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An Oral, Nonpeptide Thrombopoietin Receptor Agonist

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An Oral, Nonpeptide Thrombopoietin Receptor Agonist TISSUE-SPECIFIC STEM CELLS Preclinical Activity of Eltrombopag (SB-497115), an Oral, Nonpeptide Thrombopoietin Receptor Agonist CONNIE L. ERICKSON-MILLER,a EVELYNE DELORME,b SHIN-SHAY TIAN,b CHRISTOPHER B. HOPSON,a AMY J. LANDIS,a ELIZABETH I. VALORET,a TERESA S. SELLERS,c JON ROSEN,b STEPHEN G. MILLER,b JUAN I. LUENGO,a KEVIN J. DUFFY,a JULIAN M. JENKINSa aGlaxoSmithKline, Collegeville, Pennsylvania, USA; bLigand Pharmaceuticals, La Jolla, California, USA; cGlaxoSmithKline, King of Prussia, Pennsylvania, USA Key Words. Thrombopoietin receptor agonist • Megakaryocyte • Differentiation • Thrombocytopenia ABSTRACT Eltrombopag is a first-in-class, orally bioavailable, small- marrow cells into CD41؉ megakaryocytes. Measurements in molecule, nonpeptide agonist of the thrombopoietin receptor platelets in several species indicated that eltrombopag spe- (TpoR), which is being developed as a treatment for throm- cifically activates only the human and chimpanzee STAT bocytopenia of various etiologies. In vitro studies have dem- pathways. The in vivo activity of eltrombopag was demon- onstrated that the activity of eltrombopag is dependent on strated by an increase of up to 100% in platelet numbers expression of TpoR, which activates the signaling transduc- when administered orally (10 mg/kg per day for 5 days) to ers and activators of transcription (STAT) and mitogen- chimpanzees. In conclusion, eltrombopag interacts selec- activated protein kinase signal transduction pathways. The tively with the TpoR without competing with Tpo, leading to objective of this preclinical study is to determine if eltrom- the increased proliferation and differentiation of human bopag interacts selectively with the TpoR to facilitate bone marrow progenitor cells into megakaryocytes and in- megakaryocyte differentiation in platelets. Functional creased platelet production. These results suggest that el- thrombopoietic activity was demonstrated by the prolifera- trombopag and Tpo may be able to act additively to increase tion and differentiation of primary human CD34؉ bone platelet production. STEM CELLS 2009;27:424–430 Disclosure of potential conflicts of interest is found at the end of this article. A key concept in treating thrombocytopenia is to eliminate INTRODUCTION the underlying problem, which may include targeting the cause of the increased platelet destruction (i.e., immunosuppressive Thrombocytopenia is a condition of an unusually low level of agents or other drugs that may cause thrombocytopenia) or platelets in the blood and results from an imbalance between the increasing platelet counts by stimulating the production of production and destruction of platelets. Thrombocytopenia is new platelets. Platelet production initially originates from associated with several medical disorders, including aplastic megakaryocyte precursor cells in the bone marrow. Proliferation anemia [1], myelodysplasia [1], and idiopathic thrombocytope- and differentiation in the megakaryocytic pathway is predomi- nic purpura (ITP) [2]. Clinically significant thrombocytopenia nantly controlled by Tpo, a cytokine that is constitutively pro- can occur as a consequence of myelosuppressive or myeloabla- duced, and primarily made by the liver [6, 7]. The binding of tive chemotherapy or radiotherapy [3]. Thrombocytopenia can Tpo to the thrombopoietin receptor (TpoR) on cells in the also be associated with severe chronic liver disease due to the megakaryocyte pathway triggers the activation of the cytoplas- reduced production of the endogenous thrombopoietic growth mic tyrosine kinases Janus kinase (JAK)2 and tyrosine kinase 2, factor, thrombopoietin (Tpo), and/or the increased sequestration which in turn activate signal transducers and activators of tran- of platelets [4]. In patients infected with the hepatitis C virus scription five (STAT)5, phosphoinositide-3 kinase, and Ras- (HCV), thrombocytopenia may occur due to the myelosuppres- mitogen-activated protein kinase (MAPK) [8–10]. The subse- sive effects of the virus on the bone marrow [5]. quent changes in gene expression in precursor cells promote Author contributions: C.L.E.-M.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; E.D.: conception and design, collection and/or assembly of data, data analysis and interpretation; S.