Drug – bio-affecting and body treating compositions – Lymphokine – Interleukin
Reexamination Certificate
2000-05-22
2002-12-24
Eyler, Yvonne (Department: 1646)
Drug, bio-affecting and body treating compositions
Lymphokine
Interleukin
C514S002600, C530S351000
Reexamination Certificate
active
06497870
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel therapeutic uses of interleukin-1 receptor antagonist for conditions involving elevated levels of interleukin-18, interleukin-12 or interferon-&ggr;.
BACKGROUND
IL-1 receptor antagonist (IL-1Ra or IRAP) is a naturally occurring protein that inhibits the activity of the proinflammatory cytokine interleukin-1 (IL-1). The IL-1 pathway consists of the two agonists IL-1&agr; and IL-1&bgr;, a specific activation system (IL-1 converting enzyme), a receptor antagonist (IL-1Ra) produced in different isoforms and two high affinity receptors. IL-1&agr; and IL-1&bgr; bind to two distinct IL-1 receptor types, IL-1 receptor type I (IL-1RI) and IL-1 receptor type II (IL-1RII), both of which are members of the immunoglobulin superfamily of receptors. Both types of receptors are usually coexpressed, although type I is the predominant form in fibroblasts and T cells, while type II is preferentially expressed on B cells, monocytes and neutrophils. IL-1RI and IL-1RII have different affinities for the three ligands of the IL-1 family (IL-1&agr;, IL-1&bgr; and IL-1Ra). In particular, IL-1Ra binds to the type I receptor with an affinity similar to that of IL-1&agr;, while IL-1Ra binds to the type II receptor 100-fold less efficiently than the type I receptor. There is evidence indicating that IL-1 induced activities are mediated exclusively via the type I receptor, whereas the type II receptor has no signaling activity and inhibits IL-1 activities by acting as a decoy for IL-1.
IL-1Ra binds to the IL-1 receptor with affinity similar to that of IL-1 but has no IL-1-like activity, even at very high concentrations, and thus inhibits (antagonizes) the activity of IL-1. The purified IL-1Ra molecule has a molecular weight of approximately 25 kD and is believed to be glycosylated. An unglycosylated recombinant form of IL-1Ra that has a molecular weight of approximately 17 kD is commercially available from R&D Systems (Minneapolis, Minn.). IL-1Ra has limited sequence similarity to IL-1&agr; and IL-1&bgr; at the amino acid level (19% and 26%, respectively). There appear to be at least two isoforms of IL-1Ra, including a soluble form and an intracellular form generated by an alternative splicing event. IL-1Ra appears to be produced by monocytes, macrophages, neutrophils and fibroblasts; keratinocytes and cells of epithelial origin produce almost exclusively the intracellular form. In humans, the gene for IL-1Ra has been localized to the long arm of chromosome 2, which is the same region where IL-1&agr; and IL-1&bgr;, as well as IL-1RI and IL-1RII, are found.
Treatment of IL-1 related conditions through the administration of IL-1 Ra molecules has been extensively studied in both in vitro and animal models. These models include those for infection, local inflammation, acute or chronic lung injury, metabolic dysfunction, autoimmune disease, immune-mediated disease, malignant disease, and host responses. In addition, human recombinant IL-1Ra has been administered to humans in clinical trials for rheumatoid arthritis, septic shock, steroid resistant graft versus host disease, acute myeloid leukemia, and chronic myelogenous leukemia. [Dinarello et al.,
Intern. Rev. Immunol.,
16:457-499 (1998).] In these human clinical trials, IL-1Ra was not shown to significantly reduce mortality in humans with septic shock. [Fisher et al.,
J.A.M.A.,
271:1836-43 (1994).] Clinical trials have indicated that patients tolerate administration of human recombinant IL-1Ra well without serious adverse effects.
