SpringerLink
Log in

Mechanistic incorporation of FcRn binding in plasma and endosomes in a whole body PBPK model for large molecules

  • Original Paper
  • Published:
Journal of Pharmacokinetics and Pharmacodynamics Aims and scope Submit manuscript

Abstract

Monoclonal antibodies, endogenous IgG, and serum albumin bind to FcRn in the endosome for salvaging and recycling after pinocytotic uptake, which prolongs their half-life. This mechanism has been broadly recognized and is incorporated in currently available PBPK models. Newer types of large molecules have been designed and developed, which also bind to FcRn in the plasma space for various mechanistic reasons. To incorporate FcRn binding affinity in PBPK models, binding in the plasma space and subsequent internalisation into the endosome needs to be explicitly represented. This study investigates the large molecules model in PK-Sim® and its applicability to molecules with FcRn binding affinity in plasma. With this purpose, simulations of biologicals with and without plasma binding to FcRn were performed with the large molecule model in PK-Sim®. Subsequently, this model was extended to ensure a more mechanistic description of the internalisation of FcRn and the FcRn-drug complexes. Finally, the newly developed model was used in simulations to explore the sensitivity for FcRn binding in the plasma space, and it was fitted to an in vivo dataset of wild-type IgG and FcRn inhibitor plasma concentrations in Tg32 mice. The extended model demonstrated a strongly increased sensitivity of the terminal half-life towards the plasma FcRn binding affinity and could successfully fit the in vivo dataset in Tg32 mice with meaningful parameter estimates.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Chaudhury C, Brooks CL, Carter DC et al (2006) Albumin binding to FcRn: distinct from the FcRn-IgG interaction. Biochemistry 45:4983–4990. https://doi.org/10.1021/bi052628y

    Article  CAS  PubMed  Google Scholar 

  2. Abdiche YN, Yeung YA, Chaparro-Riggers J et al (2015) The neonatal Fc receptor (FcRn) binds independently to both sites of the IgG homodimer with identical affinity. MAbs 7:331–343. https://doi.org/10.1080/19420862.2015.1008353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Igawa T, Maeda A, Haraya K et al (2013) Engineered monoclonal antibody with novel antigen-swee** activity in vivo. PLOS ONE 8:e63236. https://doi.org/10.1371/journal.pone.0063236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Niederalt C, Kuepfer L, Solodenko J et al (2018) A generic whole body physiologically based pharmacokinetic model for therapeutic proteins in PK-Sim. J Pharmacokinet Pharmacodyn 45:235–257. https://doi.org/10.1007/s10928-017-9559-4

    Article  CAS  PubMed  Google Scholar 

  5. Lee C-H, Kang TH, Godon O et al (2019) An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence. Nat Commun 10:5031. https://doi.org/10.1038/s41467-019-13108-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mackness B, Qiu H (2021) Methods of treating antibody-mediated disorders with FcRn antagonists. https://patents.google.com/patent/US20210024620A1/en

  7. Mackness BC, Jaworski JA, Boudanova E et al (2019) Antibody Fc engineering for enhanced neonatal Fc receptor binding and prolonged circulation half-life. MAbs 11:1276–1288. https://doi.org/10.1080/19420862.2019.1633883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Andersen JT, Daba MB, Berntzen G et al (2010) Cross-species binding analyses of mouse and human neonatal Fc receptor show dramatic differences in immunoglobulin G and albumin binding. J Biol Chem 285:4826–4836. https://doi.org/10.1074/jbc.M109.081828

    Article  CAS  PubMed  Google Scholar 

  9. Li T, Balthasar JP (2018) FcRn expression in wildtype mice, transgenic mice, and in human tissues. Biomolecules 8:115. https://doi.org/10.3390/biom8040115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fan Y-Y, Avery LB, Wang M et al (2016) Tissue expression profile of human neonatal Fc receptor (FcRn) in Tg32 transgenic mice. MAbs 8:848–853. https://doi.org/10.1080/19420862.2016.1178436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Roopenian DC, Low BE, Christianson GJ et al (2015) Albumin-deficient mouse models for studying metabolism of human albumin and pharmacokinetics of albumin-based drugs. mAbs 7:344–351. https://doi.org/10.1080/19420862.2015.1008345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wong H, Chow TW (2017) Physiologically based pharmacokinetic modeling of therapeutic proteins. JPharmSci 106:2270–2275. https://doi.org/10.1016/j.xphs.2017.03.038

    Article  CAS  Google Scholar 

  13. Chetty M, Li L, Rose R et al (2015) Prediction of the pharmacokinetics, pharmacodynamics, and efficacy of a monoclonal antibody, using a physiologically based pharmacokinetic FcRn model. Front Immunol. https://doi.org/10.3389/fimmu.2014.00670

