Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Reexamination Certificate
2000-09-29
2003-02-18
Chan, Christina (Department: 1644)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
C424S185100, C424S184100, C530S350000
Reexamination Certificate
active
06521232
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to proteins having immunomodulatory activity and therapeutic agents for immune diseases. More specifically, the present invention relates to proteins derived from protein produced from helminth, which modulate the immune system in a host.
BACKGROUND OF THE INVENTION
Agents including steroids and immunosupressants, such as cyclosporine, have been used conventionally for treatment of autoimmune diseases, called intractable diseases, and allergic diseases. However, these agents have only symptomatic therapy and no effective agent exerting a markedly advantageous effect has been developed yet. Further, the steroids and cyclosporine have problems including strong side effects and drug resistance.
Recently, the dramatic advance of molecular biology and immunology has determined the detailed mechanism of immune system, various factors involved in this mechanism and receptors recognizing these factors, and has unfolded their functions and roles in the immune system. Examples of these factors include cytokines, such as various interleukins, receptors recognizing the cytokines, antibodies against the cytokines and receptors, adhesion molecules and antibodies against the adhesion molecules.
For treatment of autoimmune diseases and allergy, for example, many attempts have been made to use the above-mentioned factors as so-called “biopharmaceuticals” in the treatment where these diseases result from dysfunction of these factors.
However, these attempts are only directed to the treatment of factors functioning abnormally. These attempts therefore provide only a local immunological treatment and are considered to be an extension of conventional symptomatic treatments.
Accordingly, there is a need for a therapeutic agent based on new idea supported by the mechanism of immune system as a whole in order to cure the above intractable diseases completely.
On the other hand, parasitologists have found a tendency for patients infected with parasitic helminth to be less susceptible to allergy, based on the epidemiological correlation between helminth infection and allergy. They have also reported that patients with systemic lupus erythematosus exhibit ameliorated symptoms by parasitic infection.
However, some allergologists state that such an epidemiological correlation is groundless and absolutely unfounded because the tendency found by parasitologists has not been scientifically proved.
Regarding molecules derived from helminth, Fujita et al. has reported finding an allergen from
Dirofilaria immitis
(Fujita et al., 1979), and Horii et al. has found
Dirofilaria immitis
neutrophil chemotactic factor (DiNCF) and has determined its amino acid sequence (Horii et al., 1986). Further, C. B. Poole et al. has isolated DiNCF as Cuticular antigen produced from
Dirofilaria immitis
and has cloned its partial gene sequence, indicating that DiNCF has a structure in which the antigen molecules repeated in tandem (C. B. Poole, 1992).
The cDNA cloning of DiNCF has also been reported, for example, by J. Culpepper (J. Clupepper, 1992), Ohashi et al. (Ohashi et al., 1993), and C. B. Poole et al. (C. B. Peele et al., 1996).
These reports suggest nothing about the immunomodulatory activity of the helminth-produced molecules as defined in the present invention, because of focusing their attention only on neutrophil chemotactic activity and/or antigenicity of the molecules.
An extract of parasitic helminth has been already known to induce B cell proliferation. For example, a soluble molecule from
Ascaris suum
involved in IgE production (T. D. G. Lee et al., 1993), a crude antigen from
Toxocara canis
having the ability to increase human peripheral blood cells (Inuo et al., 1995) and an antigen from
Ascaris suum
having mitogenicity (T. D. G. Lee et al., 1995) have been reported.
However, each of these extracts was used without further isolation in each experiment, so that a single molecule isolated from the extracts has not been reported to induce B cell proliferation independently of T cells.
DISCLOSURE OF THE INVENTION
In view of the foregoing, there is still a lot of discussion among scientists of different fields and they have not reached a clear conclusion. We have focused our research effort on how the parasitic helminth infection affects the immune system in a host, and have proved that a molecule derived from parasitic helminth is effective in the treatment of immune diseases, and finally have completed the invention.
The present invention is based on the self-defense mechanism that parasites have attained over several hundreds of millions of years in order to protect themselves against immune response of their hosts. The present invention provides an agent designed according to this concept, i.e., a brand-new idea.
The present invention provides a protein of the following formula (I) having immunomodulatory activity:
X-Y-Z (I)
wherein X represents an amino acid sequence of SEQ ID NO: 1 or 2, each of Y and Z is absent or represents an amino acid sequence of SEQ ID NO: 1 or 2.
The present invention also provides the following recombinant protein (a) or (b):
(a) a protein having an amino acid sequence selected from SEQ ID NO: 7-14; and
(b) a protein having an amino acid sequence selected from SEQ ID NO: 7-14 in which one or more amino acids are deleted, substituted or added, and having immunomodulatory activity.
The present invention also provides the following recombinant protein (a) or (b):
(a) a protein having an amino acid sequence of SEQ ID NO: 15; and
(b) a protein having an amino acid sequence of SEQ ID NO: 15 in which one or more amino acids are deleted, substituted or added, and having immunomodulatory activity.
The present invention further provides an immunomodulating agent comprising the following recombinant protein (a) or (b):
(a) a protein having an amino acid sequence selected from SEQ ID NO: 1-6; and
(b) a protein having an amino acid sequence selected from SEQ ID NO: 1-6 in which one or more amino acids are deleted, substituted or added, and having immunomodulatory activity.
The present invention further provides a therapeutic agent for immune diseases, which comprises one or more proteins described above as an active ingredient.
The immune disease includes autoimmune diseases, in particular, Th1-dominant autoimmune diseases selected from the group consisting of multiple sclerosis, insulin-dependent diabetes mellitus, Crohn's disease, uveitis, chronic rheumatism, and systemic lupus erythematosus.
The immune disease also includes autoimmune diseases not known to be Th1-dominant, which are selected from the group consisting of scleroderma, multiple myositis, vasculitis syndrome, mixed connective tissue disease, Sjögren's syndrome, hyperthyroidism, Hashimoto's disease, myasthenia gravis, Guillain-Barré syndrome, autoimmune hepatopathy, ulcerative colitis, autoimmune nephropathy, autoimmune hematopathy, idiopathic interstitial pneumonia, hypersensitivity pneumonitis, autoimmune dermatosis, autoimmune cardiopathy, autoimmune infertility, and Behcet's disease.
The present invention also provides an agent for stimulating IgE production, which comprises one or more proteins described above as an active ingredient. The present invention further provides a therapeutic agent for allergic diseases, which comprises one or more proteins described above as an active ingredient.
The allergic disease includes chronic bronchitis, atopic dermatitis, pollinosis (allergic rhinitis), allergic angiitis, allergic conjunctivitis, allergic gastroenteritis, allergic hepatopathy, allergic cystitis, and allergic purpura.
The present invention also provides an immunomodulating agent which comprises one or more proteins described above as an active ingredient. The immunomodulating agent may modulate rejection reaction occurring in organ transplantation.
The present invention also provides an immunomodulation method which comprises administering one or more proteins described above in an effective amount to a patient in need of such tre
Fujita Koichiro
Imai Shinjirou
Ohashi Makoto
Chan Christina
Huynh Phuong N.
Nisshin Flour Milling Co. Ltd.
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