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Blood, Vol. 92 No. 6 (September 15), 1998:
pp. 1981-1988
An Agonist Murine Monoclonal Antibody to the Human c-Mpl Receptor
Stimulates Megakaryocytopoiesis
Bijia Deng,
Naheed Banu,
Beth Malloy,
Philip Hass,
Jian Feng Wang,
Lisa Cavacini,
Dan Eaton, and
Hava Avraham
From the Divisions of Experimental Medicine and Hematology/Oncology,
Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine,
Boston, MA and Genentech Inc, South San Francisco, CA.
Thrombopoietin (TPO) is a hematopoietic growth factor that
stimulates megakaryocytopoiesis and platelet production in vivo and
promotes the development of identifiable megakaryocytes in vitro. We
have developed a murine monoclonal antibody, BAH-1, raised against
human megakaryocytic cells, which specifically recognizes the c-Mpl
receptor and shows agonist activity by stimulating megakaryocytopoiesis
in vitro. BAH-1 antibody specifically binds to platelets and to
recombinant c-Mpl with high affinity. Similar to TPO, BAH-1 alone
supported the formation of colony-forming unit-megakaryocyte
(CFU-MK) colonies. The combination of BAH-1 plus
interleukin-3 or of BAH-1 plus human TPO significantly increased the
number of human CFU-MK colonies. In addition, BAH-1 monoclonal antibody
stimulated the proliferation and maturation of primary bone marrow
megakaryocytes in a dynamic heterogeneous liquid culture system.
Individual large megakaryocytes as well as small megakaryocytic cells
were observed in cultures of CD34+ CD41+
cells in the presence of BAH-1 antibodies. Similar to TPO, BAH-1 antibody induced a significant response of murine immature
megakaryocytes as observed by an increase in the detectable numbers of
acetylcholinesterase-positive megakaryocytes. No effects of BAH-1
antibody were observed on colony-forming unit-granulocyte-macrophage,
burst-forming unit-erythroid, or colony-forming unit-erythroid
colonies. In vivo studies showed that BAH-1, alone or in combination
with TPO, expands the numbers of megakaryocytic progenitor cells in
myelosuppressed mice. This antibody should prove useful in
understanding the structure-function aspects of the c-Mpl receptor as
well as in evaluating the effects of the sustained activation of this
receptor in preclinical models of severe thrombocytopenia.
© 1998 by The American Society of Hematology.
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