Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
1998-12-04
2002-06-18
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...
C424S185100, C424S190100, C424S192100, C424S234100, C424S282100, C435S253100, C530S300000, C530S350000, C536S023100, C536S023700
Reexamination Certificate
active
06406704
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to the detection, treatment and prevention of infectious diseases. In particular, the invention is related to compounds and methods for the treatment of mycobacterial infections including
Mycobacterium tuberculosis
and
Mycobacterium avium
. The invention is further related to compounds that function as non-specific immune response amplifiers, and the use of such non-specific immune response amplifiers as adjuvants in vaccination or immunotherapy against infectious disease, and in certain treatments for immune disorders and cancer.
BACKGROUND OF THE INVENTION
Tuberculosis is a chronic, infectious disease, that is caused by infection with
Mycobacterium tuberculosis
(
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 a chronic inflammation of the lungs, resulting in fever and respiratory symptoms. If left untreated, significant morbidity and death may 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 resistant mycobacteria.
Inhibiting the spread of tuberculosis requires effective vaccination and accurate, early diagnosis of the disease. 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
Mycobacterium 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. Diagnosis of
M. tuberculosis
infection 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, thereby indicating exposure to mycobacterial antigens. Sensitivity and specificity have, however, been a problem with this test, and individuals vaccinated with BCG cannot be distinguished from infected individuals.
A less well-known mycobacterium that has been used for immunotherapy for tuberculosis, and also leprosy, is
Mycobacterium vaccae
, which is non-pathogenic in humans. However, there is less information on the efficacy of
M. vaccae
compared with BCG, and it has not been used widely to vaccinate the general public.
M. bovis
BCG and
M. vaccae
are believed to contain antigenic compounds that are recognised by the immune system of individuals exposed to infection with
M. tuberculosis.
Several patents and other publications disclose treatment of various conditions by administering mycobacteria, including
M. vaccae
, or certain mycobacterial fractions. International Patent Publication WO 91/02542 discloses treatment of chronic inflammatory disorders in which a patient demonstrates an abnormally high release of IL-6 and/or TNF or in which the patient's IgG shows an abnormally high proportion of agalactosyl IgG. Among the disorders mentioned in this publication are psoriasis, rheumatoid arthritis, mycobacterial disease, Crohn's disease, primary biliary cirrhosis, sarcoidosis, ulcerative colitis, systemic lupus erythematosus, multiple sclerosis, Guillain-Barre syndrome, primary diabetes mellitus, and some aspects of graft rejection. The therapeutic agent preferably comprises autoclaved
M. vaccae
administered by injection in a single dose.
U.S. Pat. No. 4,716,038 discloses diagnosis of, vaccination against and treatment of autoimmune diseases of various types, including arthritic diseases, by administering mycobacteria, including
M. vaccae
. U.S. Pat. No. 4,724,144 discloses an immunotherapeutic agent comprising antigenic material derived from
M. vaccae
for treatment of mycobacterial diseases, especially tuberculosis and leprosy, and as an adjuvant to chemotherapy. International Patent Publication WO 91/01751 discloses the use of antigenic and/or immunoregulatory material from
M. vaccae
as an immunoprophylactic to delay and/or prevent the onset of AIDS. International Patent Publication WO 94/06466 discloses the use of antigenic and/or immunoregulatory material derived from
M. vaccae
for therapy of HIV infection, with or without AIDS and with or without associated tuberculosis.
U.S. Pat. No. 5,599,545 discloses the use of mycobacteria, especially whole, inactivated
M. vaccae
, as an adjuvant for administration with antigens which are not endogenous to
M. vaccae
. This publication theorises that the beneficial effect as an adjuvant may be due to heat shock protein 65 (hsp 65). International Patent Publication WO 92/08484 discloses the use of antigenic and/or immunoregulatory material derived from
M. vaccae
for the treatment of uveitis. International Patent Publication WO 93/16727 discloses the use of antigenic and/or immunoregulatory material derived from
M. vaccae
for the treatment of mental diseases associated with an autoimmune reaction initiated by an infection. International Patent Publication WO 95/26742 discloses the use of antigenic and/or immunoregulatory material derived from
M. vaccae
for delaying or preventing the growth or spread of tumors.
There remains a need in the art for effective compounds and methods for preventing, treating and detecting tuberculosis.
SUMMARY OF THE INVENTION
Briefly stated, the present invention provides compounds and methods for the prevention, treatment and diagnosis of mycobacterial infection, together with adjuvants for use in vaccines or immunotherapy of infectious diseases and cancers.
In a first aspect, polypeptides derived from
Mycobacterium vaccae
are provided comprising an immunogenic portion of an antigen, or a variant of such an antigen. In one embodiment, the antigen includes an amino acid sequence selected from the group consisting of: (a) sequences recited in SEQ ID NO: 89 and 201; (b) sequences having at least about 50% identical residues to a sequence recited in SEQ ID NO: 89 and 201; (c) sequences having at least about 75% identical residues to a sequence recited in SEQ ID NO: 89 and 201; and (d) sequences having at least about 90% identical residues to a sequence recited in SEQ ID NO: 89 and 201, as measured using alignments produced by the computer algorithm BLASTP.
DNA sequences encoding the inventive polypeptides, expression vectors comprising these DNA sequences, and host cells transformed or transfected with such expression vectors are also provided. In another aspect, the present invention provides fusion proteins comprising at least one polypeptide of the present invention.
Within other aspects, the present invention provides pharmaceutical compositions that comprise at least one of the inventive polypeptides, or a DNA molecule encoding such a polypeptide, and a physiologically acceptable carrier. The invention also provides vaccines comprising at least one of the above polypeptides and a non-specific immune response amplifier, together with vaccines comprising at least one DNA sequence encoding such polypeptides and a non-specific immune response amplifier.
In yet another aspect, methods are provided for enhancing an immune response in a patient, comprising administering to a patient an effective amount of one or more of the above pharmaceutical compositions and/or vaccines. In one embodiment, the immune response is a Th1 response.
In further aspects of this invention, methods are provided for the treatment of a disorder in a patient, compris
Prestidge Ross
Tan Paul
Visser Elizabeth
Watson James D.
Genesis Research and Development Corporation Limited
Sleath Janet
Speckman Ann W.
Swartz Rodney P
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