Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Reexamination Certificate
1997-04-30
2001-07-31
Draper, Garnette D. (Department: 1647)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
C530S351000, C514S002600, C514S008100, C514S012200
Reexamination Certificate
active
06268480
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to mammalian cytokine receptor proteins with affinity for IL-13 (including without limitation human and murine receptor proteins), fragments thereof and recombinant polynucleotides and cells useful for expressing such proteins.
BACKGROUND OF THE INVENTION
A variety of regulatory molecules, known as cytokines, have been identified including interleukin-13 (IL-13). Various protein forms of IL-13 and DNA encoding various forms of IL-13 activity are described in McKenzie et al., Proc. Natl. Acad. Sci. USA 90: 3735 (1995); Minty et al., Nature 362: 248 (1993); and Aversa et al., WO94/04680. Thus, the term “IL-13” includes proteins having the sequence and/or biological activity described in these documents, whether produced by recombinant genetic engineering techniques; purified from cell sources producing the factor naturally or upon induction with other factors; or synthesized by chemical techniques; or a combination of the foregoing.
IL-13 is a cytokine that has been implicated in production of several biological activities including: induction of IgG4 and IgE switching, including in human immature B cells (Punnonen et al., J. Immunol. 152: 1094 (1994)); induction of germ line IgE heavy chain (&egr;) transcription and CD23 expression in normal human B cells (Punnonen et al., Proc. Natl. Acad. Sci. USA 90: 3730 (1993)); and induction of B cell proliferation in the presence of CD40L or anti-CD40 mAb (Cocks et al., Int. Immunol. 5: 657 (1993)). Although many activities of IL-13 are similar to those of IL-4, in contrast to IL-4, IL-13 does not have growth promoting effects on activated T cells or T cell clones (Zurawski et al., EMBO J. 12: 2663 (1993)).
Like most cytokines, IL-13 exhibits certain biological activities by interacting with an IL-13 receptor (“IL-13R”) on the surface of target cells. IL-13R and the IL-4 receptor (“IL-4R”) sharing a common component, which is required for receptor activation; however, IL-13 does not bind to cells transfected with the 130 kD IL-4R (Zurawski et al., supra). Thus, the IL-13R must contain at least one other ligand binding chain. Cytokine receptors are commonly composed or two or three chains. The cloning of one ligand binding chain for IL-13 has been recently reported (Hilton et al., Proc. Natl. Acad. Sci. 93: 497-501).
It would be desirable to identify and clone the sequence for any other IL-13 binding chain of IL-13R so that IL-13R proteins can be produced for various reasons, including production of therapeutics and screening for inhibitors of IL-13 binding to the receptor and receptor signaling.
SUMMARY OF THE INVENTION
In accordance with the present invention, polynucleotides encoding the IL-13 binding chains of the interleukin-13 receptor are disclosed, including without limitation those from the murine and human receptors. In certain embodiments, the invention provides an isolated polynucleotide comprising a nucleotide sequence selected from the group consisting of:
(a) the nucleotide sequence of SEQ ID NO: 1 from nucleotide 256 to nucleotide 1404;
(b) the nucleotide sequence of SEQ ID NO: 3 from nucleotide 103 to nucleotide 1242;
(c) a nucleotide sequence varying from the sequence of the nucleotide sequence specified in (a) or (b) as a result of degeneracy of the genetic code;
(d) a nucleotide sequence capable of hybridizing under stringent conditions to the nucleotide specified in (a) or (b);
(e) a nucleotide sequence encoding a species homologue of the sequence specified in (a) or (b); and
(f) an allelic variant of the nucleotide sequence specified in (a) or (b).
Preferably, the nucleotide sequence encodes a protein having a biological activity of the human IL-13 receptor. The nucleotide sequence may be operably linked to an expression control sequence. In preferred embodiments, the polynucleotide comprises the nucleotide sequence of SEQ ID NO: 1 from nucleotide 256 to nucleotide 1404; the nucleotide sequence of SEQ ID NO: 1 from nucleotide 319 to nucleotide 1257; the nucleotide sequence of SEQ ID NO: 1 from nucleotide 1324 to nucleotide 1404; the nucleotide sequence of SEQ ID NO: 3 from nucleotide 103 to nucleotide 1242; the nucleotide sequence of SEQ ID NO: 3 from nucleotide 178 to nucleotide 1125; or the nucleotide sequence of SEQ ID NO: 3 from nucleotide 1189 to nucleotide 1242.
