Fc fusion protein of human granulocyte colony stimulin with enhanced bioactivity

Abstract

A human hG-CSF-L-VFC fusion protein whose bioactivity is higher than that of rhG-CSF is disclosed. It contains human G-CSF, 20 or less flexible peptide linkers, and human IgG Fc variant which can notbe cracked and can show very little poor by-effect of Fc-mediation. A process for preparing the said fusion protein with high expression level is also disclosed. This hG-CSF-L-VFC fusion protein has longer serum half-life period and higher bioactivity, so improving its pharmacodynamics and effect.

Description

Background of the invention [0001] Granulocyte colony stimulating factor (G-CSF) is a 20 kilodalton glycoprotein that promotes the proliferation of progenitor cells and induces their differentiation into neutrophils. In addition, G-CSF prolongs the survival of mature neutrophils and activates their function. Human G-CSF (hG-CSF) is produced by monocytes, macrophages, fibroblasts and endothelial cells (see, e.g., Moore, Annu. Rev. Immunol., 9: 159-191, 1991; Nicola , Annu. Rev. Biochem., 58:45-77, 1991). The biological effects of G-CSF are mediated by its interaction with the G-CSF receptor (G-CSF-Rc) expressed on the surface of myeloid hematopoietic progenitor cells and cells of the myeloid lineage. Upon binding to G-CSF, the receptor is activated and undergoes homodimerization followed by phosphorylation of the Janus family of tyrosine kinases. Subsequently, a cascade of intracellular signal transductions occurs that increases the number of progenitor cells that mature int...

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Problems solved by technology

Human IgG2 does not bind Fc γ R, but

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