TY - JOUR
T1 - The thrombopoietin mimetic JNJ-26366821 increases megakaryopoiesis without affecting malignant myeloid proliferation
AU - Adrianzen-Herrera, Diego
AU - Choudhary, Gaurav
AU - Gordon-Mitchell, Shanisha
AU - Ramachandra, Nandini
AU - Bhagat, Tushar
AU - Zhang, Hui
AU - Aluri, Srinivas
AU - Shastri, Aditi
AU - Steidl, Ulrich
AU - Will, Britta
AU - Yang, Weng Lang
AU - Mahler, Michelle
AU - Eichenbaum, Gary
AU - Guha, Chandan
AU - Verma, Amit
N1 - Funding Information:
Funding for this work was provided by Janssen R&D, LLC. M.M and G.E., coauthors from Janssen R&D LLC, are employees and shareholders of Johnson and Johnson and potentially stand to benefit financially from the development and commercialization of JNJ-26366821. Montefiore Medical Center and C.G. may potentially benefit financially from the development and commercialization of JNJ-26366821 as co-inventors on one of the patents. A.V. has received funding from Janssen, GSK, Incyte, Medpacto, and Eli Lilly and is a scientific advisor for Stelexis, Novartis, Acceleron and Celgene. C.G. has received funding from Janssen.
Funding Information:
This study was supported in part by research funding from Janssen Research & Development, LLC to Amit Verma and Chandan Guha. We thank the Albert Einstein College of Medicine Flow Cytometry Core Facility and Xenotransplantation Facility for their expert technical assistance. Mary Guilfoyle, Senior Director and Compound Development Team Leader from Johnson & Johnson provided editorial assistance to the authors during the preparation of this manuscript.
Publisher Copyright:
© 2020 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2020/8/23
Y1 - 2020/8/23
N2 - Thrombocytopenia remains a challenge in myeloid malignancies, needing safer and more effective therapies. JNJ-26366821, a pegylated synthetic peptide thrombopoietin (TPO) mimetic not homologous to endogenous TPO, has an in-vitro EC50 of 0.2 ng/mL for the TPO receptor and dose dependently elevates platelets in volunteers. We demonstrate that JNJ-26366821 increases megakaryocytic differentiation and megakaryocytic colony formation in healthy controls and samples from myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). JNJ-26366821 had no effect on proliferation of malignant myeloid cell lines at doses up to 1000 ng/mL and malignant patient-derived mononuclear cells showed no increased cell growth or leukemic colony formation capacity at concentrations between 0.2 ng/mL and 10 ng/mL. Furthermore, JNJ-26366821 did not enhance in-vivo engraftment of leukemic cells in an AML xenotransplantation murine model. Our results show that JNJ-26366821 stimulates megakaryopoiesis without causing proliferation of the malignant myeloid clones in MDS/AML and provides the rationale for clinical testing of JNJ-26366821 in myeloid malignancies.
AB - Thrombocytopenia remains a challenge in myeloid malignancies, needing safer and more effective therapies. JNJ-26366821, a pegylated synthetic peptide thrombopoietin (TPO) mimetic not homologous to endogenous TPO, has an in-vitro EC50 of 0.2 ng/mL for the TPO receptor and dose dependently elevates platelets in volunteers. We demonstrate that JNJ-26366821 increases megakaryocytic differentiation and megakaryocytic colony formation in healthy controls and samples from myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). JNJ-26366821 had no effect on proliferation of malignant myeloid cell lines at doses up to 1000 ng/mL and malignant patient-derived mononuclear cells showed no increased cell growth or leukemic colony formation capacity at concentrations between 0.2 ng/mL and 10 ng/mL. Furthermore, JNJ-26366821 did not enhance in-vivo engraftment of leukemic cells in an AML xenotransplantation murine model. Our results show that JNJ-26366821 stimulates megakaryopoiesis without causing proliferation of the malignant myeloid clones in MDS/AML and provides the rationale for clinical testing of JNJ-26366821 in myeloid malignancies.
KW - JNJ-26366821
KW - Thrombopoietin
KW - acute myeloid leukemia
KW - myelodysplastic syndrome
KW - platelets
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UR - http://www.scopus.com/inward/citedby.url?scp=85087422506&partnerID=8YFLogxK
U2 - 10.1080/10428194.2020.1775213
DO - 10.1080/10428194.2020.1775213
M3 - Article
C2 - 32578476
AN - SCOPUS:85087422506
SN - 1042-8194
VL - 61
SP - 2453
EP - 2465
JO - Leukemia and Lymphoma
JF - Leukemia and Lymphoma
IS - 10
ER -
