Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Patent
1986-06-20
1989-05-16
Welsh, Maurice J.
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
530380, 530381, 424101, 514 2, 514 21, 514834, A61K 3702, A61K 3704, A61K 3516, C07K 1506
Patent
active
048311197
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a preparation for the treatment of hemophilia A inhibitor patients and processes for producing such a preparation.
Hemophilia A is a congenital disease which is due to lack of coagulation Factor VIII:C. This factor is present in blood plasma and can be partially purified from blood. Preparations containing this factor (AHF) can be administered to hemophilia A patients so that the patients' blood will be able to coagulate. Production of this type of preparation is described e.g. in the U.S. Pat. No. 3,652,530 and International Application WO No. 84/03628. In these preparations the Factor VIII:C protein typically amounts to 0.1% of the total protein amount. Factor VIII:C of greater purity can be obtained by affinity chromatography (Zimmerman et al., U.S. Pat. No. 4,361,509, Fass et al. Blood 59, 394, 1982).
The Factor VIII:C protein has still not been fully characterized, but part of the structure is known (L. W. Hoyer, Blood 58, 1, 1981; M. Weinstein et al., Proc. Natl. Acad. Sci., USA 78, 5137, 1981; G. Kuo et al., Thromb. Haemostas. 50, 262, 1983). The molecular weight is about 300 kD.
It is known that 10 to 20% of hemophilia A patients do not only lack Factor VIII:C, but also develop antibodies against Factor VIII:C. Such patients are called inhibitor patients, and the antibodies in these patients are called inhibitor antibodies because they inhibit the procoagulant activity of Factor VIII:C (H. R. Roberts & R. Cromartie, Progress in Clinical and Biological Research 150, 1, 1984). The presence of these antibodies causes administration of AHF preparation to have no effect since Factor VIII:C is neutralized, and AHF administration induces increased antibody level.
Inhibitor antibodies can be used as reagents in immunoassays to measure Factor VIII:C antigen (VIII:CAg) (B. Dinesen, C. Fedderson, Thromb. Res. 31, 707, 1983, O. Nordfang et al., Thromb. Haemostas. 50, 111, 1983). An VIII:CAg unit is defined as the content in 1 ml of normal human plasma.
Inhibitor patients have till now been treated:
(a) By non-specific treatment with activated prothrombin complex preparations (FEIBA.RTM., Autoplex.RTM.). These preparations contain an unknown component (perhaps Factor VIIa, see U. Hedner and W. Kisiel, J. Clin. Invest. 71, 1837, 1983), which can make plasma coagulate in spite of large inhibitor amounts. However, activated prothrombin complex preparations cannot help all inhibitor patients, and the patients are not cured of their inhibitor. Moreover, the use of this type of preparations involves a great risk of thrombosis.
(b) It has been found that the inhibitor formation can be suppressed by administration of very large doses of AHF (100 to 200 units/kg daily). This makes it possible to induce immunotolerance of Factor VIII (H. H. Brackman & J. Gormsen, Lancet, p. 933, 1977). After this type of treatment the patient can be treated with AHF preparations like other hemophiliacs. However, high dosis AHF treatment is also non-specific because very large doses of irrelevant protein are administered, and the patients cannot utilize the procoagulant activity in AHF preparations during the treatment.
At the beginning of the treatment phase the inhibitor level increases, and is then gradually reduced to zero. Bleedings cannot be prevented with AHF during the treatment, but bleedings can be partly stopped with the above-mentioned FEIBA.RTM. (factor eight inhibitor bypassing activity) preparations.
This treatment is very expensive (typically U.S. $600,000 per patient, see S. Stenbjerg et al., Thromb. Res. 34, 533, 1984) and has accordingly found little application.
The invention is based on the surprising finding that a component from plasma fractions having Factor VIII:CAg reactivity and only little or no Factor VIII:C procoagulant activity is reactive to 7 of 7 antibodies from inhibitor patients. Therefore, the suppression treatment will be just as effective if a preparation is administered which contains a suitably high amount of VIII:CAg without significant VIII:C procoagulant activity
REFERENCES:
patent: 4649132 (1987-03-01), Zimmerman
Hoyer, "The Factor VIII Complex: Structure and Function", Blood, vol. 58, No. 1, pp. 1-13, 1981.
Kuo et al., "Studies on the Molecular Structure of Human Factor VIII:C", Thrombosis and Haemostasis, vol. 50, 1983.
Muller et al, "A Monoclonal Antibody to VIII:C Produced by a Mouse Hybridoma", Blood, vol. 58, No. 5, pp. 1000-1006, 1981.
Allain et al., "Response to Factor VIII Infusion in Inhibitor Patients", Progress in Clinical and Biological Research (150), 99-108, 1984.
Nordfang Ole
Rasmussen Mirella E.
Nutter Nathan M.
Welsh Maurice J.
LandOfFree
Preparation for the treatment of hemophilia A inhibitor patients does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Preparation for the treatment of hemophilia A inhibitor patients, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Preparation for the treatment of hemophilia A inhibitor patients will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2323561