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.
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.
Authors: D Schönfeld; G Matschiner; L Chatwell; S Trentmann; H Gille; M Hülsmeyer; N Brown; P M Kaye; S Schlehuber; A M Hohlbaum; A Skerra Journal: Proc Natl Acad Sci U S A Date: 2009-05-05 Impact factor: 11.205
Authors: Coby M M Laarakkers; Erwin T Wiegerinck; Siem Klaver; Maria Kolodziejczyk; Hendrik Gille; Andreas M Hohlbaum; Harold Tjalsma; Dorine W Swinkels Journal: PLoS One Date: 2013-10-04 Impact factor: 3.240
Authors: 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 Journal: Br J Pharmacol Date: 2018-02-23 Impact factor: 8.739
Authors: Laura E Diepeveen; Coby M Laarakkers; Hilde P E Peters; Antonius E van Herwaarden; Hans Groenewoud; Joanna IntHout; Jack F Wetzels; Rachel P L van Swelm; Dorine W Swinkels Journal: Pharmaceuticals (Basel) Date: 2019-08-23