Effect of recombinant human thrombopoietin in nonhuman primates with chemotherapy‐induced thrombocytopenia

Abstract

We examined the effects of recombinant human thrombopoietin (rhTPO) on myelosuppressive chemotherapy-induced thrombocytopenia in cynomolgus monkeys. After treatment with nimustine (ACNU) on day 0, the monkeys intravenously received rhTPO at a dose of 0.04, 0.2 or 1 microgram/kg/d or monkey's serum once each day from day 1 to day 28. Administration of rhTPO reduced the severity of thrombocytopenia and accelerated the rate of platelet recovery in a dose-dependent fashion. Treatment with the highest rhTPO dose completely prevented thrombocytopenia and stimulated a marked increase in platelet counts over the normal values. Animals treated with ACNU also became neutropenic and slightly anaemic. Administration of rhTPO following ACNU treatment significantly improved neutropenia with increasing doses of rhTPO, but had no effect on anaemia. Compared to the control animals, rhTPO-treated animals exhibited no significant changes in several serum parameters. C-reactive protein concentration and some blood coagulation profiles within the study period. These results suggest a therapeutic efficacy of rhTPO in improving chemotherapy-induced thrombocytopenia.

The Glycan Domain of Thrombopoietin (TPO) Acts intrans to Enhance Secretion of the Hormone and Other Cytokines

“…As a therapeutic agent TPO has been shown to speed platelet recovery following myelosuppressive therapy in cancer patients receiving chemotherapy (7,8). In addition, the biological effects of TPO are not limited to the MK lineage; the growth of erythroid (burst forming unit-erythrocyte) and myeloid (colony forming unit-granulocyte macrophage) colony-forming cells is also expanded by TPO in vitro, and its use in normal and myelosuppressed mice and non-human primates leads to enhanced recovery of multiple hematopoietic lineages (9,10). Finally, TPO affects the survival and proliferation of primitive hematopoietic stem cells in vitro (11,12) and in vivo (13).…”

Pharmacokinetics and Hematological Effects of the PEGylated Thrombopoietin Peptide Mimetic GW395058 in Rats and Monkeys After Intravenous or Subcutaneous Administration

“…Two forms of the recombinant human protein have been investigated: full-length glycosylated recombinant human protein (rHuTPO) [5] and PEGylated megakaryocyte growth and development factor (PEG-rHuMGDF) [6]. In mice, dogs, and primates [7][8][9][10][11][12][13][14], rHuTPO and PEG-rHuMGDF promote platelet production and reduce chemotherapy-induced thrombocytopienia. Unfortunately, evidence of TPO-neutralizing antibodies in patients participating in cancer and platelet donor clinical trials forced the discontinuation of PEG-rHuMGDF development [15].…”

Promegapoietin‐1a, an Engineered Chimeric IL‐3 and Mpl‐L Receptor Agonist, Stimulates Hematopoietic Recovery in Conventional and Abbreviated Schedules Following Radiation‐Induced Myelosuppression in Nonhuman Primates

“…TPO has been characterized as the primary physiologic regulator of MK and PLT development [11,27,[33][34][35][36][37]. Preclinical trials in rodents and nonhuman primates substantiate its ability to promote enhanced MK and PLT regeneration subsequent to radiation and/or chemotherapyinduced myelosuppression [11,13,14,20,38,39]. Furthermore, a wide range of studies has indicated that TPO has profound effects on early hematopoiesis.…”