Sustained plasma hepcidin suppression and iron elevation by Anticalin-derived hepcidin antagonist in cynomolgus monkey

Andreas M. Hohlbaum, Hendrik Gille, Stefan Trentmann, Maria Kolodziejczyk, Barbara Rattenstetter, Coby M. Laarakkers, Galina Katzmann, Hans Jürgen Christian, Nicole Andersen, Andrea Allersdorfer, Shane A. Olwill, Bernd Meibohm, Laurent P. Audoly, Dorine W. Swinkels, Rachel P.L. van Swelm

Research output: Contribution to journalArticle

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Abstract

Background and Purpose: Anaemia of chronic disease (ACD) has been linked to iron-restricted erythropoiesis imposed by high circulating levels of hepcidin, a 25 amino acid hepatocyte-derived peptide that controls systemic iron homeostasis. Here, we report the engineering of the human lipocalin-derived, small protein-based anticalin PRS-080 hepcidin antagonist with high affinity and selectivity. Experimental Approach: Anticalin- and hepcidin-specific pharmacokinetic (PK)/pharmacodynamic modelling (PD) was used to design and select the suitable drug candidate based on t1/2 extension and duration of hepcidin suppression. The development of a novel free hepcidin assay enabled accurate analysis of bioactive hepcidin suppression and elucidation of the observed plasma iron levels after PRS-080-PEG30 administration in vivo. Key Results: PRS-080 had a hepcidin-binding affinity of 0.07 nM and, after coupling to 30 kD PEG (PRS-080-PEG30), a t1/2 of 43 h in cynomolgus monkeys. Dose-dependent iron mobilization and hepcidin suppression were observed after a single i.v. dose of PRS-080-PEG30 in cynomolgus monkeys. Importantly, in these animals, suppression of free hepcidin and subsequent plasma iron elevation were sustained during repeated s.c. dosing. After repeated dosing and followed by a treatment-free interval, all iron parameters returned to pre-dose values. Conclusions and Implications: In conclusion, we developed a dose-dependent and safe approach for the direct suppression of hepcidin, resulting in prolonged iron mobilization to alleviate iron-restricted erythropoiesis that can address the root cause of ACD. PRS-080-PEG30 is currently in early clinical development.

Original languageEnglish (US)
Pages (from-to)1054-1065
Number of pages12
JournalBritish Journal of Pharmacology
Volume175
Issue number7
DOIs
StatePublished - Apr 1 2018

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Hepcidins
Macaca fascicularis
Iron
Erythropoiesis
Anemia
Chronic Disease
Lipocalins
Human Engineering
Hepatocytes
Homeostasis
Pharmacokinetics

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Hohlbaum, A. M., Gille, H., Trentmann, S., Kolodziejczyk, M., Rattenstetter, B., Laarakkers, C. M., ... van Swelm, R. P. L. (2018). Sustained plasma hepcidin suppression and iron elevation by Anticalin-derived hepcidin antagonist in cynomolgus monkey. British Journal of Pharmacology, 175(7), 1054-1065. https://doi.org/10.1111/bph.14143

Sustained plasma hepcidin suppression and iron elevation by Anticalin-derived hepcidin antagonist in cynomolgus monkey. / Hohlbaum, Andreas M.; Gille, Hendrik; Trentmann, Stefan; Kolodziejczyk, Maria; Rattenstetter, Barbara; Laarakkers, Coby M.; Katzmann, Galina; Christian, Hans Jürgen; Andersen, Nicole; Allersdorfer, Andrea; Olwill, Shane A.; Meibohm, Bernd; Audoly, Laurent P.; Swinkels, Dorine W.; van Swelm, Rachel P.L.

In: British Journal of Pharmacology, Vol. 175, No. 7, 01.04.2018, p. 1054-1065.

Research output: Contribution to journalArticle

Hohlbaum, AM, Gille, H, Trentmann, S, Kolodziejczyk, M, Rattenstetter, B, Laarakkers, CM, Katzmann, G, Christian, HJ, Andersen, N, Allersdorfer, A, Olwill, SA, Meibohm, B, Audoly, LP, Swinkels, DW & van Swelm, RPL 2018, 'Sustained plasma hepcidin suppression and iron elevation by Anticalin-derived hepcidin antagonist in cynomolgus monkey', British Journal of Pharmacology, vol. 175, no. 7, pp. 1054-1065. https://doi.org/10.1111/bph.14143
Hohlbaum AM, Gille H, Trentmann S, Kolodziejczyk M, Rattenstetter B, Laarakkers CM et al. Sustained plasma hepcidin suppression and iron elevation by Anticalin-derived hepcidin antagonist in cynomolgus monkey. British Journal of Pharmacology. 2018 Apr 1;175(7):1054-1065. https://doi.org/10.1111/bph.14143
Hohlbaum, Andreas M. ; Gille, Hendrik ; Trentmann, Stefan ; Kolodziejczyk, Maria ; Rattenstetter, Barbara ; Laarakkers, Coby M. ; Katzmann, Galina ; Christian, Hans Jürgen ; Andersen, Nicole ; Allersdorfer, Andrea ; Olwill, Shane A. ; Meibohm, Bernd ; Audoly, Laurent P. ; Swinkels, Dorine W. ; van Swelm, Rachel P.L. / Sustained plasma hepcidin suppression and iron elevation by Anticalin-derived hepcidin antagonist in cynomolgus monkey. In: British Journal of Pharmacology. 2018 ; Vol. 175, No. 7. pp. 1054-1065.
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AU - Kolodziejczyk, Maria

AU - Rattenstetter, Barbara

AU - Laarakkers, Coby M.

AU - Katzmann, Galina

AU - Christian, Hans Jürgen

AU - Andersen, Nicole

AU - Allersdorfer, Andrea

AU - Olwill, Shane A.

AU - Meibohm, Bernd

AU - Audoly, Laurent P.

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