    Article  PubMed  PubMed Central  Google Scholar 

  14. Shah DK, Betts AM (2012) Towards a platform PBPK model to characterize the plasma and tissue disposition of monoclonal antibodies in preclinical species and human. J Pharmacokinet Pharmacodyn 39:67–86. https://doi.org/10.1007/s10928-011-9232-2

    Article  CAS  PubMed  Google Scholar 

  15. Li T, Balthasar JP (2019) Application of physiologically based pharmacokinetic modeling to predict the effects of FcRn inhibitors in mice, rats, and monkeys. J Pharm Sci 108:701–713. https://doi.org/10.1016/j.xphs.2018.10.065

    Article  CAS  PubMed  Google Scholar 

  16. Robbie GJ, Criste R, Dall’Acqua WF, et al (2013) A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults. Antimicrob Agents Chemother 57:6147–6153. https://doi.org/10.1128/AAC.01285-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Valente D, Mauriac C, Schmidt T et al (2020) Pharmacokinetics of novel Fc-engineered monoclonal and multispecific antibodies in cynomolgus monkeys and humanized FcRn transgenic mouse models. MAbs 12:1829337. https://doi.org/10.1080/19420862.2020.1829337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Avery LB, Wang M, Kavosi MS et al (2016) Utility of a human FcRn transgenic mouse model in drug discovery for early assessment and prediction of human pharmacokinetics of monoclonal antibodies. mAbs 8:1064–1078. https://doi.org/10.1080/19420862.2016.1193660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Malik PRV, Hamadeh A, Edginton AN (2022) Model-based assessment of the contribution of monocytes and macrophages to the pharmacokinetics of monoclonal antibodies. Pharm Res 39:239–250. https://doi.org/10.1007/s11095-022-03177-2

    Article  CAS  PubMed  Google Scholar 

  20. Salerno SN, Deng R, Kakkar T (2022) Physiologically-based pharmacokinetic modeling of immunoglobulin and antibody coadministration in patients with primary human immunodeficiency. CPT: Pharmacometrics Syst Pharmacol 11:1316–1327. https://doi.org/10.1002/psp4.12847

    Article  CAS  PubMed  Google Scholar 

  21. Yang D, Giragossian C, Castellano S et al (2017) Maximizing in vivo target clearance by design of pH-dependent target binding antibodies with altered affinity to FcRn. MAbs 9:1105–1117. https://doi.org/10.1080/19420862.2017.1359455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hardiansyah D, Ng CM (2018) Minimal physiologically-based pharmacokinetic model to investigate the effect of pH dependent FcRn affinity and the endothelial endocytosis on the pharmacokinetics of anti-VEGF humanized IgG1 antibody in cynomolgus monkey. Eur J Pharm Sci 125:130–141. https://doi.org/10.1016/j.ejps.2018.09.015

    Article  CAS  PubMed  Google Scholar 

  23. Li T, Balthasar JP (2019) Development and evaluation of a physiologically based pharmacokinetic model for predicting the effects of anti-FcRn therapy on the disposition of endogenous IgG in humans. J Pharm Sci 108:714–724. https://doi.org/10.1016/j.xphs.2018.10.067

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

All authors are employees of Sanofi Research & Development. The authors are grateful to the following individuals for their contributions to this work: Liduo Shen, Sarah Nzerko, Wei Sun, Jennifer Fretland, Renee Bodinizzo, Megan Pike, Erik Zarazinski, Ekaterina Boudanova, Julie A. Jaworski and Veronique De Brabandere.

Funding

The authors did not receive support from any organization for the submitted work.

Author information

Authors and Affiliations

  1. Sanofi R&D, Ghent, Belgium

    Wilhelmus E. A. de Witte, Tom Van Bogaert & Maria Laura Sargentini-Maier

  2. esqLABS GmbH, Saterland, Germany

    Wilhelmus E. A. de Witte

  3. Sanofi R&D, Cambridge, USA

    Lindsay B. Avery, Brian C. Mackness & Anna Park

Authors
  1. Wilhelmus E. A. de Witte
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lindsay B. Avery
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Brian C. Mackness
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tom Van Bogaert
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anna Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maria Laura Sargentini-Maier
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

WdW developed the model. WdW and MS wrote and supervised the main manuscript and prepared the figures. TvB advised on the model development and manuscript preparation. BM, LA, and AP prepared, designed and supervised the in vitro and in vivo experiments. All authors reviewed the manuscript

Corresponding author

Correspondence to Wilhelmus E. A. de Witte.

Ethics declarations

Competing interest

All authors were employed at Sanofi at the time of this study. WdW is currently employed at esqLABS GmbH.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

de Witte, W.E.A., Avery, L.B., Mackness, B.C. et al. Mechanistic incorporation of FcRn binding in plasma and endosomes in a whole body PBPK model for large molecules. J Pharmacokinet Pharmacodyn 50, 229–241 (2023). https://doi.org/10.1007/s10928-023-09849-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10928-023-09849-9

Keywords

Search

Navigation