The neonatal Fc receptor (FcRn) binds independently to both sites of the IgG homodimer with identical affinity

MAbs. 2015;7(2):331-43. doi: 10.1080/19420862.2015.1008353.


The neonatal Fc receptor (FcRn) is expressed by cells of epithelial, endothelial and myeloid lineages and performs multiple roles in adaptive immunity. Characterizing the FcRn/IgG interaction is fundamental to designing therapeutic antibodies because IgGs with moderately increased binding affinities for FcRn exhibit superior serum half-lives and efficacy. It has been hypothesized that 2 FcRn molecules bind an IgG homodimer with disparate affinities, yet their affinity constants are inconsistent across the literature. Using surface plasmon resonance biosensor assays that eliminated confounding experimental artifacts, we present data supporting an alternate hypothesis: 2 FcRn molecules saturate an IgG homodimer with identical affinities at independent sites, consistent with the symmetrical arrangement of the FcRn/Fc complex observed in the crystal structure published by Burmeister et al. in 1994. We find that human FcRn binds human IgG1 with an equilibrium dissociation constant (KD) of 760 ± 60 nM (N = 14) at 25°C and pH 5.8, and shows less than 25% variation across the other human subtypes. Human IgG1 binds cynomolgus monkey FcRn with a 2-fold higher affinity than human FcRn, and binds both mouse and rat FcRn with a 10-fold higher affinity than human FcRn. FcRn/IgG interactions from multiple species show less than a 2-fold weaker affinity at 37°C than at 25°C and appear independent of an IgG's variable region. Our in vivo data in mouse and rat models demonstrate that both affinity and avidity influence an IgG's serum half-life, which should be considered when choosing animals, especially transgenic systems, as surrogates.

Keywords: CFCA, calibration-free concentration analysis; FcRn; FcRn, neonatal Fc receptor; IgG; RU, response units; Rmax, maximum binding response; SPR; SPR, surface plasmon resonance; WT, wild-type; anti-Id, anti-idiotypic; cyFcRn, cynomolgus monkey FcRn; cyIgG, cynomolgus monkey IgG; hErbB2, human ErbB2; hFcRn, human FcRn; hIgG, human IgG; label-free biosensor; mAb, monoclonal antibody; mFcRn, mouse FcRn; neonatal Fc receptor; pI, isoelectric point; rFcRn, rat FcRn; rIgG, rat IgG.

MeSH terms

  • Animals
  • Histocompatibility Antigens Class I / chemistry*
  • Histocompatibility Antigens Class I / immunology
  • Humans
  • Immunoglobulin Fc Fragments / chemistry*
  • Immunoglobulin Fc Fragments / immunology
  • Immunoglobulin G / chemistry*
  • Immunoglobulin G / immunology
  • Macaca fascicularis
  • Mice
  • Rats
  • Receptors, Fc / chemistry*
  • Receptors, Fc / immunology
  • Species Specificity
  • Surface Plasmon Resonance


  • Histocompatibility Antigens Class I
  • Immunoglobulin Fc Fragments
  • Immunoglobulin G
  • Receptors, Fc
  • Fc receptor, neonatal