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* MedImmune, Gaithersburg, MD 20878; and
Center for Immunology and Cancer Immunobiology Center, University of Texas Southwestern Medical Center, Dallas, TX 75390
Many biological functions, including control of the homeostasis and
maternofetal transfer of serum 
-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 t1/2. 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 
G (Gwild
type - Gmutant) 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.
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