The invention also provides isolated polynucleotides comprising a nucleotide sequence encoding a peptide or protein comprising an amino acid sequence selected from the group consisting of:
(a) the amino acid sequence of SEQ ID NO: 2;
(b) the amino acid sequence of SEQ ID NO: 2 from amino acids 22 to 334;
(c) the amino acid sequence of SEQ ID NO: 2 from amino acids 357 to 383;
(d) the amino acid sequence of SEQ ID NO: 4;
(e) the amino acid sequence of SEQ ID NO: 4 from amino acids 26 to 341;
(f) the amino acid sequence of SEQ ID NO: 4 from amino acids 363 to 380; and
(g) fragments of (a)-(f) having a biological activity of the IL-13 receptor binding chain. Other preferred embodiments encode the amino acid sequence of SEQ ID NO: 2 from amino acids 1 or 331 and the amino acid sequence of SEQ ID NO: 2 from amino acids 26 to 331.
Host cells, preferably mammalian cells, transformed with the polynucleotides are also provided.
In other embodiments, the invention provides a process for producing a IL-13bc protein. The process comprises:
(a) growing a culture of the host cell of the present invention in a suitable culture medium; and
(b) purifying the human IL-13bc protein from the culture.
Proteins produced according to these methods are also provided.
The present invention also provides for an isolated IL-13bc protein comprising an amino acid sequence selected from the group consisting of:
(a) the amino acid sequence of SEQ ID NO: 2;
(b) the amino acid sequence of SEQ ID NO: 2 from amino acids 22 to 334;
(c) the amino acid sequence of SEQ ID NO: 2 from amino acids 357 to 383;
(d) the amino acid sequence of SEQ ID NO: 4;
(e) the amino acid sequence of SEQ ID NO: 4 from amino acids 26 to 341;
(f) the amino acid sequence of SEQ ID NO: 4 from amino acids 363 to 380; and
(g) fragments of (a)-(f) having a biological activity of the IL-13 receptor binding chain
Preferably the protein comprises the amino acid sequence of SEQ ID NO: 2; the sequence from amino acid 22 to 334 of SEQ ID NO: 2; the sequence of SEQ ID NO: 4; or the sequence from amino acid 26 to 341 of SEQ ID NO: 4. In other preferred embodiments, the specified amino acid sequence is part of a fusion protein (with an additional amino acid sequence not derived from IL-13bc). Preferred fusion proteins comprise an antibody fragment, such as an Fc fragment. Particularly preferred embodiments comprise the amino acid sequence of SEQ ID NO: 2 from amino acids 1 to 331 and the amino acid sequence of SEQ ID NO: 2 from amino acids 26 to 331.
Pharmaceutical compositions comprising a protein of the present invention and a pharmaceutically acceptable carrier are also provided.
The present invention further provides for compositions comprising an antibody which specifically reacts with a protein of the present invention.
Methods of identifying an inhibitor of IL-13 binding to the IL-13bc or IL-13 receptor are also provided. These methods comprise:
(a) combining an IL-13bc protein or a fragment thereof with IL-13 or a fragment thereof, said combination forming a first binding mixture;
(b) measuring the amount of binding between the protein and the IL-13 or fragment in the first binding mixture;
(c) combining a compound with the protein and the IL-13 or fragment to form a second binding mixture;
(d) measuring the amount of binding in the second binding mixture; and
(e) comparing the amount of binding in the first binding mixture with the amount of binding in the second binding mixture;
wherein the compound is capable of inhibiting IL-13 binding to the IL-13bc protein or IL-13 receptor when a decrease in the amount of binding of the second binding mixture occurs. Inhibitors of IL-13R identified by these methods are pharmaceutical compositions containing them are also prov
Collins Mary
Donaldson Debra
Fitz Lori
Neben Tamlyn
Whitters Matthew
Draper Garnette D.
Genetics Institute Inc.
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