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

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 t_1/2 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 t_1/2 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.

DOI: 10.1111/bph.14143

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