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. 2018 Jul;10(5):803-813.
doi: 10.1080/19420862.2018.1458808. Epub 2018 May 9.

Hematopoietic cells as site of first-pass catabolism after subcutaneous dosing and contributors to systemic clearance of a monoclonal antibody in mice

Wolfgang F Richter  1 , Gregory J Christianson  2 , Nicolas Frances  1 , Hans Peter Grimm  1 , Gabriele Proetzel  2 , Derry C Roopenian  2
Affiliations

Hematopoietic cells as site of first-pass catabolism after subcutaneous dosing and contributors to systemic clearance of a monoclonal antibody in mice

Wolfgang F Richter et al. MAbs. 2018 Jul.

Abstract

The neonatal Fc receptor (FcRn) has been demonstrated to contribute to a high bioavailability of monoclonal antibodies (mAbs). In this study, we explored the cellular sites of FcRn-mediated protection after subcutaneous (SC) and intravenous (IV) administration. SC absorption and IV disposition kinetics of a mAb were studied in hFcRn transgenic (Tg) bone marrow chimeric mice in which hFcRn was restricted to radioresistant cells or hematopoietic cells. SC bioavailabilities close to 90% were observed in hFcRn Tg mice and chimeric mice with hFcRn expression in hematopoietic cells, whereas SC bioavailabilities were markedly lower when FcRn was missing in hematopoietic cells. Our study demonstrates: 1) FcRn in radiosensitive hematopoietic cells is required for high SC bioavailability, indicating first-pass catabolism after SC administration by hematopoietic cells; 2) FcRn-mediated transcytosis or recycling by radioresistent cells is not required for high SC bioavailability; and 3) after IV administration hematopoietic and radioresistent cells contribute about equally to clearance of the mAb. A pharmacokinetic model was devised to describe a mixed elimination via radioresistent and hematopoietic cells from vascular and extravascular compartments, respectively. Overall, the study indicates a relevant role of hematopoietic cells for first-pass clearance of mAbs after SC administration and confirms their role in the overall clearance of mAbs.

Keywords: FcRn; clearance; hematopoietic cells; subcutaneous first pass catabolism.

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Figures

Figure 1.
Figure 1.
Confirmation of BM reconstitution. A: FACS analysis of hFcRn expression by blood CD11b+ monocytes. % hFcRnhi cells detected by anti-hFcRn mAb ADM32 is shown. B: Endogenous serum albumin levels of mice cohorts 1–4 determined 12 wks after reconstitution. Errors bars indicate SEM of 16–18 mice per group. n.s., not significant; ****, p≤ 0.0001 by Tukey's multicomparison ANOVA.
Figure 2.
Figure 2.
Plasma concentration time curves (mean ± SD) after IV or SC administration of mAb1 at 10 mg/kg to the mouse cohorts 1 to 4; A: after IV administration; B: after SC administration; C: after SC administration in the initial absorption phase (first 7 h).
Figure 3.
Figure 3.
Semi-mechanistic PK model after IV administration of mAb1 in mice.
Figure 4.
Figure 4.
Observed (mean ± SD) versus predicted (5, 50 and 95 percentile prediction) plasma concentration after IV administration of mAb1 at 10 mg/kg to the different mouse cohorts.
Figure 5.
Figure 5.
Serum concentration time curves (mean ± SD) of monoclonal anti-TNP-specific IgG after intraperitoneal administration at 5 mg/kg to B6.PL-Thy1a/CyJ (Thy1.1) mice, FcRn ko mice and chimera thereof (Data from 14 ).
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