Skip to main content
SpringerLink
Log in

Plasma Pharmacokinetics of Valanafusp Alpha, a Human Insulin Receptor Antibody-Iduronidase Fusion Protein, in Patients with Mucopolysaccharidosis Type I

  • Original Research Article
  • Published:
BioDrugs Aims and scope Submit manuscript

Abstract

Background

Mucopolysaccharidosis type I (MPSI) is caused by mutations in the gene encoding the α-l-iduronidase (IDUA) lysosomal enzyme and the majority of MPSI patients have severe central nervous system (CNS) involvement. Enzyme replacement therapy (ERT) with recombinant IDUA does not treat the CNS, due to the lack of transport of the enzyme across the blood–brain barrier (BBB). Human IDUA has been re-engineered as an IgG-IDUA fusion protein, valanafusp alpha, where the IgG domain is a monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb domain binds the endogenous insulin receptor on the human BBB to trigger receptor-mediated transport across the BBB, and acts as a molecular Trojan horse to ferry the fused IDUA into the brain of patients with MPSI.

Methods

The present investigation describes the initial dosing, plasma pharmacokinetics, and plasma glucose response to the intravenous infusion of doses of valanafusp alpha ranging from 0.3 to 3 mg/kg in five adults and from 1 to 6 mg/kg in 13 pediatric subjects with MPSI.

Results

Valanafusp alpha plasma clearance is increased four-fold in children, and shows a linear pharmacokinetic response over the dose range of 0.3–3 mg/kg with a stable plasma elimination half-life (t½). The plasma pharmacokinetic parameters for valanafusp alpha overlapped with the same parameters previously reported for recombinant human IDUA (laronidase). The majority of the tested subjects had been receiving laronidase ERT for years, and some showed high levels of anti-drug antibodies (ADAs). However, the presence of these ADAs did not generally alter the rate of plasma clearance of valanafusp alpha in MPSI. The infusion of 0.3–6 mg/kg doses of valanafusp alpha had no effect on plasma glucose for up to 24 h after the drug infusion.

Conclusion

The plasma clearance of valanafusp alpha is increased four-fold in children with MPSI compared with adult subjects at a dose of 1–3 mg/kg. The plasma pharmacokinetic profile of valanafusp alpha, at a dose of 1–3 mg/kg, is comparable to that of laronidase in children with MPSI.

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

Access this article

Log in via an institution

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

Similar content being viewed by others

References

  1. Neufeld EF. Lysosomal storage diseases. Annu Rev Biochem. 1991;60:257–80.

    Article  CAS  PubMed  Google Scholar 

  2. Hopwood JJ, Morris CP. The mucopolysaccharidoses. Diagnosis, molecular genetics and treatment. Mol Biol Med. 1990;7(5):381–404.

    CAS  PubMed  Google Scholar 

  3. Kakkis ED, Muenzer J, Tiller GE, Waber L, Belmont J, Passage M, et al. Enzyme-replacement therapy in mucopolysaccharidosis I. N Engl J Med. 2001;344(3):182–8.

    Article  CAS  PubMed  Google Scholar 

  4. Wraith JE, Clarke LA, Beck M, Kolodny EH, Pastores GM, Muenzer J, et al. Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase). J Pediatr. 2004;144(5):581–8.

    Article  CAS  PubMed  Google Scholar 

  5. Boado RJ, Pardridge WM. Brain and organ uptake in the rhesus monkey in vivo of recombinant iduronidase compared to an insulin receptor antibody-iduronidase fusion protein. Mol Pharm. 2017;14(4):1271–7.

    Article  CAS  PubMed  Google Scholar 

  6. Aldenhoven M, Wynn RF, Orchard PJ, O’Meara A, Veys P, Fischer A, et al. Long-term outcome of Hurler syndrome patients after hematopoietic cell transplantation: an international multicenter study. Blood. 2015;125(13):2164–72.

    Article  CAS  PubMed  Google Scholar 

  7. Pardridge WM. Targeted delivery of protein and gene medicines through the blood-brain barrier. Clin Pharmacol Ther. 2015;97(4):347–61.

    Article  CAS  PubMed  Google Scholar 

  8. Boado RJ, Hui EK, Lu JZ, Pardridge WM. AGT-181: expression in CHO cells and pharmacokinetics, safety, and plasma iduronidase enzyme activity in Rhesus monkeys. J Biotechnol. 2009;144(2):135–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Soos MA, O’Brien RM, Brindle NP, Stigter JM, Okamoto AK, Whittaker J, et al. Monoclonal antibodies to the insulin receptor mimic metabolic effects of insulin but do not stimulate receptor autophosphorylation in transfected NIH 3T3 cells. Proc Natl Acad Sci USA. 1989;86:5217–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Pardridge WM, Eisenberg J, Yang J. Human blood-brain barrier insulin receptor. J Neurochem. 1985;44(6):1771–8.

