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Blood, 15 June 2001, Vol. 97, No. 12, pp. 3776-3782
HEMATOPOIESIS
Dimeric erythropoietin fusion protein with enhanced
erythropoietic activity in vitro and in vivo
Bruno Dalle,
Annie Henri,
Philippe Rouyer-Fessard,
Mickaël Bettan,
Daniel Scherman,
Yves Beuzard, and
Emmanuel Payen
From the Laboratoire de Thérapie
Génique Hématopoïétique, Institut
Universitaire d'Hématologie, Hôpital Saint Louis,
Paris; and the Laboratoire de Chimie Bioorganique et de Biotechnologie
Moleculaire et Cellulaire, UMR7001 CNRS-ENSCP/Aventis Gencell,
Vitry Sur Seine, France.
High doses of recombinant human erythropoietin (rhEpo) are required
for the treatment of chronic anemia. Thus, it is clear that therapy for
chronic anemia would greatly benefit from an erythropoietin derivative
with increased erythropoietic activity rather than the native
endogenous hormone. In this report, the activity of a human Epo-Epo
dimer protein, obtained by recombinant technology, is described and
compared with its Epo monomer counterpart produced under identical
conditions. Although monomer Epo and dimer Epo-Epo had similar
pharmacokinetics in normal mice, the increase in hematocrit value was
greater with the dimer than with the monomer. Moreover, in clonogenic
assays using CD34+ human hematopoietic cells, the human
dimer induced a 3- to 4-fold-greater proliferation of erythroid cells
than the monomer. Controlled secretion of dimeric erythropoietin was
achieved in  -thalassemic mice by in vivo intramuscular
electrotransfer of a mouse Epo-Epo plasmid containing the tetO element
and of a plasmid encoding the tetracycline controlled transactivator
tTA. Administration of tetracycline completely inhibited the
expression of the mEpo dimer. On tetracycline withdrawal, expression of
the Epo-Epo dimer resumed, thereby resulting in a large and sustained
hematocrit increase in -thalassemic mice. No immunologic response
against the dimer was apparent in mice because the duration of the
hematocrit increase was similar to that observed with the monomeric
form of mouse erythropoietin.
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