, Volume 32, Issue 2, pp 169–176 | Cite as

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

  • William M. PardridgeEmail author
  • Ruben J. Boado
  • Roberto Giugliani
  • Mathias Schmidt
Original Research Article



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.


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.


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.


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.



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

Author 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.


This study was funded by ArmaGen, Inc.

Compliance with Ethical Standards

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.


  1. 1.
    Neufeld EF. Lysosomal storage diseases. Annu Rev Biochem. 1991;60:257–80.CrossRefPubMedGoogle Scholar
  2. 2.
    Hopwood JJ, Morris CP. The mucopolysaccharidoses. Diagnosis, molecular genetics and treatment. Mol Biol Med. 1990;7(5):381–404.PubMedGoogle Scholar
  3. 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.CrossRefPubMedGoogle Scholar
  4. 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.CrossRefPubMedGoogle Scholar
  5. 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.CrossRefPubMedGoogle Scholar
  6. 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.CrossRefPubMedGoogle Scholar
  7. 7.
    Pardridge WM. Targeted delivery of protein and gene medicines through the blood-brain barrier. Clin Pharmacol Ther. 2015;97(4):347–61.CrossRefPubMedGoogle Scholar
  8. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Pardridge WM, Eisenberg J, Yang J. Human blood-brain barrier insulin receptor. J Neurochem. 1985;44(6):1771–8.CrossRefPubMedGoogle Scholar
  11. 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.CrossRefPubMedGoogle Scholar
  12. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 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.CrossRefPubMedGoogle Scholar
  14. 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.CrossRefPubMedGoogle Scholar
  15. 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.CrossRefPubMedGoogle Scholar
  16. 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.CrossRefPubMedGoogle Scholar
  17. 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.CrossRefPubMedGoogle Scholar
  18. 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.CrossRefPubMedGoogle Scholar
  19. 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.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.ArmaGen, Inc.CalabasasUSA
  2. 2.Department of GeneticsFederal University of Rio Grande do SulPorto AlegreBrazil
  3. 3.Medical Genetics ServiceHospital de Clinicas de Porto AlegrePorto AlegreBrazil

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