Drug – bio-affecting and body treating compositions – Lymphokine – Interferon
Reexamination Certificate
1999-01-29
2001-03-06
Saoud, Christine (Department: 1647)
Drug, bio-affecting and body treating compositions
Lymphokine
Interferon
C435S069510
Reexamination Certificate
active
06197292
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a therapeutic agent, composed of canine interferon-&ggr; and a treatment for canine intractable dermatitis using the agent.
BACKGROUND ART
Interferon-&ggr; (hereinafter interferon is referred to as “IFN”) is mainly produced by T-cells and is known to have three main functions, i.e., antiviral activity, anti-cell proliferation activity, and immunoregulation (reference 1). With the recent development in gene manipulation techniques, not only human IFN genes but also animal IFN genes, such as bovine, equine, and feline IFN genes have been isolated. Concerning canines, IFN-&agr;, &bgr;, and &ggr; have been reported (references 2 and 3). Compared with human or mouse IFN-&ggr;, however, only a little knowledge has been obtained from in vitro and in vivo studies on canine IFN-&ggr;, and there is no report using canine IFN-&ggr; as a therapeutic agent for any particular canine disease.
In humans, IFN-&ggr; has already been put into practical use as a therapeutic agent for malignant tumors. Concerning skin diseases, Hanifin et al. (reference 4) and Rheinhold et al. (references 5 and 6) reported its effectiveness for treating atopic dermatitis and steroid dependent asthma. There is doubt (reference 7), however, regarding the use of human IFN-&ggr; for human atopic dermatitis because of the following reasons: for effectively treating human atopic dermatitis with human IFN-&ggr;, daily administration for 6 consecutive weeks or more is necessary; IFN-&ggr; has adverse effects such as fever and headache and gives the patients a rather large amount of stress while its effects are rather small; and IFN-&ggr; formulations are expensive.
Concerning human dermatitis, diagnosis criteria have been established (reference 8) and a genetic background is regarded as being an important criterion. In addition, human atopic dermatitis is known to be a type I allergic reaction, in which production of an excess amount of IgE in response to foods, animal scales, insect poisons, and the like is an important component (reference 9). However, there have not been any systematic studies done on canine atopic dermatitis. Therefore, the evaluation criteria are unclear and the relationship between the production of excess canine IgE and atopic dermatitis is not clear.
In general, canine skin diseases include eczema, urticaria, allergic dermatitis, traumatic dermatitis, mange, otitis externa, pruritic dermatitis, and the like. The following agents are conventionally used for the above diseases: antihistamines (diphenhydramines), antiphlogistics (dibucaine hydrochloride, etc.), insecticides, and bacteriocides (malathion, benzalkonium chloride, etc.), and steroids (dexamethasone, etc.).
Among therapeutic agents of the prior art used for treating canine skin diseases, however, there are disadvantages in the use of non-steroidal agents as their therapeutic effects are very low. Although steroidal agents have extremely strong pharmacological effects, they occasionally show adverse effects, such as enhancement of infection at disease regions and increases in vascular-wall fragility. Also, long-term administration of steroids may cause obesity or systematic adverse effects as a result of effects on other organs.
In general, canine skin diseases cannot be cured as well as those of humans because of inferior housing conditions. Thus dogs are frequently treated with repeated doses of the above therapeutic agents of the prior art. Treatment periods are thus extended, and occasionally, diseases are not completely cured even if treatment is continued for more than half a year. In some cases, treatment is extended for several years, resulting in great stress for the dog owner. Therefore, there is a demand for a therapeutic agent with a rapid and sustained effect on canine intractable dermatitis that cannot completely be cured by long-term treatment using therapeutic agents of the prior art.
Accordingly, an object of the present invention is to provide an effective therapeutic agent for canine intractable dermatitis.
DISCLOSURE OF THE INVENTION
Inventors of the present invention accomplished the present invention by finding that canine skin diseases, which could hardly be cured by formulations of the prior art, were remarkably improved by administering a canine IFN-&ggr; formulation. In other words, the object of the present invention is to provide a therapeutic agent, containing canine IFN-&ggr; as the active ingredient, for canine intractable dermatitis, and a method for treating canine intractable dermatitis using the therapeutic agent.
BEST MODE FOR CARRYING OUT THE INVENTION
For example, canine IFN-&ggr; of the present invention is a polypeptide having an amino acid sequence shown as SEQ ID NOs:2,4,6,8,10,12,14. However, the present invention includes polypeptides which are within the spirit of the present invention, for example, even if the amino acid sequence has a replacement, insertion, or deletion of one or more amino acid residues, the polypeptide is included in the present invention as long as it shows biological activity of the original IFN-&ggr; as is shown in reference 1. This is because in such a case the polypeptide is regarded as having the effect of the present invention.
Although canine IFN-&ggr; may be produced by an isolation and purification process from natural biomaterials, by chemical synthesis, or by recombinant DNA techniques, the use of canine IFN-&ggr; produced by recombinant DNA techniques is preferable from an economic point of view. The method for producing canine IFN-&ggr; by recombinant DNA techniques is not particularly limited. For example, canine IFN-&ggr; can be produced by using host cells or host animals into which a gene, coding for the whole or part of an amino acid sequence of canine IFN-&ggr; shown in SEQ ID NOs:2,4,6,8,10,12,14, has been transduced by an already established conventional method. For example, after proliferating
Escherichia coli,
into which cDNA of the whole or part of a base sequence of canine IFN-&ggr; shown in SEQ ID NOs:2,4,6,8,10,12,14 has been transduced, canine IFN-&ggr; can be obtained from the bacterial cells or supernatants of the bacterial cultures by isolation and purification. Furthermore, after infecting cells of a cultured insect cell line such as
Spondoptera frugiperda
or bombyx mori or silk worms with Baculovirus, into which cDNA of the whole or part of the base sequence of canine IFN-&ggr; shown in SEQ ID NOs:2,4,6,8,10,12,14 has been transduced, canine IFN-&ggr; can be obtained by purification from the cultured cells, supernatants of cell cultures, or hemolymph of silk worms. In the above cases, the base sequence of canine IFN-&ggr; is not limited to that of SEQ ID NOs:2,4,6,8,10,12,14, as long as it is translated into the amino acid sequence of SEQ ID NOs:2,4,6,8,10,12,14. In addition, canine IFN-&ggr; having similar effects to the present invention can be produced by using cDNA having a base sequence coding for a poypeptide which is included in the spirit of the present invention, even if the amino acid sequence has a replacement, insertion, or deletion of one or more amino acid residues.
The method for isolating and purifying canine IFN-&ggr; produced by recombinant DNA techniques is not particularly limited, and conventional protein purification methods can be employed. For example, with the antiviral activity of canine IFN-&ggr; as an index, canine IFN-&ggr; can be purified and isolated by combining the following methods for desalting or concentration: chromatography employing silica gel carriers, ion exchange carriers, gel filtration carriers, chelate carriers, pigment ligand carriers, or the like; ultrafiltration; gel filtration; dialysis; salting out; and the like. In the above procedure, the antiviral activity of canine IFN-&ggr; can be measured according to the CPE method of reference 10 using vesicular stomatitis virus (VSV) as the virus and canine MDCK cells (ATCC CCL-34) as the sensitive cells.
In the present invention, canine intractable dermatitis is defined as a group of skin disease
Kawakami Isao
Okano Fumiyoshi
Satoh Masahiro
Uchino Tomiya
Yamada Katsushige
Birch & Stewart Kolasch & Birch, LLP
Hamud Fozia
Saoud Christine
Toray Industries Inc.
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