FcMediated Effects

Molecules that contain an IgG Fc domain have long half-lives because of the MHC-like neonatal Fc receptor (FcRn), a heterodimer composed of FcRn and p2-microglobulin (60,61). FcRn binds and stabilizes Fc-containing proteins within acidic endosomal vesicles and provides a recycling pathway via transcytosis and exocytosis (62,63). FcRn is widely expressed on vascular endothelial cells, upper airway epithelial cells, myeloid cells, and in kidney, the podocytes and proximal convoluted tubule. In addition to its role in IgG homeostasis, FcRn has been shown to extend the serum half-life of albumin (64). Some Fc engineering efforts have utilized the unique Fc binding functions of FcRn to enhance drug delivery and to extend the half-life of therapeutic mAbs (65-67). The known biological functions and potential therapeutic uses of FcRn have recently been reviewed (68).

Polymorphisms have been reported in the gene encoding FcRn (FCGRT) (69,70). Although the coding region appears to harbor only synonymous polymorphisms, the number of alleles sequenced is small, and very few studies have been published on the effect of FCGRT polymorphisms. Given the attention to Fc modifications in mAb design, it is surprising that no Pgx investigations have been published for FGCRT.

Large variance in IgG levels at birth has been observed, presumably because of variance in FcRn activity. Birth IgG level was not associated with carriage of synonymous SNP in the coding region of FGCRT. Furthermore, the rare nonsynonymous coding polymorphisms of FGCRT are unlikely to explain this variability (69). One study showed that a variable number of tandem repeats (VNTR) polymorphism in the FcRn promoter region were associated with differential transcriptional activity of FCGRT. Monocytes from individuals homo-zygous for the major allele (VNTR3/3) showed a pH-dependent increase in IgG binding compared with monocytes from VNTR2 carriers (70).

Other investigations focused on the DMPK gene in type 1 dystrophia myotonica (DM1), a disease associated with IgG deficiencies. In this case, carriage of a CTG repeat in the 3' untranslated region of the DMPK gene, which might influence expression levels of the nearby FCTRT, has been studied. A small study in Japanese DM1 patients showed a correlation between CTG repeat number and serum IgG levels, but a larger study in Swedish patients showed no association between either serum IgG levels or FcRn a chain transcripts (71,72). In cattle, FCGRT haplotypes have been associated with the risk of falling into extreme IgG phenotypes at birth. This large, population-based study in cattle suggests that additional investigation of human FCGRT polymorphisms may be warranted (73).

Pharmacogenomic studies of immune effector cells FcR are discussed in section "Effects of Upstream and Downstream Processes."

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