Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-15
2003-09-02
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C424S449000
Reexamination Certificate
active
06613788
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to methods of treating cancer or infectious disease in which histamine is administered in conjunction with additional agents. The additional agent may be an agent which stimulates the proliferative and/or cytotoxic activity of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) in a synergistic fashion with histamine. Alternatively, the additional agent may be a chemotherapeutic, antiviral, vaccine or antibiotic agent. Methods combining histamine, agents which act synergistically with histamine to enhance the cytotoxicity of NK cells and CTLs, and chemotherapeutic agents are also contemplated.
The invention also relates to a method of elevating circulating blood histamine levels for prolonged periods of time in individuals with decreased circulating histamine levels. Such decreased levels may be due to cancer, viruses or other infectious agents or pathological situations.
The invention is based on the surprising observation that despite previous reports of histamine's short half life in the body, it is possible to attain stable beneficial levels of circulating blood histamine and to maintain these beneficial levels for hours or days after the last administration of histamine. This observation facilitates treatments in which histamine administration to obtain beneficial levels of circulating blood histamine is combined with treatment with other agents. The invention also relates to improvements in the method of administering histamine. A brief review of the observations leading to the present invention is provided below to place the present invention in context.
A. Cell Types Involved in the Generation of an Immune Response
Recent anticancer and antiviral strategies have focussed on utilizing the host immune system as a means of cancer or antiviral treatment or therapy. The immune system has evolved complex mechanisms for recognizing and destroying foreign cells or organisms present in the body of the host. Harnessing the body's immune mechanisms is an attractive approach to achieving effective treatment of malignancies and viral infections.
A wide array of effector cells, each having its own characteristics and role, implement the immune response. One type of effector cell, the B cell, generates antibodies targeted against foreign antigens encountered by the host. In combination with the complement system, antibodies direct the destruction of cells or organisms bearing the targeted antigen.
Another type of effector cell, the T cell, is divided into subcategories which play different roles in the immune response. Helper T cells secrete cytokines which stimulate the proliferation of other cells necessary for mounting an effective immune response, while suppressor T cells down regulate the immune response. A third category of T cell, the cytotoxic T cell (CTL), is capable of directly lysing a targeted cell presenting a foreign antigen on its surface.
An additional type of effector cell is the natural killer cell (NK cell), a type of lymphocyte having the capacity to spontaneously recognize and destroy virally infected cells and a variety of malignant cell types. This characteristic of NK cells makes them an attractive candidate for exploitation in anticancer and antiviral treatments and therapies based on using the host's immune system as a weapon against malignant tumors and viruses.
B. Cytokines Involved in Mediating the Immune Response
The interplay between the various effector cells listed above is influenced by the activities of a wide variety of chemical factors which serve to enhance or reduce the immune response as needed. Such chemical modulators may be produced by the effector cells themselves and may influence the activity of immune cells of the same or different type as the factor producing cell.
One category of chemical mediators of the immune response is cytokines, molecules which stimulate a proliferative response in the cellular components of the immune system.
Interleukin-2 (IL-2) is a cytokine synthesized by T cells which was first identified in conjunction with its role in the expansion of T cells in response to an antigen (Smith, K.A. Science 240:1169 (1988). It is well known that IL-2 secretion is necessary for the full development of cytotoxic effector T cells (CTLs), which play an important role in the host defense against viruses. Several studies have also demonstrated that IL-2 has antitumor effects that make it an attractive agent for treating malignancies (see e.g. Lotze, M.T. et al, in “Interleukin 2”, ed. K.A. Smith, Academic Press, Inc., San Diego, Calif., p. 237 (1988); Rosenberg, S., Ann. Surgery 208:121 (1988)). In fact, IL-2 has been utilized to treat subjects suffering from malignant melanoma, renal cell carcinoma, and acute myelogenous leukemia. (Rosenberg, S.A. et al., N. Engl. J. Med. 316:889-897 (1978); Bukowski, R. M. et al., J. Cliin. Oncol. 7:477-485 (1989); Foa, R. et al., Br. J. Haematol. 77:491-496 (1990)).
It appears likely that NK cells are responsible for the anti-tumor effects of IL-2. For example, IL-2 rapidly and effectively augments the cytotoxicity of isolated human NK cells in vitro (Dempsey, R.A., et al., J. Immunol. 129:2504 (1982); Phillips, J. H., et al. J. Exp. Med. 170:291 (1989)). Thus, the cytotoxic activity of NK cells treated with IL-2 is greater than the constitutive levels of cytotoxicity observed in untreated cells. Furthermore, depletion of NK-cells from animals eliminates IL-2's antitumor effects. (Mule, J. J. et al, J. Immunol. Invest. 139:285 (1987); Lotze, M.T. et al., supra). Additional evidence for the role of NK cells results from the observation that NK cells are the only resting human peripheral blood lymphocytes expressing the IL-2 receptor on their cell surface. (Caliguri, M. A. et al., J. Clin. Invest. 91:123-132 (1993)).
Another cytokine with promise as an anti-cancer and antiviral agent is interferon-&agr;. Interferon-a (IFN-&agr;) has been employed to treat leukemias, myeloma, and renal cell carcinomas. Isolated NK cells exhibit enhanced cytotoxicity in the presence of IFN-&agr;. Thus, like IL-2, IFN-&agr; also acts to augment NK cell mediated cytotoxicity. (Trinchieri, G. Adv. Immunol. 47:187-376 (1989)).
C. In vivo Results of Histamine and Histamine Agonist Treatments
Histamine is a biogenic amine, i.e. an amino acid that possesses biological activity mediated by pharmacological receptors after decarboxylation. The role of histamine in immediate type hypersensitivity is well established. (Plaut, M. and Lichtenstein, L. M. 1982 Histamine and immune responses. In
Pharmacology of Histamine Receptors
, Ganellin, C. R. and M. E. Parsons eds. John Wright & Sons, Bristol pp. 392-435.) Examinations of whether histamine or histamine antagonists can be applied to the treatment of cancer have yielded contradictory results. Some reports suggest that administration of histamine alone suppressed tumor growth in hosts having a malignancy. (Burtin, Cancer Lett. 12:195 (1981)). On the other hand, histamine has been reported to accelerate tumor growth in rodents (Nordlund, J. J. et al., J. Invest. Dermatol. 81:28 (1983)).
Similarly, contradictory results were obtained when the effects of histamine receptor antagonists were evaluated. Some studies report that histamine receptor antagonists suppress tumor development in rodents and humans (Osband, M.E. et al., Lancet 1 (8221):636 (1981)). Other studies report that such treatment enhances tumor growth and may even induce tumors (Bama, B.P. et al., Oncology 40:43 (1983)).
D. Synergistic Effects of Histamine and IL-2
Despite the conflicting results when histamine is administered alone, recent reports clearly reveal that histamine acts synergistically with cytokines to augment the cytotoxicity of NK cells and CTLs. Thus, therapies employing the combination of histamine and cytokines represent an attractive approach to anti-cancer strategies based on using the host immune system to attack the malignancy. Similarly, antiviral treatments using any of the well known antiviral agents is
Gehlsen Kurt R.
Hellstrand Kristoffer
Hermodsson Svante
Criares Theodore J.
Kim Jennifer
Knobbe Martens Olson & Bear LLP
Maxim Pharmaceuticals, Inc.
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