Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving blood clotting factor
Reexamination Certificate
2001-12-13
2004-02-17
Park, Hankyel T. (Department: 1648)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving blood clotting factor
C514S008100
Reexamination Certificate
active
06692931
ABSTRACT:
The invention relates to novel recombinant glycoproteins that act as messenger substances, signaling substances, promoters, stimulators and initiators in a multitude of ways in th animal, especially human, circulation system; to processes for their preparation, to pharmaceutical compositions containing them and to their uses. The invention in particular relates to new recombinant human glycoproteins (rh glycoproteins), preferably novel rh differentiation factors, especially rh erythropoietin; to novel rh growth factors, especially rh CSF (colony-stimulating-factor), rh GMCSF (granulocytes-monocytes-stimulating factor); to novel rh thrombolytic agents, especially rh tPA (tissue-plasminogen-activator) and rh urokinase; to novel rh thromboprophylactic agents, especially rh antithrombin III; to novel rh coagulation factors, especially rh factor VIII and rh factor IX; to novel rh interferons, especially rh &agr;-, &bgr;- and &ggr;-interferons; and to novel rh interleukins, especially rh IL-2, IL-15, IL-16 and IL-17; to processes for their preparation; to novel pharmaceutical compositions containing them and to the uses thereof.
Glycoproteins are proteins containing covalently-bound carbohydrates (sugars). Glycoproteins, especially human glycoproteins, act as messenger substances, signaling substances, promoters, stimulators and initiators in metabolic processes of animals and human beings, which directly or indirectly influence these metabolic processes. Usually they are formed in vivo in the body or biosynthetically and, after having fulfilled their specific function, they are again excreted thereof or broken down therein. The glycoproteins having been formed in a natural way within the body (so called “native glycoproteins”) are characterized in that they are substituted at the amine group of the aminoglycan radical by an acetyl group. These native glycoproteins formed in a natural manner in vivo or by biosynthesis (see German patent 4 311 580) in human and animal are effective means for stimulating the growth and the differenciation of human and animal cells of the immune system and for inhibiting the adhesion of leucocytes, thrombocytes and tumor cells at the endothelial cells of blood vessels; for stimulating the immune system, especially the T-lymphocytes, for defense against infection, for treating immune deficiencies, tumor diseases including metastasing processes, infectious diseases and circulatory collapse, especially occlusions of vessels and septicemia; for inhibiting the bonding of a ligand at its sialylated cell surface receptor to a host cell; for inhibiting the bonding of a microphage or a toxin to the host cell via a sialylated receptor by an in vivo-modulation of neuraminic acids; for the biosynthetic preparation of ligands or receptors having a modified neuraminic acid radical and for the use thereof for the competition of physiological or pathological ligand-receptor-interactios; for influencing in vitro the course of infection by human immunodeficiency viruses as well as the in vivo-prevention of an infection by human immunodeficiency viruses; and for the treatment of parasitic diseases.
The glycoproteins occuring in animal organisms are important components of cell membranes as well as soluble components of body fluids and of the extracellular matrix. The carbohydrates are linked to form chains (oligosaccharides) and they can be linked to the protein backbone in different ways. As important components of the cell membrane they contain sialic acid (derivatives of 2-keto-3-deoxy-D-glycero-D-galacto-nonulopyranosidonic acid (KDN)), which plays an important role in biological processes.
The oligosaccharides of glycoproteins are classified according to their mode of linkage to the protein. The oligosaccharide of thioacidglycoproteins are mostly bound N-glycosidically to an asparagine radical of the polypeptide chain (N-glycans). This group comprises dissected glycoproteins having different functions, e.g. soluble enzymes, immunoglobulins and hormones on the one hand, and membrane glycoproteins, e.g. membrane enzymes, transport proteins as well as receptor proteins on the other hand. A further group are the oligosaccharides which are bound O-glycosidically via a galatose, N-acetyl-galactosamine or xylose radical to a serine- or threonine radical of the polypeptide chain (O-glycans). They occur together with N-glycans also in immunoglobulins and other glycoproteins. The O-glycans also comprise the oligosaccharides of proteoglycans which are characterized by a particularly high proportion of carbohydrates. In these glycoconjugates occuring in the extracellular matrix the oligosaccharides can be bound via a galactose, N-acetylgalactosamine or xylose radical to a polypeptide backbone.
The glycoproteins consisting of monosaccharides and protein often are summarized with the glycolipids as glycoconjugates. The sugar component of the glycoproteins comprising, with a few exceptions, less than 50% of the total glycoproteins are linked via splittable O- or N-glycosidic bonds to the peptide part. As carbohydrates in the glycoproteins hexoses (galactose, mannose, more seldom glucose), N-acetylhexosamines, N-acetylneuraminic acid, fucose and others can be found. For identification and determination of the glycoproteins mainly affinity chromatography using plant lectins as ligands (e.g. concanavalin A, wheat germ agglutinins and others) is suited.
Almost all membrane glycoproteins, serum proteins, plasma proteins, and blood group substances are glycoproteins as are many enzymes and proteohormones, all antibodies, the chalones, mucins, lectins, bindins, fibronectins, the intrinsic factor and similar proteins. As membrane or cell surface proteins some glycoproteins play an important role in the pathogenicity of viruses. In this case, as in other receptor-specific cellular interactions, the carbohydrate components are responsible for the recognition process at the molecular level. Some bacteria and viruses adhere to their target cells via specific sugar structures on receptors.
Oligosaccharide structures are particularly important also in view of cell-cell and cell-matrix interactions. Thus, the oligosaccharides of glycoproteins mediate the adhesion of neuronal cells and the bonding of lymphocytes to specific endothelial cells. Furthermore, oligosaccharides can serve as the antigenic determinants of glycoproteins. Also during embryogenesis and organogenesis, carbohydrate-carbohydrate interactions are essential to specific cell recognition. The malignant transformation of cells is accompanied by characteristic changes in the oligosaccharide structures of glycoproteins. The extent to which altered oligosaccharide structures of membrane and intercellular glycoproteins of tumor cells are the cause or result of tumorigenesis and metastasis is not known until yet.
For the treatment of diseases related to the immune system, substances have to be administered that reinforce the immune response by stimulating the cells of the immune system. The search for active substances that stimulate the immune system is therefore a preferred goal of pharmacological research. Active immunstimulants having minimal side effects, however, are not known until yet.
Therefore, the object of the invention was to find new substances by means of which it is possible to influence the metabolic processes controlled by glycoproteins as messenger substances, signaling substances, promoters, stimulators and initiators, more effectively, more specifically and more selectively than until today. It was in particular the object of the invention to find such novel glycoproteins acting as messenger substances, signaling substances, promoters, stimulators and initiators in human and animal metabolism and which can be administered in lower doses and therefore have lower side effects than the corresponding native substances.
Now it has been found that this object can be achieved according to the present invention by novel glycoproteins which are different from the abovementioned native glycoproteins in that the naturally occ
Gohlke Martin
Hauser Charlotte
Horstkorte Rüdiger
Nöhring Sabine
Nuck Rolf
Park Hankyel T.
Reutter Werner
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