Abstract
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 α 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.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.106.011734.
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ABBREVIATIONS: FcRn, neonatal Fc receptor; β2m, β2-microglobulin; t1/2β, terminal phase half-life; TNFα, tumor necrosis factor α; WT, wild-type; H-FcRn, human FcRn; C-FcRn, cynomolgus monkey FcRn; M-FcRn, murine FcRn; CHO, Chinese hamster ovarian; PAGE, polyacrylamide gel electrophoresis; PBS, phosphate-buffered saline; IMAC, immobilized metal-affinity column; ELISA, enzyme-linked immunosorbent assay; SPR, surface plasmon resonance; kon, association rate; koff, dissociation rate; KD, equilibrium dissociation constant; pH50, pH at which 50% of the FcRn-antibody complexes dissociate; HRP, horseradish peroxidase; AUC0-∞, area under the plasma concentration curve from zero to infinity; CL, clearance; Vss, volume of distribution at steady state.
- Received June 29, 2006.
- Accepted October 11, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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