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...
Reexamination Certificate
2000-07-28
2002-06-18
Russel, Jeffrey E. (Department: 1653)
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...
C210S661000, C210S691000, C210S692000, C530S415000, C604S005020
Reexamination Certificate
active
06407212
ABSTRACT:
The present invention concerns a method for the removal of the causative agent(s) of transmissible spongiform encephalopathies (TSEs) from protein solutions, particularly from blood products that will be used for therapeutic and other medical purposes. The protein solution is brought into contact with an adsorbent to which the agent(s) will be bound.
In world war II a method was developed in the USA for the isolation of proteins from human blood plasma. These isolated proteins are used medically as therapeutic agents. Albumin, immunoglobulins, fibrinogen, coagulation factors and numerous other proteins are examples of products of this method. Albumin is used, e.g., for bum patients or more generally in diseases in which the blood volume has to be increased. Immunoglobulins may be used in patients who are not able to synthesize protective antibodies themselves. Coagulation factor concentrates (in particular factor VIII and factor IX) are being used for hemophilia patients. In many cases these preparations are life-saving and therefore they have no substitute.
The methods for the separation of blood plasma in individual proteins are based on several different principles. The older methods which are still being used on a large scale are based on fractional precipitation of the proteins with ethanol and subsequent separation of the phases by centrifugation or filtration. In newer fractionation schemes, other separation methods are used as well, e.g., ion exchange chromatography or (immune) affinity chromatography. An integrated separation scheme usually comprises several different methods which are combined in an optimized process.
In the first years of use of plasma proteins in humans it became clear that products made from human blood also have disadvantages: they may transmit some infectious diseases which are caused by viruses. The most important virus in the beginning was viral hepatitis (hepatitis B). Later on other forms of hepatitis became known (non-A non-B hepatitis which was recently identified and named hepatitis C). The best known virus which is transmitted by blood and blood products is the HIV (Human Immunodeficiency Virus), the causative agent of AIDS (Acquired Immune Deficiency Syndrome). Apart from those mentioned so far, there are some other viruses that may also be transmitted by plasma and plasma derivatives.
In recent years other transmissible diseases with some common features became known. They are called TSEs and believed to be transmitted by non-conventional transmissible agents (NCTA). The human diseases Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), fatal familial insomnia (FFI), and kuru all belong in this group, as do some animal diseases, the best known of which are scrapie in sheep and bovine spongiform encephalopathy (BSE; “mad cow disease”) in cattle. Affected humans and animals all show symptoms of neurodegeneration and the diseases are invariably fatal. CJD, the best known human disease in this group, most often develops sporadically; in some cases, however, clustering in certain families was observed latrogenic transmissions through pituitary gland extracts, contaminated instruments used in neurosurgical procedures, and transplantation of cornea or dura mater has also been described. A transmission of any of the human diseases by blood transfusion has never been shown. A retrospective epidemiological study among recipients of transfused blood did not show an increased rate of CJD when compared with non-transfused controls [T. F. G. Esmonde, R. G. Will, J. M. Slattery et al.: Creutzfeldt-Jakob disease and blood transfusion. Lancet 1993, 341: 205-207]. A look-back among recipients of erythrocyte concentrates donated by a man who later on died of confirmed CJD did not show a single case of abnormal neurological or psychiatric findings [N. Heye, S. Hensen, N. Müller: Creutzfeldt-Jakob disease and blood transfusion. Lancet 1994, 343: 298-299]. Transmission of TSEs by blood transfusion must therefore be either extremely rare or extremely inefficient or both. The public and the regulatory authorities are nevertheless aware of a potential problem, and need reassurance that utmost care is exercised to protect the patients from a possible exposure to NCTAs.
The existence of an infectious agent is proven beyond the shadow of a doubt. The exact nature of this agent is, however, still debated. In the past, most researchers believed the disease to be caused by a slow virus; the more popular hypothesis now is that the infectious agent is a proteinaceous particle which may or may not contain nucleic acid, a so-called prion. Prions occur in at least two different forms, one normally found in cells which is called PrP
c
, and another form which only occurs in individuals affected by the disease which is called PrP
sc or PrP
res
for its association with scrapie or for its resistance to degradation by proteases, most notably protease K. The difference between PrP
c
and PrP
res
is brought about by changes in folding, or tertiary structure, of the protein, a predominantly &agr;-helical conformation being changed mostly to &bgr;-sheets. PrP
res
is associated with, or may be the cause of, the TSEs. The involvement of other factors (cofactors, i.e., nucleic acids, other proteins) is also being discussed.
The safety of blood and blood derivatives may be increased by 5 measures taken on different levels: (1) the collecting agencies try to exclude donors who are known to pose a high risk for transmitting infectious diseases. This is done with the aid of a questionnaire which allows exclusion of people with increased risk factors. Persons with increased risk factors are, e.g., those who suffer from certain diseases, those who visited certain countries shortly before donation, those who incur risks through their sexual activity or drug addicts who use contaminated needles, recipients of corneal or dura mater transplants, people who have been treated with pituitary hormones or whohave CJD-cases in their family. (2) Laboratory analyses allow the determination of infectious donations which can then be removed from further processing. Those two measures taken together result in removal of most infectious donations but not all: (a) the sensitivity of the test methods may be insufficient; (b) a test for a particular infectious agent may not yet be available; for practical and economic reasons it is not possible to screen for all potential infectious agents; (c) the test does not detect the infectious agent itself, but rather the antibodies that are elicited in the infected person as a response to the infection. From the time of infection until detectable antibodies appear, usually a few days or weeks elapse (so called window). Antibody tests are useless during this period; (d) an infected donation may be released because of a clerical error. (3) The safety with respect to transmission of infectious agents is further improved by special steps that are introduced into the production process which either inactivate or eliminate infectious agents. (4) Strict adherence to good manufacturing practice (GMP) guarantees the efficiency of the steps mentioned under (3). (5) Full traceability of every donation to the corresponding products and from the final products back to the individual donation allows directed recalls of products, should this become necessary.
Methods for detection, inactivation, and elimination of infectious viruses in blood and plasma products are now widely established. Commercial detection systems are used world-wide for detecting, e.g., antibodies to human immunodeficiency virus or to hepatitis C virus. Inactivation of viruses may be achieved by various heat treatments (either in solution or in the dry state; at different temperatures and for different periods of time), by chemical (with a combination of solvents and detergents or with iodine), or photochemical treatments (e.g., exposure to &bgr;-propiolactone and ultraviolet light; illumination of a protein solution to which a suitable dye has been added), or
Maring Jacques-Andre
Morgenthaler Jean-Jacques
Rentsch Markus
Russel Jeffrey E.
ZLB Bioplasma AG
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