08/752,912, filed November 20, 1996; and Ser. No. 08/800,826, filed February 14, 1997; all of which are incorporated by reference herein.

FIELD OF THE INVENTION The present invention provides novel polynucleotides and proteins encoded by such polynucleotides, along with therapeutic, diagnostic and research utilities for these polynucleotides and proteins.

BACKGROUND OF THE INVENTION Technology aimed at the discovery of protein factors (including e.g., cytokines, such as lymphokines, interferons, CSFs and interleukins) has matured rapidly over the past decade. The now routine hybridization cloning and expression cloning techniques clone novel polynucleotides "directly" in the sense that they rely on information directly related to the discovered protein (i.e., partial DNA/amino acid sequence of the protein in the case of hybridization cloning; activity of the protein in the case of expression cloning). More recent "indirect" cloning techniques such as signal sequence cloning, which isolates DNA sequences based on the presence of a now well-recognized secretory leader sequence motif, as well as various PCR-based or low stringency hybridization cloning techniques, have advanced the state of the art by making available large numbers of DNA/amino acid sequences for proteins that are known to have biological activity by virtue of their secreted nature in the case of leader sequence cloning, or by virtue of the cell or tissue source in the case of PCR-based techniques. It is to these proteins and the polynucleotides encoding them that the present invention is directed.

SUMMARY OF THE INVENTION In one embodiment, the present invention provides a composition comprising an isolated polynucleotide selected from the group consisting of: (a) a polynucleotide comprising the nucleotide sequence of SEQ ID NO:2; (b) a polynucleotide comprising the nucleotide sequence of SEQ ID NO:2 from nucleotide 390 to nucleotide 563; (c) a polynucleotide comprising the nucleotide sequence of the full- length protein coding sequence of clone BD441~1 deposited under accession number ATCC 98264; (d) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone BD441~1 deposited under accession number ATCC 98264; (e) a polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of clone BD441~1 deposited under accession number ATCC 98264; (f) a polynucleotide encoding the mature protein encoded by the cDNA insert of clone BD441~1 deposited under accession number ATCC 98264; (g) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO:3; (h) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO:3 having biological activity; (i) a polynucleotide which is an allelic variant of a polynucleotide of (a)-(f) above; (j) a polynucleotide which encodes a species homologue of the protein of (g) or (h) above ; and (k) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a)-(h).

Preferably, such polynucleotide comprises the nucleotide sequence of SEQ ID NO:2 from nucleotide 390 to nucleotide 563; the nucleotide sequence of the full-length protein coding sequence of clone BD441~1 deposited under accession number ATCC 98264; or the nucleotide sequence of the mature protein coding sequence of clone BD441~1 deposited under accession number ATCC 98264. In other preferred embodiments, the polynucleotide encodes the full-length or mature protein encoded by the cDNA insert of clone BD441~1 deposited under accession number ATCC 98264.

Other embodiments provide the gene corresponding to the cDNA sequence of SEQ ID NO:2, SEQ ID NO:1 or SEQ ID NO:4 .

In other embodiments, the present invention provides a composition comprising a protein, wherein said protein comprises an amino acid sequence selected from the group consisting of: (a) the amino acid sequence of SEQ ID NO:3; (b) fragments of the amino acid sequence of SEQ ID NO:3; and (c) the amino acid sequence encoded by the cDNA insert of clone BD441~1 deposited under accession number ATCC 98264; the protein being substantially free from other mammalian proteins. Preferably such protein comprises the amino acid sequence of SEQ ID NO:3.

In one embodiment, the present invention provides a composition comprising an isolated polynucleotide selected from the group consisting of: (a) a polynucleotide comprising the nucleotide sequence of SEQ ID NO:5; (b) a polynucleotide comprising the nucleotide sequence of SEQ ID NO:5 from nucleotide 583 to nucleotide 756; (c) a polynucleotide comprising the nucleotide sequence of the full- length protein coding sequence of clone BD441~2 deposited under accession number ATCC 98264; (d) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone BD441~2 deposited under accession number ATCC 98264; (e) a polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of clone BD441~2 deposited under accession number ATCC 98264; (f) a polynucleotide encoding the mature protein encoded by the cDNA insert of clone BD441~2 deposited under accession number ATCC 98264; (g) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO:6; (h) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO:6 having biological activity; (i) a polynucleotide which is an allelic variant of a polynucleotide of (a)-(f) above;

(j) a polynucleotide which encodes a species homologue of the protein of (g) or (h) above ; and (k) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a)-(h).

