Alloferons—immunomodulatory peptides

Details Alloferons—immunomodulatory peptides Alloferons—immunomodulatory peptides

2000-12-27

2004-02-17

Park, Hankyel T. (Department: 1648)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

C424S185100, C530S300000

Reexamination Certificate

active

06692747

ABSTRACT:

The present invention is concerned with immunomodulatory materials of natural origin. In particular, the present invention is concerned with peptides of invertebrate origin and pharmaceutical preparations comprising such peptides which are useful in the treatment of immune deficient conditions, infections and oncological diseases.
In the state of the art various pharmaceutical preparations of natural origin containing materials of animal, including insect, and plant tissues able to stimulate the immune system's efficacy are known.
A process for obtaining cellular protein having anti-HIV activity from CD4-positive T cells or myeloid cells is disclosed in U.S. Pat. No. 5,480,782.
A topic formulation comprising a Ginkgo biloba extract exhibiting antibacterial and antiviral properties is disclosed in DE 43 34 600 A1.
WO 96/04005 discloses a pharmaceutical composition for stimulation of the immune response of an organism comprising as the active ingredient major histocompatibility complex antigens extracted from animal tissues, serum or cells. The tissues, cells or sera are chosen from goat, veal or pig liver and bovine red blood cells.
A pharmaceutical composition containing an extract of the plant
Nigella sativa
is disclosed in U.S. Pat. No. 5,482,711 for treating cancer, preventing the side effects of anticancer chemotherapy, and for increasing the immune functions in humans.
WO 81/03124 discloses a polypeptide fraction isolated from the mussel
Mytilus edulis
and used as antibiotic composition effective against various viruses, bacteria and protozoa.
Antibacterial peptides from honey bees and a process for their isolation, production and applications have been disclosed in EP 0 299 828 A1.
Antibacterial peptides isolated from the Coleopteran insects,
Tenebdo molitor
and
Leptinotarsa decemlineata
are disclosed in WO 90/14098.
Antibacterial protein isolated from the Lepidopteran insect,
Hyalophora gloveri
is disclosed in EP 0 856 519 A2.
Antimicrobial peptides structurally similar with arginine-containing fragments of lentivirus transmembrane proteins are disclosed in U.S. Pat. No. 5,714,577.
Antiviral and antimicrobial peptides isolated from porcine leucocytes are disclosed in U.S. Pat. No. 5,804,558.
Immunomodulatory peptides specifically binding major histocompatibility complex class II antigens and decreasing in that way a possibility of autoimmune disease are disclosed in U.S. Pat. No. 5,827,516.
EP 0 320 528 A1 discloses the use of hemocyanins and arylphorins isolated from various molluscs and arthropods including the insect
Calliphora erythrocephala
as stimulants the production of specific antibodies and the antitumor activity of antibody-dependent T-lymphocytes.
The preparations mentioned above and analogous natural pharmaceutical preparations enhance the recent arsenal of medicines suitable for treatment of immune deficient conditions, infections and oncological diseases. However, the pharmaceuticals which are available up to now do not cover existing demands in immunomodulatory medicines.
Therefore, it is an object of the present invention to provide a pharmaceutical preparation having immunomodulatory activity and in particular being useful for the treatment of immune deficient conditions, infections and oncological diseases.
It has now surprisingly been found that specific peptides exhibit the desired immunomodulatory activity.
Thus, the present invention relates to a peptide consisting of up to 30 amino acid residues and having the following general structural formula (1) (SEQ ID NO: 31):
X
1
-His-Gly-X
2
-His-Gly-Val-X
3
  (1)
wherein
X
1
is absent or represents at least one amino acid residue,
X
2
is a peptide bound or represents at least one amino acid residue, and
X
3
is absent or represents at least one amino acid residue,
or a pharmaceutically acceptable salt or ether thereof,
the peptide exhibiting immunomodulatory activity.
