Effects of Site-Specific Polyethylene Glycol Modification of Recombinant Human Granulocyte Colony-Stimulating Factor on its Biologic Activities
Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is a long-chain cytokine that is administered to stimulate the production of white blood cells (WBCs) to reduce the risk of serious infection in immunocompromized patients. However, to achieve sustained stimulation of WBC production, rhG-CSF must be administered frequently, thus limiting its clinical use.
We conjugated rhG-CSF with linear monomethoxy-polyethylene glycol (PEG) maleimide at amino acid residue Cys17 to test our hypothesis that this could extend the in vivo half-life of rhG-CSF in blood.
The mono-PEG rhG-CSF became more stable to pH, temperature, and enzyme degradation in vitro, and had granulopoietic activity that was superior to the unmodified form in vivo. The granulopoietic activity of PEG-G-CSF was 2.82-fold greater than that of unmodified G-CSF.
These results indicate that the thiol-specific PEGylation remarkably prolonged the half-life of rhG-CSF and represents a novel strategy to address the more clinically acceptable therapeutic application of hemopoietic growth factor.
- 4.Metcalf D. The hemopoietic colony stimulating factors. Amsterdam: Elsevier, 1984Google Scholar
- 5.Weite K, Gabrilove J, Bronchud MH, et al. Filgrastim (r-metHuG-CSF): the first 10 years. Blood 1996; 88: 1907–29Google Scholar
- 6.Lie AK W, Hui CH, Rawling T, et al. Granulocyte colony-stimulating factor (G-CSF) dose-dependent efficacy in peripheral blood stem cell mobilization in patients who had failed initial mobilization with chemotherapy and G-CSF. Bone Marrow Transpl 1998; 22(9): 853–7Google Scholar
- 10.Holmes FA, O’Shaughnessy JA, Vukelja S, et al. Blinded, randomized, multicenter study to evaluate single administration PEG filgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol 2002; 20: 727–31PubMedCrossRefGoogle Scholar
- 16.Kubota N, Orita T, Hattori K, et al. Structural characterization of natural and recombinant human granulocyte colony-stimulating factors. J Biochem (Tokyo) 1990; 107(3): 486–92Google Scholar
- 20.de Haan G, Ausema A, Wilkens M, et al. Efficient mobilization of haematopoietic progenitors after a single injection of pegylated recombinant human granulocyte colony-stimulating factor in mouse strains with distinct marrow-cell pool sizes. Br J Haematol 2000; 110: 638–46PubMedCrossRefGoogle Scholar