Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
2000-01-03
2003-06-03
Swartz, Rodney P (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C424S009100, C424S009200, C424S184100, C424S185100, C424S190100, C424S234100, C530S300000, C530S350000, C536S023100, C536S023700
Reexamination Certificate
active
06572865
ABSTRACT:
I. BACKGROUND
A. The Rise of Tuberculosis
Over the past few years the editors of the
Morbidity and Mortality Weekly Report
have chronicled the unexpected rise in tuberculosis cases. It has been estimated that one billion people are infected with
M. tuberculosis
worldwide, with 7.5 million active cases of tuberculosis. Even in the United States, tuberculosis continues to be a major problem especially among the homeless, Native Americans, African-Americans, immigrants, and the elderly. HIV-infected individuals represent the newest group to be affected by tuberculosis. Of the 88 million new cases of tuberculosis expected in this decade, approximately 10% will be attributable to HIV infection.
The emergence of multi-drug resistant strains of
M. tuberculosis
has complicated matters further and even raises the possibility of a new tuberculosis epidemic. In the U.S. about 14% of
M. tuberculosis
isolates are resistant to at least one drug, and approximately 3% are resistant to at least two drugs.
M. tuberculosis
strains have even been isolated that are resistant to all seven drugs in the repertoire of drugs commonly used to combat tuberculosis. Resistant strains make treatment of tuberculosis extremely difficult: for example, infection with
M. tuberculosis
strains resistant to isoniazid and rifampin leads to mortality rates of approximately 90% among HIV-infected individuals. The mean time to death after diagnosis in this population is 4-16 weeks. One study reported that, of nine immunocompetent health care workers and prison guards infected with drug-resistant
M. tuberculosis
, five died. The expected mortality rate for infection with drug-sensitive
M. tuberculosis
is 0%.
The unrelenting persistence of mycobacterial disease worldwide, the emergence of a new, highly susceptible population, and the recent appearance of drug-resistant strains point to the need for new and better prophylactic and therapeutic treatments of mycobacterial diseases.
B. Tuberculosis and the Immune System
Infection with
M. tuberculosis
can take on many manifestations. The growth in the body of
M. tuberculosis
and the pathology that it induces is largely dependent on the type and vigor of the immune response. From mouse genetic studies it is known that innate properties of the macrophage play a large role in containing disease, Skamene,
Ref Infect. Dis.
11:S394-S399, 1989. Initial control of
M. tuberculosis
may also be influenced by reactive T &ggr;&dgr; cells. However, the major immune response responsible for containment of M. tuberculosis is via helper T cells (Th1) and to a lesser extent cytotoxic T cells, Kaufmann,
Current Opinion in Immunology
3:465-470, 1991. Evidence suggests that there is very little role for the humoral response. The ratio of responding Th1 to Th2 cells has been proposed to be involved in the phenomenon of suppression.
Th1 cells are thought to convey protection by responding to
M. tuberculosis
T cell epitopes and secreting cytokines, particularly INF-&ggr;, that stimulate macrophages to kill
M. tuberculosis
. While such an immune response normally clears infections by many facultative intracellular pathogens, such as Salmonella, Listeria, or Francisella, it is only able to contain the growth of other pathogens such as
M. tuberculosis
and Toxoplasma. Hence, it is likely that
M. tuberculosis
has the ability to suppress a clearing immune response, and mycobacterial components such as lipoarabinomannan are thought to be potential agents of this suppression. Dormant
M. tuberculosis
can remain in the body for long periods of time and can emerge to cause disease when the immune system wanes due to age or other effects such as infection with HIV-1.
Historically it has been thought that one needs replicating mycobacteria in order to effect a protective immunization. An hypothesis explaining the molecular basis for the effectiveness of replicating mycobacteria in inducing protective immunity has been proposed by Orme and co-workers, Orme et al.,
Journal of Immunology
148:189-196, 1992. These scientists suggest that antigens are pinocytosed from the mycobacterial-laden phagosome and used in antigen presentation. This hypothesis also explains the basis for secreted proteins effecting a protective immune response.
