Pegfilgrastim — designing an improved form of rmetHuG-CSF

Abstract

rmetHuG-CSF is the recombinant version of natural granulocyte colony-stimulating factor, the dominant stimulator in the production of neutrophilic leukocytes (neutrophils). Neutrophils represent the first line of defense against invading pathogens and when neutrophil numbers are suppressed by cancer chemotherapy, patients become liable to life-threatening infections. The clearance of rmetHuG-CSF is effected by a combination of neutrophil mediated degradation and renal filtration. Site-directed addition of a single, linear PEG molecule yielded a form of G-CSF (peg-filgrastim) that was shown to be resistant to renal elimination yet remained sensitive to neutrophil-mediated destruction. This semi-synthetic cytokine drug can persist in the plasma for extended periods in neutropenic conditions, yet is cleared rapidly when neutrophils recover. This lends a degree of automation to the therapeutic control of neutrophil numbers which has been exploited in clinical practice since its approval for human use in 2002.