IN-VIVO EFFECTS OF PEGYLATED RECOMBINANT HUMAN MEGAKARYOCYTE GROWTH AND DEVELOPMENT FACTOR ON HEMATOPOIESIS IN NORMAL MICE

The in vivo effects of pegylated recombinant human megakaryocyte growt h and development factor (PEG-rHuMGDF), a truncated molecule of recomb inant human thrombopoietin modified with polyethylene glycol, were inv estigated in normal Balb/c mice. PEG-rHuMGDF was more potent in produc ing platelets and the dose-response curve was steeper compared with th e case of the nonpegylated form of this molecule, Five consecutive inj ections with PEG-rHuMGDF caused a dose-dependent increase in periphera l platelet counts with a peak on day 8. There was a dose-dependent ris e in platelet counts on day 8 at daily doses from 0.333 to 30 mu g/kg. Intermediate doses of PEG-rHuMGDF (1.111 to 10 mu g/kg/day) caused a significant decrease in mean platelet volume, and conversely, higher d oses of PEG-rHuMGDF (30 to 270 mu g/kg/day) induced a dose-dependent i ncrease in mean platelet volume. There was a dose-dependent decrease i n hemoglobin concentration with a minimum on day 8 but no significant reduction in reticulocyte counts following PEG-rHuMGDF administration. White blood cell counts were unchanged by PEG-rHuMGDF treatment. Marr ow megakaryocyte size enlarged to 1.5-fold and the number of marrow me gakaryocytes increased to sixfold by consecutive administration of PEG -rHuMGDF at 30 mu g/kg/day. A twofold increase in the number of marrow megakaryocytic progenitor cells (colony-forming units-megakaryocyte) was also observed. Marrow erythroid progenitor (colony-forming units-e rythroid) counts decreased but splenic colony-forming units-erythroid, marrow and splenic erythro/myeloid progenitor cell counts, and spleni c granulocyte/macrophage progenitor cell counts increased with PEG-rHu MGDF treatment. Marrow and splenic erythroid burst-forming cells were unchanged. These results indicate that PEG-rHuMGDF, a truncated molecu le of thrombopoietin, is a potent stimulator for megakaryopoiesis and thrombopoiesis, and also affects the development of other hematopoieti c cells in normal mice.