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Comparative Study
. 2013 May-Jun;5(3):397-405.
doi: 10.4161/mabs.23836. Epub 2013 Apr 2.

Correlations between pharmacokinetics of IgG antibodies in primates vs. FcRn-transgenic mice reveal a rodent model with predictive capabilities

Susan H Tam  1 , Stephen G McCarthy  1 , Kerry Brosnan  2 , Kenneth M Goldberg  3 , Bernard J Scallon  1
Affiliations
Comparative Study

Correlations between pharmacokinetics of IgG antibodies in primates vs. FcRn-transgenic mice reveal a rodent model with predictive capabilities

Susan H Tam et al. MAbs. 2013 May-Jun.

Abstract

Transgenic mice expressing human neonatal Fc receptor (FcRn) instead of mouse FcRn are available for IgG antibody pharmacokinetic (PK) studies. Given the interest in a rodent model that offers reliable predictions of antibody PK in monkeys and humans, we set out to test whether the PK of IgG antibodies in such mice correlated with the PK of the same antibodies in primates. We began by using a single research antibody to study the influence of: (1) different transgenic mouse lines that differ in FcRn transgene expression; (2) homozygous vs. hemizygous FcRn transgenic mice; (3) the presence vs. absence of coinjected high-dose human intravenous immunoglobulin (IVIG), and (4) the presence vs. absence of coinjected high-dose human serum albumin (HSA). Results of those studies suggested that use of hemizygous Tg32 mice (Tg32 hemi) not treated with IVIG or HSA offered potential as a predictive model for PK in humans. Mouse PK studies were then done under those conditions with a panel of test antibodies whose PK in mice and primates is not significantly affected by target binding, and for which monkey or human PK data were readily available. Results from the studies revealed significant correlations between terminal half-life or clearance values observed in the mice and the corresponding values reported in humans. A significant relationship in clearance values between mice and monkeys was also observed. These correlations suggest that the Tg32 hemi mouse model, which is both convenient and cost-effective, can offer value in predicting antibody half-life and clearance in primates.

Keywords: FcRn; HSA; IVIG; PK; Tg276; Tg32; antibody; correlations; primates; transgenic mice.

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Figures

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Figure 1. Comparison of human FcRn transgenic mouse lines. Tg32 and Tg276 mice were IV-injected via tail vein with 2 mg/kg doses of either (A) B21M WT or (B) B21M-Fc2, a variant of B21M WT with enhanced affinity for FcRn at pH 6. Serum concentrations are shown for the 21 d study. (C) PK profile of B21M WT in Tg32 homo vs. Tg32 hemi mice. (D) Results of measuring endogenous mouse IgG levels by ELISA in sera of different mice that had not been injected with human IgG. (E) PK profiles in Tg32 mice IV-dosed at 2 mg/kg with B21M WT in the presence or absence of a coinjected 200 mg/kg dose of human IVIG. For Tg32 homo mice, t1/2 values of the group without IVIG were derived from 2 mice, whereas values from the group with IVIG was derived from 4 mice. (F) Results of measuring endogenous mouse serum albumin levels by ELISA in sera of different mice that had not been injected with human IgG. In (A), (B), (C) and (E), B21M serum levels were measured at different time points by ELISA, and results are shown as the mean ± SEM of 4 animals/group unless stated otherwise. Half-life values are reported with ± 1 standard deviation in parentheses, except for Tg32 mice in (E) which are reported as mean values.
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Figure 2. Mouse PK and comparison to human PK data. (A) PK profile from an initial study using 8 clinical antibodies. Data are shown relative to day 1 serum levels and each point is the mean serum level ± SEM of 4 mice/group. (B) Comparison of half-life values from Tg32 hemi mice with half-life values from available human clinical data. Data points from mice with high immune response to the injected antibody, demonstrated by mouse anti-human antibody titers of greater than 1 to 1000 and corresponding to abrupt PK changes, were excluded in the analyses. The relationship between human and mice half-life values showed a significant correlation, Pearson r = 0.92, p = 0.026.
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Figure 3. Mouse PK in the presence of coinjected IVIG and comparison of observed half-life values to human data. (A) PK profiles are shown using 125I-labeled antibodies in Tg32 hemi mice. Serum concentration is reported as mean ± SEM of 4 mice/group, calculated from the cpms/ml and specific activity of the 125I-labeled test antibody. (B) Relationship between human half-life values that were available and mice half-life values showed a significant correlation, Pearson r = 0.86, p = 0.030.
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Figure 4. Mouse PK data in the absence of coinjected IVIG and comparison of observed half-life values to human data. (A) PK profiles in a study done in the absence of coinjected IVIG. Serum levels normalized to day 2 are reported as mean ± SEM of 4 mice/group. (B) The comparison of half-lives from available human data vs. half-lives in mice are shown. Outliers with immunogenicity, demonstrated by an abrupt drop in the PK profile, were excluded from both graphs. The correlation was significant: Pearson r = 0.81, p = 0.027.
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Figure 5. Relationships between clearance values in monkeys, humans, and mice. (A) Correlation between monkey and mouse CL data are shown from the average values in the two studies that did not include coinjected IVIG, (Pearson r = 0.88, p = 0.008). (B) PK correlation between human and mouse data are shown from the average values of these studies (Pearson r = 0.99, p < 0.001). (C) Correlation between monkey and human data are shown from the average values collected from internal studies and the literature (Pearson r = 0.90, p = 0.001).
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