-S.T.: conception and design, collection and/or assembly of data, data analysis and interpretation; C.B.H.: collection and/or assembly of data, data analysis and interpretation; A.J.L.: collection and/or assembly of data; E.I.V.: collection and/or assembly of data, data analysis and interpretation; T.S.S.: conception and design, collection and/or assembly of data, data analysis and interpretation; J.R.: conception and design, collection and/or assembly of data, data analysis and interpretation, final approval of manuscript; S.G.M.: conception and design, collection and/or assembly of data, data analysis and interpretation; J.I.L.: conception and design, collection and/or assembly of data, data analysis and interpretation; K.J.D.: provision of study material or patients, data analysis and interpretation; J.M.J.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript. Correspondence: Connie L. Erickson-Miller, Ph.D., GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA. Telephone: 610-917-4509; Fax: 610-917-4181; e-mail: [email protected] Received April 11, 2008; accepted for publication November 5, 2008; first published online in STEM CELLS EXPRESS November 26, 2008; available online without subscription through the open access option. ©AlphaMed Press 1066-5099/2009/$30.00/0 doi: 10.1634/stemcells.2008-0366 STEM CELLS 2009;27:424–430 www.StemCells.com Erickson-Miller, Delorme, Tian et al. 425 differentiation along the megakaryocytic lineage and have an 5% CO2 at 37°C. BAF3/hTpoR cells were grown for 44 hours, antiapoptotic effect, which ultimately leads to platelet develop- labeled with BrdU, and returned to the incubator for four more ment and release. hours. The plates were developed using a BrdU cell proliferation kit Following the purification of Tpo in the mid-1990s, recom- (Roche Diagnostics, Indianapolis, IN, http://www.roche-diagnostics. binant human Tpo (rhTpo) and a similar protein, megakaryocyte us) and were read on an enzyme-linked immunosorbent assay plate reader at 380 nm. growth and development factor, were extensively tested for their Thymidine incorporation assays were conducted using cyto- ability to overcome thrombocytopenia, and were shown to sig- kine-starved N2C-Tpo cells plated in 96-well plates (1.4 ϫ 105 nificantly increase circulating platelet levels in mice, primates, cells/ml final concentration), grown in a white view plate, and and humans [7, 11–15]. However, because of the induction of exposed to eltrombopag (0.003–3 ␮M) and/or rhTpo (1–100 immunogenicity [7, 16], megakaryocyte growth and develop- ng/ml) for 72 hours at 37°C. Tritiated thymidine (1 ␮Ci/well) ment factor is no longer being tested in clinical trials. Nonpep- was added for the final 4 hours of incubation. Cells were har- tide, small-molecule TpoR agonists are an attractive alternative vested onto glass fiber filter mats and read on a Wallac 1,450 to protein therapeutics because they are more likely to be orally Microbeta scintillation counter (PerkinElmer, Inc., Waltham, bioavailable and less likely to be immunogenic. MA, http://www.perkinelmer.com). In this report, we present preclinical results for eltrombopag Caspase-3 and Caspase-7 Assays (SB-497115, Promacta௡/Revolade™; GlaxoSmithKline, Re- search Triangle Park, NC, http://www.gsk.com, and Ligand The Caspase-Glo 3/7 assay (Promega) is a luminescent assay that Pharmaceuticals, Inc., San Diego, CA, http://www.ligand.com), measures caspase-3 and caspase-7 activity. The addition of the an orally bioavailable, small-molecule, nonpeptide TpoR ago- Caspase-Glo reagent results in cell lysis, followed by caspase cleav- age of the substrate and generation of a luminescent signal; the nist. We show that eltrombopag interacts specifically with the amount of luminescence is proportional to the amount of caspase TpoR without competing with Tpo, thereby activating intracel- present. Cytokine-starved N2C-Tpo cells (1.4 ϫ 105 cells/ml final lular signal transduction pathways additively with endogenous concentration) were grown in a white view plate and exposed to Tpo, leading to the increased proliferation and differentiation of eltrombopag (0.003–3 ␮M) and/or rhTpo (1–100 ng/ml) for 72 human bone marrow progenitor cells into megakaryocytes, and hours at 37°C. Caspase-Glo (100 ␮l) was added, and cells were ultimately, increased platelet production. incubated for 90 minutes at room temperature. Luminescence was measured using the Envision plate reader (PerkinElmer, Inc.). MATERIALS AND METHODS Western Blot Analysis of STAT5 and MAPK N2C-Tpo cells (1 ϫ 106) were starved of rhTpo overnight in IMDM-containing glutamine and 0.5% FBS. Cells were treated for Cytokines and Cell Lines up to 120 minutes with eltrombopag (30 ␮M) or rhTpo (75 ng/ml), rhTpo, recombinant human stem cell factor (rhSCF), and recombi- pelleted by centrifugation, and placed on dry ice. Lysates were nant murine interleukin-3 (rmIL-3) were obtained from R&D Sys- prepared, proteins were separated by gel electrophoresis, and im- tems, Inc. (Minneapolis, MN, http://www.rndsystems.com). Re- munoblotting
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