Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
1999-04-16
2002-01-29
Priebe, Scott D. (Department: 1633)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S320100, C435S325000, C435S335000, C435S455000, C536S023100, C536S023500, C530S350000, C530S351000
Reexamination Certificate
active
06342371
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to newly identified polypeptides and polynucleotides encoding such polypeptides, to their use in therapy and in identifying compounds which may be agonists, antagonists and/or inhibitors which are potentially useful in therapy, and to production of such polypeptides and polynucleotides.
BACKGROUND OF THE INVENTION
The drug discovery process is currently undergoing a fundamental revolution as it embraces ‘functional genomics’, that is, high throughput genome- or gene-based biology. This approach is rapidly superseding earlier approaches based on ‘positional cloning’. A phenotype, that is a biological function or genetic disease, would be identified and this would then be tracked back to the responsible gene, based on its genetic map position.
Functional genomics relies heavily on the various tools of bioinformatics to identify gene sequences of potential interest from the many molecular biology databases now available. There is a continuing need to identify and characterize further genes and their related polypeptides/proteins, as targets for drug discovery.
Interleukin 1 refers to two proteins (IL1&agr; and IL1&bgr;) which play a key role early in the inflammatory response [see (see C. A. Dinarello, Blood 87:2095-2147 (1996)]. Both proteins are made as 31kD) intracellular precursor proteins which are cleared upon secretion to yield mature carboxy-terminal 17kD fragments which are biologically active. In the case of IL-1&bgr;, this cleavage involves an intracellular cysteine protease, known as ICE, which is required to release the active to fragment from the inactive precursor. The precursor of IL-1&agr; is active.
These two proteins act by binding to cell surface receptors found on almost all cell types and triggering a range of responses either alone or in concert with other secreted factors. These range from effects on proliteration (e.g. of fibroblasts, and T cells), apoptosis (e.g. A375 melanoma cells), cytokine induction (e.g. of TNF, IL-1, and IL-8), receptor activation (e.g. E-selectin), eicosanoid production (e.g. PGE-2) and the secretion of degradative enzymes (e.g. collagenase). To achieve this, IL-1 activates transcription factors such as NF-&kgr;B and AP-1. Several of the activities of IL-1 action on target cells are believed to be mediated through activation of kinase cascades that have also been associated with cellular stresses, such as the stress activated MAP kinases JNK/SAPK and p38.
A third member of the IL-1 family was subsequently discovered which sets as a natural antagonist of IL-1&agr; and IL-1&bgr; by binding to the IL-1 receptor but not transducing an intracellular signal or a biological response. The protein was called IL-1ra (for IL-1 receptor antagonist IRAP (for IL-1 receptor antagonist protein). At least three alternatively splice forms of IL-1ra exist: one encodes a secreted protein, and the other two encode intracellular proteins. The relative role of the three forms and reason for their different localization is not known. All three proteins, IL-1&agr;, IL-1&bgr; and IL-1ra share approximately 25-30% amino acid identity and a similar three-dimensional structure consisting of twelve &bgr;-strands folded into a &bgr;-barrel, with an internal thrice repeated structural motif.
There are three known IL-1 receptor subunits. The active receptor complex consists of the type I receptor and IL1RAcP (for IL-1 accessory protein). The type I receptor is responsible for binding of the three ligands, and is able to do so in the absence of the IL1RAcP. However, signal transduction requires interaction of IL-1&agr; or &bgr; with the IL1RAcP. IL-1ra does not interact with the IL-1RAcP and hence cannot signal. A third receptor subunit, the type II receptor, binds IL-1&agr; and IL-1&bgr; but cannot signal due to its lack of an intracellular domain. Rather, it acts as a decoy either in its membrane form or an antogonist in a cleaved secreted form, and hence inhibits IL-1 activity. It only weakly binds IL-1ra.
