Abnormally short serum half-lives of chimeric and human IgGs in NOD-SCID mice

Abstract The immunodeficient mice are the standard animal model in antibody research, which include the inbred NOD-SCID strain. We report here the aberrant pharmacokinetics of chimeric and human IgGs with a human IgG1 Fc domain in NOD-SCID mice. These IgGs displayed very short in vivo half-lives (25.0±0.4 hrs and 27.6±1.3 hrs, respectively) when injected at a dose of 10 μg. At a dose of 500 μg the half-lives were extended (131.1±3.1 hrs and 220.3±14.3 hrs, respectively), but still shorter than those observed in other strains of mice. The half-lives of these IgGs in NOD MrkTac, BALB/c, Swiss Webster and another immunodeficient strain of mice, C.B-17 SC-R, were similar to previous reports (300-400 hrs). In contrast, no differences in half-lives were observed for murine, rat, bovine and goat IgGs in any mouse strain studied here. RT-PCR for FcRn cDNA showed no difference in FcRn gene sequence and the binding affinity of chimeric and human IgGs to the FcRn-positive intestinal brush border of suckling mice was similar for all mice. However, chimeric and human IgGs showed higher in vitro binding affinities for Fc gamma receptors on macrophages from NOD-SCID mice vs. other strains of mice studied, suggesting that at low doses, these antibodies might bind preferentially to Fc gamma receptors-expressing macrophages, impairing their pharmacokinetics. Taken together, the NOD-SCID mice and their derivatives may not be suitable models for studying the in vivo activity of chimeric and human IgGs.