Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Patent
1997-03-11
1999-03-16
Jacobson, Dian C.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
435 698, 43525233, 4353201, 435476, 514 12, 514822, 530350, 536 235, C07K 1444, C07K 14475, C12N 1530, A61K 3817
Patent
active
058828877
DESCRIPTION:
BRIEF SUMMARY
The invention refers to a process of manufacture of a modified collagen-induced platelet aggregation inhibitor, called Pallidipin. Further the invention comprises the substance Pallidipin which is modified.
Collagen is the most potent inducer known of human platelet aggregation. For instance, upon injury of the vessel wall and exposure to collagen, blood platelets rapidly adhere and become activated. (H. R. Baumgartner (1977) Thromb. Haemostas. 37:1-16; J. Hawiger (1987) Human Pathol. 18:111-122.)
Collagen-induced platelet aggregation of human platelets thus represents a risk factor for patients undergoing blood vessel-affecting procedures, e.g., angioplasty or sepsis, for those suffering myocardial infarction, for those recovering from treatment for myocardial infarction, inter alia.
In some cases it is necessary to inhibit collagen-induced platelet aggregation. Some compounds are known to inhibit such aggregation. For example, synthetic oligopeptides inhibit collagen-induced platelet aggregation by binding to the platelets. See, e.g., Bevers et al. (1985) "Collagen Derived Octapeptide Inhibits Platelet Procoagulant Activity Induced by the Combined Action of Collagen and Thrombin", Thrombosis Research, 37:365-370; Karniguian et al. (1983) "Effect of a Collagen Derived Octapeptide on Different Steps of the Platelet/Collagen Inter-action", Thrombosis Research 32:593-604; Caen et al. (1981) "Oligo-peptides with specific inhibiting properties of collagen-induced aggregation, process for preparing the same and pharmaceutical compositions containing them"; and EPA 0 040 149.
Another source of collagen-induced platelet aggregation inhibitor is an inhibitor identified in a snake venom having an unknown structure. See Smith et al., "Identification of 50 kDalton snake venom proteins which specifically inhibit platelet adhesion to collagen." (1991) FEBS 283:307-310.
A third such inhibitor, from the saliva of a medicinal leech, is described by Munro et al. (1991) "Calin--a platelet adhesion inhibitor from the saliva of the medicinal leech", Blood Coagulation and Fibrinolysis 2:179-184. The publication of the European patent application EP 0 480 651 (Merck & Co. Inc. published 15 Apr. 1992) describes a protein having a molecular weight of about 16 kDalton (kD) and a capacity to inhibit collagen-induced aggregation of human platelets which protein is derived from the salivary gland of the leech Haemaenteria officinalis. LAPP is 16 kDa protein from the leech Haemaenteria officinalis described in Connolly et al. (1992) J. Biol. Chem. 267:6893-6898. See also Moubatin, described in Waxman and Connolly (1993) J. Biol. Chem. 268:5445-5449.
Yet another type of collagen-induced platelet aggregation is isolatable from insects as described in the European Publication EP 0 530 937. These proteins are designated "Pallidipins".
Alkaline phosphatase (APase) is an E. coli protein which is secreted into the periplasmic space. APase is synthesized as a precursor protein, have a 21-amino acid long leader sequence which is clipped off by the leader peptidase in the course of translocation across the bacterial inner membrane into the periplasmic space (Y. Kikuchi et al. (1981) Nucl. Acids Res. 9:5671-5678). Its biosynthesis is regulated by the phosphate concentration of the culture medium, and export of the products of heterologous genes placed downstream of the APase promoter is achieved by using low phosphate concentrations (C. Monteilhet et al. (1993) Gene 125:223-228).
The natural source of Pallidipin protein is limited. Processes using biotechnological methods are a logical solution for manufacturing of Pallidipin. The expression of Pallidipin in baby hamster kidney cells (EP 0 530 937) occurs at a rate of production which should be increased in order to express Pallidipin in industrial amounts. Therefore, an improved system of expression was necessary.
Thus, there was a need for an improved process for the manufacture of recombinant Pallidipin, which inhibits collagen-induced platelet aggregation, and which process has a high yield
REFERENCES:
patent: 5723312 (1998-03-01), Noeske-Jungblut
Chan, B.M.C. et al. Science 251:1600-1602 (1991).
Chelberg, M.K. et al. J. Cell Biology 111:261-270 (1990).
Becker, R.C. et al. Science & Medicine Jul./Aug. 1996, pp. 12-21.
Becker Andreas
Haendler Bernard
Noeske-Jungblut Christiane
Jacobson Dian C.
Schering Aktiengesellschaft
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