Differences in promiscuity for antibody-FcRn interactions across species: implications for therapeutic antibodies.
Preclinical tests of therapeutic antibodies are frequently carried out in mice to evaluate pharmacokinetics and efficacy. However, the observation that mouse IgG are cleared rapidly from the human circulation suggests that mice may not always be an ideal model. The Fc receptor, FcRn, regulates the serum half-lives of IgG in mice and most likely has a similar function in humans. In the current study we have carried out an extensive analysis of the interaction of the human or mouse forms of FcRn with IgG from various species using surface plasmon resonance. We show that in contrast to mouse FcRn, human FcRn is surprisingly stringent in its binding specificity for IgG derived from different species. Human FcRn binds to human, rabbit and guinea pig IgG, but not significantly to rat, bovine, sheep or mouse IgG (with the exception of weak binding to mouse IgG2b). In contrast, mouse FcRn binds to all IgG analyzed. The lack of binding of human FcRn to mouse IgG1 has been confirmed using transfectants that have been engineered to express human FcRn on the cell surface. Our results provide a molecular explanation for the enigmatic observation that mouse IgG behave anomalously in humans. These studies have implications for the successful application of therapeutic antibodies.
Ober
R J
RJ
Cancer Immunobiology Center and Center for Immunology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-8576, USA.
Radu
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Ghetie
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Ward
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D000818:Animals; D000831:Animals, Newborn; D001666:Binding Sites, Antibody / Q000235:genetics; D018938:Caco-2 Cells; D002417:Cattle; D006168:Guinea Pigs; D015395:Histocompatibility Antigens Class I; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use*; D007231:Infant, Newborn; D019169:Jurkat Cells; D051379:Mice; D011817:Rabbits; D051381:Rats; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012756:Sheep; D013045:Species Specificity; D020349:Surface Plasmon Resonance; D014162:Transfection
D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; D011994:Recombinant Proteins; C100688:Fc receptor, neonatal