Antigens that stimulate T cells from mice infected with
M. tuberculosis
or from PPD-positive humans are found in both the whole mycobacterial cells and also in the culture supernatants, Orme et al.,
Journal of Immunology
148:189-196, 1992; Daugelat et al.,
J. Infect. Dis.
166:186-190, 1992; Barnes et al.,
J. Immunol.
143:2656-2662, 1989; Collins et al.,
Infect. Immun.
56:1260-1266, 1988; Lamb et al.,
Rev. Infect. Dis.
11:S443-S447, 1989; and Hubbard et al.,
Clin. exp. Immunol.
87: 94-98, 1992. Recently Pal and Horwitz,
Infect. Immun.
60:4781-4792, 1992, induced partial protection in guinea pigs by vaccinating with
M. tuberculosis
supernatant fluids. Similar results were found by Andersen using a murine model of tuberculosis, Andersen,
Infection & Immunity
62:2536, 1994. Other studies include Hubbard et al.,
Clin. exp. Immunol.
87: 94-98, 1992, and Boesen et al.,
Infection and Immunity
63:1491-1497, 1995. Although these works are far from definitive, they do strengthen the notion that protective epitopes can be found among secreted proteins and that a non-living vaccine can protect against tuberculosis.
II. SUMMARY OF THE INVENTION
For the purposes of vaccine development one needs to find epitopes that confer protection but do not contribute to pathology. An ideal vaccine would contain a cocktail of T-cell epitopes that preferentially stimulate Th1 cells and are bound by different MHC haplotypes. Although such vaccines have never been made, there is at least one example of a synthetic T-cell epitope inducing protection against an intracellular pathogen, Jardim et al.,
J. Exp. Med.
172:645-648, 1990.
It is an object of this invention to provide
M. tuberculosis
DNA sequences that encode bacterial peptides having an immunostimulatory activity. Such immunostimulatory peptides will be useful in the treatment, diagnosis, and prevention of tuberculosis.
The present invention provides inter alia, DNA sequences isolated from
Mycobacterium tuberculosis
. Peptides encoded by these DNA sequences stimulate the production of the macrophage-stimulating cytokine, gamma interferon (“INF-&ggr;”), in mice. Critically, the production of INF-&ggr; by CD4 cells in mice correlates with maximum expression of protective immunity against tuberculosis, Orme et al.,
J. Immunology
151:518-525, 1993. Furthermore, in human patients with active “minimal” or “contained” tuberculosis, it appears that the containment of the disease may be attributable, at least in part, to the production of CD4 Th-1-like lymphocytes that release INF-&ggr;, Boesen et al.,
Infection and Immunity
63:1491-1497, 1995.
Hence, the DNA sequences provided by this invention encode peptides that can of stimulate T-cells to produce INF-&ggr;. That is, these peptides act as epitopes for CD4 T-cells in the immune system. Studies have demonstrated that peptides isolated from an infectious agent and which are shown to be T-cell epitopes can protect against the disease caused by that agent when administered as a vaccine, Mougneau et al.,
Science
268:536-566, 1995 and Jardim et al.,
J. Exp. Med
172:645-648, 1990. For example, T-cell epitopes from the parasite
Leishmania major
have been shown to be effective when administered as a vaccine, Jardim et al.,
J. Exp. Med.
172:645-648, 1990; Mougneau et al.,
Science
268:536-566, 1995; and Yang et al.,
J. Immunology
145:2281-2285, 1990. Therefore, the immunostimulatory peptides (T-cell epitopes) encoded by the DNA sequences according to the invention may be used, in purified form, as a vaccine against tuberculosis.
As noted, the nucleotide sequences of the present invention encode immunostimulatory peptides. In a number of instances, these nucleotide sequences are only a part of a larger open reading frame (ORF) of an
M. tuberculosis
Swartz Rodney P
University of Victoria Innovation and Development Corporation
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