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E. Sally Ward
University of Texas
Southwestern Medical Center
Dallas, TX

Molecular Mechanisms of Serum IgG Homeostasis: Implications for Modulating Pharmacokinetics of Therapeutic Antibodies

Recent data has suggested that the MHC Class I related receptor, FcRn (n=neonatal), regulates the serum half-lives of gammaglobulins (IgGs) in mice in addition to its known role in transferring IgGs from mother to young (1-3). The region of IgG that controls its serum persistence closely overlaps with that involved in binding to FcRn and encompasses amino acids at the CH2-CH3 domain interface that are conserved across species (4). In mice that do not express functional FcRn due to homozygous deletion of b2-microglobulin, the half-lives of IgGs are abnormally short (1-3). The current hypothesis is that FcRn binds and protects IgGs against lysosomal degradation and recycles them into the serum (5), and this is consistent with the observation that a good correlation between serum half-life and binding affinity for FcRn is seen (4, 6). In addition, FcRn is expressed throughout adult tissues (1, 7) and the available data suggest that endothelial cells may be the site where FcRn carries out its role in maintaining serum IgG homeostasis (8, 9). Understanding how FcRn functions at the molecular level has relevance, for example, to using protein engineering to modulate the pharmacokinetics of a therapeutic antibody. Furthermore, the isolation of a human homolog of rodent FcRn (10) suggests that studies in mice have significance to improving the knowledge by which serum IgG levels are maintained in humans.

1. Ghetti, V., Hubbard, J.G., Kim, J-K., Tsen, M.F., Lee, Y. and Ward, E.S. (1996) Eur. J. Immunol., 26, 690-696.

2. Junghans, R.P. and Anderson, C.L. (1996) Proc. Natl. Acad. Sci. USA., 93, 5512-5516.

3. Israel, E.J., Wilsker, D.F., Hayes, K.C., Schoenfeld, D. and Simister, N.E. (1996) Immunol., 89, 573-578.

4. Medesan, C., Matesoi, D., Radu, C., Gheti, V. and Ward, E.S. (1997) J. Immunol., 158, 2211-2217.

5. Gheti, V. and Ward, E.S. (1997) Immunol. Today, 18, 592-598.

6. Gheti, V., Popov, S., Borvak, J., Radu, C., Matesoi, D., Medesan, C., Ober, R.J. and Ward, E.S. (1997) Nature Biotech., 15, 637-640.

7. Simister, N.E., and Mostov, K.E. (1989) Cold Spring Harbor Symp. Quant. Biol., Vol. LIV, 571-580.

8. Junghans, R. (1997) Immunol. Res., 17, 29-57.

9. Borvak, J., Richardson, J., Medesan, C., Antohe, F., Radu, C., Simionescu, M., Gheti, V. and Ward, E.S. (1998) Int. Immunol., submitted.

10. Story, C.M., Mikulska, J.E. and Simister, N.E. (1994) J. Exp. Med., 180, 2377-2381.