RECOMBINANT HUMAN LIGAND FOR MPL, MEGAKARYOCYTE GROWTH AND DEVELOPMENT FACTOR (MGDF), STIMULATES THROMBOPOIESIS IN-VIVO IN NORMAL AND MYELOSUPPRESSED BABOONS

Megakaryocyte growth and development factor (MGDF) is a ligand for c-m pl and a member of the hematopoietic growth factor superfamily. Recomb inant murine MGDF specifically stimulates thrombopoiesis in mice. Reco mbinant human (rHu) MGDF stimulates megakaryocytic differentiation of baboon CD34(+) marrow cells in vitro. Therefore, we determined the in vivo biological effects of rHuMGDF administered to normal baboons in t he absence and presence of myelosuppression with 5-fluorouracil (5-FU) . rHuMGDF was administered to normal baboons as a single s.c. injectio n at doses of 1, 10, 25 and 50 mu g/kg/day for 10 days and, as a contr ol, heat-inactivated MGDF was administered at a dose of 10 mu g/kg/day . Platelet counts were markedly increased in all animals administered native rHuMGDF but not in animals given heat-inactivated rHuMGDF. Plat elet counts began to increase between three and six days after startin g rHuMGDF administration and the maximum average increases were 1.7-, 3.4-, 5.1- and 4.0-fold above baseline in animals administered 1, 10, 25 and 50 mu g/kg/day, respectively. Maximum platelet counts were reac hed between 7 and 10 days after starting rHuMGDF and maintained for fo ur days after the last dose. Thereafter, platelet counts decreased, re aching stable pretreatment values between 11 and 14 days after the las t dose of rHuMGDF. No changes in red cell mass, peripheral blood white blood cell counts or differentials were observed during rHuMGDF treat ment. For animals administered 10, 25 and 50 mu g/kg/day of rHuMGDF, m egakaryocytes increased more than threefold in marrow, were markedly e nlarged, and had increased numbers of lobes. Overall marrow cellularit y remained unchanged, as did red cell and white cell morphology. No ma rrow fibrosis was detected. Progenitor cells were not increased in mar row but did increase modestly in the peripheral blood, associated with increased numbers of CD34(+) cells in the circulation. Following a si ngle dose of 5-FU (120 mg/kg) animals were given either saline or pegy lated (PEG) rHuMGDF (25 mu g/kg/day) for 14 days. Platelet counts reco vered to baseline by 13.8 +/- 1.8 days for PEG-rHuMGDF-treated baboons compared with 16.8 +/- 0.6 days for saline treated controls. Marrow b iopsies revealed more rapid recovery of overall marrow cellularity and megakaryocytes in PEG-rHuMGDF-treated animals compared with controls. Thus, rHuMGDF specifically stimulates thrombopoiesis in normal and my elosuppressed baboons. rHuMGDF may be useful for stimulating thrombopo iesis in humans in clinical settings after myelosuppression.