Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving virus or bacteriophage
Reexamination Certificate
1998-05-19
2001-02-20
Park, Hankyel (Department: 1645)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving virus or bacteriophage
C435S007100, C435S343200, C530S387500, C530S388350, C424S130100
Reexamination Certificate
active
06190863
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel sugar-chain-recognizing antibodies, and more particularly to antibodies which belong to the class IgM and which recognize sugar chains expressed in HIV-infected cells, as well as to remedies for treating HIV-patients containing the antibodies as effective ingredients.
BACKGROUND ART
AIDS (acquired immunodeficiency syndrome) was first discovered in San Francisco in 1981 as a fatal immunodeficiency disease of homosexual males (Gottlieb, M. S., Schroff, R., et al., N. Engl. J. Med., 305, 1425-1430(1981)). Two years later, the Montanie group of the Pasteur Institute in France discovered the virus that causes AIDS (Barre-Sinoussi, F., Chermann, J. C., et al., Science, 220, 868-871(1983)). In 1985, this virus was univocally named HIV (human immunodeficiency virus) (Coffin, J., Haase, A., et al., Science, 232, 697(1986)).
AIDS is a disease having the following features and effects: When an individual is infected with HIV through sexual intercourse, blood transfusion, etc., the virus destroys the immunological functions of the infected individual, causing acquired immunodeficiency of the host, i.e., the infected individual. Eventually, the host manifests a variety of symptoms such as diarrhea and pneumonia, resulting in a final outcome of death of the host.
Presently, many researchers are attempting to develop remedies for AIDS. For example, since the discovery of azidothymidine (AZT) by Mitsuya et al. (Mitsuya, H., et al., Proc. Natl. Acad. Sci., USA.,
82
,
7096
(1985)), ddI (2′,3′dideoxyinosine), ddC (2′,3′-dideoxycytidin), and other substances have been studied in clinical situations. However, pharmaceuticals providing satisfactory results have not yet been reached.
Although the incubation period from infection with HIV to onset of disease greatly varies depending on the individual, about 50% of humans who are infested with HIV manifest the disease with certainty within 10 years after infection, and almost all the infected patients die within 1 to 3 years after manifestation of the disease. Adults over 40 years of age and children rapidly develop the disease after they are infected with HIV. Reasons that explain the grace period between infection and development of AIDS-related complex (ARC) may include the patients' general health conditions, genetic predisposition, complications with other infection disease, and other host-dependent causes, as well as differences in the strain of infectious virus.
In cases of infection due to transfusion of blood components, most HIV-infected individuals manifest AIDS and die. However, some infected individuals do not manifest AIDS even after 10 years have passed after infection, and some other infected individuals take an even longer time before manifestation of AIDS. Such cases are seen worldwide, and it has been reported that 5% of HIV-infected individuals survive for long periods. So-called long-time survivors among HIV-infected persons, who stay asymptomatic for long periods, have received much attention, because they are considered to offer a clue for elucidation of the mechanism of their resistance to HIV virus or preventing the manifestation of the pathological symptoms. Therefore, a variety of studies and research have been performed on such long-time survivors.
However, the reason why longtime survivors do not manifest AIDS in spite of having been infected with HIV has not yet been clearly understood. Thus, it is desired to clarify the reason of HIV resistance, and to develop remedies for treating HIV diseases on the basis of the reason.
