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Impact of altered endogenous IgG on unspecific mAb clearance

  • Saskia Fuhrmann
  • Charlotte Kloft
  • Wilhelm HuisingaEmail author
Original Paper

Abstract

Immunodeficient mice are crucial models to evaluate the efficacy of monoclonal antibodies (mAbs). When studying mAb pharmacokinetics (PK), protection from elimination by binding to the neonatal Fc receptor (FcRn) is known to be a major process influencing the unspecific clearance of endogenous and therapeutic IgG. The concentration of endogenous IgG in immunodeficient mice, however is reduced, and this effect on the FcRn protection mechanism and subsequently on unspecific mAb clearance is unknown, yet of great importance for the interpretation of mAb PK data. We used a PBPK modelling approach to elucidate the influence of altered endogenous IgG concentrations on unspecific mAb clearance. To this end, we used PK data in immunodeficient mice, i.e. nude and severe combined immunodeficiency mice. To avoid impact of target-mediated clearance processes, we focussed on mAbs without affinity to a target antigen in these mice. In addition, intravenous immunoglobulin (IVIG) data of immunocompetent mice was used to study the impact of increased total IgG concentrations on unspecific therapeutic antibody clearance. The unspecific clearance is linear, whenever therapeutic IgG concentrations, i.e. mAb and IVIG concentrations are lower than FcRn; it can be non-linear if therapeutic IgG concentrations are larger than FcRn and endogenous IgG concentrations (e.g., under IVIG therapy). Unspecific mAb clearance of immunodeficient mice is effectively linear (under mAb doses as typically used in human). Studying the impact of reduced endogenous IgG concentrations on unspecific mAb clearance is of great relevance for the extrapolation to clinical species, e.g., when predicting mAb PK in immunosuppressed cancer patients.

Keywords

mAb disposition PBPK FcRn salvage mechanism Immunodeficient mice models Unspecific antibody clearance 

Notes

Acknowledgements

S.F. acknowledges fruitful discussions with Hans Peter Grimm (F. Hoffmann-La Roche Ltd, Basel, Switzerland).

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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Saskia Fuhrmann
    • 1
    • 2
  • Charlotte Kloft
    • 3
  • Wilhelm Huisinga
    • 4
    Email author
  1. 1.Institute of Biochemistry and BiologyUniversität PotsdamPotsdamGermany
  2. 2.Graduate Research Training Program PharMetrX: Pharmacometrics & Computational Disease ModelingFreie Universität Berlin and Universität PotsdamBerlin/PotsdamGermany
  3. 3.Department of Clinical Pharmacy and Biochemistry, Institute of PharmacyFreie Universität BerlinBerlinGermany
  4. 4.Institute of MathematicsUniversität PotsdamPotsdamGermany

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