Drug – bio-affecting and body treating compositions – Lymphokine
Reexamination Certificate
2000-12-08
2003-08-12
Spector, Lorraine (Department: 1696)
Drug, bio-affecting and body treating compositions
Lymphokine
C530S350000, C530S351000
Reexamination Certificate
active
06605271
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel T1Receptor (T1R)-like ligand II protein. In particular, isolated nucleic acid molecules are provided encoding the T1R-like ligand II protein. T1R-like ligand II polypeptides are also provided, as are recombinant vectors and host cells for expressing the same. This invention further relates to pharmaceutical compositions and formulations comprising T1R-like ligand II. Also provided are methods of using T1R-like ligand II polynucleotides, polypeptides, antibodies or agonists/antagonists for therapeutic and diagnostic purposes. Diagnostic kits are further provided.
2. Related Art
Interleukin-1 (IL-1).
Interleukin-1 (IL-1&agr; and IL-1&bgr;) is a “multifunctional” cytokine that affects nearly every cell type, and often in concert with other cytokines or small mediator molecules. (Dinarello, C. A.,
Blood
87:2095-2147 (Mar. 15, 1996).) There are three members of the IL-1 gene family: IL-1&agr;, IL-1&bgr;, and IL-1 receptor antagonist (IL-1Ra). IL-1&agr; and IL-1&bgr; are agonists and IL-1Ra is a specific receptor antagonist. IL-1&agr; and &bgr; are synthesized as precursors without leader sequences. The molecular weight of each precursor is 31 kD. Processing of IL-1&agr; or IL-1&bgr; to “mature” forms of 17 kD requires specific cellular proteases. In contrast, IL-1Ra evolved with a signal peptide and is readily transported out of the cells and termed secreted IL-1Ra (sIL-1Ra).
IL-1 Receptor and Ligands.
The receptors and ligands of the IL-1 pathway have been well defined (for review, see Dinarello, C. A.,
FASEB J.
8:1314-1325 (1994); Sims, J. E. et al.,
Interleukin
-1
signal transduction: Advances in Cell and Molecular Biology of Membranes and Organelles,
Vol.3, JAI Press, Inc., Greenwich, Conn. (1994), pp. 197-222). Three ligands, IL-1&agr;, IL-1&bgr;, and IL-1 receptor antagonist (IL-1Ra) bind three forms of IL-1 receptor, an 80-kDa type I IL-1 receptor (IL-IR1) (Sims, J. E. et al.,
Science
241:585-589 (1988)), a 68-kDa type II IL-1 receptor (IL-1RII) (McMahan, C. J. et al.,
EMBO J.
10:2821-2832 (1991)), and a soluble form of the type II IL-1R (sIL-1RII) (Colotta, F. et al.,
Science
261:472-475 (1993)).
The interactions between the IL-1 ligands and receptors play an essential role in the stimulation and regulation of the IL-1 -mediated host response to injury and infection. Cells expressing IL-1RI and treated with IL-1&agr; or IL-1&bgr; respond in several specific ways, including stimulating nuclear localization of the rel-related transcription factor, NF-&kgr;&bgr; (for review, see Thanos, D. & Maniatis, T.,
Cell
80:529-532 (1996)), activation of protein kinases of the mitogen-activated protein kinase superfamily that phosphorylate residue threonine 669 (Thr-669) of the epidermal growth factor receptor (EGFR) (Guy, G. R. et al.,
J. Biol. Chem.
267:1846-1852(1992); Bird, T. A. et al.,
J. Biol. Chem.
268:22861-22870(1991); Bird, T. A. et al.,
J. Biol. chem.
269:31836-31844 (1994)), and stimulation of transcription of the IL-8 gene (Mukaida, N. et al.,
J. Biol. chem.
265:21128-21133 (1990)).
IL-1RI-like Family.
Many proteins from diverse systems show homology to the cytoplasmic domain of the IL-1RI. This expanding IL-1RI-like family includes mammalian proteins, Drosophila proteins, and a plant (tobacco) protein. (Gay, N. J. & Keith, F. J.,
Nature
351:355-356 (1991); Hashimoto, C. et al.,
Cell
52:269-279 (1988); Schneider, D. S. et al.,
Genes
&
Dev.
5:797-807 (1991); Edon, E. et al.,
Development
120:885-899 (1994); Mitchan, J. L. et al.,
J. Biol. Chem
271:5777-5782 (Mar. 8, 1996)).
The mammalian IL-1RI-like receptor family members include a murine protein MyD88 (Lord, K. A. et al.,
Oncogene
5:1095-1097 (1990)) and a human gene, rsc786 (Nomura, N. et al.,
DNA Res.
