Hematopoietic cells as site of first-pass catabolism after subcutaneous dosing and contributors to systemic clearance of a monoclonal antibody in mice
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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.
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The inverse correlation between subcutaneous bioavailability and intravenous clearance may be due to the involvement of hematopoietic cells (e.g. macrophages or dendritic cells) in both subcutaneous first-pass clearance and systemic clearance after intravenous dosing.
“This correlation may be due to the involvement of hematopoietic cells (e.g. macrophages or dendritic cells) in both subcutaneous first-pass clearance and systemic clearance after intravenous dosing [88].”
From Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities (2018) · cites this paper as [88]
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Adeluola, A. A., Thomas, J., Remaily, B., Xie, Z., Kim, K., Partey, A., Young, G., Hai, M., Montgomery, E. J., Lee, S., et al. (2026) · International Immunopharmacology · doi:10.1016/j.intimp.2026.116788
A Review on Lymphatic Uptake of Large Therapeutic Proteins after Subcutaneous Injection
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Introduction to PBPK Modelling: Core Concepts for Small and Large Molecules
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- Authors
- Richter, W. F., Christianson, G. J., Frances, N., Grimm, H. P., Proetzel, G., & Roopenian, D. C.
- Affiliations
- F. Hoffmann-La Roche AG (CH)
- Jackson Laboratory (US)
- Corresponding author
- Richter, Wolfgang F.
- Roopenian, Derry C.
- ORCID
- Venue
- mAbs
- Publisher
- Informa UK Limited
- Published
- 2018-05-09
- Volume
- 10
- Issue
- 5
- Pages
- 803-813
- ISSN
- 1942-0862 (ISSN-L)
- 1942-0870
- PMC
- PMC6150636
- OpenAlex
- W2796108325
- Cited by
- 39
- References
- 60
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 3 · 2023: 5 · 2022: 7 · 2021: 4 · 2020: 2 · 2019: 5 · 2018: 5
- FWCI
- 2.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- mAbs (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- National Cancer Institute (P30CA034196)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › Biosimilars and Bioanalytical Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
- Keywords
- neonatal Fc receptor, monoclonal antibodies, subcutaneous administration, hematopoietic cells, systemic clearance, bioavailability, bone marrow chimeric mice, radioresistant cells, pharmacokinetic modeling
- MeSH terms
- Animals, Antibodies, Monoclonal, Biological Availability, Hematopoietic Stem Cells, Humans, Injections, Subcutaneous, Metabolic Clearance Rate, Mice, Transgenic, Receptors, Fc, Histocompatibility Antigens Class I, Hematopoietic Stem Cell Transplantation, Mice, Administration, Intravenous
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