Spoil-1 protein and nucleic acid molecules and uses therefor

Details Spoil-1 protein and nucleic acid molecules and uses therefor Spoil-1 protein and nucleic acid molecules and uses therefor

1998-01-27

2001-03-06

Hauda, Karen (Department: 1632)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Using tissue cell culture to make a protein or polypeptide

C435S071100, C435S320100, C435S325000, C435S455000, C536S024300, C536S023500

Reexamination Certificate

active

06197551

ABSTRACT:

BACKGROUND OF THE INVENTION
Interleukin-1 (IL-1) is a multifunctional cytokine which comprises a family of two polypeptides, IL-1&agr; and IL-1&bgr;, with a wide spectrum of activities. IL-1&agr; and IL-1 &bgr; have been found to possess inflammatory, metabolic, physiologic, hematopoeitic and immunologic properties. Although both forms of IL-1 are distinct gene products, they recognize the same cell surface receptors (i.e. IL-1 receptors, IL-1RtI and IL-1RtII).
Besides skin keratinocytes, some epithelial cells and certain cells in the central nervous system, significant amounts of mRNA encoding IL-1 are not observed in most other healthy cells. However, IL-1 production is dramatically increased by a variety of cells in response to infection, microbial toxins, inflammatory agents, products of activated lymphocytes, complement and clotting components. In addition, IL-1 has been recognized as a prototype of proinflammatory cytokines in that it induces the expression of a variety of genes and the synthesis of several proteins that in turn, induce acute and chronic inflammation. Thus, circulating IL-1 has been implicated in various disease states including sepsis, rheumatoid arthritis, stroke and diabetes. Dinarello (1991) Blood 77(8):1627-1652.
In addition, IL-1 has been shown to regulate bone reabsorption and bone formation with its major activity in bone metabolism being osteoclast activation. See Gowen et al. (1983)
Nature
306:378-380. In fact, IL-1 has been reported to be a potent stimulator of bone reabsorption and has also been reported to increase prostaglandin synthesis in bone. Lorenzo et al. (1987)
Endocrinology
121:1164-1170.
A natural occurring inhibitor of IL-1 which specifically inhibits IL-1 activity has also been identified. Carter et al. (1990)
Nature
344:633. This protein, called IL-1 receptor antagonist protein (IL-1ra), has been shown to compete with the binding of IL-1 to its surface receptors. Thus, significant interest has arisen in administering IL-1ra to block the activity of IL-1 in various diseases including septic shock (Ohlsson et al. (1990)
Nature
348:550-556), immune complex-induced colitis (Cominelli (1990)
J. Clin. Invest
. 86:972-979), acute myelogenous leukemia (Rambaldi et al. (1990)
Blood
76:114-120) and osteoporosis (Pacifici et al. (1993)
J. Clin. Endocrinol. Metab
. 77:1135-1141).
SUMMARY OF THE INVENTION
The present invention is based, at least in part, on the discovery of novel IL-1 receptor antagonist (IL-1ra) -like molecules, referred to herein as SPOIL-1 nucleic acid and protein molecules. The SPOIL-1 molecules of the present invention are useful as modulating agents in regulating a variety of cellular processes. Accordingly, in one aspect, this invention provides isolated nucleic acid molecules encoding SPOIL-1 proteins and biologically active portions thereof, as well as nucleic acid fragments suitable as primers or hybridization probes for the detection of SPOIL-1-encoding nucleic acids.
In one embodiment, a SPOIL-1 nucleic acid molecule is 65% homologous to the nucleotide sequence shown in SEQ ID NO:3, SEQ ID NO:4, or a complement thereof In a preferred embodiment, an isolated SPOIL-1 nucleic acid molecule encodes the amino acid sequence of murine SPOIL-1.
In another embodiment, a SPOIL-1 nucleic acid molecule further comprises nucleotides 135-431 of SEQ ID NO:1. In yet another preferred embodiment, a SPOIL-1 nucleic acid molecule further comprises nucleotides 186-431 of SEQ ID NO:1.
In yet another preferred embodiment, an isolated SPOIL-1 nucleic acid molecule has the nucleotide sequence shown SEQ ID NO:3 or SEQ ID NO:4.
