Effects of mpl ligands on platelet production and function in nonhuman primates

Abstract

Endogenous thrombopoietin (TPO) stimulates platelet production in nonhuman primates by inducing dose-dependent megakaryocyte development from early marrow hematopoietic progenitors and subsequent proliferation and endoreduplication. Recombinant human TPO, nonpegylated or pegylated recombinant human megakaryocyte growth and development factor produce log-linear responses in peak peripheral platelet counts (or peripheral platelet mass turnover), platelet TPO receptor density, and marrow megakaryocyte volume, ploidy, number and mass. Mpl ligand therapy sustains normal peripheral platelet concentrations following myelosuppressive chemotherapy in baboons and corrects peripheral platelet counts in HIV-infected chimpanzees with severe thrombocytopenia.Whereas Mpl ligands do not directly induce platelet aggregation in vitro, they enhance aggregatory responsiveness of platelets to physiologic agonists both in vitro and transiently ex vivo following treatment with Mpl ligands. However, platelet recruitment into forming thrombus is not augmented by these agents when evaluated in quantitative rabbit or baboon models of platelet-dependent thrombus formation, except for the direct effect of platelet concentration per se. These findings indicate that appropriate dosing of these agents prevents thrombocytopenia without increasing the risk of platelet-dependent thrombo-occlusive complications. Stem Cells 1998;(suppl2): 107-1 I9 MEGAKARYOCYTE DEVELOPMENTThe proto-oncogene c-mpl is an orphan hematopoietic growth factor receptor [I, 21 important for megakaryocytopoiesis [3]. Thrombopoietin (TPO), the endogenous Mpl ligand [4-61, is a 353-residue p r e tein consisting of a 154-residue aminoterminal erythropoietin-like functional domain, and a 178-residue carboxyterminal domain without homology to any known proteins and without known function. Two Mpl ligands, full-length glycosylated recombinant human (rHu)TPO and poIyethyleneglycol (PEG)-derivitized 163-residue aminoterminus, known as PEG-rHu megakaryocyte growth and development factor (MGDF), are currently under clinical development. rHuTPO and PEG-rHuMGDF induce TPO receptor signaling of CD34' murine and human marrow cells to undergo hematopoietic stem cell differentiation into megakaryocyte progenitors [7, 81, and