Preferably, such polynucleotide comprises the nucleotide sequence of SEQ ID NO:5 from nucleotide 583 to nucleotide 756; the nucleotide sequence of the full-length protein coding sequence of clone BD441~2 deposited under accession number ATCC 98264; or the nucleotide sequence of the mature protein coding sequence of clone BD441~2 deposited under accession number ATCC 98264. In other preferred embodiments, the polynucleotide encodes the full-length or mature protein encoded by the cDNA insert of clone BD441~2 deposited under accession number ATCC 98264.

Other embodiments provide the gene corresponding to the cDNA sequence of SEQ ID NO:5 or SEQ ID NO:7.

In other embodiments, the present invention provides a composition comprising a protein, wherein said protein comprises an amino acid sequence selected from the group consisting of: (a) the amino acid sequence of SEQ ID NO:6; (b) fragments of the amino acid sequence of SEQ ID NO:6; and (c) the amino acid sequence encoded by the cDNA insert of clone BD441~2 deposited under accession number ATCC 98264; the protein being substantially free from other mammalian proteins. Preferably such protein comprises the amino acid sequence of SEQ ID NO:6.

In one embodiment, the present invention provides a composition comprising an isolated polynucleotide selected from the group consisting of: (a) a polynucleotide comprising the nucleotide sequence of SEQ ID NO:8; (b) a polynucleotide comprising the nucleotide sequence of SEQ ID NO:8 from nucleotide 426 to nucleotide 581; (c) a polynucleotide comprising the nucleotide sequence of SEQ ID NO:8 from nucleotide 495 to nucleotide 581; (d) a polynucleotide comprising the nucleotide sequence of SEQ ID NO:8 from nucleotide 354 to nucleotide 503;

(e) a polynucleotide comprising the nucleotide sequence of the full- length protein coding sequence of clone BG102~3 deposited under accession number ATCC 98264; (f) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone BG102~3 deposited under accession number ATCC 98264; (g) a polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of clone Big102~3 deposited under accession number ATCC 98264; (h) a polynucleotide encoding the mature protein encoded by the cDNA insert of clone BG102~3 deposited under accession number ATCC 98264; (i) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO:9; (j) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO:9 having biological activity; (k) a polynucleotide which is an allelic variant of a polynucleotide of (a)-(h) above; (1) a polynucleotide which encodes a species homologue of the protein of (i) or (j) above ; and (m) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a)-(j).

Preferably, such polynucleotide comprises the nucleotide sequence of SEQ ID NO:8 from nucleotide 426 to nucleotide 581; the nucleotide sequence of SEQ ID NO:8 from nucleotide 495 to nucleotide 581; the nucleotide sequence of SEQ ID NO:8 from nucleotide 354 to nucleotide 503; the nucleotide sequence of the full-length protein coding sequence of clone BG102~3 deposited under accession number ATCC 98264; or the nucleotide sequence of the mature protein coding sequence of clone BG102~3 deposited under accession number ATCC 98264. In other preferred embodiments, the polynucleotide encodes the full-length or mature protein encoded by the cDNA insert of clone BG102~3 deposited under accession number ATCC 98264. In yet other preferred embodiments, the present invention provides a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO:9 from amino acid 1 to amino acid 26.

Other embodiments provide the gene corresponding to the cDNA sequence of SEQ ID NO:8.

In other embodiments, the present invention provides a compositibn comprising a protein, wherein said protein comprises an amino acid sequence selected from the group consisting of: (a) the amino acid sequence of SEQ ID NO:9; (b) the amino acid sequence of SEQ ID NO:9 from amino acid 1 to amino acid 26; (c) fragments of the amino acid sequence of SEQ ID NO:9; and (d) the amino acid sequence encoded by the cDNA insert of clone BG102~3 deposited under accession number ATCC 98264; the protein being substantially free from other mammalian proteins. Preferably such protein comprises the amino acid sequence of SEQ ID NO:9 or the amino acid sequence of SEQ ID NO:9 from amino acid 1 to amino acid 26.