Many studies using IL-1ra, soluble IL-1R, derived from the extracellular domain of the type I IL-1R, antibodies to IL-1&agr; or &bgr;, and transgenic knockouts of these genes have shown conclusively that the IL-1s play a key role in a number of pathophysiologies (see C. A. Dinarello, Blood 87:2095-2147 (1996)). For example, IL-1ra has been shown to be effective in animal models of septic shock, rheumatoid arthritis, graft versus host disease, stroke, cardiac ischemia, and is currently in clinical trials for some of these indications. Moreover, IL-1&agr; and &bgr; have shown some potential as hemaopoietic stem cell stimulators with potential as radio- and chemoprotectants.
More recently, a more distant member of the IL-1 family was identified. This protein, originally isolated through its ability to induce interferon gamma in T cells and hence called Interferon Gamma Inducing Factor (IGIF) [H. Okamura et al., Nature 378:88-91 (1995)], was subsequently shown to fold in a similar structure to the IL-1s and share weak amino acid identity [Bazan et al., Nature 379:591 (1996)]. The name IL-1&ggr; was proposed, but the name IL-18 has been officially adopted. IGIF appears to play a direct role in the liver damage that occurs during toxic shock and is therefore like the other IL-1s in playing an early role in inflammatory and stressful conditions. Like IL-1, it binds to two receptor subunits which belong to the IL-1 family of receptors [Torigoe et al. J. Boil. Chem. 272:25737 (1997); Born et al., J. Biol. Chem. 273:29445 (1998)].
SUMMARY OF THE INVENTION
The present invention relates to IL-1H4, in particular IL-1H4 polypeptides and IL-1H4 polynucleotides, recombinant materials and methods for their production. In another aspect, the invention relates to methods for using such polypeptides and polynucleotides, including the treatment of chronic and acute inflammation, septicemia, autoimmune diseases (e.g. inflammatory bowel disease, psoriasis, and arthritis), transplant rejection, graft vs. host disease, infection, stroke, ischemia acute respiratory disease syndrome, allergies, asthma, restenosis, brain injury, AIDS, bone diseases (e.g. osteoporosis), cancer (e.g. lymphoproliferative disorders), congestive heart failure, atherosclerosis, and Alzheimer's disease, hereinafter referred to as “the Diseases”, amongst others. In a further aspect, the invention relates to methods for identifying agonists and antagonists/inhibitors using the materials provided by the invention, and treating conditions associated with IL-1H4 imbalance with the identified compounds. In a still further aspect, the invention relates to diagnostic assays for detecting diseases associated with inappropriate IL-1H4 activity or levels.
DESCRIPTION OF THE INVENTION
In a first aspect, the present invention relates to IL-1 H4 polypeptides. Such peptides include isolated polypeptides comprising an amino acid sequence which has at least 70% identity, preferably at least 80% identity, more preferably at least 90% identity, yet more preferably at least 95% identity, most preferably at least 97-99% identity, to that of SEQ ID NO:2 over the entire length of SEQ ID NO:2. Such polypeptides include those comprising the amino acid of SEQ ID NO:2.
Further peptides of the present invention include isolated polypeptides in which the amino acid sequence has at least 70% identity, preferably at least 80% identity, more preferably at least 90% identity, yet more preferably at least 95% identity, most preferably at least 97-99% identity, to the amino acid sequence of SEQ ID NO:2 over the entire length of SEQ ID NO:2. Such polypeptides include the polypeptide of SEQ ID NO:2.
Further peptides of the present invention include isolated polypeptides encoded by a polynucleotide comprising the sequence contained in SEQ ID NO:1.
Polypeptides of the present invention are believed to be members of the Interleukin-1 family of polypeptides. They are therefore of interest because these proteins play a role in chronic and acute disease and coul
McDonnell Peter C
Young Peter R
Hecht Elizabeth J.
Kaushal Sumesh
King William T.
Priebe Scott D.
Ratner & Prestia
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