Mechanism of action and clinical trials of Mpl ligand

Current Opinion in Hematology

Volumn 4, Issue 5, 1997, Pages 312-316

  Sheridan, William P ^a   Kuter, David J ^b  

^a AMGEN INC   (United States)

^b MASSACHUSETTS GENERAL HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; CARBOPLATIN; CYCLOPHOSPHAMIDE; HEMOPOIETIC GROWTH FACTOR; MEGAKARYOCYTE GROWTH AND DEVELOPMENT FACTOR; PACLITAXEL; RECOMBINANT PROTEIN; THROMBOPOIETIN;

CANCER; CANCER CHEMOTHERAPY; CLINICAL TRIAL; ERYTHROID PRECURSOR CELL; HEMATOPOIETIC STEM CELL; HUMAN; INTRAVENOUS DRUG ADMINISTRATION; KIDNEY; LIVER; MEGAKARYOCYTE; MEGAKARYOPOIESIS; PRIORITY JOURNAL; SHORT SURVEY; SUBCUTANEOUS DRUG ADMINISTRATION; THROMBOCYTE; THROMBOCYTE COUNT; THROMBOCYTOPENIA; THROMBOCYTOPOIESIS;

EID: 0030880201     PISSN: 10656251     EISSN: None     Source Type: Journal    
DOI: 10.1097/00062752-199704050-00003     Document Type: Short Survey

References (35)