In one embodiment, the present invention provides a composition comprising an isolated polynucleotide selected from the group consisting of: (a) a polynucleotide comprising the nucleotide sequence of SEQ ID NO:10; (b) a polynucleotide comprising the nucleotide sequence of SEQ ID NO:10 from nucleotide 112 to nucleotide 978; (c) a polynucleotide comprising the nucleotide sequence of SEQ ID NO:10 from nucleotide 436 to nucleotide 1048; (d) a polynucleotide comprising the nucleotide sequence of the full- length protein coding sequence of clone BK158~1 deposited under accession number ATCC 98264; (e) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone BK158~1 deposited under accession number ATCC 98264; (f) a polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of clone BK158~1 deposited under accession number ATCC 98264; (g) a polynucleotide encoding the mature protein encoded by the cDNA insert of clone BK158~1 deposited under accession number ATCC 98264; (h) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO:11; (i) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO:11 having biological activity;

(j) a polynucleotide which is an allelic variant of a polynucleotide of (a)-(g) above; (k) a polynucleotide which encodes a species homologue of the protein of (h) or (i) above; and (1) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a)-(i).

Preferably, such polynucleotide comprises the nucleotide sequence of SEQ ID NO:10 from nucleotide 112 to nucleotide 978; the nucleotide sequence of SEQ ID NO:10 from nucleotide 436 to nucleotide 1048; the nucleotide sequence of the full-length protein coding sequence of clone BK158~1 deposited under accession number ATCC 98264; or the nucleotide sequence of the mature protein coding sequence of clone BK158~1 deposited under accession number ATCC 98264. In other preferred embodiments, the polynucleotide encodes the full-length or mature protein encoded by the cDNA insert of clone BK158~1 deposited under accession number ATCC 98264.

Other embodiments provide the gene corresponding to the cDNA sequence of SEQ ID NO:10.

In other embodiments, the present invention provides a composition comprising a protein, wherein said protein comprises an amino acid sequence selected from the group consisting of: (a) the amino acid sequence of SEQ ID NO:11; (b) fragments of the amino acid sequence of SEQ ID NO:11; and (c) the amino acid sequence encoded by the cDNA insert of clone BK158~1 deposited under accession number ATCC 98264; the protein being substantially free from other mammalian proteins. Preferably such protein comprises the amino acid sequence of SEQ ID NO:11.

In one embodiment, the present invention provides a composition comprising an isolated polynucleotide selected from the group consisting of: (a) a polynucleotide comprising the nucleotide sequence of SEQ ID NO:12; (b) a polynucleotide comprising the nucleotide sequence of SEQ ID NO:12 from nucleotide 16 to nucleotide 492; (c) a polynucleotide comprising the nucleotide sequence of the full- length protein coding sequence of clone BP163~1 deposited under accession number ATCC 98264;

(d) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone BP163~1 deposited under accession number ATCC 98264; (e) a polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of clone BP163~1 deposited under accession number ATCC 98264; (f) a polynucleotide encoding the mature protein encoded by the cDNA insert of clone BP163~1 deposited under accession number ATCC 98264; (g) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO:13; (h) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO:13 having biological activity; (i) a polynucleotide which is an allelic variant of a polynucleotide of (a)-(f) above; (j) a polynucleotide which encodes a species homologue of the protein of (g) or (h) above; and (k) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a)-(h).

Preferably, such polynucleotide comprises the nucleotide sequence of SEQ ID NO:12 from nucleotide 16 to nucleotide 492; the nucleotide sequence of the full-length protein coding sequence of clone BP163~1 deposited under accession number ATCC 98264; or the nucleotide sequence of the mature protein coding sequence of clone BP163~1 deposited under accession number ATCC 98264. In other preferred embodiments, the polynucleotide encodes the full-length or mature protein encoded by the cDNA insert of clone BP163~1 deposited under accession number ATCC 98264.

