Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,...
Reexamination Certificate
1997-12-22
2001-12-25
Ungar, Susan (Department: 1642)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
C424S141100, C424S152100, C424S158100, C424S172100, C514S002600
Reexamination Certificate
active
06333032
ABSTRACT:
FIELD OF INVENTION
The present invention is a method to treat autoimmune diseases and conditions in a patient, which are caused by the disturbance of the synthesis of interferons (IFNs) and certain other substances (e.g., tumor necrosis factors (TNFs)) and the production of autoantibodies to target cells, including CD4 cells, which damage the patient's immune system and have a direct pathological action on the patient's cells.
BACKGROUND OF THE INVENTION
The ability of the immune system to discriminate between “self” and “non-self” antigens is vital to the functioning of the immune system as a specific defense against invading microorganisms. “Non-self” antigens are those antigens on substances entering or in the body which are detectably different or foreign from the animal's own constituents, whereas “self” antigens are those which, in the healthy animal, are not detectably different or foreign from its own constituents. However, under certain conditions, including in certain disease states, an individual's immune system will identify its own constituents as “non-self,” and initiate an immune response against “self” material, at times causing more damage or discomfort as from an invading microbe or foreign material, and often producing serious illness in an individual. Autoimmune disease results when an individual's immune system attacks his own organs or tissues, producing a clinical condition associated with the destruction of that tissue, as exemplified by diseases such as rheumatoid arthritis, insulin-dependent diabetes mellitus, acquired immunodeficiency syndrome (“AIDS”), hemolytic anemias, rheumatic fever, Crohn's disease, Guillain-Barre syndrome, psoriasis, thyroiditis, Graves' disease, myasthenia gravis, glomerulonephritis, autoimmune hepatitis, multiple sclerosis, systemic lupus erythematosus, etc. Blocking, neutralizing or inhibiting the immune response or removing its cause in these cases is, therefore, desirable.
Autoimmune disease may be the result of a genetic predisposition, alone or as the result of the influence of certain exogenous agents such as, viruses, bacteria, or chemical agents, or as the result of the action of both. Some forms of autoimmunity come about as the result of trauma to an area usually not exposed to lymphocytes, such as neural tissue or the lens of the eye. When the tissues in these areas become exposed to lymphocytes, their surface proteins can act as antigens and trigger the production of antibodies and cellular immune responses which then begin to destroy those tissues. Other autoimmune diseases develop after exposure of the individual to antigens which are antigenically similar to, that is cross-reactive with, the individual's own tissue. For example, in rheumatic fever an antigen of the streptococcal bacterium, which causes rheumatic fever, is cross-reactive with parts of the human heart. The antibodies cannot differentiate between the bacterial antigens and the heart muscle antigens, consequently cells with either of those antigens can be destroyed.
Other autoimmune diseases, for example, insulin-dependent diabetes mellitus (involving the destruction of the insulin producing beta-cells of the islets of Langerhans), multiple sclerosis (involving the destruction of the conducting fibers of the nervous system) and rheumatoid arthritis (involving the destruction of the joint lining tissue), are characterized as being the result of a mostly cell-mediated autoimmune response and appear to be due primarily to the action of T-cells (See, Sinha et al.,
Science
248:1380 (1990)). Yet others, such as myesthenia gravis and systemic lupus erythematosus, are characterized as being the result of primarily a humoral autoimmune response (Id.). Nevertheless, the autoimmune diseases share a common underlying pathogenesis, resulting in the need for safe and effective therapy. Yet none of the presently available drugs are completely effective for the treatment of autoimmune disease, and most are limited by severe toxicity.
