Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-01-30
2003-04-22
Ketter, James (Department: 1636)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S320100, C536S023100
Reexamination Certificate
active
06552006
ABSTRACT:
FIELD OF THE INVENTION
The invention relates generally to the field of prevention and treatment of infectious diseases, particularly infection by intracellular pathogens such as Mycobacterium.
BACKGROUND OF THE INVENTION
The broad classification of intracellular pathogens includes viruses, bacteria, protozoa, fungi, and intracellular parasites. These virulent pathogens multiply within the cells of the infected host organism rather than extracellularly and are major causes of morbidity and fatality world-wide. For example, intracellular pathogens are responsible for an estimated 10,000,000 new cases of tuberculosis per year in the world (approximately 25,000 per year in the United States), approximately 3,000,000 deaths per year from tuberculosis, an estimated 12,000,000 cases of leprosy, and an estimated 10,000,000 cases of American trypanosomiasis (Chagas disease). Furthermore, intracellular pathogens also cause other important diseases including cutaneous and visceral leishmaniasis, listeriosis, toxoplasmosis, histoplasmosis, trachoma, psittacosis, Q-fever, and Legionellosis including Legionnaires' disease. Few vaccines are available against such diseases and the pathogens are developing resistance to commonly used drugs.
One particular genus of intracellular bacteria, Mycobacteria, is a significant cause of morbidity and mortality, particularly among immunocompromised or elderly individuals and in countries with limited medical resources. Ninety-five percent of human infections are caused by seven species:
Mycobacterium tuberculosis, M. avium
(also known as the mycobacterium avium complex or
M. avium
-
intracellulare
),
M. leprae, M. kansasii, M. fortuitum, M. chelonae
, and
M. absecessus
. The most common mycobacterial infections in the United States are pulmonary infections by
M. tuberculosis
or
M. avium
. Such mycobacterial infections have been of increasing concern over the past decade, particularly in light of the increasing incidence of multi-drug resistant strains.
M. tuberculosis
is the causative agent of tuberculosis, the classic human mycobacterial disease. Disease is spread by close person-to-person contact through inhalation of infectious aerosols; infection can be established if as few as one to three bacilli reach the alveolar spaces. Estimates indicates that one-third of the world's population, including 10 million in the U.S., are infected with
M. tuberculosis
, with 8 million new cases and 3 million deaths reported world wide each year. Although incidence of tuberculosis steadily decreased since the early 1900s, this trend changed in 1984 with increased immigration from endemic countries and increased infection in the homeless, drug and alcohol abusers, prisoners, and HIV-infected individuals ((1995)
Morbid. Mortal. Weekly Rep
44:1-87). Due to the difficulties in eradicating disease in most of these populations, tuberculosis has again threatened to pose a significant public health risk.
Mycobacterium avium
is generally less of a health risk for individuals with normal immune responses;
M. avium
can transiently colonize these individuals, but disease due to
M. avium
is rare. However,
M. avium
infection can cause serious disease in patients having compromised pulmonary function (e.g., patients with chronic bronchitis, obstructive pulmonary disease, or pre-existing pulmonary damage (e.g., due to previous pulmonary infections or other disease). Infection in individuals having compromised pulmonary function is clinically very similar to infection by
M. tuberculosis.
M. avium
infection poses the greatest health risk to immunocompromised individuals, and is one of the most common opportunistic infections in patients with AIDS (Horsburgh (1991)
New Eng. J. Med
. 324:1332-1338). In contrast with disease in other patients,
M. avium
infection can be very serious in immunocompromised individuals (e.g., AIDS patients, who have a low CD4+ T-cell count (Crowe, et al. (1991)
J. AIDS
4:770-776)), and can result in disseminated infection in which virtually no organ is spared. The magnitude of such disseminated
M. avium
infections is overwhelming, with the bacterial load in some patients resulting in tissues that are literally filled with mycobacteria and with hundreds to thousands of bacilli per milliliter of blood. When disseminated disease occurs,
M. avium
infection results in considerable morbidity, and is a significant contributor to mortality in AIDS patients. Although highly active anti-retroviral therapy currently used to treat HIV-infected patients prevents the onset of
M. avium
infection to some extent (Autran, et al. (1997)
Science
. 277:112-116), this infection is extremely difficult to treat when encountered because of its poor responsiveness to anti-mycobacterial therapy (Chin, et al. (1994)
J. Infect. Dis
. 170:578-584; Masur (1993)
New Eng. J. Med
. 329:898-904).
