The MHC class I-related receptor, FcRn, plays an essential role in the maternofetal transfer of gamma-globulin in humans.
The transfer of maternal gamma-globulin (IgG) provides the neonate with humoral immunity during early life. In humans, maternal IgG is transported across the placenta during the third trimester of pregnancy. The expression of the MHC class I-related receptor, FcRn, in the human placenta suggests that this Fc receptor might be involved in the delivery of maternal IgG, but direct evidence to support this is lacking. In the current study an ex vivo placental model has been used to analyze the maternofetal transfer of a recombinant, humanized (IgG1) antibody in which His435 has been mutated to alanine (H435A). In vitro binding studies using surface plasmon resonance indicate that the mutation ablates binding of the antibody to recombinant mouse and human FcRn. Relative to the wild-type antibody, the H435A mutant is deficient in transfer across the placenta. Significantly, the mutation does not affect binding to Fc gamma RIII, an FcR that has been suggested in earlier studies to mediate the transfer of maternal IgG. The analyses demonstrate that binding of an IgG to FcRn is a prerequisite for transport across the perfused placenta. FcRn therefore plays a central role in the maternofetal delivery of IgG and this has implications for the use of protein engineering to improve the properties of therapeutic antibodies.
Firan
M
M
Center for Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Bawdon
R
R
Radu
C
C
Ober
R J
RJ
Eaken
D
D
Antohe
F
F
Ghetie
V
V
Ward
E S
ES
D000818:Animals; D001666:Binding Sites, Antibody / Q000235:genetics / Q000276:immunology; D005260:Female; D006207:Half-Life; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007112:Immunity, Maternally-Acquired / Q000276:immunology*; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D066298:In Vitro Techniques; D008431:Maternal-Fetal Exchange / Q000276:immunology*; D051379:Mice; D009154:Mutation / Q000235:genetics; D010920:Placenta / Q000276:immunology / Q000378:metabolism; D010957:Plasmids / Q000096:biosynthesis / Q000276:immunology; D011247:Pregnancy; D011961:Receptors, Fc / Q000097:blood / Q000502:physiology*; D017452:Receptors, IgG / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism
D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; D017452:Receptors, IgG; D011994:Recombinant Proteins; C100688:Fc receptor, neonatal