Increasing the affinity of a human IgG1 for the neonatal Fc receptor: biological consequences.
Many biological functions, including control of the homeostasis and maternofetal transfer of serum gamma-globulins, are mediated by the MHC class I-related neonatal FcR (FcRn). A correlation exists in mice between the binding affinity of IgG1/Fc fragments to FcRn at pH 6.0 and their serum t(1/2). To expand this observation, phage display of mutagenized Fc fragments derived from a human IgG1 was used to increase their affinity to both murine and human FcRn. Ten variants were identified that have a higher affinity toward murine and human FcRn at pH 6.0, with DeltaDeltaG (DeltaG(wild type) - DeltaG(mutant)) from 1.0 to 2.0 kcal/mol and from 0.6 to 2.4 kcal/mol, respectively. Those variants exhibit a parallel increase in binding at pH 7.4 to murine, but not human, FcRn. Although not degraded in blood in vitro, accumulated in tissues, nor excreted in urine, their serum concentration in mice is decreased. We propose that higher affinity to FcRn at pH 7.4 adversely affects release into the serum and offsets the benefit of the enhanced binding at pH 6.0.
Dall'Acqua
William F
WF
MedImmune, Gaithersburg, MD 20878, USA. dall'acquaw@medimmune.com
Woods
Robert M
RM
Ward
E Sally
ES
Palaszynski
Susan R
SR
Patel
Nita K
NK
Brewah
Yambasu A
YA
Wu
Herren
H
Kiener
Peter A
PA
Langermann
Solomon
S
D000818:Animals; D000831:Animals, Newborn / Q000235:genetics / Q000276:immunology*; D017104:Bacteriophage M13 / Q000235:genetics / Q000276:immunology; D001666:Binding Sites, Antibody / Q000235:genetics; D015395:Histocompatibility Antigens Class I; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000097:blood / Q000235:genetics / Q000378:metabolism; D007231:Infant, Newborn; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D051379:Mice; D008807:Mice, Inbred BALB C; D016297:Mutagenesis, Site-Directed; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D019151:Peptide Library; D011233:Precipitin Tests; D011961:Receptors, Fc / Q000008:administration & dosage / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D017452:Receptors, IgG / Q000008:administration & dosage / Q000097:blood / Q000235:genetics / Q000378:metabolism; D020349:Surface Plasmon Resonance
D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D019151:Peptide Library; D011961:Receptors, Fc; D017452:Receptors, IgG; C100688:Fc receptor, neonatal