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

• Published in: mAbs 2018-07, Vol.10 (5), p.803-813
• Main Authors: Richter, Wolfgang F, Christianson, Gregory J, Frances, Nicolas, Grimm, Hans Peter, Proetzel, Gabriele, Roopenian, Derry C
• Format: Article
• Language: English
• Subjects: Administration, Intravenous; Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - pharmacokinetics; Biological Availability; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells - metabolism; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - metabolism; Humans; Injections, Subcutaneous; Metabolic Clearance Rate; Mice; Mice, Transgenic; Receptors, Fc - genetics; Receptors, Fc - metabolism
• ISSN: 1942-0862; 1942-0870
• DOI: 10.1080/19420862.2018.1458808

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.