In another embodiment, a SPOIL-1 nucleic acid molecule includes a nucleotide sequence encoding a protein having an amino acid sequence sufficiently homologous to the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:5. In yet another embodiment, a SPOIL-1 nucleic acid molecule includes a nucleotide sequence encoding a protein having an amino acid sequence at least 60% homologous to the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:5. In a preferred embodiment, a SPOIL-1 nucleic acid molecule includes a nucleotide sequence encoding a protein having the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:5.
In another embodiment, an isolated nucleic acid molecule of the present invention encodes a SPOIL-1 protein which includes an interleukin-1 (IL-1) signature domain, optionally, a signal sequence and is secreted. In another embodiment, an isolated nucleic acid molecule of the present invention encodes a SPOIL-1 protein which includes an IL-1 signature domain and has SPOIL-1 biological activity. The SPOIL-1 nucleic acid molecule can also encode a SPOIL-1 protein and is a naturally occurring nucleotide sequence. In yet another embodiment, an isolated nucleic acid molecule of the present invention encodes a SPOIL-1 protein and comprises a nucleotide sequence which hybridizes under stringent hybridization conditions to a nucleic acid molecule having the nucleotide sequence of SEQ ID NO:3 or SEQ ID NO:4.
In another embodiment, the SPOIL-1 nucleic acid molecule is at least 500 nucleotides in length and hybridizes under stringent conditions to a nucleic acid molecule comprising the nucleotide sequence shown in SEQ ID NO:3, SEQ ID NO:4, or a complement thereof
Another embodiment the invention provides an isolated nucleic acid molecule which is antisense to the coding strand of a SPOIL-1 nucleic acid.
Another aspect of the invention provides a vector comprising a SPOIL-1 nucleic acid molecule. In certain embodiments, the vector is a recombinant expression vector. In a preferred embodiment, the vector comprises the SPOIL-1 nucleic acid sequence of SEQ ID NO:3 or SEQ ID NO:4. In another embodiment, the invention provides a host cell containing a vector of the invention. The invention also provides a method for producing SPOIL-1 protein by culturing in a suitable medium, a host cell of the invention containing a recombinant expression vector such that SPOIL-1 protein is produced.
Another aspect of this invention features isolated or recombinant SPOIL-1 proteins and polypeptides. In one embodiment, an isolated SPOIL-1 protein has an IL-1 signature domain, optionally, a signal sequence, and is secreted. In another embodiment, an isolated SPOIL-1 protein has an IL-1 signature domain and a SPOIL-1 biological activity. In yet another embodiment, an isolated SPOIL-1 protein has an amino acid sequence sufficiently homologous to the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:5. In a preferred embodiment, a SPOIL-1 protein has an amino acid sequence at least about 60% homologous to the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:5. In another embodiment, a SPOIL-1 protein has the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:5.
Another embodiment of the invention features an isolated SPOIL-1 protein which is encoded by a nucleic acid molecule having a nucleotide sequence at least about 65% homologous to a nucleotide sequence of SEQ ID NO:3, SEQ ID NO:4, or a complement thereof. This invention also features an isolated SPOIL-1 protein which is encoded by a nucleic acid molecule having a nucleotide sequence which hybridizes under stringent hybridization conditions to a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:3, SEQ ID NO:4, or a complement thereof.
The SPOIL-1 proteins of the present invention, or biologically active portions thereof, can be operatively linked to a non-SPOIL-1 polypeptide to form SPOIL-1 fusion proteins. The invention further features antibodies that specifically bind SPOIL-1 proteins, such as monoclonal or polyclonal antibodies. In addition, the SPOIL-1 proteins or biologically active portions thereof can be incorporated into pharmaceutical compositions, which optionally include pharmaceutically acceptable carriers.
In another aspect, the present invention provides a method for detecting SPOIL-1 expression in a biological sample by contacting the biological sample with an agent capable of detecting a SPOIL-1 nucleic acid molecule, protein or polypeptide such that the pre

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