EUROCALIN

EUROpean consortium for antiCALINs as next generation high-affinity protein therapeutics

 Partecipanti

Mappa

 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

 Obiettivo del progetto (Objective)

'The consortium aims to develop and produce an Anticalin, a member of a novel high-affinity scaffold derived from the lipocalin protein family. The Anticalin is specific for hepcidin which is a central regulator of iron homeostasis, and will be used to antagonize hepcidin for the treatment of “anemia of chronic disease” (ACD). Anticalins are genetically modified lipocalins that can target almost any desired molecule. Unlike Immunoglobulins, they can be produced at low cost in microbial expression systems, are expected to be non immunogenic and offer therapeutic advantages where antibody effector functions are not desired. ACD, the most frequent anemia in hospitalized patients, develops in subjects suffering from infections, inflammatory and auto-immune disease, cancer and chronic kidney disease. It is often successfully treated by administering Erythropoiesis-Stimulating Agents. However, a significant number of patients are hypo- or non-responsive to ESA. Anti-hepcidin therapies, alone or together with ESAs, may improve anemia and the patients’ erythropoietic response and enable the use of no or even much lower ESA doses, avoiding the potential detrimental effects of high doses of ESA. The Consortium has already generated proof-of-concept data in an animal model with early candidates. The project aims at identifying, validating, and developing a specific, high affinity drug candidate based on the lipocalin scaffold as promising alternatives to immunoglobulins and a therapeutic approach based on the neutralization of hepcidin. Animal models will be developed and utilized to characterize pharmacokinetic and pharmacodynamic relationships, optimize dosing, to determine safety, biomarker responses and potential synergy with ESA’s. Furthermore, production processes will be optimized leading to a scalable GMP process which provides material for preclinical and clinical studies to establish the safety, tolerability, and PK/PD of an Anticalin hepcidin blocker (Phase Ia/b).'

Introduzione (Teaser)

Anaemia, associated with chronic kidney disease, is a serious complication affecting millions of European patients. Using anticalin scaffolds, an EU-funded study aims to develop a novel therapy for tackling anaemia.

Descrizione progetto (Article)

Functional iron-deficient anaemia is characterised by elevated blood levels of hepcidin. Hepcidin is a peptide that regulates the entry of iron into the circulation. Elevated hepcidin levels cause accumulation of iron in the cells and reduced iron availability for red blood cell production, or erythropoiesis.

A therapeutic approach of hepcidin inhibition will lead to increased erythropoiesis, normalising haemoglobin levels and reversing anaemia. The EU-funded project 'European consortium for anticalins as next generation high-affinity protein therapeutics' (http://www.eurocalin-fp7.eu/ (EUROCALIN)) aims to develop and test this approach.

Partners from four EU countries already developed and will be clinically testing a novel therapeutic drug candidate antagonising hepcidin. The therapeutic drug candidate is a specific binder called Anticalin. It is a novel scaffold-derived protein from the lipocalin family of binding proteins.

Significant progress achieved during the first three years has brought the project to the point of the beginning of the clinical study. The proof-of-concept of reversing anaemia by inhibiting hepcidin was demonstrated in animals. Rat hepcidin-specific Anticalin reversed anaemia in animals in two weeks. The immunogenicity risk of the drug was found to be low.

A 28-day toxicity study established the safety of the drug. No undue tissue accumulation or adverse effects were observed, including for the group with the highest administered dose level. The team has established the manufacturing process for the drug and produced materials for the phase I study. The phase I clinical study of PRS-080-PEG30 in healthy volunteers was approved.

This project unifies the research efforts of European academia and industry in the field of new protein scaffolds. Anti-hepcidin therapies hold great promise to improve anaemia and patients' erythropoietic responses. They can reduce or eliminate the need for potentially toxic parenteral iron repletion, benefiting patients in Europe and internationally. Clinical validation of a unique, safe and effective therapeutic drug candidate is an area of high medical need.