Other embodiments provide the gene corresponding to the cDNA sequence of SEQ ID NO:12 or SEQ ID NO:14.

In other embodiments, the present invention provides a composition comprising a protein, wherein said protein comprises an amino acid sequence selected from the group consisting of: (a) the amino acid sequence of SEQ ID NO:13; (b) fragments of the amino acid sequence of SEQ ID NO:13; and (c) the amino acid sequence encoded by the cDNA insert of clone BP163~1 deposited under accession number ATCC 98264;

the protein being substantially free from other mammalian proteins. Preferably such protein comprises the amino acid sequence of SEQ ID NO:13.

In one embodiment, the present invention provides a composition comprising an isolated polynucleotide selected from the group consisting of: (a) a polynucleotide comprising the nucleotide sequence of SEQ ID NO:16; (b) a polynucleotide comprising the nucleotide sequence of SEQ ID NO:16 from nucleotide 72 to nucleotide 569; (c) a polynucleotide comprising the nucleotide sequence of the full- length protein coding sequence of clone BZ16~3 deposited under accession number ATCC 98264; (d) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone BZ16~3 deposited under accession number ATCC 98264; (e) a polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of clone BZ16~3 deposited under accession number ATCC 98264; (f) a polynucleotide encoding the mature protein encoded by the cDNA insert of clone BZ16~3 deposited under accession number ATCC 98264; (g) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO:17; (h) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO:17 having biological activity; (i) a polynucleotide which is an allelic variant of a polynucleotide of (a)-(f) above; (j) a polynucleotide which encodes a species homologue of the protein of (g) or (h) above; and (k) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a)-(h).

Preferably, such polynucleotide comprises the nucleotide sequence of SEQ ID NO:16 from nucleotide 72 to nucleotide 569; the nucleotide sequence of the full-length protein coding sequence of clone BZ16~3 deposited under accession number ATCC 98264; or the nucleotide sequence of the mature protein coding sequence of clone BZ16~3 deposited under accession number ATCC 98264. In other preferred embodiments, the polynucleotide encodes the full-length or mature protein encoded by the cDNA insert of

clone BZ16~3 deposited under accession number ATCC 98264. In yet other preferred embodiments, the present invention provides a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO:17 from amino acid 1 to amino acid 124.

Other embodiments provide the gene corresponding to the cDNA sequence of SEQ ID NO:16 or SEQ ID NO:15.

In other embodiments, the present invention provides a composition comprising a protein, wherein said protein comprises an amino acid sequence selected from the group consisting of: (a) the amino acid sequence of SEQ ID NO:17; (b) the amino acid sequence of SEQ ID NO:17 from amino acid 1 to amino acid 124; (c) fragments of the amino acid sequence of SEQ ID NO:17; and (d) the amino acid sequence encoded by the cDNA insert of clone BZ16~3 deposited under accession number ATCC 98264; the protein being substantially free from other mammalian proteins. Preferably such protein comprises the amino acid sequence of SEQ ID NO:17 or the amino acid sequence of SEQ ID NO:17 from amino acid 1 to amino acid 124.

In one embodiment, the present invention provides a composition comprising an isolated polynucleotide selected from the group consisting of: (a) a polynucleotide comprising the nucleotide sequence of SEQ ID NO:18; (b) a polynucleotide comprising the nucleotide sequence of SEQ ID NO:18 from nucleotide 405 to nucleotide 662; (c) a polynucleotide comprising the nucleotide sequence of SEQ ID NO:18 from nucleotide 519 to nucleotide 662; (d) a polynucleotide comprising the nucleotide sequence of SEQ ID NO:18 from nucleotide 1 to nucleotide 584; (e) a polynucleotide comprising the nucleotide sequence of the full- length protein coding sequence of clone CC182~1 deposited under accession number ATCC 98264; (f) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone CC182~1 deposited under accession number ATCC 98264;

(g) a polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of clone CC182~1 deposited under accession number ATCC 98264; (h) a polynucleotide encoding the mature protein encoded by the cDNA insert of clone CC182~1 deposited under accession number ATCC 98264; (i) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO:19; (j) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO:19 having biological activity; (k) a polynucleotide which is an allelic variant of a polynucleotide of (a)-(h) above; (1) a polynucleotide which encodes a species homologue of the protein of (i) or (j) above; and (m) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a)-(j).

