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
1993-07-09
1995-01-03
Schain, Howard E.
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...
530384, A61K 3516, A61K 3702, A61K 3706, C07G 700
Patent
active
053788117
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a pure Factor I protein, essentially free of infectious virus, Factor B and C3. The invention also relates to an injectable preparation containing the pure Factor I protein, and derived from plasma. Such a preparation may be used in the treatment of Factor I deficiency and in the treatment of autoimmune diseases. The invention also relates to a process for producing the pure factor I protein, recovered from plasma.
The complement system is an enzyme cascade system consisting of more than 20plasma proteins. The system is important in the defence against microbial infections. It is activated partly by antigen antibody complexes via the classical pathway, partly by e.g. bacterial membranes and soluble substances via the alternative pathway. In both situations, the activation leads to formation of some active enzyme complexes, C3 covertases, having the central component C3 as a substrate. The C3 protein is cleaved in a small fragment, C3a, and in a larger fragment, C3b. C3b forms part of the C3 convertase of the alternative pathway. Thus, an amplification principle of the alternative pathway of the complement system is incorporated. The C3 convertase of the alternative pathway also includes a Factor Bb, a degradation product from the complement factor, Factor B.
The system is regulated by several proteins which inhibit the activated enzyme complexes. Factor I (C3b inactivator or KAF is such a regulator protein since it enzymatically degrades the C3b fragment to an intermediate fragment iC3b and further to C3c and C3d.
Factor I deficiency entails that C3b cannot be degraded to smaller cleavage products. This results in a continuous and uncontrolled formation of the alternative C3 convertase, with a consequent reduction or depletion of proteins from the alternative pathway. This involves less resistance to certain types of infections. Thus, increased frequency of e.g. cerebrospinal menigitis and pneumonia has been reported in Factor I deficient patients, cf. S. C. Ross et al., Medicine (1984) 63(5), 243.
Treatment with intravenous infusion of Factor I preparation, purified from plasma, has been described, cf. J. B. Ziegler et al., J. Clin. Invest. (1975) 55,668. This treatment has been found to be effective in providing near normalization of most plasma protein concentrations in a Factor I deficient patient. However, the preparation was not virus inactivated.
Treatment with plasma infusions has likewise been found effective, cf. D. J. Barret et al., J. Pediatri. (1984) 104(1), 76, V. Wahn et al., Allergol. Immunopathol. (1980) 8(4), 422 as well as V. Wahn et al, J. Clin. Immunol. (1981) 1(4), 228. However, this treatment has some serious drawbacks:
Factor I deficient patients have large amounts of C3 convertase in the blood. C3, administered via the plasma, is therefore immediately cleaved to C3a and C3b, as described above. C3a, which is an anaphylotoxin, can cause anaphylactic reactions in connection with plasma infusion, cf. V. Wahn et al., J. Pediatr. (1984) 105(4), 673. Further, the resulting C3b, in combination with Factor B, likewise administered with the plasma, has a stimulating effect on the alternative pathway. The presence of the complement components C3 and Factor B in the administered plasma thus weakens the efficacy of Factor I regulation of the alternative pathway. Finally, it is not possible to eliminate the risk of viral transmission by plasma infusions.
Temporary decreased levels of Factor I and Factor H are observed in patient suffering from systemic lupus erythematosus (SLE). Kaneko (EP 0 222 611) showed that administration of Factor H and/or Factor I to mice suffering from autoimmune diseases resembling those of human SLE, rheumatoid arthritis and glomerulonephritis, were effective in improving or preventing the proteinuria, that represents the pathological conditions of the autoimmune diseases. Kaneko, however, did not submit the Factor I preparation to neither a virus inactivation step nor a specific Factor B depletion step. As essential problem in the therapeutic
REFERENCES:
patent: 4440679 (1984-04-01), Fernandes et al.
patent: 4623717 (1991-11-01), Fernandez et al.
Seya and Nagasawa, 1988, J. Biochem. 103:792-796.
Ziegler et al., 1975, J. Clin. Investig. 55:668-672.
Rasmussen et al., 1988, Clin. exp. Immunol. 74:131-136.
Barrett and Boyle, 1984, J. Pediatr. 104:76.
Alsoe Karina O.
Kihl Jesper
Agris Cheryl H.
Novo Nordisk A S
Schain Howard E.
Touzeau P. Lynn
Zelson Steve T.
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