Inhibition of TNF activity

Details Inhibition of TNF activity Inhibition of TNF activity

2000-11-20

2003-08-19

Jones, Dwayne C. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S002600, C514S825000, C536S021000, C536S054000

Reexamination Certificate

active

06608044

ABSTRACT:

CROSS REFERENCE TO RELATED APPLICATION
The present application is the national stage under 35 U.S.C. 371 of PCT/IL99/00709, filed Dec. 30, 1999.
FIELD OF THE INVENTION
The present invention is directed to a method and pharmaceutical compositions for inhibiting activity of tumor necrosis factor (TNF).
BACKGROUND OF THE INVENTION
Tumor necrosis factor (TNF) is a pro-inflammatory cytokine produced by a wide spectrum of cells. It has a key role in defending the host, mediating complex cellular responses of different, and even contrasting, nature (Aggarwal et al, 1996). In excess, TNF may have detrimental systemic effects. Two specific high affinity cell surface receptors, the p55 TNF-receptor (p55 TNF-R) and the p75 TNF-receptor (p75 TNF-R), function as transducing elements, providing the intracellular signal for cell responses to TNF. The extracellular parts of the TNF-Rs, known as soluble TNF-Rs, were formerly referred to as TBP-I and TBP-II respectively (see Wallach, U.S. Pat. No. 5,359,037 and Tartaglia et al., 1992; Loetscher et al., 1991).
The biological effects of TNF depend upon its concentration and site of production. At low concentrations. TNF may produce desirable homeostatic and defense functions. For example, these effects may destroy tumor cells or virus infected cells and augment antibacterial activities of granulocytes. In this way, TNF contributes to the defense of the organism against infectious agents and to recovery from injury. However, at higher concentrations, systemically or in certain tissues, TNF can synergize with other cytokines, notably interleukin-1, to aggravate many inflammatory responses. Additionally, the effects of TNF-&agr;, primarily on the vasculature, are now known to be a major cause for symptoms of septic shock (Tracey et al, 1986). In some diseases, TNF may cause excessive loss of weight (cachexia) by suppressing activities of adipocytes and by causing anorexia.
TNF has been found to induce the following activities (together with interleukin-2): fever, slow-wave sleep, hemodynamic shock, increased production of acute phase protein, decreased production of albumin, activation of vascular endothelial cells, increased expression of major histocompatibility complex molecules, decreased lipoprotein lipase, decreased cytochrome P450, decreased plasma zinc and iron, fibroblast proliferation, increased synovial cell collagenase, increased cyclo-oxygenase activity, activation of T cells and B cells, and induction of secretion of the cytokines, TNF itself, interleukin-1 and interleukin-6.
Because of its pleiotropic effects, TNF has been implicated in a variety of pathologic states in many different organs of the body. In blood vessels, TNF promotes hemorrhagic shock, down-regulates endothelial cell thrombomodulin, and enhances a procoagulant activity. It causes adhesion of white blood cells, and probably of platelets, to the walls of blood vessels, and so may promote processes leading to atherosclerosis, as well as to vasculitis.
TNF activates blood cells and causes the adhesion of neutrophils, eosinophils, monocytes/macrophages and T and B lymphocytes. By inducing interleukin-6 and interleukin-8, TNF augments the chemotaxis of inflammatory cells and their penetration into tissues. Thus, TNF has a role in the tissue damage of autoimmune disease, allergies and graft rejection.
TNF has also been called cachectin because it modulates the metabolic activities of adipocytes and contributes to the wasting and cachexia accompanying cancer, chronic infections, chronic heart failure and chronic inflammation. TNF may also have a role in tissue damage of autoimmune diseases, allergies, and graft rejection.
TNF also has metabolic effects on skeletal and cardiac muscle. It also has marked effects on the liver: it depresses albumin and cytochrome P450 metabolism and increases production of fibrinogen, &agr;-Acid Glycoprotein (AGP) and other acute phase proteins. It can also cause necrosis of the bowel.
