Compounds isolated from M. vaccae and their use in...

Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...

Reexamination Certificate

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C424S184100, C424S185100, C424S192100, C424S234100, C424S248100, C435S253100, C435S320100, C530S300000, C530S350000

Reexamination Certificate

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06361776

ABSTRACT:

TECHNICAL FIELD
The present invention relates generally to compositions for modulating immune responses. In certain embodiments, the invention is related to polypeptides and polynucleotides isolated from
Mycobacterium vaccae
and their use in the enhancement of immune responses to heterologous antigens.
BACKGROUND OF THE INVENTION
Mycobacterium vaccae
(
M. vaccae
) is a mycobacterium that is non-pathogenic in humans and that has been used for immunotherapy of tuberculosis and also leprosy.
M vaccae
is believed to contain antigenic compounds that are recognized by the immune system of individuals exposed to infection with
M. tuberculosis
and other infectious and/or inflammatory disorders.
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.
In addition to being antigenic,
M. vaccae
has immunogenic properties. 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 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. Heat-killed
M. bovis
BCG and
M. tuberculosis
have no protective properties when employed in vaccines. For example,
M. tuberculosis
BCG vaccines, used for vaccination against tuberculosis, employ live strains. A number of compounds have been isolated from a range of mycobacterial species which have adjuvant properties. The effect of such adjuvants is essentially to stimulate a particular immune response mechanism against an antigen from another species.
Certain pathogens, such as
M. tuberculosis,
as well as certain cancers, are effectively contained by an immune attack directed by CD4
+
T cells, known as cell-mediated immunity. Other pathogens, such as poliovirus, also require antibodies, produced by B cells, for containment. These different classes of immune attack (T cell or B cell) are controlled by different subpopulations of CD4
+
T cells, commonly referred to as Th1 and Th2 cells.
The two types of Th cell subsets have been well characterised in a murine model and are defined by the cytokines they release upon activation. The Th1 subset secretes IL-2, IFN-&ggr; and tumor necrosis factor, and mediates macrophage activation and delayed-type hypersensitivity response. The Th2 subset releases IL-4, IL-5, IL-6 and IL-10, which stimulate B cell activation. The Th1 and Th2 subsets are mutually inhibiting. For example, IL-4 inhibits Th1-type responses, and IFN-&ggr; inhibits Th2-type responses. Similar Th1 and Th2 subsets have been found in humans, with release of cytokines identical to those observed in the murine model. Amplification of Th2-type immune responses is central to protecting against metazoan parasites, e.g. Schistosoma and Leishmania. In addition, a Th2-type response is important in the induction and maintenance of allograft tolerance and the maintenance of successful pregnancy. In contrast, suppression of a Th2-type response and amplification of a Th1-type immune response is of key important in the treatment of diseases including cancers and disorders of the respiratory system, such as tuberculosis, sarcoidosis, asthma, allergic rhinitis and lung cancers.
Asthma is a common disease, with a high prevalence in the developed world. Asthma is characterized by increased responsiveness of the tracheobronchial tree to a variety of stimuli, the primary physiological disturbance being reversible airflow limitation, which may be spontaneous or drug-related, and the pathological hallmark being inflammation of the airways. The immune response producing airway inflammation in asthma is brought about by the Th2 class of T cells which secrete IL-4, IL-5 and IL-10. It has been shown that lymphocytes from the lungs of atopic asthmatic patients produce IL-4 and IL-5 when activated. Both IL-4 and IL-5 are cytokines of the Th2 class and are required for the production of IgE and involvement of eosinophils in asthma. Thus reversal of a Th2 response and enhancement of a Th1 response is highly beneficial in the treatment of asthma.
Another disorder with a similar immune abnormality to asthma is allergic rhinitis. Allergic rhinitis is a common disorder and is estimated to affect at least 10% of the population. Allergic rhinitis may be seasonal (hay fever) and caused by allergy to pollen. Non-seasonal (perennial) rhinitis is caused by allergy to antigens such as those from house dust mite or animal dander. The abnormal immune response in allergic rhinitis is characterised by the excess production of IgE antibodies specific against the allergen. The inflammatory response occurs in the nasal mucosa rather than further down the airways as in asthma. Like asthma, local eosinophilia in the affected tissues is a major feature of allergic rhinitis. As with asthma, the reversal of a Th2 immune response and enhancement of a Th1 response is central to successful treatment.
SUMMARY OF THE INVENTION
Briefly stated, the present invention provides compositions isolated from
Mycobacterium vaccae
(
M. vaccae
), together with methods for their use in eliciting and/or enhancing an immune response to a heterologous antigen. In a first aspect, isolated polypeptides derived from
M. vaccae
are provided, together with variants of such polypeptides. In one embodiment, the inventive polypeptides include an amino acid sequence selected from the group consisting of: (a) sequences recited in SEQ ID NO: 6-9; (b) sequences having at least about 55% identical residues to a sequence recited in SEQ ID NO: 6-9; (c) sequences having at least about 65% identical residues to a sequence recited in SEQ ID NO: 6-9; (d) sequences having at least about 75% identical residues to a se

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