Interleukin-18 (IL-18) is a 18.3 kD cytokine which is a strong inducer of interferon-&ggr; (IFN-&ggr;). Even though IL-18 exhibits low sequence identity to the interleukin-1 (IL-1) family members (IL-1&agr;, IL-1&bgr;, IL-1Ra), it is structurally similar to this family of cytokines. Particularly, IL-18 exhibits a 12&bgr; sheet structure that is common among IL-1 cytokine family members and shares features of the IL-1 like-signature sequences. This indicates that IL-18 is a structurally distinct cytokine compared to the IL-1 family. (See Gillespie and Horwood, Cytokine and Growth Factor Review, 9: 109-116, 1998).
The IL-18 receptor (IL-18R) was initially denoted as IL-1 receptor binding protein even though it does not bind IL-1&agr;, IL-&bgr;, or IL-1Ra. It does however, transmit signals similar to that of IL-1R. Radiolabeled IL-18 binding studies have revealed the presence on IL-18R of high and low affinity sites for IL-18. The low affinity sites are normally available on IL-18R, while the high affinity binding sites become available when IL-18R is complexed with an accessory protein-like receptor. A soluble decoy receptor that binds IL-18 has also been identified, similar to what is observed in the IL-1 receptor system.
IL-18 is known to be expressed by activated macrophages, osteoblasts, keratinocytes, epithelial cells, pancreas cells, adrenal cells, skeletal muscle cells, liver cells, lung cells and unstimulated PBMC cells. The known functions of IL-18 include induction of IFN-&ggr; expression in spleen cells such as T-cells, B-cells and NK cells, stimulation of T cell proliferation, enhancement of NK cell lytic cycle, enhancement of Fas ligand expression and function in T cells and NK cells, and induction of GM-CSF secretion. IL-18 also exhibits anti-viral and anti-microbial activity and suppresses tumor growth. IL-18 has also been associated with the progression of chronic inflammatory diseases including endotoxin shock, hepatitis, and autoimmune disease.
The biological activities of IL-18 are exerted in synergy with interleukin-12 (IL-12). The combination of these two cytokines are known to markedly enhance production of IFN-&ggr; in T cells and B cells. In addition to IFN-&ggr;, the combination of IL-12 and IL-18 increases production of IL-3, IL-6 and TNF. IL-18 has also been shown to potentiate IL-12-driven Th1 cell development. Studies have indicated that IL-12 will increase expression of IL-18 receptor, which may be the mechanism for this synergy. There is evidence that this synergistic effect is carried out in vivo as well as in vitro. (See Okumura et al., Advances in Immunology, 70: 281-312, 1998). IL-18 and IL-12 are structurally different, bind different receptors and transduce signals through different signaling components.
IL-12 is a pro-inflammatory cytokine which was initally characterized for its potent ability to induce production of IFN&ggr;. IL-12 exhibits sequence homology to IL-6 and G-CSF. Unlike most cytokines, IL-12 is biologically active as a heterodimeric protein consisting of a heavy chain (p40) covalently associated with a lighter chain (p35). The cells which produce IL-12 include dendritic cells, macrophages, Langerhans cells, EBV-transformed B cells, neutrophils, keratinocytes, microglia and astrocytes.
IL-12 exhibits pleiotrophic effects on multiple lymphoid cell subsets including promoting the expansion of T cells, T lymphocytes and NK-lymphokine activated killer cells. In addition, IL-12 potentiates the cytolytic activity of NK cells and cytotoxic lymphocytes. Clinically, theses effects on the immune system result in enhanced host protection from infectious diseases and therefore IL-12 exhibits anti-bacterial, anti-microbial and anti-viral activity.
Antitumor activity is also induced by IL-12 enhancement of the host's natural immunity to tumorgenesis. IL-12 has also been shown to inhibit angiogenesis in tumor systems which prevents blood flow to the growing tumors. The antitumor effects are potentiated by synergism with IL-2 in vivo. Clinical studies have shown that administration of the combination of IL-12 and IL-2 significantly increases systemic production of IFN&ggr; which leads to severe toxicity in the patient, resulting in shock and mortality.
The pro-inflammatory effects of IL-12 promote autoimmune diseases such as multiple sclerosis and arthritis. In addition, IL-12 promotes transplant rejection.
There exists a need in the art for new methods of treating conditions involving elevated levels or act
Ford John
Ho Alice Suk-Yue
Andres Janet L.
Eyler Yvonne
Hyseq Inc.
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