    Article  CAS  PubMed  Google Scholar 

  11. Pardridge WM, Kang YS, Buciak JL, Yang Y. Human insulin receptor monoclonal antibody undergoes high affinity binding to human brain capillaries in vitro and rapid transcytosis through the blood-brain barrier in vivo in the primate. Pharm Res. 1995;12:807–16.

    Article  CAS  PubMed  Google Scholar 

  12. Boado RJ, Hui EK, Lu JZ, Pardridge WM. Glycemic control and chronic dosing of rhesus monkeys with a fusion protein of iduronidase and a monoclonal antibody against the human insulin receptor. Drug Metab Dispos. 2012;40(10):2021–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Boado RJ, Hui EK, Lu JZ, Pardridge WM. IgG-enzyme fusion protein: pharmacokinetics and anti-drug antibody response in rhesus monkeys. Bioconjug Chem. 2013;24(1):97–104.

    Article  CAS  PubMed  Google Scholar 

  14. Kakkis ED, Matynia A, Jonas AJ, Neufeld EF. Overexpression of the human lysosomal enzyme alpha-l-iduronidase in Chinese hamster ovary cells. Protein Expr Purif. 1994;5(3):225–32.

    Article  CAS  PubMed  Google Scholar 

  15. Xue Y, Richards SM, Mahmood A, Cox GF. Effect of anti-laronidase antibodies on efficacy and safety of laronidase enzyme replacement therapy for MPS I: a comprehensive meta-analysis of pooled data from multiple studies. Mol Genet Metab. 2016;117(4):419–26.

    Article  CAS  PubMed  Google Scholar 

  16. Wraith JE, Beck M, Lane R, van der Ploeg A, Shapiro E, Xue Y, et al. Enzyme replacement therapy in patients who have mucopolysaccharidosis I and are younger than 5 years: results of a multinational study of recombinant human alpha-l-iduronidase (laronidase). Pediatrics. 2007;120(1):e37–46.

    Article  PubMed  Google Scholar 

  17. Boado RJ, Hui EK, Lu JZ, Pardridge WM. Very high plasma concentrations of a monoclonal antibody against the human insulin receptor are produced by subcutaneous injection in the Rhesus monkey. Mol Pharm. 2016;13(9):3241–6.

    Article  CAS  PubMed  Google Scholar 

  18. Ballesteros M, Scott CD, Baxter RC. Developmental regulation of insulin-like growth factor-II/mannose 6-phosphate receptor mRNA in the rat. Biochem Biophys Res Commun. 1990;172(2):775–9.

    Article  CAS  PubMed  Google Scholar 

  19. Nissley P, Kiess W, Sklar M. Developmental expression of the IGF-II/mannose 6-phosphate receptor. Mol Reprod Dev. 1993;35(4):408–13.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors are indebted to Dr. Stuart Swiedler for valuable discussions. Phuong Tram and Yuen Yin Lee skillfully performed the ELISA assays.

Funding

This study was funded by ArmaGen, Inc.

Author information

Authors and Affiliations

  1. ArmaGen, Inc., Calabasas, CA, USA

    William M. Pardridge, Ruben J. Boado & Mathias Schmidt

  2. Department of Genetics, Federal University of Rio Grande do Sul, Porto Alegre, Brazil

    Roberto Giugliani

  3. Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil

    Roberto Giugliani

Authors
  1. William M. Pardridge
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ruben J. Boado
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Roberto Giugliani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mathias Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

RG conducted the clinical study. RJB and MS analyzed the data. WMP performed the pharmacokinetic analysis. WMP wrote and revised the manuscript. All authors revised and approved the final version.

Corresponding author

Correspondence to William M. Pardridge.

Ethics declarations

Conflict of interest

Drs. Ruben Boado and Mathias Schmidt are employees of, and Drs. William M. Pardridge and Roberto Giugliani are consultants to, ArmaGen, Inc.

Ethical approval

The study was conducted in accordance with Good Clinical Practice, the Declaration of Helsinki, and current guidelines for studies in patients in Brazil, and was approved by the National Ethics Committee (CONEP) in Brazil.

Informed consent

All participants, or their representatives, gave their written consent prior to the start of any study-related activities.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pardridge, W.M., Boado, R.J., Giugliani, R. et al. Plasma Pharmacokinetics of Valanafusp Alpha, a Human Insulin Receptor Antibody-Iduronidase Fusion Protein, in Patients with Mucopolysaccharidosis Type I. BioDrugs 32, 169–176 (2018). https://doi.org/10.1007/s40259-018-0264-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40259-018-0264-7

Search

Navigation