Preferably, such polynucleotide comprises the nucleotide sequence of SEQ ID NO:18 from nucleotide 405 to nucleotide 662; the nucleotide sequence of SEQ ID NO:18 from nucleotide 519 to nucleotide 662; the nucleotide sequence of SEQ ID NO:18 from nucleotide 1 to nucleotide 584; the nucleotide sequence of the full-length protein coding sequence of clone CC182~1 deposited under accession number ATCC 98264; or the nucleotide sequence of the mature protein coding sequence of clone CC182~1 deposited under accession number ATCC 98264. In other preferred embodiments, the polynucleotide encodes the full-length or mature protein encoded by the cDNA insert of clone CC182~1 deposited under accession number ATCC 98264. In yet other preferred embodiments, the present invention provides a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO:19 from amino acid 1 to amino acid 60.

Other embodiments provide the gene corresponding to the cDNA sequence of SEQ ID NO:18.

In other embodiments, the present invention provides a composition comprising a protein, wherein said protein comprises an amino acid sequence selected from the group consisting of: (a) the amino acid sequence of SEQ ID NO:19;

(b) the amino acid sequence of SEQ ID NO:19 from ainino acid 1 to amino acid 60; (c) fragments of the amino acid sequence of SEQ ID NO:19; and (d) the amino acid sequence encoded by the cDNA insert of clone CC182~1 deposited under accession number ATCC 98264; the protein being substantially free from other mammalian proteins. Preferably such protein comprises the amino acid sequence of SEQ ID NO:19 or the amino acid sequence of SEQ ID NO:19 from amino acid 1 to amino acid 60.

In one embodiment, the present invention provides a composition comprising an isolated polynucleotide selected from the group consisting of: (a) a polynucleotide comprising the nucleotide sequence of SEQ ID NO:20; (b) a polynucleotide comprising the nucleotide sequence of SEQ ID NO:20 from nucleotide 311 to nucleotide 409; (c) a polynucleotide comprising the nucleotide sequence of SEQ ID NO:20 from nucleotide 24 to nucleotide 414; (d) a polynucleotide comprising the nucleotide sequence of the full- length protein coding sequence of clone CG109~1 deposited under accession number ATCC 98264; (e) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone CG109~1 deposited under accession number ATCC 98264; (f) a polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of clone CG109~1 deposited under accession number ATCC 98264; (g) a polynucleotide encoding the mature protein encoded by the cDNA insert of clone CG109~1 deposited under accession number ATCC 98264; (h) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO:21; (i) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO:21 having biological activity; (j) a polynucleotide which is an allelic variant of a polynucleotide of (a)-(g) above; (k) a polynucleotide which encodes a species homologue of the protein of (h) or (i) above ; and

(1) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a)-(i).

Preferably, such polynucleotide comprises the nucleotide sequence of SEQ ID NO:20 from nucleotide 311 to nucleotide 409; the nucleotide sequence of SEQ ID NO:20 from nucleotide 24 to nucleotide 414; the nucleotide sequence of the full-length protein coding sequence of clone CG109~1 deposited under accession number ATCC 98264; or the nucleotide sequence of the mature protein coding sequence of clone CG109~1 deposited under accession number ATCC 98264. In other preferred embodiments, the polynucleotide encodes the full-length or mature protein encoded by the cDNA insert of clone CG109~1 deposited under accession number ATCC 98264.

Other embodiments provide the gene corresponding to the cDNA sequence of SEQ ID NO:20.

In other embodiments, the present invention provides a composition comprising a protein, wherein said protein comprises an amino acid sequence selected from the group consisting of: (a) the amino acid sequence of SEQ ID NO:21; (b) fragments of the amino acid sequence of SEQ ID NO:21; and (c) the amino acid sequence encoded by the cDNA insert of clone CG109~1 deposited under accession number ATCC 98264; the protein being substantially free from other mammalian proteins. Preferably such protein comprises the amino acid sequence of SEQ ID NO:21.