The present invention provides a new class of immunomodulatory peptides, designated “alloferons” herein, representative members of which were isolated from the blood of bacteria challenged larvae of an insect, blow fly
Calliphora vicina
R.-D. (Diptera, Calliphoridae).
The alloferons of the invention have been found to stimulate cytotoxic anticancer activity of animal (mouse) and human natural killer cells. Experimental data on the alloferons' immunomodulatory activity show that they are able to stimulate the cytotoxic anticancer activity of human and mouse lymphocytes at extreme low concentrations. The minimum effective concentration was determined to be about 0.0005 nanogram/ml. The optimum concentration was found to be 0.05-0.5 nanogram/ml. Assuming the important role of natural cytotoxicity as effector mechanism of innate immunity (Trinchieri G., Advances in Immunology, 1989, vol. 47, 187-375; Brittenden J., Heys S. D., Ross J. and Eremin O., 1996, vol. 77, 1126-1243), alloferons may be useful as antiviral, antimicrobial and anticancer medicines of immunomodulatory mode of action.
Moreover, with regard to the stimulation of the anticancer activity of the cytotoxic lymphocytes, alloferons were found to induce intensive and prolonged interferon synthesis in experimental animals. Interferons are a group of key antiviral (alpha- and beta-interferons) and immunomodulatory (gamma-interferon) cytokins produced in the organism in response to viral infection and some other external stimuli. Elevation of interferons concentration in the blood helps to cure or mitigate a broad range of viral, oncological and autoimmune disorders. Injections of recombinant or natural interferons are successfully used in the immunotherapy of hepatitis C (Bekkering et al., J. Hepathology, 1998, 28, 6, p. 960-964), herpes (Cardamakis et al., Gynecol. Obstet. Invest., 1998, 46, 1, p.54-57), multiple myeloma (Zee et al., J. Clin. Oncol., 1998, 16, 8, p. 2834-2839), Hodgkin's disease (Aviles et al., Leuk. Lymphoma, 1998, 30, 5-6, p. 651-656), myeloid leukemia (Gilbert H. S., Cancer, 1998, 83, 6, p.1205-13), multiple sclerosis (Durelli et al., Mult. Scler, 1995, 1, suppl. 1, p. 32-37), atopic dermatitis (Schneider et al., Ann. Allergy Asthma Immunol., 1998, 80, 3, p. 263-268), fungal infections (Kullberg, Eur. J. Clin. Microbiol. Infect. Dis., 1997, 16, p. 51-55) etc. Moreover exogenic interferons, inducers of endogenic interferon synthesis such as bropirimine, a phenylpyrimidinone analog, might be used to achieve similar therapeutic results (Akaza et al., Eur. Urol., 1998, 34, p. 107-110).
Experimental data show that alloferons effectively induce interferon synthesis and stimulate some immunological reactions (natural killers activity) in a manner similar to interferons. Therefore alloferons are believed to have similar therapeutic use compared to interferons and interferon inducers including but not limited to treatment of interferon-sensitive viral and cancer diseases. Direct confirmation of this hypothesis is obtained in experiments with virus infected mice. It is shown that alloferon administration significantly increase the survival rate in mice intrapulmonary infected with a lethal dose of human influenza virus A and B.
The chemical structure of alloferons has no similarity with interferons, other known cytokines and interferon inducers as well as any other materials of medical importance. The chemical structure of alloferons and the mode of biological activity are also quite different of those of arylphorin isolated from Calliphora and demonstrating immunologic and antitumor activity as it is disclosed in EP 0 320 528 A1. Alloferons preferably have a molecular mass close to 1200 Da and belong to the unique peptide family which has not been described so far. Calliphora arylphorin has a molecular mass of about 500 000 Da (Naumann U. and Scheller K. Biochem. Biophys. Res. Communications, 1991, 177, p. 963-971) and is proposed to be used as an adjuvant in the course of specific vaccination and specific stimulation of antibody-dependent T-lymphocytes antitumor activity as it is disclosed in EP 0 320 528 A1. No data concerning a

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