In the central nervous system, TNF crosses the blood-brain barrier and induces fever, increased sleep and anorexia. Increased TNF concentration is also associated with multiple sclerosis. It also causes adrenal hemorrhage and affects production of steroid hormones, enhances collagenase and PGE-2 in the skin, and causes the breakdown of bone and cartilage by activating osteoclasts.
Thus, TNF is involved in the pathogenesis of many undesirable inflammatory conditions, in autoimmune disease, graft, rejection, vasculitis and atherosclerosis. It appears to have a role in heart failure, in the response to cancer and in anorexia nervosa. For these reasons, means have been sought to inhibit the activity of TNF as a way to control a variety of diseases.
While exploring ways for antagonizing the destructive potential of TNF in certain clinical conditions, investigators looked for natural TNF inhibitors (Engelmann et al, 1989; Engelmann et al, 1990; Seckinger et al, 1989; Olsson et al, 1989). Such agents, first detected in urine, were structurally identical to the extracellular cytokine binding domains of the two membrane associated TNF-Rs (Nophar et al, 1990). These shed soluble TNF-Rs (sTNF-Rs) can compete for TNF with the cell surface receptors and thus block the cytokine activity.
However, interactions between the TNF-Rs and their ligand are much more complex than initially thought. At physiological concentrations, the trimeric and bioactive TNF molecules decay, dissociating into inactive monomeric forms (Petersen et al, 1989; Aderka et al, 1992). Addition of sTNF-Rs to the TNF trimers promotes formation of complexes between them, which can preserve and prevent the decay of the active, trimeric forms of TNF (Aderka et al, 1991; De Groote et al, 1993). This bioactive TNF may dissociate from this complex to replace free TNF which decayed, thus maintaining a constant concentration of free, bioactive, trimeric cytokine. This reversible interaction between the soluble receptors and their ligand expands the functions attributable to the TNF receptors. In their soluble form, the TNF-Rs may serve as:
(a) TNF antagonists (when present in large excess relative to TNF);
(b) TNF carrier proteins (between body compartments);
(c) slow release reservoirs for bioactive TNF;
(d) stabilizers of the TNF's bioactive form (which may also prolong the half-life of TNF); and
(e) TNF “buffers”, by inhibiting the effects of high TNF concentrations and presenting it at low and well-controlled levels to the cells (Aderka et al, 1992).
The functions of the TNF receptors, thus, are not limited to signal transduction but include, in their soluble forms, extracellular regulatory roles affecting local and systemic bioactive TNF availability.
TNF and Disease
Examination of patients with septic shock due to meningococcemia revealed that the ratio of TNF/sTNF-Rs was higher in patients with a fatal outcome compared to patients who recovered, suggesting a critical imbalance between the ligand and its inhibitors (Girardin et al, 1994). Neutralization of the excess TNF seemed to be the preferred next step.
Indeed, dimeric Fc fusion constructs of the p55 sTNF-R, but not of the p75 sTNF-R, were found to protect mice from lethal doses of LPS (Evans et al, 1994) if administered not later than 1-3 hours post LPS (Peppel et al, 1991; Mohler et al, 1993; Ashkenazi et al, 1991; Lesslauer et al, 1991). This suggests that septic shock manifestations occur if the initial high TNF concentrations generated are not buffered by adequate soluble receptor concentrations during that narrow window of time.
To add to the growing confusion, neutralization of TNF with monoclonal anti-TNF Ab (Abraham et al, 1995; Kaul, et al, 1996) or p55 sTNF-R IgG1 (Leighton et al, 1996) in patients with severe sepsis or septic shock yielded conflicting results. In one study, the antibodies proved ineffective (Abraham et al, 1995), while in the other, administration of the antibodies benefited only those patients with baseline interleukin-6 levels higher than 1000 pg/ml but increased the mortality of those with lower interleukin-6 levels (Ka

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