In one embodiment, the present invention provides a composition comprising an isolated polynucleotide selected from the group consisting of: (a) a polynucleotide comprising the nucleotide sequence of SEQ ID NO:23; (b) a polynucleotide comprising the nucleotide sequence of SEQ ID NO:23 from nucleotide 471 to nucleotide 611; (c) a polynucleotide comprising the nucleotide sequence of the full- length protein coding sequence of clone CJ397~1 deposited under accession number ATCC 98264; (d) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone CJ397~1 deposited under accession number ATCC 98264;

(e) a polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of clone CJ397~1 deposited under accession number ATCC 98264; (f) a polynucleotide encoding the mature protein encoded by the cDNA insert of clone CJ3971 deposited under accession number ATCC 98264; (g) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO:24; (h) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO:24 having biological activity; (i) a polynucleotide which is an allelic variant of a polynucleotide of.

(a)-(f) above; (j) a polynucleotide which encodes a species homologue of the protein of (g) or (h) above; and (k) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a)-(h).

Preferably, such polynucleotide comprises the nucleotide sequence of SEQ ID NO:23 from nucleotide 471 to nucleotide 611; the nucleotide sequence of the full-length protein coding sequence of clone CJ3971 deposited under accession number ATCC 98264; or the nucleotide sequence of the mature protein coding sequence of clone CJ397~1 deposited under accession number ATCC 98264. In other preferred embodiments, the polynucleotide encodes the full-length or mature protein encoded by the cDNA insert of clone CJ397~1 deposited under accession number ATCC 98264.

Other embodiments provide the gene corresponding to the cDNA sequence of SEQ ID NO:23, SEQ ID NO:22 or SEQ ID NO:25 .

In other embodiments, the present invention provides a composition comprising a protein, wherein said protein comprises an amino acid sequence selected from the group consisting of: (a) the amino acid sequence of SEQ ID NO:24; (b) fragments of the amino acid sequence of SEQ ID NO:24; and (c) the amino acid sequence encoded by the cDNA insert of clone CJ397~1 deposited under accession number ATCC 98264; the protein being substantially free from other mammalian proteins. Preferably such protein comprises the amino acid sequence of SEQ ID NO:24.

In certain preferred embodiments, the polynucleotide is operably linked to an expression control sequence. The invention also provides a host cell, including bacterial, yeast, insect and mammalian cells, transformed with such polynucleotide compositions.

Processes are also provided for producing a protein, which comprise: (a) growing a culture of the host cell transformed with such polynucleotide compositions in a suitable culture medium; and (b) purifying the protein from the culture.

The protein produced according to such methods is also provided by the present invention. Preferred embodiments include those in which the protein produced by such process is a mature form of the protein.

Protein compositions of the present invention may further comprise a pharmaceutically acceptable carrier. Compositions comprising an antibody which specifically reacts with such protein are also provided by the present invention.

Methods are also provided for preventing, treating or ameliorating a medical condition which comprises administering to a mammalian subject a therapeutically effective amount of a composition comprising a protein of the present invention and a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS Figures 1A and 1B are schematic representations of the pED6 and pNOTs vectors, respectively, used for deposit of clones disclosed herein.

DETAILED DESCRIPTION ISOLATED PROTEINS AND POLYNUCLEOTIDES Nucleotide and amino acid sequences, as presently determined, are reported below for each clone and protein disclosed in the present application. The nucleotide sequence of each clone can readily be determined by sequencing of the deposited clone in accordance with known methods. The predicted amino acid sequence (both full-length and mature) can then be determined from such nucleotide sequence. The amino acid sequence of the protein encoded by a particular clone can also be determined by expression of the clone in a suitable host cell, collecting the protein and determining its sequence. For each disclosed protein applicants have identified what they have determined to be the reading frame best identifiable with sequence information available at the time of filing.

As used herein a "secreted" protein is one which, when expressed in a suitable host cell, is transported across or through a membrane, including transport as a result of signal sequences in its amino acid sequence. "Secreted" proteins include without limitation proteins secreted wholly (e.g., soluble proteins) or partially (e.g., receptors) from the cell in which they are expressed. "Secreted" proteins also include without limitation proteins which are transported across the membrane of the endoplasmic reticulum.

