Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
2000-11-08
2004-04-20
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, C424S234100, C424S278100, C424S282100, C435S253100
Reexamination Certificate
active
06723327
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to methods for the treatment of immunologically-mediated disorders. In certain embodiments, the invention is related to the use of compositions comprising components prepared from
Mycobacterium vaccae
, Mycobacterium tuberculosis and
Mycobacterium smegmatis
for the treatment of immunologically-mediated disorders of the respiratory system, such as sarcoidosis, asthma and lung cancers, for treatment of allergic disorders such as atopic dermatitis and eczema, for treatment of diseases that benefit from the reduction of eosinophilia, for treatment and prevention of infectious diseases, such as infection with Mycobacterium tuberculosis or
Mycobacterium avium
, and for the treatment of atherosclerosis, hypercholesterolemia and other disorders that may be improved by modulating EL-10 production.
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 Bacille Calmette-Guerin (BCG), an avirulent strain of
Mycobacterium bovis
(
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. 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
(
M. 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 recognized 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. 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 that are not endogenous to
M. vaccae
. This publication theorizes that the beneficial effect as an adjuvant may be due to heat shock protein 65 (hsp65). 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. International Patent Publication WO 91/02542 discloses the use of autoclaved
M. vaccae
in the 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.
M. vaccae
is apparently unique among known mycobacterial species in that heat-killed preparations retain vaccine and immunotherapeutic properties. For example,
M. bovis
BCG vaccines, used for vaccination against tuberculosis, employ live strains. Heat-killed
M. bovis
BCG and M. tuberculosis have no protective properties when employed in vaccines. A number of compounds have been isolated from a range of mycobacterial species that have adjuvant properties. The effect of such adjuvants is essentially to stimulate a particular immune response mechanism against an antigen from another species.
There are two general classes of compounds that have been isolated from mycobacterial species that exhibit adjuvant properties. The first are water-soluble wax D fractions (White et al.,
Immunology
1:54, 1958; U.S. Pat. No. 4,036,953). The second are muramyl dipeptide-based substances (N-acetyl glucosamine and N-glycolymuramic acid in approximately equimolar amounts) as described in U.S. Pat. No. 3,956,481 and 4,036,953. These compounds differ from the delipidated and deglycolipidated
M. vaccae
(DD-
M. vaccae
) of the present invention in the following aspects of their composition:
1. They are water-soluble agents, whereas DD-
M. vaccae
is insoluble in aqueous solutions.
2. They consist of a range of small oligomers of the mycobacterial cell wall unit, either extracted from bacteria by various solvents, or digested from the cell wall by an enzyme. In contrast, DD-
M. vaccae
comprises processed mycobacterial cells.
3. All protein has been removed from their preparations by digestion with proteolytic enzymes. The only constituents of their preparations are the components of the cell wall peptidoglycan structure, namely alanine, glutamic acid, diaminopimelic acid, N-acetyl glucosamine, and N-glycolylmuramic acid. In contrast, DD-
M. vaccae
contains 50% w/w protein, comprising a number of distinct protein species.
Sarcoidosis is a disease of unknown cause characterized by granulomatous inflammation affecting many organs of the body and especially the lungs, lym
Abernethy Nevin
Prestidge Ross
Tan Paul L. J.
Watson James D.
Genesis Research and Development Corporation
Sleath Janet
Speckman Ann W.
Swartz Rodney P
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