Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Lymphokines – e.g. – interferons – interlukins – etc.
Patent
1991-09-12
1993-11-09
Hill, Jr., Robert J.
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Lymphokines, e.g., interferons, interlukins, etc.
424 851, 530399, C07K 1500, C07K 1506
Patent
active
052604179
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a novel protein factor which stimulates the growth of megakaryocytes and augments the differentiation or maturation of megakaryocytes. Also provided are processes for obtaining the factor in homogeneous form and producing it by recombinant genetic engineering techniques.
BACKGROUND OF THE INVENTION
Megakaryocytes are the hematopoietic cells, largely found in the bone marrow, but also in peripheral blood and perhaps other tissues as well, which produce platelets (also known as thrombocytes) and subsequently release them into circulation. Megakaryocytes, like all of the hematopoietic cells of the human hematopoietic system, ultimately derive from a primitive pluripotent marrow stem cell after passing through a complex pathway comprising many cellular divisions and considerable differentiation and maturation. Mature megakaryocytes ultimately undergo subdivisions and release the cytoplasmic fragments which are circulating platelets.
The platelets derived from these megakaryocytic cells are critical for initiating blood clot formation at the site of injury Platelets also release growth factors at the site of clot formation that speed the process of wound healing and may serve other functions. Clinical experience has shown that control mechanisms exist to maintain effective platelet numbers in humans, but that at times these specific controls are either inadequate or ineffective and lead to depressed levels of platelets (thrombocytopenia) or thrombocytosis despite normal numbers of red blood cells and white blood cells.
The inability to form clots is the most immediate and serious consequence of a low platelet count, a potentially fatal complication of many therapies for cancer. Such cancer patients are generally treated for this problem with platelet transfusions. Other patients frequently requiring platelet transfusions are those undergoing bone marrow transplantation or patients with aplastic anemia.
Platelets for such procedures are obtained by plateletphoresis from normal donors Like most human blood products, platelets for transfusion have a relatively short shelf-life and also expose the patients to considerable risk of exposure to dangerous viruses, such as the human immunodeficiency virus (HIV) or the various hepatitis viruses.
The ability to stimulate endogenous platelet formation in thrombocytopenic patients with a concomitant reduction in their dependence on platelet transfusion would be of great benefit. In addition the ability to correct or prevent thrombocytopenia in patients undergoing radiation therapy or chemotherapy for cancer would make such treatments safer and possibly permit increases in the intensity of the therapy thereby yielding greater anti-cancer effects.
For these reasons considerable research has been devoted to the identification and purification of factors involved in the regulation of megakaryocyte and platelet production. Although there is considerable controversy, the factors regulating the growth and differentiation of hematopoietic cells into mature megakaryocyte cells and the subsequent production of platelets by these cells are believed to fall into two classes.
Megakaryocyte colony-stimulating factors (meg-CSFs) are the first group of regulatory factors which function to support the proliferation and differentiation of megakaryocytic progenitors (CFU-M) in culture. The second group of factors have been defined by their activity towards megakaryocytes in either in vivo or in vitro bioassays. Factors which elicit an in vivo response, such as an increase in the circulating level of platelets have been defined as thrombopoietin ("TPO"). Factors which support either the differentiation, maturation or development of megakaryocytes in an in vitro culture system have been termed megakaryocyte stimulating activity, megakaryocyte potentiating activity, or thrombopoietin-like activity. It is unclear whether thrombopoietic factors are structurally identical or related to any of the in vitro defined megakaryocyte stimulating activities.
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Grant Barbara W.
Mann Kenneth G.
Cermak Shelly G.
DesRosier Thomas
Eisen Bruce
Genetics Institute Inc.
Hill Jr. Robert J.
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