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.