I. A bioactive designer cytokine for human hematopoietic progenitor cell expansion.
Efficient expansion of hematopoietic progenitor cells requires, at least, the simultaneous stimulation of the receptors c-kit and gp130. While c-kit is activated by SCF; gp130, in cells which do not express sufficient amounts of IL-6R, can be activated by the complex of soluble IL-6R (sIL-6R) and IL-6. The therapeutic use of IL-6/sIL-6R, however, has been hampered by the high concentrations of the sIL-6R protein required. We have designed a fusion protein of sIL-6R and IL-6, linked by a flexible peptide chain, that was expressed to high levels. On gp130 expressing cells the fusion protein turned out to be fully active at 100 to 1,000-fold lower concentration than the combination of unlinked IL-6 and IL-6R. The fusion protein was used to effectively expand human hematopoietic progenitor cells ex vivo in a dose dependent fashion.
Fischer
M
M
Department of Medicine-Section-Pathophysiology, Mainz University, Germany.
Goldschmitt
J
J
Peschel
C
C
Brakenhoff
J P
JP
Kallen
K J
KJ
Wollmer
A
A
Grötzinger
J
J
Rose-John
S
S
D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000032:analysis / Q000096:biosynthesis / Q000737:chemistry* / Q000502:physiology; D018952:Antigens, CD34 / Q000032:analysis; D006528:Carcinoma, Hepatocellular; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D016207:Cytokines / Q000096:biosynthesis / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000737:chemistry* / Q000494:pharmacology; D008113:Liver Neoplasms; D008961:Models, Structural; D017433:Protein Structure, Secondary; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000737:chemistry* / Q000502:physiology; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000737:chemistry* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D018952:Antigens, CD34; D016207:Cytokines; D015850:Interleukin-6; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; C104543:interleukin 6-interleukin 6 receptor fusion protein, recombinant