Preclinical evaluation of Hematide, a novel erythropoiesis stimulating agent, for the treatment of anemia.

Abstract

OBJECTIVE:

To evaluate the preclinical erythropoiesis stimulating properties of Hematide, a novel, PEGylated, synthetic peptide for the treatment of anemia associated with chronic kidney disease and cancer.

METHODS:

The in vitro activity of Hematide was assessed in competitive binding, proliferation, signal transduction, and apoptosis assays, and in erythroid colony-forming assays with CD34(+) cells purified from human bone marrow. Erythropoiesis and pharmacokinetics were evaluated in rat, monkey, and a rat chronic renal insufficiency (CRI) model following single administration. Erythropoiesis and immunogenicity were also evaluated following repeat administration in rats.

RESULTS:

Hematide binds and activates the erythropoietin receptor and causes proliferation and differentiation of erythroid progenitor cells. Sustained circulatory persistence of Hematide is observed in rats and monkeys. In a rat CRI model, Hematide exhibited twofold lower clearance than in the normal rat, with hypothesis consistent with Hematide being cleared, at least partially, via the kidney. A dose-dependent rise in hemoglobin (Hgb) and duration of response was observed following single administration in rats and monkeys. Hematide was able to alleviate anemia in an experimental CRI rodent model. Repeat intravenous (IV) and subcutaneous (SC) administration in rats yielded similar erythrogenic responses, with no anti-Hematide antibodies being detected.

CONCLUSIONS:

Hematide is a potent erythropoiesis stimulating agent with a prolonged half-life and slow clearance times. It is anticipated that similar prolonged clearance and activity will be observed in the clinic, potentially enabling dosing intervals of 3 to 4 weeks that may translate into improved patient convenience for the treatment of anemia.

• Authors: Qing Fan, Kerstin K Leuther, Christopher P Holmes, Kei-Lai Fong, Jim Zhang, Svetlana Velkovska, Min-Jia Chen, Richard B Mortensen, Karen Leu, Jennifer M Green, Peter J Schatz, Kathryn W Woodburn
• Journal: Experimental hematology (Exp Hematol) Vol. 34 Issue 10 Pg. 1303-11 (Oct 2006) ISSN: 0301-472X [Print] Netherlands
• PMID: 16982323 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Antibodies
• Peptides
• Receptors, Erythropoietin
• hematide
• Polyethylene Glycols

Topics

• Anemia (drug therapy, etiology, immunology, metabolism)
• Animals
• Antibodies (immunology, metabolism)
• Cell Line
• Cell Proliferation (drug effects)
• Chronic Disease
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• Erythroid Precursor Cells (metabolism)
• Erythropoiesis (drug effects, immunology)
• Half-Life
• Humans
• Kidney (immunology, metabolism)
• Macaca fascicularis
• Male
• Neoplasms (complications, drug therapy, immunology)
• Peptides (immunology, pharmacokinetics, pharmacology, therapeutic use)
• Polyethylene Glycols (pharmacokinetics, pharmacology, therapeutic use)
• Protein Binding
• Rats
• Rats, Sprague-Dawley
• Receptors, Erythropoietin (metabolism)
• Renal Insufficiency (drug therapy, immunology, metabolism)
• Signal Transduction (drug effects, immunology)
• Stem Cells
• Time Factors