Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
1995-03-20
2003-04-01
Kunz, Gary L. (Department: 1647)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S388100, C435S069500, C435S069700, C435S173300, C435S320100, C536S023400, C536S023520
Reexamination Certificate
active
06541610
ABSTRACT:
BACKGROUND OF THE INVENTION
A number of cytokines are known to bind to specific receptor proteins on the surface of target cells. Among the specific receptor proteins that have been identified are tumor necrosis factor receptors and interleukin-1 receptors. Much effort is being directed toward isolation and characterization of a number of receptors in order to study their physiological roles and to explore possible therapeutic uses. The binding of a particular target molecule by a soluble receptor administered to a patient may alleviate disorders mediated by the target molecule.
Tumor necrosis factor-&agr; (TNF&agr;, also known as cachectin) and tumor necrosis factor-&bgr; (TNF&bgr;, also known as lymphotoxin) are homologous mammalian endogenous secretory proteins capable of inducing a wide variety of effects on a large number of cell types. The great similarities in the structural and functional characteristics of these two cytokines have resulted in their collective description as “TNF.” Complementary cDNA clones encoding TNF&agr; (Pennica et al.,
Nature
312:724, 1984) and TNF&bgr; (Gray et al.,
Nature
312:721, 1984) have been isolated, permitting further structural and biological characterization of TNF.
TNF proteins initiate their biological effect on cells by binding to specific TNF receptor (TNF-R) proteins expressed on the plasma membrane of a TNF-responsive cell. TNF&agr; and TNF&bgr; were first shown to bind to a common receptor on the human cervical carcinoma cell line ME-180 (Aggarwal et al.,
Nature
318:665, 1985). Hohmann et al. (
J. Biol. Chem.
264:14927, 1989) reported that at least two different cell surface receptors for TNF exist on different cell types, although the relationship between these TNF-Rs is unclear. These receptors have an apparent molecular mass of about 75-80 kDa and about 55-60 kDa, respectively. In addition to cell surface receptors for TNF, soluble proteins from human urine capable of binding TNF have also been identified (Peetre et al.,
Eur. J. Haematol.
41:414, 1988; Seckinger et al.,
J. Exp. Med.
167:1511, 1988; Seckinger et al.,
J. Biol. Chem.
64:11966, 1989; UK Patent Application, Publ. No. 2 218 101 A to Seckinger et al.; Engelmann et al.,
J. Biol. Chem.
264:11974, 1989).
Interleukin-1&agr; (IL-1&agr;) and interleukin-1&bgr; (IL-1&bgr;) are distantly related polypeptide hormones that play a central role in the regulation of immune and inflammatory responses. These two proteins act on a variety of cell types and have multiple biological activities. The biological activities ascribed to IL-1&agr; and IL-1&bgr; are mediated via at least two classes of plasma membrane bound receptors which bind both IL-1&agr; and IL-1&bgr;. The IL-1 receptors expressed on B cells (referred to herein as type II IL-1 receptors) are different from IL-1 receptors detected on T cells and other cell types (referred to herein as type I IL-1 receptors).
SUMMARY OF THE INVENTION
The present invention is directed to receptors comprising a first tumor necrosis factor receptor (TNF-R) polypeptide covalently linked to a second TNF-R polypeptide. Alternatively, the receptor comprises one or two TNF-R polypeptides covalently linked to one or two interleukin-1 receptor (IL-1R) polypeptides.
The receptors preferably are produced as fusion proteins via recombinant DNA technology. The present invention provides fusion proteins comprising, as one of at least two biologically active polypeptide components, a TNF-R polypeptide. One fusion protein of the present invention comprises two TNF-R polypeptides, preferably joined via a peptide linker.
In another embodiment of the invention, the fusion protein comprises TNF-R and IL-1R. The fusion protein preferably comprises two TNF-R polypeptides and either one or two IL-1R polypeptides.
The present invention also provides isolated DNA sequences encoding the fusion proteins, recombinant expression vectors comprising such DNA sequences, host cells containing the expression vectors, and processes for producing the recombinant fusion proteins by culturing the host cells. Pharmaceutical compositions comprising a purified fusion protein as described above and a suitable diluent, carrier, or excipient are also provided by the present invention. Such compositions are useful in therapy, diagnosis, and assays for conditions mediated by tumor necrosis factor or interleukin-1.
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Immunex Corporation
Kit Gordon
Kunz Gary L.
Sughrue & Mion, PLLC
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