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Humanized IgG₁ Variants with Differential Binding Properties to the Neonatal Fc Receptor: Relationship to Pharmacokinetics in Mice and Primates

Departments of Drug Disposition Development/Commercialization (A.D.-M., V.J.W.) and Biotechnology Discovery Research (D.R.W.), Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana; Discovery Research, Applied Molecular Evolution, San Diego, California (Y.T., J.W.); and Discovery Research, VasGene Therapeutics, Los Angeles, California (W.J.)

It is well established that the neonatal Fc receptor (FcRn) plays a critical role in regulating IgG homeostasis in vivo. As such, modification of the interaction of IgG with FcRn has been the focus of protein-engineering strategies designed to generate therapeutic antibodies with improved pharmacokinetic properties. In the current work, we characterized differences in interaction of IgG between mouse and primate receptors using three humanized anti-tumor necrosis factor antibodies with variant IgG₁ Fc regions. The wild-type and variant IgG showed a differential combination of improved affinity, modified dissociation kinetics, and altered pH-dependent complex dissociation when evaluated on the primate and murine receptors. The observed in vitro binding differences within and between species allowed us to more completely relate these parameters to their influence on the in vivo pharmacokinetics in mice and cynomolgus monkeys. The variant antibodies have different pharmacokinetic behavior in cynomolgus monkeys and mice, which appears to be related to the unique binding characteristics observed with the murine receptor. However, we did not observe a direct relationship between increased binding affinity to the receptor and improved pharmacokinetic properties for these molecules in either species. This work provides further insights into how the FcRn/IgG interaction may be modulated to develop monoclonal antibodies with improved therapeutic properties.

This article has been cited by other articles:

				N. A. Goebl, C. M. Babbey, A. Datta-Mannan, D. R. Witcher, V. J. Wroblewski, and K. W. Dunn Neonatal Fc Receptor Mediates Internalization of Fc in Transfected Human Endothelial Cells Mol. Biol. Cell, December 1, 2008; 19(12): 5490 - 5505. [Abstract] [Full Text] [PDF]