Drug – bio-affecting and body treating compositions – Extract – body fluid – or cellular material of undetermined... – Digestive system
Reexamination Certificate
2001-01-17
2003-07-22
Witz, Jean C. (Department: 1651)
Drug, bio-affecting and body treating compositions
Extract, body fluid, or cellular material of undetermined...
Digestive system
C424S551000
Reexamination Certificate
active
06596319
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to immunomodulating compositions, pharmaceutical compositions comprising the same, and the use of such compositions in the treatment of mammals. In particular, the compositions are directed to the treatment of diseases associated with immune system disorders.
BACKGROUND OF THE INVENTION
Therapies are continuously being developed for the prophylaxis and treatment of cancer and autoimmune, infectious and inflammatory diseases, all of which may be a direct result of an inadequate immune system response. Some of these therapies attempt to use the immune system therapeutically.
One approach is based on the antigen-specific elements of the immune system, namely antibodies and T-cells. For example, research has been aimed at developing vaccines against foreign agents, or against certain endogenous chemical messengers, such as interleukins, to control or induce certain antibody reactions. A second approach is based on the isolation, cloning, expression and production of peptides and proteins from the nonantigen-specific parts of the immune system. For example, proteins, such as cytokines, which comprise the interleukins produced by white blood cells, and interferons, which stimulate lymphocytes and scavenger cells that digest foreign antigens, offer possibilities for therapies.
The treatment of cancer, for example, could be greatly enhanced if the early immune response to a tumor could be augmented so that the tumor does not reach a critical size. Strategies that have been suggested to augment the immune response to a tumor include: vaccines specific for tumor-associated antigens; the use of monoclonal antibodies against antigens on the surface of tumor cells, such as against the IL-2 receptor; the use of bispecific molecules containing antitumor antibodies and superantigens.
Relatively recently, the role of the physiologically active polypeptide, known as tumor necrosis factor (TNF), has been studied. In particular, TNF has been shown to induce necrosis of tumors, with no effect upon the normal tissues of the living body. The amino acid sequence of TNF, as well as the base sequence of the DNA coding for TNF, have been disclosed in U.S. Pat. No. 4,879,226.
Because TNF has been shown to have a role in inducing necrosis of tumors, any agent that can stimulate the production or bioavailability of TNF in vivo has potential utility as a treatment for various tumorous conditions. Additionally, any agent that can stimulate human monocytes and macrophages to produce TNF in vitro, is useful as a means for providing a source of TNF for therapeutic administration, as well as for analytical and diagnostic purposes.
Other diseases also have or involve an impaired immune system response. For example, autoimmune diseases are disorders in which the immune system produces an antibody against substances that are not foreign to the body, resulting in inflammation and consequent tissue damage. For example, rheumatoid arthritis (RA) is an autoimmune disease in which the body's immune system mistakenly recognizes normal cells of the lining of joints, called synovium, as foreign. The autoimmune attack may destroy the lining completely. In the most severe cases, the joints cease to function and are replaced surgically with artificial joints. TNF is a mediator of the damage in RA. Progression from mild symptoms to severe disfigurement can be very rapid. As yet, no treatment is available for RA patients. Other essentially untreatable autoimmune diseases include lupus erythematosus, multiple sclerosis, and amyotrophic lateral sclerosis.
Infectious diseases, such as those caused by bacteria, virus, and other opportunistic pathogens, can only succeed by avoiding or defeating the body's immune system. The immune system mounts or elicits either or both non-specific immune responses and specific immune response factors to fight such pathogens.
Non-specific immune responses are focused on cytokine production, principally by macrophages, and serve as a prelude to specific antibody responses. The inflammatory cytokines include TNF-&agr; and mediate an acute response directed to the injury or infection sites, which is manifested by an increased blood supply. The pathogenic bacteria or viruses are engulfed by neutrophils and macrophages in an attempt to contain the infection to a small tissue space. Macrophages, therefore, play a key role in the defense against infectious diseases as follows:
(1) processing and presentation of antigens to lymphocytes so that antibody-mediated and cell-mediated immune responses can occur;
(2) secretion of cytokines central to immune response; and
(3) destruction of antibody-coated bacteria, tumor cells or host cells.
Macrophages can ingest and kill a wide variety of pathogens, such as bacteria, fungi, and protozoa (parasites). This ability is augmented when the macrophages are “activated.” Secreted products of activated macrophages are more diverse than those from any other immune cell. These regulate both pro- and anti-inflammatory effects and regulate other cell types. These products include TNF-&agr;, IL-1&bgr;, IL-6, hydrolytic enzymes, and products of oxidative metabolism Bacteria that are eliminated primarily through this cell-mediated immune process include tuberculosis and other related mycobacterial infections, such as atypical mycobacterial infections seen in up to 50% of AIDS patients, and anthrax, a potential bacteriological warfare agent. Fungal infections are common problems in immuno-suppressed patients, such as those afflicted with AIDS or organ transplant patients. Protozoa include organisms such as malaria.
Inflammatory diseases include endometriosis and inflammatory bowel disease, which also is mediated by immune processes. Endometriosis is an obscure disease of unknown cause and histogenesis that affects menstruating women. The disease is characterized by inappropriate implantation, growth, and function of endometrial cells. Endometrial cells and fragments, which are normally discharged during the menstrual cycle, are transported through the fallopian tubes into the peritoneal cavity where, in some women, they implant, proliferate, and develop into endometriotic lesions. However, because it appears the endometrial cells are present in the peritoneal cavity of all menstruating females, it is presently unclear why endometriosis develops in some, but not all, women. Endometriosis can result in painfully inflamed tissue, abnormal bleeding, widespread scaring, painful urination or defecation, and damage to a woman's reproductive organs, even leading to infertility. No known treatment for endometriosis exists, short of pregnancy, which provides temporary relief, or surgery to remove the source of endometrial cells, which also causes sterility.
Recently, numerous reports have suggested that endometriosis is associated with changes in the immune system. Early reports indicate that immunosuppressive treatments are associated with an increase in endometriosis in rhesus monkeys. Since that time, alterations in both cell-mediated and humoral immunity have been observed in humans with endometriosis.
During the past several years, studies have focused on the role of macrophages in endometriosis. The underlying hypothesis for these studies was that the monocyte/macrophage system regulates endometrial cell growth and prevents proliferation of misplaced endometrial cells in normal, healthy women. In women with endometriosis, the misplaced endometrial cells are allowed to implant, giving origin to endometriosis. Development of endometriosis then is a stimulus to auto-antibody production against endometrial cells and cell-derived antigens. These auto-antibodies, together with products from activated macrophages, may then interfere with fertility and reproductive performance of affected women.
The cumulative results from these studies have revealed the following pertinent facts:
(1) the peritoneal disposal system (consisting primarily of macrophages) that is thought to be responsible for the destruction of ectopic endome
Percheson Paul B.
Rang Romeo G.
Goldberg Joshua B.
Juneau Todd L.
Lorus Therapeutics Inc.
Nath Gary M.
Witz Jean C.
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