Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Hormone or other secreted growth regulatory factor,...
Reexamination Certificate
1995-06-06
2003-11-11
Duffy, Patricia A. (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Hormone or other secreted growth regulatory factor,...
C424S184100, C424S278100
Reexamination Certificate
active
06645504
ABSTRACT:
FIELD OF THE INVENTION
This invention pertains to an improvement in the treatment of autoimmune diseases. More specifically, the invention is directed to the use of bystander antigens (i.e. antigens that suppress cells involved in the autoimmune process) for the treatment of autoimmune diseases. The invention also includes pharmaceutical formulations comprising bystander antigens useful in the treatment of autoimmune diseases in mammals.
BACKGROUND OF THE INVENTION
Autoimmune diseases are characterized by an abnormal immune response directed against normal autologous (self) tissues.
Based on the type of supranormal immune response involved, autoimmune diseases in mammals can generally be classified in one of two different categories: cell-mediated (i.e., T-cell-mediated) or antibody-mediated disorders. Non-limiting examples of cell-mediated autoimmune diseases include multiple sclerosis (MS), rheumatoid arthritis (RA), autoimmune thyroiditis (AT), diabetes mellitus (juvenile onset or Type 1 diabetes) and autoimmune uveoretinitis (AUR). Antibody-mediated autoimmune diseases include myasthenia gravis (MG) and systemic lupus erythematosus (SLE).
Both categories of autoimmune diseases are currently being treated with drugs which suppress immune responses in a non-specific manner, i.e., drugs which are incapable of suppressing selectively the abnormal immune response. Non-limiting examples of such drugs include methotrexate, cyclophosphamide, Imuran (azathioprine) and cyclosporin A. Steroid compounds such as prednisone and methylprednisolone (also non-specific immunosuppressants) are also employed in many instances. All of these currently employed drugs have limited efficacy against both cell- and antibody-mediated autoimmune diseases. Furthermore, such drugs have significant toxic and other side effects and, more important, eventually induce “global” immunosuppression in the subject being treated. In other words, prolonged treatment with the drugs downregulates the normal protective immune response against pathogens thereby increasing the risk of infections. In addition, patients subjected to prolonged global immunosuppression have an increased risk of developing severe medical complications from the treatment, such as malignancies, kidney failure and diabetes.
In an effort to overcome the drawbacks of conventional treatments for autoimmune disease the present inventors and their coworkers have devised methods and pharmaceutical formulations useful for treating autoimmune diseases based on the concept of oral tolerization (or tolerization by inhalation) using as the tolerizers autoantigens, or disease-suppressive fragments or analogs of autoantigens alone or in combination with so-called “synergists”, i.e., compounds which enhance the tolerizing effect of the autoantigens.
Autoantigens are antigens normally found within and specific for an organ or tissue under autoimmune attack which are themselves the primary target of autoimmune response.
Although the above methods and pharmaceutical formulations represent a substantial improvement in the treatment of autoimmune diseases, their therapeutic availability is delayed because in each case the specific autoantigens involved in eliciting and maintaining the disease state have to be identified. In other words, the specific substances that are the subject of attack by the immune system have to be determined. In many instances, this is both difficult and time-consuming, as those of ordinary skill in the art will appreciate. For example, more than one autoantigen may be the subject of autoimmune attack at any one time and the identity of the autoantigen(s) may change as the disease progressively destroys more and more of the tissue involved.
Therefore, what is needed in the art are improved agents, methods and compositions for treating individuals suffering from autoimmune diseases which would be more readily available for therapeutic use, e.g., which would not require prior identification of autoantigens. There is also a need in the art for additional methods and compositions for treating autoimmune disease, which methods and compositions could be used in addition to or instead of autoantigens.
Furthermore, there is a need in the art for elucidating the mechanisms by which autoimmune disease can be combatted and for identifying novel methods and compositions in light of this newly acquired knowledge that can be used to combat autoimmune disease.
Accordingly, one object of the present invention is to provide improved methods and compositions for treating mammals suffering from autoimmune diseases, said methods and compositions to be used alone or optionally in combination with one or more autoantigens, synergists and other immune response regulators.
A further object of the present invention is to provide methods and compositions for treating mammals suffering from autoimmune diseases which can effectively be used to treat, alleviate the symptoms of, or prevent such diseases and do not require prior identification of the autoantigens involved in eliciting or maintaining the autoimmune disease.
Yet another object of the present invention is to provide methods and compositions for treating mammals afflicted with or susceptible to autoimmune diseases, which methods and compositions involve nontoxic agents, which are also, preferably, disease-specific.
SUMMARY OF THE INVENTION
The present invention is based on the unexpected and surprising discovery that oral or enteral administration (or administration by inhalation) of certain antigens (called “bystander antigens” and defined below) causes T-cells to be elicited that in turn suppress cells that contribute to immune attack of the organ or tissue involved in an autoimmune disease. The T-cells elicited by the bystander antigen mediate the release of transforming growth factor beta (TGF-&bgr;) which suppresses the cells contributing to the immune attack that are found in the same vicinity.
For this type of suppression mechanism to work, it is not necessary that the TGF-&bgr; releasing T-cells recognize the disease-contributing cells. All that is necessary is that both types of cells be found in the same vicinity when TGF-&bgr; is released. One way to achieve this is to use as the bystander antigen an antigen that (a) has the ability to elicit T-cells that cause release of TGF-&bgr; and (b) is itself specific to the tissue or organ under attack so that the suppressor T-cells that cause release of TGF-&bgr; (and that are elicited pursuant to oral administration of the bystander antigen) will be directed to the same organ or tissue which is also a location where the disease-promoting cells are concentrated.
The bystander antigens may but do not need to be autoantigens, i.e. they do not need to be the same antigen(s) that is (are) under attack by the disease-inducing cells. It is an interesting feature of the present invention that oral administration of a bystander antigen can stave off tissue damage done by cells specific for another antigen or antigen fragment. This second antigen (or fragment) does not even need to have been identified.
Therefore, in one aspect the present invention is directed to a method for treating an autoimmune disease in a mammal, the method comprising administering to said mammal an effective amount for treating said disease of a bystander antigen, said antigen eliciting the release of transforming growth factor beta (TGF-&bgr;) at a locus within the body of said mammal wherein T cells contributing to autoimmune response are found to suppress the T-cells contributing to said response.
In another aspect, the present invention is directed to compositions and dosage forms comprising amounts of a bystander antigen effective to treat an autoimmune disease in a mammal.
In yet another aspect, the present invention provides a pharmaceutical inhalable dosage form for treating an autoimmune disease in a mammal, the form comprising an effective amount for treating said disease of a bystander antigen, said antigen upon administration eliciting the release of transforming growth fac
Al-Sabbagh Ahmad
Miller Ariel
Weiner Howard
Zhang Zhengyi
AutoImmune Inc.
Darby & Darby
Duffy Patricia A.
LandOfFree
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