1. Bartley TD, Bogenberger J, Hunt P, Li YS, Lu HS, Martin F, Chang MS, Samal B, Nichol JL, Swift S, et al.: Identification and cloning of a megakaryocyte growth and development factor that Is a ligand for the cytokine receptor Mpl. Cell 1994, 77:1117-1124.
2. de Sauvage FJ, Mass PE, Spencer SD, Malloy BE, Gurney AL, Spencer SA, Darbonne WC, Henzel WJ, Wong SC, Kuang WJ, et al.: Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature 1994, 369:533-538.
3. Kuter DJ, Beeler DL, Rosenberg RD: The purification of megapoietin: a physiological regulator of megakaryocyte growth and platelet production. Proc Natl Acad Sci U S A 1994, 91:11104-11108.
4. Kaushansky K, Lok S, Holly RD, Broudy VC, Lin N, Bailey MC, Forstrom JW, Buddle MM, Oort PJ, Hagen FS, et al.: Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin. Nature 1994, 369:568-571.
5. Lok S, Kaushansky K, Holly RD, Kuijper JL, Lofton-Day CE, Oort PJ, Grant FJ, Heipel MD, Burkhead SK, Kramer JM, et al.: Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production In vivo. Nature 1994, 369:565-568.
6. Kato T, Ogami K, Shimada Y, Iwamatsu A, Sohma Y, Akahori H, Horie K, Kokubo A, Kudo Y, Maeda E, et al.: Purification and characterization of thrombopoietin. J Biochem 1995, 118:229-236.
7. Kuter DJ, Hunt P, Sheridan W, Zucker-Franklin D, eds.: Thrombopoiesis and Thrombopoietins: Molecular, Cellular, Preclinical, and Clinical Biology. Totawa, NJ: Humana Press; 1997:377-395.
8. Alexander WS, Roberts AW, Nicola NA, Li R, Metcalf D: Deficiencies in progenitor cells of multiple hematopoietic lineases and defective megakaryocytopoiesis in mice lacking the thrombopoietin receptor cmpl. Blood 1996, 87:2621-2170. Using gene-targeting techniques, c-Mpl-deficient mice were generated and developed normally. These animals had only 6% of the platelets found in control animals and had a similar reduction in the number of bone marrow megakaryocytes. Significantly, the total number of multipotential, blast-cell, and committed progenitors of multiple lineages also were decreased despite normal numbers of erythrocytes and leukocytes in the peripheral blood. This is compelling evidence that c-Mpl is critical for the maintenance of normal megakaryocytes and platelet numbers and has an important role in the production of primitive pluripotential progenitor cells.
9. de Sauvage FJ, Carver-Moore K, Luoh S-M, Ryan A, Dowd M, Eaton DL, Moore MW: Physiological regulation of early and late stages of megakaryocytopoiesis by thrombopoietin. J Exp Med 1996, 183:651-656. This paper describes a "classic" experiment in which the TPO gene was knocked out. It complements this group's previous work, in which c-Mpl-deficient mice were generated. Homozygous TPO-deficient mice had platelet counts 20% of normal, whereas heterozygous TPO-deficient mice had platelet counts 60% of normal. This gene-dosage effect is the strongest evidence yet that the level of TPO gene expression is not regulated by platelet count.
10. Harker LA, Marzec UM, Hunt P, Kelly AB, Tomer A, Cheung E, Hanson SR, Stead RB: Dose-response effects of pegylated human megakaryocyte growth and development factor on platelet production and function in nonhuman primates. Blood 1996, 88:511-521. This study provides a comprehensive review of the effects of PEG-rHuMGDF on platelet number and function in baboons. Doses of PEG-rHuMGDF ranging from 0.05 to 2.5 μg/kg/d were injected, and the log-linear relationship of dose to response was demonstrated for megakaryocyte number, ploidy, and platelet concentration. Effects on platelet function were analyzed by aggregometry and by measuring platelet and fibrin deposition in blood vessels and Dacron vascular grafts (CR Bard, Billerica, MA).
11. Carver-Moore K, Broxmeyer HE, Luoh S-M, Cooper S, Peng J, Burstein SA, Moore MW, de Sauvage FJ: Low levels of erythroid and myeloid progenitors In thrombopoietin and c-mpl deficient mice. Blood 1996, 88:803-808. The c-Mpl and TPO-deficient mice are examined in more detail in this comprehensive work. The bone marrow precursors for megakaryocytes were decreased, as expected, but precursors for all other lineages were also decreased for both groups of mice, despite an absence of effect on leukocyte and erythrocyte counts. This is the best demonstration to date of the multilineage effect of TPO. Administration of rTPO to the TPO-deficient but not to the c-Mpl-deficient mice corrected the precursor-cell defect. The effect of administration of interleukin-6, interleukin-11, and stem-cell factor in these mice was also examined.
12. Sitnicka E, Lin N, Priestley GV, Fox N, Broudy VC, Wolf NS, Kaushansky K: The effect of thrombopoietin on the proliferation and differentiation of murine hematopoietic stem cells. Blood 1996, 87:4998-5005.
13. Ku H, Yonemura Y, Kaushansky K, Ogawa M: Thrombopoietin, the ligand for the mpl receptor, synergizes with steel factor and other early acting cytokines In supporting proliferation of primitive hematopoietic progenitors of mice. Blood 1996, 87:4544-4551.
14. Young JC, Bruno E, Luens KM, Wu S, Backer M, Murray U: Thrombopoietin stimulates megakaryocytopoiesis, myelopoiesis, and expansion of CD34+ progenitor cells from single CD34+thy1 -linprimitive progenitor cells. Blood 1996, 88:1619-1631.
15. Kobayashi M, Laver JH, Kato T, Miyazaki H, Ogawa M: Thrombopoietin supports proliferation of human primitive hematopoietic cells In synergy with steel factor and/or Interleukin-3. Blood 1996, 88:429-436.
16. Kato T, Horie K, Hagiwara T, Maeda E, Tsumura H, Ohashi H, Miyazaki H: GpIIb/IIIa+ subpopulation of rat megakaryocyte progenitor cells exhibits high responsiveness to human thrombopoietin. Exp Hematol 1996, 24:1209-1214.
17. Kieran MW, Perkins AC, Orkin SH, Zon LI: Thrombopoietin rescues In vitro erythroid colony formation from mouse embryos lacking the erythropoietin receptor. Proc Natl Acad Sci U S A 1996, 93:9126-9131. Mice lacking the erythropoietin receptor were generated and found to be severely anemic, and they died in utero at embryonic day 11 to 12.5. Hepatic erythroid precursors were blocked at the proerythroblast stage. Although erythroid colony-forming cells and erythroid blast-forming cells were not detected in cultures from fetal liver in the presence of erythropoietin, erythroid blast-forming cell colonies were detected when the cells were cultured in the presence of TPO plus either c-kit ligand or interleukin-3 and interleukin-11. This demonstrates that signal transduction through the TPO receptor of c-Mpl can stimulate proliferation and terminal differentiation of erythroid progenitors.
