Compositions and methods of their use in the treatment,...

Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives

Reexamination Certificate

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C424S248100, C514S04400A

Reexamination Certificate

active

06465633

ABSTRACT:

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
Not applicable.
FIELD OF THE INVENTION
The present invention relates to
Mycobacterium tuberculosis
antigens. In particular, the invention relates to
M. tuberculosis
secretory polypeptides, polynucleotides that encode the polypeptides, and methods-of using such compositions in the treatment, prevention and diagnosis of
M. tuberculosis
infection.
BACKGROUND OF THE INVENTION
Tuberculosis is a chronic infectious disease caused by infection with
M. tuberculosis.
It is a major disease in developing countries, as well as an increasing problem in developed areas of the world, with about 8 million new cases and 3 million deaths each year. Although the infection may be asymptomatic for a considerable period of time, the disease is most commonly manifested as an acute inflammation of the lungs, resulting in fever and a nonproductive cough. If untreated, serious complications and death typically result.
Although tuberculosis can generally be controlled using extended antibiotic therapy, such treatment is not sufficient to prevent the spread of the disease. Infected individuals may be asymptomatic, but contagious, for some time. In addition, although compliance with the treatment regimen is critical, patient behavior is difficult to monitor. Some patients do not complete the course of treatment, which can lead to ineffective treatment and the development of drug resistance.
In order to control the spread of tuberculosis, effective vaccination, and accurate early diagnosis of the disease are of utmost importance. Currently, vaccination with live bacteria is the most efficient method for inducing protective immunity. The most common Mycobacterium employed for this purpose is Bacillus Calmette-Guerin (BCG), an avirulent strain of
M. bovis.
However, the safety and efficacy of BCG is a source of controversy and some countries, such as the United States, do not vaccinate the general public with this agent.
Diagnosis of tuberculosis is commonly achieved using a skin test, which involves intradermal exposure to tuberculin PPD (protein-purified derivative). Antigen-specific T cell responses result in measurable induration at the injection site by 48-72 hours after injection, which indicates exposure to Mycobacteria antigens. Sensitivity and specificity have, however, been a problem with this test, and individuals vaccinated with BCG cannot be distinguished from infected individuals.
While macrophages have been shown to act as the principal effectors of
M. tuberculosis
immunity, T cells are the predominant inducers of such immunity. The essential role of T cells in protection against
M. tuberculosis
infection is illustrated by the frequent occurrence of
M. tuberculosis
in Acquired Immunodeficiency Syndrome patients, due to the depletion of CD4
+
T cells associated with human immunodeficiency virus (HIV) infection. Mycobacterium-reactive CD4
+
T cells have been shown to be potent producers of gamma-interferon (IFN-&ggr;), which, in turn, has been shown to trigger the anti-mycobacterial effects of macrophages in mice. While the role of IFN-&ggr; in humans is less clear, studies have shown that 1,25-dihydroxy-vitamin D3, either alone or in combination with IFN-&ggr; or tumor necrosis factor-alpha, activates human macrophages to inhibit
M. tuberculosis
infection. Furthermore, it is known that IFN-&ggr; stimulates human macrophages to make 1,25-dihydroxy-vitamin D3. Similarly, interleukin-12 (IL-12) has been shown to play a role in stimulating resistance to
M. tuberculosis
infection. For a review of the immunology of
M. tuberculosis
infection, see Chan & Kaufmann, 1994,
Tuberculosis: Pathogenesis, Protection and Control,
Bloom (ed.), ASM Press, Washington, D.C.
Accordingly, there is a need for improved vaccines and diagnostic agents, as well as methods for preventing, treating and detecting tuberculosis. Although the genome of one strain of
M. tuberculosis
has been sequenced recently (Cole et al., 1998,
Nature
393:537-544), it has not been determined which of the gene sequences would encode immunogenic or antigenic products. Thus, there remains a need for the identification and characterization of
M. tuberculosis
antigens suitable for use in the prevention, treatment and diagnosis of the disease.
SUMMARY OF THE INVENTION
The present invention relates to
M. tuberculosis
antigens. In particular, it relates to
M. tuberculosis
polypeptides, polynucleotides encoding the polypeptides, methods of using the polypeptides and polynucleotides in the diagnosis, treatment and prevention of
M. tuberculosis
infection.
The present invention is based, in part, on Applicants' discovery of a large number of polypeptides produced in a
M. tuberculosis
expression library that were reactive with an antiserum raised to
M. tuberculosis
polypeptides. Since the antiserum was generated against
M. tuberculosis
polypeptides that had been purified from bacterial culture supernatants, the antiserum preferentially reacted with bacterial secretory products. The antibody-reactive clones were isolated, and their nucleotide sequences were determined. Sequence comparison of these clones with publicly available gene sequences revealed that many of the isolated clones encoded previously unknown
M. tuberculosis
antigens. The nucleotide sequences of these coding sequences are recited in SEQ ID NOS:1-91, and their amino acid sequences can be deduced therefrom. Both the coding sequences and their encoded polypeptide products are suitable for a variety of uses.
In a specific embodiment of the invention, the isolated or purified
M. tuberculosis
polypeptides of the invention may be formulated as pharmaceutical compositions for administration into a subject in the prevention and/or treatment of
M. tuberculosis
infection. In that regard, the polypeptides may be used individually or in combination, including their use as fusion proteins. The immunogenicity of the antigens may be enhanced by the inclusion of an adjuvant.
It is also an object of the invention that the polypeptides be used in in vitro assays for detecting humoral antibodies or cell-mediated immunity against
M. tuberculosis
for diagnosis of infection or monitor of disease progression. Additionally, the polypeptides may be used as an in vivo diagnostic agent in the form of an intradermal skin test. Alternatively, the polypeptides may be used as immunogens to generate anti-
M. tuberculosis
antibodies in a non-human animal. The antibodies can be used to detect the target antigens in vivo and in vitro.
In another aspect of the invention, the isolated or purified polynucleotides are used to produce recombinant polypeptide antigens in vitro. Alternatively, the polynucleotides may be administered directly into a subject as DNA vaccines to cause antigen expression in the subject, and the subsequent induction of an anti-
M. tuberculosis
immune response. Additionally, the polynucleotides, portions thereof, or their complements may be used as molecular probes or primers to detect the presence of bacteria in a biologic sample.
BRIEF DESCRIPTION OF THE DRAWINGS
Not applicable.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to Mycobacterium antigens, optionally from a species such as
M. tuberculosis, M. bovis, M. smegmatis,
BCG,
M. leprae, M. scrofulaceum, M. avium-intracellulare, M. marinum, M ulcerans, M kansasii, M. xenopi, M. szulgai, M fortuium,
or
M. chelonei.
In particular, the invention relates to
M. tuberculosis
secretory polypeptides and immunogenic fragments thereof, polynucleotides that encode the polypeptides and immunogenic fragments thereof, and methods of using such compositions in the treatment, prevention and diagnosis of
M. tuberculosis
infection. In one embodiment of the invention, the polypeptides of the invention are used to diagnose tuberculosis. In another embodiment of the invention, the polypeptides of the invention are used to induce an immune response in a patient in order to prevent tu

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