Drug – bio-affecting and body treating compositions – Extract – body fluid – or cellular material of undetermined... – Derived from arthropod
Reexamination Certificate
1999-12-02
2002-01-08
Tate, Christopher R. (Department: 1651)
Drug, bio-affecting and body treating compositions
Extract, body fluid, or cellular material of undetermined...
Derived from arthropod
Reexamination Certificate
active
06337093
ABSTRACT:
The present invention is concerned with immunomodulatory and antimicrobial materials of invertebrate origin. In particular, the present invention is concerned with a composition, comprising a peptide or a peptide mixture of invertebrate origin and pharmaceutical preparations comprising such composition 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 extractive materials of animal and plant tissues able to stimulate the immune system's efficacy as well as to kill pathogenic microorganisms directly 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.
It is known from scientific literature that insect tissues also contain antimicrobial proteins and peptides (Gillespie J. P., Kanost M. R. and Trenczek T. Biological mediators of insect immunity. Annu. Rev. Entomol., 1997, 42, 611-643; Hoffmann J. A. and Reichhart J-M. Drosophila immunity Trends in Cell Biology, 1997, 7, 309-316). These materials posses direct toxicity to bacteria and fungi.
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 and antibiotic medicines.
Therefore, it is an object of the present invention to make available a pharmaceutical composition useful for treatment of immune deficient conditions, infections and oncological diseases.
It has been found that compositions comprising a peptide or a peptide mixture of invertebrate and in particular insect origin exhibit an immunomodulatory and antimicrobial activity. Therefore, the present invention is related to a composition, comprising a peptide or a peptide mixture, preparable by a process comprising the steps of collecting, centrifugating and chromatographically separating the body fluid of an invertebrate.
Moreover, the present invention is directed to pharmaceutical preparations, comprising the above composition.
The compositions of the present invention comprise a peptide or a peptide mixture. Herein, the term “peptide” refers to oligo- and polypeptides as well as to proteins. The peptides are believed to be the active principles in the pharmaceutical preparations prepared from these compositions. Nevertheless, the compositions may comprise further components which however should not interfere with the active principles in order to obtain useful pharmaceutical preparations.
The compositions of the present invention are preparable by a process comprising the steps of collecting, centrifugating and separating the body fluid of an invertebrate. The separation step can for example be carried out using a chromatographic column like a Sep-Pak C18 chromatographic column available from Waters Co., but other separation methods may also be used. If desired, further purification and concentration steps like lyophilisation may follow.
As source for the body fluid used for the isolation of the compositions of the present invention the following invertebrates have been found to be especially useful in the course of comparative investigations:
Calliphora vicina, Musca domestica, Limnephilus stigma, Sialis lutaria, Isogenus nubecula, Palomena prasina, Podisus maculiventris, Pachyiulus flaviceps, Hemophisalis longicornis, Arenicola marina, Mitilus edulis, Mya arenaria, Asterias rubens, Stychopus japonicus, Halocynthia roretzi and Aurelia aurita.
Preferably the hemolymph of an insect may be used as the body fluid of an invertebrate. The hemolymph of an insect
Calliphora vicina
Robineau-Desvoidy (
C. vicina
, Diptera, Calliphoridae) is especially preferred.
It should be understood that the compositions of the present invention may be obtained by extraction from the body fluid of a single invertebrate as well as from the body fluids of two or more different invertebrates.
Moreover, it has been found that the hemolymph of septically injured
C. vicina
larvae accumulates unusual high concentrations of antimicrobial materials as compared to other species investigated. This allows to use
C. vicina
hemolymph as raw material for the production of pharmaceutical preparations with combinative antibiotic and immunomodulatory activity.
The
C. vicina
larvae may for example be septically injured by pricking off cuticle with a needle soaked in a suspension of heat-killed
Escherichia coli
and
Micrococcus luteus
cells. It is of course also possible to use other pathogenic or nonpathogenic bacteriae like
Staphylococcus aureus
or different strains of Salmonella.
Another aspect of the present invention are pharmaceutical preparations comprising one or more of the above compositions.
These pharmaceutical preparations are useful as antibiotics. Due to their antibiotic activity the pharmaceutical preparations of the present invention directly kill pathogenic microorganisms thereby exhibiting antibacterial and/or anti-fungal activity.
In vitro studies showed that the pharmaceutical preparations of the present invention have strong antibiotic activity against a variety of Gram-positive and Gram-negative bacteria including important human pathogens. The pharmaceutical preparations are also found to be effective in vivo. Particularly, they are able to cure mice infected with a lethal dose of human pathogenic strains of
Klebsiella pneumonia
and
Salmonella typhimurium
. Their fungicidal activity includes both yeast like
Candida albicans
and
filamentous
fungi.
Moreover, the pharmaceutical preparations of the present invention possess an immunomodulatory activity on human and mammalian immune cells and are thus useful for the treatment or prevention of immune deficient conditions like oncological diseases, especially cancer, and viral infections.
The basic mode of the immunomodulatory action of the pharmaceutical preparations of the present invention is a stimulation of cytotoxic lymphocytes such as natural killer cells able to kill malignant or virus-infected cells. The pharmaceutical preparations for example enforce mouse spleen lymphocytes to attack cancer cells of various origin in vitro and in vivo. Furthermore, the preparations when injected to mice induce strong and prolonged synthesis of endogenous interferon, the principal cytokin activating various defense mechanisms of the immune system.
Extensive studies of the response of lymphocytes of human donor blood to the pharmaceutical preparations of the present invention confirm that the pharmaceutical preparations also have a strong immunomodulatory effect on a significant part of the human population.
It is known that mechanisms of natural cytotoxicity play an important role in the organism's protection against infection diseases as well as in the killing of the organism's own malignant cells (Trinchieri G. Biology of natural killer cells, Advances in Immunology, 1989, vol. 47, 187-375; Brittenden J., Heys S. D., Ross J. and Eremin O. Natural killer cells and cancer, Cancer, 1996, vol. 77, 1126-1243). Therefore, stimulators of the lymphocytes' natural cytotoxicity potentially may be used for the tr
Bekker German
Chernysh Sergey I.
Kim Soo In
Heller Ehrman White & McAuliffe LLP
Patten Patricia D.
Tate Christopher R.
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