Drug – bio-affecting and body treating compositions – Lymphokine – Interleukin
Reexamination Certificate
2000-04-27
2004-03-16
Mertz, Prema (Department: 1647)
Drug, bio-affecting and body treating compositions
Lymphokine
Interleukin
C435S069100, C514S002600, C514S008100, C530S351000
Reexamination Certificate
active
06706261
ABSTRACT:
The present invention relates to the use of muteins of a specific wild-type cytokine, that are also receptor antagonists of the latter, as immunogens to elicit antibodies against the wild-type cytokine, said antibodies being capable of neutralising the biological activity of the wild-type cytokine in diseases caused by an excessive production of the latter.
It is a known fact, for example, that human interleukin 6 (hIL-6) is a polypeptide of 184 aminoacids belonging to the class of helical cytokines. Interleukin 6 is a multi-functional cytokine produced by various cell types. It acts as a differentiation and growth factor on cells of various types, for example the cells of the immune system, hepatocytes, kidney cells, haematopoietic stam cells, keratinocytes and neurons. However, excessive production of hIL-6 is causes a number of diseases, such as chronic auto-immune disorders, systemic lupus erythematosus, myeloma/plasmacytoma, post-menopausal osteoporosis and cancer cachexy.
There is thus a need in this specific sector to counteract the excessive production of a wild-type cytokine in general, and of hIL-6 in particular, both in terms of prevention and of cure.
The use of the present invention enables this need to be satisfied, offering at the same time other advantages which will become clear from the following.
A subject of the present invention is in fact the use of mutants of a wild-type cytokine for the preparation of pharmaceutical compounds for the treatment or prevention or diseases caused by an overproduction of this specific wild-type cytokine.
A further subject of the present invention are pharmaceutical compounds for treatment of diseases caused by the excessive production of a wild-type cytokine, or vaccines for the prevention of said diseases containing as an active principle at least one mutant of that wild-type cytokine.
The pharmaceutical compounds according to the present invention may be formulated according to known methods, which requires for example the presence of a pharmaceutically acceptable vehicle. Examples of these vehicles and methods of formulation can be found in Remington's Pharmaceutical Sciences. To form a pharmaceutically acceptable compound suitable for effective administration, these compounds must contain an effective amount of the active principle according to the present invention. The pharmaceutical compounds of the present invention are administered to an individual in amounts adequate to the disease, the weight, the sex and the age of the individual in question. Other factors include the method of administration. The pharmaceutical compounds according to the invention may be administered in a wide range of manners, for example subcutaneously, topically, orally and by intramuscular injection.
The pharmaceutical compounds according to the present invention, containing as an active ingredient at least one mutein of a wild-type cytokine, may be administered at therapeutic doses in a wide variety of forms, in conventional administration vehicles.
For example, they can be administered in doses to be taken orally in the form of tablets, capsules, pills, powders, granules, elixirs, ointments, solutions, suspensions, syrups and emulsions, or by injection. In the same way, these compounds according to the invention may be administered endovenously, intraperitoneally, subcutaneously, topically with or without occlusion, or intramuscularly. All the above formes of dosage are well known to those skilled in the pharmaceutical field. In any case an effective, but non toxic amount of the active principle according to the invention must be used.
The daily dose of this active principle may vary within a wide range of between 0.01 to 1000 mg per adult/per day. An effective amount of the active principle according to the invention is usually provided at a dosage of between approximately 0.001 mg/kg and approximately 100 mg/kg of body weight per day.
According to the present invention, the active principle, which is made up of muteins of a specific wild-type cytokine, may be administered typically in a mixture with suitable diluents, excipients or pharmaceutical vehicles (generally referred to by the general term “vehicles”) suitably selected so as to bear in mind the form of administration desired.
The preparation of vaccines according to the present invention is known to persons skilled in this field. Typically, these vaccines are prepared in an injectable form, either, as solution or as suspensions. The preparation can be emulsionated, or the active principle can be incapsulated in lyposomes. The active immungenic ingredient is often mixed with pharmaceutically acceptable excipients that are compatible with the active ingredient. Suitable excipients are, for example, water, dextrose, glycerol, ethanol or the like and combinations thereof. Furthermore, if desired, the vaccine may contain small amounts of additional substances, such as, for example, wetting or emulsionating agents, pH buffering agents, and/or adjuvants to increase the effectiveness of the vaccine.
The vaccines according to the invention are preferably administered parenterally, for example by means of either intramuscular or subcutaneous injection. Other formulations suitable for other methods of administration include suppositories and oral formulations. These compounds contain from 10 to 95% of active ingredient, preferably between 25 and 70%.
Up to this point a general description has been given of the present invention. With the aid of the following examples a more detailed description will now be given, indicating specific situations that can be referred to the present invention, and aimed at giving a clearer understanding of the aims, characteristics, advantages and possible applications thereof.
REFERENCES:
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patent: WO 97/10338 (1997-03-01), None
De Hon e t al. Development of an IL-6 receptor antagonist that inhibits IL-6 dependent growth of human myeloma cell. Journal o Experimental medicine. Dec. 1994. vol. 180, pp. 2395-2400.*
Blood 87 (11). 1996. 4510-4519, XP000612195. Sporeno E. et al., “Human interleukin-6 receptor super-antagonists with high potency and wide spectrum on multiple myeloma cells.”
Brakenhoff, Just P.J. et al. “Development of a Human Interleukin-6 Receptor Antagonist.”The Journal of Biological Chemistry. (1994) 269(1): 86-93.
Brakenhoff, Just P.J. et al. “Structure-Function Analysis of Human IL-6: Epitope Mapping of Neutralizing Monoclonal Antibodies with Amino-and Carboxyl-Terminal Deletion Mutants.”The Journal of Immunology. (1990) 145(2): 561-568.
Ciliberto Gennaro
Cortese Riccardo
Savino Rocco
Beusse Brownlee Wolter Mora & Maire P.A.
Fischer Joseph
Hamud Fozia
Istituto di Ricerche di Biologia Molecolare P. Angeletti S.p.A.
Mertz Prema
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