18. Debili N, Coulombel L, Croisille L, Katz A, Guichard J, Breton-Gorius J, Vainchenker W: Characterization of a bipotent erythro-megakaryocytic progenitor in human bone marrow. Blood 1996, 88:1284-1296.
19. Era T, Takahashi T, Sakai K, Kawamura K, Nakano T: Thrombopoietin enhances proliferation and differentiation of murine yolk sac erythroid progenitors. Blood 1997, 89:1207-1213.
20. Dolzhanskiy A, Basch RS, Karpatkin S: The development of human megakaryocytes: III. Development of mature megakaryocytes from highly purified committed progenitors In synthetic culture media and inhibition of thrombopoietin-induced polyploldization by interleukin-3. Blood 1997, 89:426-434.
21. Arnold JT, Daw NC, Stenberg PE, Jayawardene D, Srivastava DK, Jackson CW: A single Injection of pegylated murine megakaryocyte growth and development factor (MGDF) Into mice Is sufficient to produce a profound stimulation of megakaryocyte frequency, size, and ploidization. Blood 1997, 89:823-833.
22. Choi ES, Hokom MM, Chen J-L, Skrine J, Faust J, Nichol J, Hunt P: The role of megakaryocyte growth and development factor in terminal stages of thrombopoiesis. Br J Haematol 1996, 95:227-233.
23. Nagahisa H, Nagata Y, Ohnuki T, Osada M, Nagasawa T, Abe T, Todokoro K: Bone marrow stromal cells produce thrombopoietin and stimulate megakaryocyte growth and maturation but suppress proplatelet formation. Blood 1996, 87:1309-1316.
24. Ito T, Ishida Y, Kashiwagi R, Kuriya S: Recombinant human c-mpl ligand is not a direct stimulator of proplatelet formation in mature human megakaryocytes. Br J Haematol 1996, 94:387-390.
25. Sungaran R, Markovic B, Chong BH: Localization and regulation of thrombopoietin mRNA expression in human kidney, liver, bone marrow, and spleen using in situ hybridization. Blood 1997, 89:101-107.
26. Kuter DJ, Rosenberg RD: The reciprocal relationship of thrombopoietin (c-Mpl ligand) to changes in the platelet mass during busulfan-induced thrombocytopenia in the rabbit Blood 1995, 85:2720-2730.
27. Emmons RV, Reid DM, Cohen RL, Meng G, Young NS, Dunbar CE, Shulman NR: Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction. Blood 1996, 87:4068-4071.
28. Stoffel R, Wiestner A, Skoda RC: Thrombopoietin In thrombocytopenic mice: evidence against regulation at the mRNA level and for a direct regulatory role of platelets. Blood 1996, 87:567-573.
29. Fielder PJ, Gurney AL, Stefanich E, Marian M, Moore MW, Carver-Moore K, de Sauvage FJ: Regulation of thrombopoietin levels by c-mpl-mediated binding to platelets. Stood 1996, 87:2154-2161.
30. Basser RL, Rasko JEJ, Clarke K, Cebon J, Green MD, Hussein S, Alt C, Menchaca D, Tomita D, Marty J, et al.: Thrombopoietic effects of pegylated recombinant human megakaryocyte growth and development factor In patients with advanced cancer, Lancet 1996, 348:1279-1281. The first publication demonstrating the effect of Mpl ligands in humans. Seventeen patients with cancer were injected with various doses of PEG-rHuMGDF or placebo before chemotherapy. A dose-dependent increase in platelet count at effective doses of 0.3 and 1.0 μg/kg/d and an increase in bone marrow megakaryocytes were seen. Leukocyte and erythrocyte counts did not change, and rHuPEG-MGDF was well tolerated.
31. O'Malley CJ, Rasko JEJ, Basser RL, McGrath KM, Cebon J, Grigg AP, Hopkins W, Cohen B, O'Byrne J, Green MD, et al.: Administration of pegylated recombinant human megakaryocyte growth and development factor to humans stimulates the production of functional platelets that show no evidence of in vivo activation. Blood 1996, 88:3288-3298. This paper reports the platelet function results from the phase I study of PEGrHuMGDF in humans [30··]. At doses of 0.3 and 1.0 μg/kg/d, a three-fold increase in the platelet count was seen after 16 days. These platelets had normal aggregation responses when stimulated with a range of agonists, and no change was observed in platelet expression of P-selectin or glycoprotein IIb/IIIa. These results demonstrate that platelets produced under the stimulation of PEGrHuMGDF are fully functional and possess no altered activation properties.
32. Rasko JEJ, Basser RL, O'Malley CJ, Mansfield R, Boyd J, Grigg A, McGrath K, Marty J, Sheridan W, Hussein S, el al.: In vitro studies from a phase I randomized, blinded trial of pegylated megakaryocyte growth and development factor (PEG-rHuMGDF) [abstract]. Blood 1995, 86:497a.
33. 9/L) and earlier recovery to baseline platelet counts (14 days compared with > 21 days) than did those receiving placebo.
34. Basser RL, Rasko J, Clarke K, Cebon J, Green MD, Grigg AP, Zalcberg J, Cohen B, O'Byrne J, Menchaca DM, el al.: Randomised, blinded, placebo-controlled phase 1 trial of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) with filgrastim after dose-Intensive chemotherapy In patients with advanced cancer. Blood 1997, 89:3118-3128. In this comprehensive study, patients with cancer receiving carboplatin and cyclophosphamide plus filgrastim were randomly assigned to receive PEGrHuMGDF or placebo. Patients receiving PEG-rHuMGDF had an earlier platelet nadir. At PEG-rHuMGDF doses from 0.3 to 5.0 μg/kg/day, a dose-dependent reduction was seen in the duration of thrombocytopenia (17 days) compared with patients receiving placebo (22 days). Platelet function did not change. Levels of peripheral blood progenitor cells were markedly elevated in patients receiving PEG-rHuMGDF.
35. Vadhan-Raj S, Murray U, Bueso-Ramos C, Patel S, Reddy SP, Hoots WK, Johnston T, Papadopolous NE, Hittelman WN, Johnston DA, et al.: Stimulation of megakaryocyte and platelet production by a single dose of recombinant human thrombopoietin in patients with cancer. Ann Intern Med 1997, 126:673-681. The first publication to detail the effects of a full-length form of Mpl ligand in humans. Twelve patients with sarcoma had single intravenous injections of 0.3 to 1.2 μg/kg/d of rHuTPO. There was a dose-related increase in platelet count, and the number of megakaryocytes increased. The drug was well tolerated.