Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Binds hormone or other secreted growth regulatory factor,...
Reexamination Certificate
1999-10-28
2002-02-12
Saunders, David (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Binds hormone or other secreted growth regulatory factor,...
C424S139100, C424S804000, C424S810000, C530S861000, C530S868000
Reexamination Certificate
active
06346247
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to therapeutics for the prevention and treatment of autoimmune disease, and in particular the prevention and treatment of autoimmune disease in humans through the use of luminally administered polyclonal antibody.
BACKGROUND OF THE INVENTION
A progressive and maintained response by the immune system against self-components is termed autoimmunity. Normally self-tolerance mechanisms prevent the immune response from acting on self-components. However, all mechanisms have a risk of breakdown and occasionally the immune system turns on its host environment in an aggressive manner as to cause disease. This breakdown leads to the copious production of autoreactive B cells producing autoantibodies and/or autoreactive T cells leading to destructive autoimmune disease. The cellular mechanisms of autoimunity are the same as those involved in beneficial immune responses to foreign components which include antibody-dependent cell cytotoxicity, delayed-type hypersensitivity (DTH), and T-cell lympholysis.
Human autoimmune diseases can be divided into two categories: organ-specific and systemic. In organ-specific autoimmune disease, autoreactivity is directed to antigens unique to a single organ. In systemic autoimmune disease, autoreactivity is largely directed toward a broad range of antigens and involves a number of tissues. Disease in either type results from the generation of one or both autoreactive cell types (B or T cells). Autoreactive B cells leads to the generation of autoantibodies or immune complexes. Autoreactive T cells leads to the cellular DTH responses from T
DTh
cells or cytotoxic responses from T
C
cells. Some autoimmune diseases in humans and the immune response and antigen(s) involved are shown in Table 1.
TABLE 1
Human Autoimmune Diseases
Disease
SeIf-Antigen
Immune Response
Organ-Specific Autoimmune Disease
Addison's disease
Adrenal cells
Autoantibodies
Autoimmune hemolytic anemia
Red blood cells
Autoantibodies
Goodpasture's disease
Renal and lung membranes
Autoantibodies
Graves' disease
Thyroid-stimulating hormone
Autoantibodies
receptor
Hashimoto's thyroiditis
Thyroid proteins
T
DTH
cells, autoantibodies
Idiopathic thrombocytopenia
Platelet membranes
Autoantibodies
Insulin-dependent diabetes
Pancreatic beta cells
T
DTH
cells, autoantibodies
mellitus (IDDM)
Myasthenia gravis
Acetylcholine receptors
Autoantibodies
Myocardial infarction
Heart muscle
Autoantibodies
Pernicious anemia
Gastric intrinsic factor
Autoantibodies
Poststreptococcal
Kidney
Immune complexes
glomerulonephritis
Spontaneous infertility
Sperm
Autoantibodies
Systemic Autoimmune Disease
Ankylosing spondylitis
Vertebrae
Immune complexes
Multiple sclerosis
Brain or white matter
T
DTH
and T
c
cells,
autoantibodies
Rheumatoid arthritis
Connective tissue
Autoantibodies, immune
complexes
Scleroderma
Nuclei, heart, lungs, GI tract,
Autoantibodies
kidney
Sjogren's syndrome
Salivary gland, liver, kidney,
Autoantibodies
thyroid
Systemic lupus erythematosus
DNA, nuclear protein, RBC
Autoantibodies, immune
(SLE)
and platelet membranes
complexes
The current view of the etiology of autoimmune diseases posulates that both autoreactive T and B cells exist normally in the body. Control of these cells involves immune surveillance mechanisms which can induce tolerance to these cells and/or the selective elimination of these cells. Factors which overcome immune surveillance are thought to be responsible for the proliferation of these autoreactive cells leading to autoimmune disease.
Immune surveillance can be circumvented in several proposed ways: (1) Autoreactive cells can be stimulated through molecular mimicry by cross-reactive microbial antigens. A number of viruses and bacteria have been shown to possess antigenic determinants that are identical to normal host-cell components. Thus, antibodies generated against these microbial antigens can also recognize and damage host cells. Cross-reacting antibodies to heart muscle developed after a Streptococcus infection, for example, is thought of be the cause of an rheumatic fever. (2) In some cases, foreign antigen can directly stimulate autoreactive cells. Lipopolysaccharides or viral antigens from Epstein-Barr virus (EBV) or cytomegalovirus causes the direct stimulation of certain B cells. During mononucleosis, a disease caused by EBV, a variety of autoantibodies reactive to self-components are generated. Specifically, EBV can activate B cells to produce autoantibodies to nuclear DNA and immune cells. (3) Release of antigens normally sequestered from the immune system is another example of the breakdown of immune surveillance leading to autoimmune disease. Experimentally, animals injected parenterally with basic myelin protein, an antigen primarily found in the brain, develop experimental autoimmune encephalomyelitis. (4) Expression of specific HLA alleles has been associated with autoimmune individuals. It is thought that cells expressing these HLA's may act as a prime target for autoreactive cells. Individuals with the B27 HLA allele has a 90% increased relative risk of developing ankyosing spondylitis.
Current therapies for autoimmune diseases are not cures, but are aimed at reducing symptoms to provide the patient with a acceptable quality of life. In organ-specific autoimmune disorders, the symptoms can be corrected by the removal of the organ if possible. In some autoimmune diseases such as myasthenia gravis some success have been achieved by removing the thymus. In addition, in organ-specific autoimmune disorders, symptoms can be corrected by metabolic control with biologically active compounds. For example, hypothroidism can be controlled by the administration of thryroxine or perrrnicious anemia can be treated with injections of vitamin B
12
. Drugs used in most cases of autoimmune disease, especially systemic autoimmune disease, provide general nonspecific suppression of the immune system. For the most part these drugs do not distinguish between the pathological immune response and the protective immune response. Immunosuppressive drugs (e.g., corticosteroids, azathioprine, cyclophoshamide and cyclosporin) are often given to suppress the proliferation of autoreactive lymphocytes. Anti-inflammatory drugs also are prescribed to patients with rheumatoid arthritis. Unfortunately these drugs, besides not working in many patients, have very serious side-effects. The general suppression of the immune response puts the patient at greater risk to infection and cancer.
Clearly there is a significant need for agents capable of preventing and treating autoimmune diseases. It would be desirable if such therapy could be administered in a cost-effective and timely fashion, with a minimum of adverse side effects.
SUMMARY OF THE INVENTION
The present invention relates to therapeutics for the prevention and treatment of autoimmune disease. Specifically, the present invention contemplates the prevention and treatment of autoimmune disease in humans as well as other animals through the use of ligands directed to cytokines. The examples of the present invention demonstrate the production of antibodies to the proinflammatory cytokines IL-2, TNF, IL-12 and IFN-gamma (although other ligands to such cytokines are also contemplated). The examples of the present invention demonstrate a novel finding that ligands (such as antibodies) against pro-inflammatory cytokines such IL-2 or IL-12 administered orally are effective (as demonstrated in two experimental models of autoimmune disease) at delaying the onset of autoimune disease.
In one embodiment, the present invention contemplates a method of treatment, comprising: a) providing: i) a human patient who is either at risk for autoimmune disease or who has symptoms of autoimmune disease, ii) a therapeutic formulation comprising one or more ligands directed to a proinflammatory cytokine, and; b) administering said formulation to said patient. It is not intended that the present invention be limited to the type of patient. In one embodiment, the patient is a c
Kink John A.
Stafford Douglas C.
DeCloux Amy
Medlen & Carroll LLP
Promega Corporation
Saunders David
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