In recent years, a new point of view on the pathogenesis of autoimmune diseases, including AIDS, has developed, in which it has been suggested that autoimmune disease is connected with a disturbance in the synthesis of interferons and other cytokines induced by interferons (Skurkovich et al.,
Nature
217:551-2 (1974); Skurkovich et al.,
Annals of Allergy
35:356 (1975); Skurkovich et al.,
J. IFN Res
. 12
, Suppl
. 1:S110 (1992); Skurkovich et al.,
Med Hypoth
. 41:177-185 (1993); Skurkovich et al.,
Med. Hypoth
. 42:27-35 (1994); Gringeri et al.,
Cell. Mol. Biol
. 41(3):381-387 (1995); Gringeri et al.,
J. Acquir. Immun. Defic. Syndr
. 13:55-67 (1996)). IFN has been found in the circulation of patients with autoimmune diseases, and it has been neutralized in vivo with antibody to leukocyte (alpha) IFN (“IFN&agr;”). Healthy people do not have interferon in their blood (Skurkovich et al., 1975). In addition, it has been shown that hyperproduced IFN&agr; is found not only in the circulation of patients with classic autoimmune diseases, but also in patients with HIV infection (DeStefano et al.,
J. Infec. Disease
146:451 (1982)), where its presence is a predictive marker of AIDS progression (Vadhan-Raj et al.,
Cancer Res
. 46:417 (1986)). The IFN induced by HIV has low anti-(HIV) viral activity (Gendelman et al.,
J. Immunol
. 148:422 (1992)). It was shown that the circulating IFN&ggr; possesses antigenic specificity like natural IFN&agr;, which is pH stable, but this interferon is pH labile like IFN&ggr; (Preble et al., Science 216:429 (1982)); thus, it is known as aberrant IFN&agr;.
Investigators have also shown that tumor necrosis factors (TNF&agr; and TNF&bgr;) also play a significant role in the pathology of autoimmune diseases. For example, the presence of TNF&agr; has been correlated with rheumatoid arthritis (RA)(Brennan et al.,
Brit. J. Rheum
. 31(5):293-8 (1992)), and TNF&agr; has been to be found related to an increase in the severity of collagen induced arthritis in animal models (Brahn et al.,
Lymphokine and Cytokine Res
. 11 (5):253(1992)), while it has also been shown that anti-TNF alpha antibody administration ameliorates collagen induced arthritis (Williams et al.,
Clin. & Exp. Immunol
. 87(2):183 (1992)). TNF-&agr; is increased in the serum of RA patients (Holt et al.,
Brit. J. Rheum
. 21 (11):725 (1992); Altomonte et al.,
Clin. Rheum
. 11 (2):202 (1992), and both the cytokine (Chu et al.,
Brit. J. Rheum
. 31(10):653-661 (1992)) and its receptors have been identified in rheumatoid synovium, as well as at the cartilage-pannus junction (Deleuran et al.,
Arthritis Rheum
. 35 (10):1180 (1992)).
In addition, increased circulating levels of TNF&agr; have been found to be associated with disease progression in patients with multiple sclerosis (Shariff et al.,
N. Engl. J. Med
. 325 (7):467-472 (1992)); while increased serum levels of soluble TNF receptor and interferon &ggr;(“INF&ggr;”) have been independently correlated with disease activity in individuals, e.g., those with systemic lupus erythematosus (Aderka et al.,
Arthritis Rheum
. 36(8):1111-1120 (1993); Machold et al.,
J. Rheumat
. 17 (6):831-832 (1990)). The spontaneous release of interferon and TNF in HIV-positive subjects (Vilcek et al., In
AIDS: The Epidemic of Karposi's Syndrome and Opportunistic Infections
, A. E. Friedman-Kien & L. J. Laubenstein, eds. Masson Publishing, New York, N.Y., 1986; Hess et al.,
Infection
19
, Suppl
. 2:S93-97 (1991); Biglino et al.,
Infection
19 (1):11/7-11/17 (1991)), and the decline seen in the serum levels of TNF-&agr; in RA patients following long term administration of the disease modifying drug sulfasalazine (Danis et al.,
Ann. Rheum. Diseas
. 51(8):946 (1992)), further suggest that the concentrations of cytokines and/or their receptors is reflected in the clinical course of autoimmune disease.
IFN is known to induce tumor necrosis factor (TNF) and its receptors (Lau et al.,
AIDS Research and Human Retroviruses
7:545 (1991)), which enhances virus replication (
Skurkovich Boris
Skurkovich Simon V.
Advanced Biotherapy Concepts, Inc.
Morgan, Lewis & Bockius, L.L.P.
Ungar Susan
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