Clone"BD441 1" A polynucleotide of the present invention has been identified as clone "BD441~1".

BD441~1 was isolated from a human fetal kidney cDNA library using methods which are selective for cDNAs encoding secreted proteins (see U.S. Pat. No. 5,536,637), or was identified as encoding a secreted or transmembrane protein on the basis of computer analysis of the amino acid sequence of the encoded protein. BD441~1 is a full-length clone, including the entire coding sequence of a secreted protein (also referred to herein as "BD441~1 protein").

The nucleotide sequence of the 5' portion of BD441~1 as presently determined is reported in SEQ ID NO:1. An additional internal nucleotide sequence from BD441~1 as presently determined is reported in SEQ ID NO:2. What applicants believe is the proper reading frame and the predicted amino acid sequence encoded by such internal sequence is reported in SEQ ID NO:3. Additional nucleotide sequence from the 3' portion of BD441~1, including the polyA tail, is reported in SEQ ID NO:4.

The EcoRI/NotI restriction fragment obtainable from the deposit containing clone BD441~1 should be approximately 2400 bp.

The predicted amino acid sequence disclosed herein for BD441~1 was searched against the GenPept and GeneSeq amino acid sequence databases using the BLASTX search protocol. The predicted BD441~1 protein demonstrated at least some similarity to sequences identified as X61615 (leukemia inhibitory factor receptor [Homo sapiens]).

Based upon sequence similarity, BD441~1 proteins and each similar protein or peptide may share at least some activity.

Clone "BD441 2" A polynucleotide of the present invention has been identified as clone "BD441~2".

BD441~2 was isolated from a human fetal kidney cDNA library using methods which are selective for cDNAs encoding secreted proteins (see U.S. Pat. No. 5,536,637), or was

identified as encoding a secreted or transmembrane protein on the basis of computer analysis of the amino acid sequence of the encoded protein. BD441~2 is a full-length clone, including the entire coding sequence of a secreted protein (also referred to herein as "BD441~2 protein").

The nucleotide sequence of the 5' portion of BD441~2 as presently determined is reported in SEQ ID NO:5. What applicants presently believe is the proper reading frame for the coding region is indicated in SEQ ID NO:6. The predicted amino acid sequence of the BD441~2 protein corresponding to the foregoing nucleotide sequence is reported in SEQ ID NO:6. Additional nucleotide sequence from the 3' portion of BD441~2, including the polyA tail, is reported in SEQ ID NO:7.

The EcoRI/NotI restriction fragment obtainable from the deposit containing clone BD441~2 should be approximately 1200 bp.

The predicted amino acid sequence disclosed herein for BD441~2 was searched against the GenPept and GeneSeq amino acid sequence databases using the BLASTX search protocol. The predicted BD441~2 protein demonstrated at least some similarity to sequences identified as X61615 (leukemia inhibitory factor receptor [Homo sapiens]).

Based upon sequence similarity, BD441~2 proteins and each similar protein or peptide may share at least some activity.

Clone "BG102 3" A polynucleotide of the present invention has been identified as clone "BG102~3".

BG102~3 was isolated from a human adult brain cDNA library using methods which are selective for cDNAs encoding secreted proteins (see U.S. Pat. No. 5,536,637), or was identified as encoding a secreted or transmembrane protein on the basis of computer analysis of the amino acid sequence of the encoded protein. BG102~3 is a full-length clone, including the entire coding sequence of a secreted protein (also referred to herein as "BG102~3 protein").

The nucleotide sequence of BG102~3 as presently determined is reported in SEQ ID NO:8. What applicants presently believe to be the proper reading frame and the predicted amino acid sequence of the BG102~3 protein corresponding to the foregoing nucleotide sequence is reported in SEQ ID NO:9. Amino acids 11 to 23 are a predicted leader/signal sequence, with the predicted mature amino acid sequence beginning at amino acid 24, or are a transmembrane domain.

The EcoRI/NotI restriction fragment obtainable from the deposit containing clone BG102~3 should be approximately 1100 bp.

