New thrombopoietic growth factors.
Although development of first-generation thrombopoietic growth factors (recombinant human thrombopoietin [TPO] and pegylated recombinant human megakaryocyte growth and development factor [PEG-rHuMGDF]) was stopped due to development of antibodies to PEG-rHuMGDF, nonimmunogenic second-generation thrombopoietic growth factors with unique pharmacologic properties have been developed. TPO peptide mimetics contain TPO receptor-activating peptides inserted into complementarity-determining regions of Fab (Fab 59), attached to the IgG Fc region (AMG 531), or pegylated (Peg-TPOmp). Orally available, TPO nonpeptide mimetics (eltrombopag, AKR-501) bind and activate the TPO receptor by a mechanism different from TPO and may have an additive effect to TPO. TPO agonist antibodies are monoclonal antibodies activating the TPO receptor but modified in size [TPO minibodies; ie, VB22B sc(Fv)(2)] or immunoglobuln type (domain subclass-converted TPO agonist antibodies; ie, MA01G4G344). All second-generation thrombopoietic growth factors stimulate growth of TPO-dependent cell lines via JAK2/STAT signaling pathways and increase platelet counts in animals. When tested in healthy humans, TPO peptide and nonpeptide mimetics produced a dose-dependent rise in platelet count. AMG 531 and eltrombopag markedly increase platelet counts in patients with immune thrombocytopenic purpura, without significant adverse effects. One or more second-generation thrombopoietic growth factors should soon be clinically available for treating thrombocytopenic disorders.
Kuter
David J
DJ
Hematology Division, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. kuter.david@MGH.harvard.edu
D002626:Chemistry, Pharmaceutical / Q000379:methods / Q000639:trends; D015195:Drug Design; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000627:therapeutic use; D008954:Models, Biological; D008956:Models, Chemical; D010455:Peptides / Q000737:chemistry; D011092:Polyethylene Glycols / Q000378:metabolism; D015398:Signal Transduction; D034061:Thrombopoiesis / Q000502:physiology*; D013926:Thrombopoietin / Q000737:chemistry / Q000378:metabolism / Q000502:physiology
D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D011092:Polyethylene Glycols; D013926:Thrombopoietin