DISCLOSURE OF THE INVENTION
The present inventors studied the difference between the silent cases and active cases of virus replication among HIV-infected persons. During the studies, they found that specific IgMs found among natural antibodies for certain sugar chains carried by some infected patients might explain the delay of disease development. The sugar chains that serve as antigens are considered not to exist in the body under usual circumstances' or to exist in a limited amount. However, when cells are infected with HIV, the sugar chains appear on the surfaces of T cells or macrophages. (Generally speaking, it is well known that then cells becomes tumor or are infected with a virus, special sugar chains appear on the surfaces of the cells). If antibodies for such sugar chains belonging to the class IgM are present in serum as natural antibodies, the antibodies recognize HIV-infected cells and are bound to the infected alls. Complements cascade is activated at the local site, where IgM bound to the sugar antigen, and results in lysis of the HIV-infected cells. Thus, serum that contains the aforementioned natural IgM antibodies establishes a special environment in which HIV-infected cells do not easily proliferate. Also, the present inventors found that the HIV-infected cells have enhanced complement sensitivity. These facts have been confirmed not only in vitro but also in patients who had been infected with HIV whose manifestation of AIDS was delayed. Namely, it was actually confirmed that such long lived patients bare antibodies belonging to the class IgM that are reactive with HIV-infected cells.
It was also found that cells that are usually resistant against complements are lysed by the complements after antibodies for gangliotetraose (Gg4) are bound to such cells. In addition, antibodies Belonging to the class IgM having binding capacity to the infected cells eliminate infected cells as a result of cytolysis mediated by complements activation and make a hole to the HIV infected cells. Accordingly, it has been learned that administration of antibodies belonging to the class IgM a nd having reactivity with HIV-infected cells is useful for the treatment of HIV-carriers.
Accordingly, the present intention provides a sugar-chain-recognizing antibody which belongs to the class IgM and which recognizes Gg4Cer(Gal&bgr;1-3GalNAc&bgr;1-4Gal&bgr;1-4GlcCer) or GM2.
The present invention also provides a remedy for HIV diseases (AIDS) containing the sugar-chain-recognizing antibody as an effective substances
The present invention also provides a composition for treating HIV diseases with the sugar-chain-recognizing antibody.
The present invention also provides the use of the sugar-chain-recognizing antibody and the manufacturing method for a thrapeutics for HIV diseases.
The present invention also provides a method for treating HIV-infected patients, which is characterized by the administration of an effective amount of the sugar-chain-recognizing antibody to HIV patients.
REFERENCES:
Wu, et al., IgM natural antibody against an asialo-oligosaccharide, gangliotetraose (Gg4), sensitizes HIV-1 infected cells for cytolysis by homologous complement, Intern. Immunol. vol. 8, No. 1, pp. 153-158, see Fig. 3A, 3B and 4; p. 153, column 2, firs, Jan. 1996.
Fahey et al., Status of immune-based therapies in HIV infection and AIDS, Clin. exp. Immunol. 88, 1-5, see page 3, second column, third full paragraph, Jan. 1992.
Fox, J. L., No winners against AIDS, Bio/Tech, vol. 12, p. 128, see entire page, Feb. 1994.
Xiaoshan Wu et al., “Complement-Mediated Anti-HIV-1 Effect Induced by Human IgM Monoclonal Antibody Against Ganglioside GM1”, 1999, The American Association of Immunologists, pp. 533-539.
Watarai, Shinobu et al., “Application of Liposomes to Generation of Monoclonal Antibody to Glycosphingolipid: Production of Monoclonal Antibody to GgOse4Cer”, J. Biochem. 1987, vol. 102, No. 1, pp. 59-67.
Sanai, Yutaka et al., “Monoclonal antibody directed to a Hanganutziu-Deicher active ganglioside, GM2(NeuGc)”, Biochimica et Biophysica Acta, 1988, vol. 958, pp. 368-374.
Vrionis, Fotios D. et al., “Five New Epitope-defined Monoclonal Antibodies Reactive with GM2and Human Glioma and Medulloblastoma Cell Lines”, Cancer Res., 1989, vol. 49, pp. 6645-6651.
Livingston, Philip O. et al., “Characterization of IgG and IgM Antibodies Induced in Melanoma Patients by Immunization with Purified GM2Ganglioside”, Cancer Res., 1989, vol. 49, pp. 7045-
Okada Hidechika
Okada Noriko
Otsuka Pharmaceutical Co. Ltd.
Park Hankyel
Sughrue Mion Zinn Macpeak & Seas, PLLC
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