Chemical Properties and Marketing Information for TPOs
Factors responsible for megakaryocyte development and platelet
production, the TPOs, include the Mpl ligands (TPO and MGDF) and (IL)-11. TPO
and MGDF are Mpl ligands; IL-11s not. For convenience, all three molecules will
be referred to as TPOs, although it must be remembered that IL-11’s receptor is
different from those of TPO/MGDF and that IL-11 has also other biologic
functions.
The existence of a TPO was suggested in 1958 and activity was
demonstrated in the early 1960s. In 1990, studies investigating murine leukemia
and oncogenes led to the recognition of a new hemato-poietin receptor
superfamily, Mpl, which was found to be the receptor of an important regulator
of thrombo-poiesis (Souyri et al., 1990; Vigon et al., 1992). Two forms of Mpl
ligand were produced through recombi-nant DNA technology. The book edited by
Kuter et al. (1994a) is a compilation of the biology, molecular, and cellular
information about TPO, MGDF, and IL-11; Kaushansky (2005) reviews the molecular
mechanisms that control thrombopoiesis.
The gene for TPO is located on chromosome 3. Depending on the source,
the mature polypeptide has between 305 and 355 amino acids, which may undergo
cleavage to a smaller polypeptide that retains biologic activity. A wide range
of molecular weights (18–70 kDa) has been reported for active molecules
(Kaushansky, 1995). At this time, no recombinant Mpl ligands are commercially
available.
The gene for IL-11 is located on chromosome 19. IL-11 has multilineage
effects. The precursor protein consists of 199 amino acids. IL-11 is rich in
proline residues, and it lacks cysteine residues and disulfide bonds common to
other HGFs (Du and Williams, 1997).
Oprelvekin (rhIL-11) is a non-glycosylated poly-peptide, 177 amino acids
in length and approximately 19 kDa in molecular weight. Oprelvekin differs from
endogenous IL-11 by a single amino acid—the amino terminal proline—but this
difference does not affect bioactivity. Oprelvekin is marketed as Neumega in
the United States.
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