at pH 6.0-6.5 and release at pH 7.0-7.4. The FcRn-IgG interaction has been extensively characterized at the amino acid level and shown to depend on conserved histidine residues in the IgG-Fc part that interact with negatively charged residues in the a-2 domain of FcRn. The recently discovered FcRn-albumin interaction remains to be elucidated. Guided by the pH dependence of the FcRn-albumin interaction, we compared the sequence of the FcRn a-2 domain from eleven different species, and identified histidine residues that were conserved in all (H166) or seven (H161) of these. Both residues are located directly opposite to the IgG interaction site in the folded molecule. We did in vitro mutagenesis (H161A or H166A) in combination with interaction studies (ELISA and surface plasmon resonance) with recombinant, soluble, purified receptors and IgG and albumin to investigate the role of the two histidine residues. Our results show clear evidence that the conserved H166 is a key player in the FcRn-albumin interaction.

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Section: Fcrn Sequence Analysismentioning

confidence: 99%

The conserved histidine 166 residue of the human neonatal Fc receptor heavy chain is critical for the pH‐dependent binding to albumin

2006

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“…4,8,9 A pivotal molecule responsible for the transfer of maternal IgG is neonatal Fc receptor (FcRn), which was first identified in the small intestine of neonatal rats where it mediates uptake of IgG from milk. 10 FcRn is a major histocompatibility complex class I related molecule consisting of an a-chain and b2-microglobulin and its major roles are to protect both IgG and albumin from catabolism and so extend their half-lives 3,11,12 in addition to transporting IgG through multiple mucosal barriers.…”

Section: Introductionmentioning

confidence: 99%

Over‐expression of the bovine FcRn in the mammary gland results in increased IgG levels in both milk and serum of transgenic mice

Lü

Zhao

et al. 2007

Immunology

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SummaryThe neonatal Fc receptor (FcRn) protects immunoglobulin G (IgG) from catabolism and is also responsible for IgG absorption in the neonatal small intestine. However, whether it mediates the transfer of IgG from plasma to milk still remains speculative. In the present study, we have generated transgenic mice that over-express the bovine FcRn (bFcRn) in their lactating mammary glands. Significantly increased IgG levels were observed in the sera and milk from transgenic animals, suggesting that the over-expressed bFcRn could bind and protect endogenous mouse IgG and thus extend its lifespan. We also found that injected human IgG showed a significantly longer half-life (7-8 days) in the transgenic mice than in controls (2Á9 days). Altogether, the data suggested that bFcRn could bind both mouse and human IgG, showing a cross-species FcRnIgG binding activity. However, we found no selective accumulation of endogenous mouse IgG or injected bovine IgG in the milk of the transgenic females, supporting a previous hypothesis that IgG was transported from serum to milk in an inverse correlation to its binding affinity to FcRn.

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“…This prolonged half-life of IgG can be explained by the interaction with neonatal FcR (FcRn). FcRn is a heterodimer of the MHC class I-like H chain and the b 2 -microglobulin (b 2 m) L chain (2). Although this receptor was originally studied as a transporter of IgG from mother to fetus, subsequent studies have shown that this receptor also plays a critical role in regulating IgG homeostasis (3,4).…”

mentioning

confidence: 99%

Importance of Neonatal FcR in Regulating the Serum Half-Life of Therapeutic Proteins Containing the Fc Domain of Human IgG1: A Comparative Study of the Affinity of Monoclonal Antibodies and Fc-Fusion Proteins to Human Neonatal FcR

Suzuki

Ishii‐Watabe

Tada

et al. 2010

The Journal of Immunology

304

239

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The neonatal FcR (FcRn) binds to the Fc domain of IgG at acidic pH in the endosome and protects IgG from degradation, thereby contributing to the long serum half-life of IgG. To date, more than 20 mAb products and 5 Fc-fusion protein products have received marketing authorization approval in the United States, the European Union, or Japan. Many of these therapeutic proteins have the Fc domain of human IgG1; however, the serum half-lives differ in each protein. To elucidate the role of FcRn in the pharmacokinetics of Fc domain-containing therapeutic proteins, we evaluated the affinity of the clinically used human, humanized, chimeric, or mouse mAbs and Fc-fusion proteins to recombinant human FcRn by surface plasmon resonance analysis. The affinities of these therapeutic proteins to FcRn were found to be closely correlated with the serum half-lives reported from clinical studies, suggesting the important role of FcRn in regulating their serum half-lives. The relatively short serum half-life of Fc-fusion proteins was thought to arise from the low affinity to FcRn. The existence of some mAbs having high affinity to FcRn and a short serum half-life, however, suggested the involvement of other critical factor(s) in determining the serum half-life of such Abs. We further investigated the reason for the relatively low affinity of Fc-fusion proteins to FcRn and suggested the possibility that the receptor domain of Fc-fusion protein influences the structural environment of the FcRn binding region but not of the FcγRI binding region of the Fc domain.

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An Fc receptor structurally related to MHC class I antigens

Cited by 662 publications

References 29 publications

The conserved histidine 166 residue of the human neonatal Fc receptor heavy chain is critical for the pH‐dependent binding to albumin

The conserved histidine 166 residue of the human neonatal Fc receptor heavy chain is critical for the pH‐dependent binding to albumin

Over‐expression of the bovine FcRn in the mammary gland results in increased IgG levels in both milk and serum of transgenic mice

Importance of Neonatal FcR in Regulating the Serum Half-Life of Therapeutic Proteins Containing the Fc Domain of Human IgG1: A Comparative Study of the Affinity of Monoclonal Antibodies and Fc-Fusion Proteins to Human Neonatal FcR

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