Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
1998-08-28
2003-07-29
Smith, Lynette R. F. (Department: 1641)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C424S252100, C424S184100, C424S085200, C424S085400, C424S203100, C435S007240, C435S184000
Reexamination Certificate
active
06599509
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the treatment of Inflammatory Bowel Disease in mammals, including humans. More particularly, the present invention relates to immunogens and immunization with bacterial antigens, including but not limited to Helicobacter antigens, to prevent or treat Inflammatory Bowel Disease.
BACKGROUND OF THE INVENTION
Inflammatory Bowel Disease (IBD) refers to a group of gastrointestinal disorders characterized by a chronic non-specific inflammation of portions of the gastrointestinal tract. Ulcerative colitis and Crohn's Disease are the most prominent examples of IBD in humans. They are associated with many symptoms and complications, including growth retardation in children, rectal prolapse, blood in stools (e.g., melena and/or hematochezia), wasting, iron deficiency, and anemia (e.g. iron deficiency anemia and anemia of chronic disease or of chronic inflammation).
The etiology (or etiologies) and pathogenesis of IBD are still unclear. Previous understanding of the pathogenesis was limited to a three-stage process: (a) an irritant, which could be an immune process or infectious agent, activates (b) leukocytes which release enzymes such as proteases and inflammatory mediators such as histamine, serotonin and prostaglandins, and (c) these products cause edema, pain, heat and loss of function. See Wyngaarden and Smith (eds.) Cecil's Textbook of Medicine (W. B. Saunders Co. 1985), Berkow (ed.). The Merck Manual of Diagnosis and Therapy (Merck Sharp & Dohme Research Laboratories, 1982), and Harrison's Principles of Internal Medicine, 12th Ed., McGraw-Hill, Inc. (1991).
Numerous theories implicate multiple factors leading up to IBD including genetic predisposition, environmental factors, infectious agents and immunologic alterations. See Kirsner, J. B., et al. (eds), Inflammatory Bowel Disease, 3rd ed., Lea and Febiger, Philadelphia (1988); Zipser, R. D., (ed.),
Dig. Dis. Sci.,
33 Suppl.:1S-87S (1988). The immunologic alterations in IBD appear to be autoimmune in nature, with colonic autoantibodies and lymphocyte-cytotoxicity directed against colonic epithelial cells. However, even the latest developments in the immunologic aspects of the pathogenesis of IBD cannot answer the basic question, i.e., whether the detected changes in humoral and cellular immunity reflect a primary defect or secondary response to injury.
Treatment for IBD currently includes steroids, sulphasalazine and its derivatives, and immunosuppressive drugs such as cyclosporin A, mercaptopurine and azathioprine. Such therapies are directed toward suppression of the general immune response. Such an approach often results in poor success, has little or no selectivity, and can be accompanied by unwanted and sometimes dangerous consequential side effects.
Thus, there exists a need for effective treatment, both prophylactic and curative, for IBD. Such a therapy should be specific and should not be accompanied by unwanted side effects.
SUMMARY OF THE INVENTION
The present invention relates to the treatment of Inflammatory Bowel Disease (IBD) in mammals, including humans. More particularly, the present invention relates to immunogens and immunization with antigens expressed by Helicobacter as well as other bacteria (e.g. organisms considered to be normal resident flora and organisms known to be pathogenic) to prevent or treat Inflammatory Bowel Disease.
The present invention contemplates both passive immunization and active immunization. Where passive immunization is employed, antibodies to bacterial antigens (e.g. Helicobacter antigens) are made in one host (e.g. goats, horses, chickens, rabbits, etc.) and administered to a host having symptoms of (or at risk for) inflammatory bowel disease. In a preferred embodiment, active immunization is employed and a host is immunized directly with a bacterial antigen (e.g. Helicobacter antigen) preparation, in order to achieve a protective immune response. While it is not essential to the use of the present invention to understand the precise mechanism by which a therapeutic benefit is achieved, it is believed that immunization with such antigens result in the normalization of cytokine Th1/Th2 levels and/or the consequent production of antibodies which are protective against acute infection by microorganisms causing IBD.
According to one aspect of the present invention, there is provided a method of eliciting in a mammalian host a protective immune response to Helicobacter-associated IBD. This method comprises orally administering to the host an immunogenically effective amount of
Helicobacter hepaticus
antigen preparation to elicit the desired protective immune response.
According to another aspect of the present invention, there is provided a vaccine composition comprising an amount of said Helicobacter antigen preparation, effective to elicit a protective response in a human patient, in association with a pharmaceutically acceptable adjuvant.
In addition, there is provided a vaccine composition comprising an amount of bacterial antigens isolated from a bacteria other than Helicobacter, effective to elicit a protective response in a human patient.
In one embodiment, the present invention contemplates a method, comprising a) providing i) a host having symptoms of inflammatory bowel disease and ii) a source of bacterial antigens (e.g. Helicobacter antigens); b) orally administering to the host an effective amount of said bacterial antigen to elicit an immune response. In another embodiment, the present invention contemplates a method, comprising a) providing i) a host at risk for inflammatory bowel disease and ii) a source of bacterial antigens (e.g. Helicobacter antigens); b) orally administering to the host an effective amount of said bacterial antigen to elicit an immune response. All animal hosts are contemplated, including humans.
It is not intended that the invention be limited by the species of bacteria or by the source of antigen. In a preferred embodiment, the source of antigen is selected from the group consisting of inactivated whole organisms, whole cell lysates and purified bacterial antigen. It is also not intended that the present invention be limited by the means of inactivating whole organisms or the means of preparing cell lysates. In one embodiment, the whole organisms are inactivated by formalin or gamma irradiation. In another embodiment, the cell lysates are prepared with SDS and/or proteinase K.
It is also not intended that the antigen preparation be limited to antigen alone. In a preferred embodiment, antigen is administered with adjuvant, and in particular a mucosal adjuvant. In one embodiment, the mucosal adjuvant is selected from the group consisting of cholera toxin and heat labile enterotoxin of
Escherichia coli
. The antigen(s) may be administered in a preparation where the antigen is in association with a pharmaceutically acceptable carrier or diluent.
A variety of Helicobacter species are contemplated as sources of antigen, including but not limited to
H. fenelliae, H. cinaedi, H. pullorum, H. rappini
and
H. muridarum.
In a preferred embodiment, the Helicobacter species is selected from the group consisting of
Helicobacter hepaticus
and
Helicobacter bilis
. The different species (such as
Helicobacter hepaticus
) are conveniently cultured for preparation of antigen as described in U.S. Pat. No. 5,610,060 which issued Mar. 3, 1997, the entire contents of which are hereby incorporated by reference. Other sources of antigens include any pathogens or members of the normal flora shown to contribute to the induction of IBD.
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patent: 5262156 (1993-11-01), Alemohammad
patent: 5368854 (1994-11-01), Rennick
patent: 5538729 (1996-07-01), Czinn et al.
patent: 5610060 (1997-03-01), Ward et al.
patent: 5830675 (1998-11-01), Targan et al.
patent: 5871749 (1999-02-01), Doidge et al.
patent: 5985631 (1999-11-01), Soman et al.
patent: 93/20843 (1993-10-01), None
patent: 95/03824 (1995-02-01), None
patent: 95/22563 (1995-08-01), None
patent:
Fox James J.
Lee Adrian
Schauer David
Whary Mark
AllenPortner Ginny
Massachusetts Institute of Technology
Medlen & Carroll LLP
Smith Lynette R. F.
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