Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Albumin
Reissue Patent
1999-10-01
2001-07-17
Nutter, Nathan M. (Department: 1711)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Albumin
C530S387100, C530S413000, C530S414000, C530S417000, C530S506000
Reissue Patent
active
RE037286
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a method of cleansing protein from multivalent metal ions bound thereto.
BACKGROUND ART
Many biologically active proteins have obtained wide use as important drugs. As a result primarily of different cleaning methods, these proteins are liable to contain relatively large quantities of different metals. An investigation into the proportions of metals in various biological products was published in 1986 (May J C Rains T C, Maienthal F J et al.: A survey of the concentrations of eleven metals in vaccins, allergenic extracts, toxoids, blood, blood derivatives, and other biological products. J Biol Stand 1986, 14, 363-375), and it is evident from this investigation that the proportions of metals in, for instance, human serum albumin can reach values which are harmful to patients.
The metals normally derive from the various additives used when working-up and cleansing the proteins. For instance, these processes normally involve the use of filter aids and filters having a relatively high proportion of filter aids for the purpose of clear-filtering solutions in various process stages. These filter aids have often been found to contain metals which are able to bind to the protein in ion form. The problems can be overcome by using other filtering methods, using filters based on inert materials. Such filters, however, are at present particularly expensive in comparison with the filter materials conventionally used.
In the case of many proteins, multivalent metal ions are bound strongly to the protein, probably due to chelate formation and ion-exchange effects.
Endeavours have also been made to remove the bound metals ions by treatment with various complex formers, such as EDTA or citrate ions. The metal ions, however, are bound so strongly to the proteins that these endeavours have met with no success.
The contaminating multivalent metal ions in the proteins may, for instance, consist of one or more of the metals aluminium, chromium, lead, mercury, iron, nickel, copper and magnesium. Of these metal ions, the removal of aluminium, iron and lead is the most important.
Aluminium, which is the most common metal in the earth's crust has been assumed to constitute an ethiological factor in a number of clinical illness conditions, such as senile demens of the Alzheimer type (Crapper D. R, Kishnan S S, Quittat S. Aluminium, neurofibrillary degeneration and Alxheimer's disease. Brian 1976, 99, 67-80; and
Crapper D R, Quittat S, Krishnan S S et al.: Intranuclear aluminium content in Alzheimer's disease, dialysis encephalo-Acta Neuropath 1980, 50, 19-24) and dialysis encephalopath (Alfrey A C, Le Gendre G R, Kaehny W D: The dialysis encephalopathy syndrome. Possible aluminium intoxication. N Eng. Med 1976, 294 184-188;
Alfrey A C, Hegg A, Craswell P: Metabolism and toxicity of aluminium in renal failure. Am J Clin Nutr 1980, 33, 1509-1516; and
Per D P, Gajdusek D C, Garruto R M et al.: Intraneuronal aluminium accumulation in amyothropic lateral sclerosis and Parkinson-dementia of Guam. Science 1982, 217, 1053-1055), etc. It has been clearly established that aluminium is accumulated in the tissues and has a toxic effect on patients suffering from kidney function disorders.
The injurous effect of other metals, such as iron, chromium, nickel and lead, is previously known, either due to their normal toxicity, or due to their ability to promote allergies, for instance.
SUMMARY OF INVENTION
The aforesaid disadvantages are avoided by the present invention, which provides a method of cleansing proteins of the multivalent metal ions bound thereto, so as to obtain as the end product one or more proteins in which the proportion of strongly bound multivalent metal ions is greatly reduced.
In accordance with the present invention, a protein is cleansed of multivalent metal ions bound thereto by releasing the multivalent metal ions by exchanging said multivalent ions with monovalent metal ions and removing the replaced multivalent metal ions. In accordance with one particular embodiment of the invention, the monovalent metal ions are subsequently also removed.
The monovalent metal ions used to substitute the multivalent metal ions are primarily alkali metal cations, and then particularly sodium or potassium, or ammonium cations.
REFERENCES:
patent: Re. 36259 (1999-07-01), Tenold
patent: 4116948 (1978-09-01), Mittenzwei et al.
patent: 4256631 (1981-03-01), Yokoo et al.
Welch, A.G. et al, Improvement in the Quality of Albumin Products (Stable Plasma Protein Solution) Using Ultrafiltration, XX Congress of the International Society of Blood Transfusion (British Blood Transfusion Society), London, Jul. 11-15, 1988.
Nutter Nathan M.
Pharmacia & Upjohn Aktiebolag
Pollock Vande Sande & Amernick
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