Design Rationale and Development Approach for Pegfilgrastim as a Long-Acting Granulocyte Colony-Stimulating Factor

摘要: Filgrastim, a recombinant methionyl human granulocyte colony-stimulating factor (G-CSF) (r-metHuG-CSF), is efficacious in stimulating neutrophil production and maturation to prevent febrile neutropenia (FN) response chemotherapy. Because of its relatively short circulating half-life, daily filgrastim injections are required stimulate recovery. In an effort develop long-acting form that was as safe but had longer vivo residence time, number strategies were considered. Ultimately, fusion polyethylene glycol (PEG) selected. Following extensive analysis conjugation chemistries well vitro characterization panel PEGylated proteins, construct containing 20 kDa PEG moiety covalently conjugated the N-terminus chosen for advancement pegfilgrastim. Pegfilgrastim primarily cleared by neutrophils precursors (rather than kidneys), meaning clearance from circulation self-regulating pegfilgrastim eliminated only after start recover. Importantly, addition did not alter mechanism action safety profile compared filgrastim. Clinical evaluation revealed single 6 mg dose effectively reduces duration risk FN patients receiving This work demonstrates benefit using PEGylation generate pegfilgrastim, which allows once-per-chemotherapy cycle administration while maintaining similar efficacy profiles those multiple Approaches may provide advances therapeutic agonists G-CSF receptor also discussed.