Peptide antagonists of tumor necrosis factor alpha

Details Peptide antagonists of tumor necrosis factor alpha Peptide antagonists of tumor necrosis factor alpha

1999-07-08

2002-02-05

Borin, Michael (Department: 1631)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S016700, C530S327000, C530S329000, C435S007800

Reexamination Certificate

active

06344443

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Technical Field
The present invention relates to compositions that interfere with the function of Tumor Necrosis Factor Alpha (TNF-&agr;) for use as therapeutics and diagnostics.
2. Background Art
Cytokines are peptide/protein immunomodulators that are produced by activated immune cells including thymus-derived T lymphocytes (T-cells), B lymphocytes and monocyte/macrophages. The cytokines include interleukins (IL-1 through IL-18), colony stimulating factors (CSFs) for granulocytes and/or macrophages (CSF-G, CSF-M, CSF-GM), tumor necrosis factors (TNFs &agr; & &bgr;), and interferons (IFN &agr;, &bgr; & &ggr;). There is a large body of evidence currently available which supports the roles of IL-1 and TNF as major mediators of the systemic response to diseases such as sepsis and as activators of the remaining members of the cytokine cascade (Dinarello et al., 1993).
More specifically, tumor necrosis factor (TNF)-&agr; has a broad range of effects on numerous different cell types throughout the body. It induces proliferation in some cell types, activation in other cell types, and release of other cytokines in some cell types. In many pathologic conditions, including inflammatory diseases such as arthritis, inflammatory bowel diseases, and dermatologic disorders, TNF-&agr; is felt to be a major or the major cytokine responsible for inducing the inflammatory changes. TNF-&agr; also may be involved in the survival and proliferation of some malignant cell types. Therefore, it is of considerable interest and potential clinical significance to identify compounds that interfere with the function of TNF-&agr;. Currently, soluble TNF receptors and antibodies to TNF-&agr; are being used clinically and in clinical studies to attempt to compete for TNF-&agr; binding, so as to prevent binding of TNF-&agr; to cellular TNF receptors, which in turn should prevent activation of the receptors on inflammatory cells and prevent and possibly reverse the inflammatory changes that occur in certain types of patients with arthritis.
It would therefore be beneficial to find alternative means to inhibit TNF-&agr; function, particularly discovery of small peptides that could bind to TNF receptors and interfere with the ability of TNF-&agr; to bind to and activate cellular TNF-&agr; receptors. Such molecules are very useful in research studies in vitro. However, more importantly, these molecules have significant clinical usefulness in treating a broad range of inflammatory conditions, arthritis, and cancers.
SUMMARY OF THE INVENTION
According to the present invention, there is provided a method of inhibiting TNF-&agr; from binding to TNF receptors by administering an effective amount of an inhibitory peptide. Also provided is a method of inhibiting TNF-&agr; functions by administering an effective amount of an inhibitory peptide. There is also provided a peptide which has TNF-&agr; inhibitory properties. Also provided is a method of inhibiting TNF-&agr; binding to TNF receptors by administering an effective amount of a peptide having the amino acid sequence shown in SEQ ID No. 1,2,3,4, wherein the peptides can be administered either singly or in combination.


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