As noted above, mycobacterial infection is normally acquired through inhalation of aerosolized infectious particles. Following inhalation, mycobacteria predominately infect and multiply within macrophages (Edwards, et al. (1986)
Am. Rev. Respir. Dis
. 134:1062-1071). The bacteria attach to and enter macrophages with the help of specific receptors expressed on the surface of these cells (Bermudez, et al. (1991)
Infect. Immun
. 59:1697-1702; Rao, et al. (1993)
Infect. Immun
. 61:663-670; Roecklein, et al. (1992)
J. Lab. Clin. Med
. 119:772-781). Studies have shown that macrophages secrete several cytokines such as tumor necrosis factor (TNF)-&bgr;, interleukin (IL)-1&bgr;, IL-6, granulocyte macrophage colony stimulating factor (GM-CSF), and granulocyte colony stimulating factor (Fattorini, et al. (1994)
J. Med. Microbiol
. 40:129-133; Newman, et al. (1991)
J. Immunol
. 147:3942-3948) in response to infection with mycobacteria. T cell products such as interferon (IFN)-&ggr; and IL-12 are known to be extremely important for anti-mycobacterial activity of macrophages (Fattorini, et al. (1994)
J. Med. Microbiol
. 40:129-133) as well as in vivo in humans and mice (Appelberg, et al. (1994)
Infect. Immun
. 62:3962-3971; Holland, et al. (1994)
New Eng. J. Med
. 330:1348-1355; Kobayashi, et al. (1995)
Antimicrob. Agents Chemotherapy
. 39:1369-1371).
Treatment of mycobacterial infections is complicated and difficult. For example, treatment of
M. tuberculosis
and of
M. avium
infections requires a combination of relatively toxic agents, usually three different drugs, for at least six months. The toxicity and intolerability of these medications usually result in low compliance and inadequate treatment, which in turn increases the chance of therapeutic failure and enhances the selection for drug-resistant organisms. Treatment of mycobacterial infections is further complicated in pregnant women, patients with pre-existing liver or renal diseases, and immunocompromised patients, e.g., AIDS patients.
Immunomodulatory sequences (hereinafter referred to as “ISS”) were initially discovered in the mycobacterial genome as DNA sequences that selectively enhance NK cell activity (Yamamoto, et al. (1992)
Microbiol. Immunol
. 36:983-997). Uptake of mycobacterial DNA or ISS has been shown to activate cells of the innate immune system, such as NK cells and macrophages and stimulating a type-1 like response (Roman, et al. (1997)
Nature Med
. 3:849-854). Further, administration of ISS has been shown activate NK cells (Krieg, A et al. (1995)
Nature
. 374:546-549), stimulate B cells to proliferate and to produce IgM antibodies (Krieg, A et al. (1995)
Nature
. 374:546-549; Messina, et al. (1991)
J. Immunol
. 147:1759-1764; ), stimulate production of cytokines, such as IFNs, IL-12, IL-18 and TNF-&agr; (Sparwasser, et al. (1998)
Eur. J. Immunol
. 28:2045-2054; Sparwasser, et al. (1997)
Eur. J. Immunol
. 27:1671-1679; Stacey, et al. (1999)
Infect. Immun
. 67:3719-3726; Stacey, et al. (1996)
J. Immunol
. 157:2116-2122; Halpern, et al (1996)
Cell. Immunol
. 167:72-78; Klinman, et al. (1996)
Proc. Natl. Acad. Sci. U.S.A
. 93:2879-2883) and up-regulate co-stimulatory
Carson Dennis
Catanzaro Antonio
Hayashi Tomoko
Kornbluth Richard
Raz Eyal
Borden Paula A.
Bozicevic Field & Francis LLP
Francis Carol L.
Ketter James
Sullivan Daniel M.
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