Chemistry: molecular biology and microbiology – Maintaining blood or sperm in a physiologically active state...
Reexamination Certificate
2002-12-31
2004-07-06
Kunz, Gary (Department: 1647)
Chemistry: molecular biology and microbiology
Maintaining blood or sperm in a physiologically active state...
C435S068100, C424S184100, C424S529000
Reexamination Certificate
active
06759188
ABSTRACT:
The present invention relates to a method for producing prophylactically or therapeutically active proteins and to the means employed therefor, in particular syringes.
Therapeutically active proteins such as erythropoietin, insulin or interferons have been known for a long time. Many of these proteins have already been approved as medicaments and are accordingly employed frequently. Because of the large costs associated with the development and approval of these medicaments, however, there is a need for simple and cost-effective alternatives for the preparation of therapeutically active proteins. In addition, not all therapeutically active proteins are approved as medicaments. Nevertheless, however, there is frequently a need for these proteins also to be administered to the patient. Particularly important in this connection, because they are presumed to be well tolerated by the body, are autologous proteins, that is to say those intrinsic to the body. These proteins include the interleukin 1 receptor antagonist, interleukin 4, interleukin 10 and the type I or type II tumor necrosis factor receptor. Proteins intrinsic to the body moreover have the advantage that the natural post-translational modifications such as glycosylations are already present. This is not the case with most normally obtainable recombinant proteins because they are produced in prokaryotic hosts.
Stimulation of monoctyes by adherent immunoglobulin G to form the interleukin 1 receptor antagonist is described by Arend and Leung in Immunological Reviews (1994) 139, 71-78 and Moore et al. in Am. J. Respir. Cell Mol. Biol. (1992) 6, 569-575. Andersen et al. in Autommunity (1995) 22, 127-133 explains that the therapeutic effect of immunoglobulin G to be observed in vivo cannot be attributed to an enhanced formation of interleukin 1 receptor antagonist, and that the in vitro formation of the interleukin 1 receptor antagonist (IRAP, IL-1Ra) by monocytes depends on serum and plasma constituents adsorbed on polypropylene. The therapeutic use of adsorbed serum and plasma constituents to stimulate the formation of therapeutically interesting proteins in therapies is not only very costly but also involves the risk of contamination with infectious particles with which the serum and plasma constituents may be contaminated. Methods for producing IL-1Ra which can be employed directly in the therapy without using adsorbed serum and plasma constituents are not described in the aforementioned publications.
The technical problem on which the present invention is based is thus to provide methods and means for producing IL-1Ra which serve as safe, cost-effective alternatives which can be carried out quickly for the use and for the production of conventional pharmaceutical products.
The invention solves this problem by providing a method for producing IL-1Ra in a syringe made of glass, quartz or a plastic, the syringe being filled with a body fluid from an organism, for example a human or animal body, and incubated, and the IL-1Ra being formed.
A preferred embodiment of the present invention provides for the internal structure of the syringe to consist of a special material, in particular a glass, plastic, quartz and/or corundum, whose surface is, in a particularly preferred embodiment of the invention, modified, in particular with the aid of a corrosive agent, for example an acid or an alkali, in particular chromosulphonic acid, and subsequently, after removal of the agent and washing the syringe where appropriate, that is to say in a particularly preferred manner, the surface of the internal structure of the syringe is sterilized, in particular by autoclaving. The syringe is then filled with a patient's body fluid and incubated, and IL-1Ra is formed thereby. The body fluid enriched with the protein can then be reinjected into the patient, for example into a diseased joint. However, to increase the purity of the IL-1Ra which has been formed, the body fluid is preferably centrifuged and the supernatant is sterilized by filtration, divided into aliquots and stored for a later treatment. The invention thus provides in a preferred embodiment in a first step of the method for the surface of the internal structure of the syringe to be modified, in particular with the aid of a corrosive agent, such as an acid or an alkali, in particular chromosulphonic acid, and then, if desired, the surface of the internal structures of the syringe is sterilized, in particular by autoclaving. A drying can be provided before and/or after the sterilization. After the modification and the sterilization which takes place where appropriate, the syringe is filled in a second step of the method with a body fluid, in particular blood, lymph, saliva or urine, and incubated. The body fluid is preferably taken from the patient directly with the syringe. The, preferably modified, surface of the internal structure of the syringe induces in the body fluid specifically, to an extent which differs quantitatively depending on the material employed, the internal structure of the syringe, modification employed, in particular etching of the internal structure, sterilization employed, in particular autoclaving, and body fluid employed, the formation of IL-1Ra which, accordingly, becomes enriched or is formed in the body fluid present in the syringe. The body fluid enriched in this way can be stored sterile in the syringe and be returned to the patient as required directly without further treatment or, preferably, after centrifugation and/or sterilization by filtration.
The invention thus also relates to a method for the prophylactic or therapeutic treatment of the human or animal body, for example for the treatment of rheumatism, osteoarthritis and/or back symptoms, wherein a body fluid, for example blood, is taken from the human or animal body by means of a syringe according to the present invention, this body fluid is incubated in the syringe, and IL-1Ra is formed or enriched thereby, and the body fluid is returned using this syringe to the same or a different human or animal body.
The IL-1Ra which is formed can advantageously be modified, for example glycosylated. It is self-evident that the invention also encompasses the formation of other modifications or variants of IL-1Ra, such as truncated forms, mutants or other derivatives.
In conjunction with the present invention, an internal structure of a syringe means any region or any structure of the syringe which is present in its interior, that is to say in the sample reception region and may come into contact with the body fluid to be received. The internal structure of a syringe is particularly advantageously its inner surface, preferably a surface with a texturing to increase the surface area. It is self-evident that the present invention can also be carried out using a commercially available syringe without a special configuration in its internal cavity. In such a case the internal structure is the inner surface of the syringe barrel and the part of the piston present in the barrel. The internal structure can, in a particularly preferred embodiment, additionally be formed by articles introduced into the interior of the syringe, such as particles, spheres, beads, gels, glass wool, corundum, quartz, sand, plastic or glass granules or powder or the like in order to enlarge the internal surface area of the syringe and thus provide a larger inducing surface. The material of which the internal structure consists or which is present in the internal structure can be a material different from that of which the remainder of the syringe consists. For example, the syringe may consist of plastic and parts of its internal structure may, for example, consist of glass granules.
Additional structures of these types, such as, for example, glass beads with a diameter of from 1 to 5 mm, should, according to a preferred embodiment of the invention, however occupy not more than 50% of the internal volume of the syringes employed. The syringes employed may be, for example, 10 to 100 ml syringes.
In connection with the present invent
Meijer Hans
Reinecke Julio
Wehling Peter
Dickstein , Shapiro, Morin & Oshinsky, LLP
Kunz Gary
Nichols Christopher James
Orthogen AG
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