1:27-35 (1994)). Another murine receptor member, T1/ST2, was previously characterized as a novel primary response gene expressed in BALB/c-3T3 cells (Klemenz, R. et al.,
Proc. Natl. Acad. Sci. USA
86:5708-5712 (1989); Tominaga, S.,
FEBS Lett.
258:301-304 (1989); Tominga, S. et al.,
FEBS Lett.
318:83-87 (1993)). The transmembrane protein mulL-1R AcP (Greenfeder, S. A. et al.,
J. Biol. Chem.
270:13757-13765 (1995)) has homology to both the type I and type II IL-1R. IL-1R AcP has recently been shown to increase the affinity of IL-1RI for IL-1&bgr; and may be involved in mediating the IL-1 response.
T1 Receptors.
T1/ST2 receptors (hereinafter, “T1 receptors”), as a member of the IL-1 receptor family (Bergers, G., et al.,
EMBO J.
13:1176 (1994)), have various homologs in different species. In the rat, it is called Fit-1, an estrogen-inducible, c-fos-dependent transmembrane protein that shares 26% to 29% amino acid homology to the mouse IL-1RI and II, respectively. In the mouse, the Fit-1 protein is called ST2 and in the human it is called T1. The organization of the two IL-1 receptors and the Fit-1/ST2/T1 genes indicates they are derived from a common ancestor (Sims, J. E., et al.,
Cytokine
7:483 (1995)). Fit-1 exists in two forms: a membrane form (Fit-1M) with a cytosolic domain similarly to that of the IL-1RI and Fit-1S, which is secreted and composed of the extracellular domain of Fit-M.
In many ways, these two forms of the Fit-1 protein are similar to those of the membrane-bound and soluble IL-1RI. It has been shown that the IL-1sRI is derived from proteolytic cleavage of the cell-bound form (Sims, J. E., et al.,
Cytokine
7:483 (1995)). On the other hand, the Fit-1 gene is under the control of two promoters, which results in two isoforms coding for either the membrane or soluble form of the receptor. Two RNA transcripts result from alternative RNA splicing of the 3′ end of the gene. Although IL-1&bgr; binds weakly to Fit-1 and does not transduce a signal (Reikerstorger, A., et al.,
J. Biol. Chem.
270:17645 (1995)), a chimeric receptor consisting of the extracellular murine IL-1RI fused to the cytosolic Fit-1 transduces an IL-1 signal (Reikerstorger, A., et al.,
J. Biol. Chem.
270:17645 (1995)). The cytosolic portion of Fit-1 align with GTPase-like sequences of IL-1RI (Hopp, T. P.,
Protein Sci.
4:1851 (1995)) (see below).
IL-1 Production in Various Disease States.
Increased IL-1 production has been reported in patients with various viral, bacterial, fungal, and parasitic infections; intravascular coagulation; high-dose IL-2 therapy; solid tumors; leukemias; Alzheimer's disease; HIV-1 infection; autoimmune disorders; trauma (surgery); hemodialysis; ischemic diseases (myocardial infarction); noninfectious hepatitis; asthma; UV radiation; closed head injury; pancreatitis; periodontitis; graft-versus-host disease; transplant rejection; and in healthy subjects after strenuous exercise. There is an association of increased IL-1&bgr; production in patients with Alzheimer's disease and a possible role for IL-1 in the release of the amyloid precursor protein (Vasilakos, J. P., et al.,
FEBS Lett.
354:289 (1994)). However, in most conditions, IL-1 is not the only cytokine exhibiting increased production and hence the specificity of the IL-1 findings as related to the pathogenesis of any particular disease is lacking. In various disease states, IL-1, but not IL-1&agr;, is detected in the circulation.
IL-1 in Therapy.
Although IL-1 has been found to exhibit many important biological activities, it is also found to be toxic at doses that are close to therapeutic dosages (Dinarello, C. A.,
Blood
87:2095-2147 (Mar. 15,1996)). In general, the acute toxicities of either isoform of IL-1 were greater after intravenous compared with subcutaneous injection. Subcutaneous injection was associated with significant local pain, erythema, and swelling (Kitamura, T., & Takaku, F.,
Exp. Med.
7:170 (1989); Laughlin, M. J.,
Ann. Hematol.
67:267 (1993)). Patients receiving intravenous IL-1 at doses of 100 ng/kg or greater experienced significant hypotension. In patients receiving IL-1&bgr; from 4 to 32 ng/kg subcutaneously, there was only one episode of hypotension at the highest dos
Gentz Reiner L.
Ni Jian
Ruben Steven M.
Human Genome Sciences Inc.
Human Genome Sciences Inc.
Jiang Dong
Spector Lorraine
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