The nucleotide sequence disclosed herein for BG102~3 was searched against the GenBank and GeneSeq nucleotide sequence databases using BLASTN/BLASTX and FASTA search protocols. BG102~3 demonstrated at least some similarity with sequences identified as AC002078 (Human BAC clone RGlllH14 from 7q22, complete sequence), L11910 (Human retinoblastoma susceptibility gene exons 1-27, complete cds), U62317 (Chromosome 22q13 BAC Clone CIT987SK-384D8 complete sequence), Z54147 (Human DNA sequence from cosmid L129H7, Huntington's Disease Region, chromosome 4p16.3 contains CpG island), Z75747 (Human DNA sequence from cosmid U96H1, between markers DXS366 and DXS87 on chromosome X *), and Z80899 (Human DNA sequence from cosmid F1121 on chromosome 6). The predicted amino acid sequence disclosed herein for BG102~3 was searched against the GenPept and GeneSeq amino acid sequence databases using the BLASTX search protocol. The predicted BG102~3 protein demonstrated at least some similarity to sequences identified as M13100 (unknown protein [Rattus norvegicus]) and U15647 (reverse transcriptase [Mus musculus]). Based upon sequence similarity, BG102 3 proteins and each similar protein or peptide may share at least some activity. The nucleotide sequence of BG102~3 indicates that it may contain an L1 repetitive element.

Clone "BK158 1" A polynucleotide of the present invention has been identified as clone "BK158~1".

BK158~1 was isolated from a human adult muscle cDNA library using methods which are selective for cDNAs encoding secreted proteins (see U.S. Pat. No. 5,536,637), or was identified as encoding a secreted or transmembrane protein on the basis of computer analysis of the amino acid sequence of the encoded protein. BK158~1 is a full-length clone, including the entire coding sequence of a secreted protein (also referred to herein as "BK158~1 protein").

The nucleotide sequence of BK158~1 as presently determined is reported in SEQ ID NO:10. What applicants presently believe to be the proper reading frame and the predicted amino acid sequence of the BK158~1 protein corresponding to the foregoing nucleotide sequence is reported in SEQ ID NO:11.

The EcoRI/NotI restriction fragment obtainable from the deposit containing clone BK158~1 should be approximately 1150 bp.

The nucleotide sequence disclosed herein for BK158~1 was searched against the GenBank and GeneSeq nucleotide sequence databases using BLASTN/BLASTX and FASTA search protocols. BK158~1 demonstrated at least some similarity with sequences identified as N39195 (yv26e08.sl Homo sapiens cDNA clone 243878 3') and N45263 (yv26e08.rl Homo sapiens cDNA clone 243878 5'). Based upon sequence similarity, BK158~1 proteins and each similar protein or peptide may share at least some activity.

Clone "BP163 1" A polynucleotide of the present invention has been identified as clone "BP163~1".

BP163~1 was isolated from a human fetal kidney cDNA library using methods which are selective for cDNAs encoding secreted proteins (see U.S. Pat. No. 5,536,637), or was identified as encoding a secreted or transmembrane protein on the basis of computer analysis of the amino acid sequence of the encoded protein. BP163~1 is a full-length clone, including the entire coding sequence of a secreted protein (also referred to herein as "BP163~1 protein").

The nucleotide sequence of the 5' portion of BP163~1 as presently determined is reported in SEQ ID NO:12. What applicants presently believe is the proper reading frame for the coding region is indicated in SEQ ID NO:13. The predicted amino acid sequence of the BP163~1 protein corresponding to the foregoing nucleotide sequence is reported in SEQ ID NO:13. Additional nucleotide sequence from the 3' portion of BP163~1, including the polyA tail, is reported in SEQ ID NO:14.

The EcoRI/NotI restriction fragment obtainable from the deposit containing clone BP163~1 should be approximately 1240 bp.

The nucleotide sequence disclosed herein for BP163~1 was searched against the GenBank and GeneSeq nucleotide sequence databases using BLASTN/BLASTX and FASTA search protocols. BP163~1 demonstrated at least some similarity with sequences identified as AA187086 (zp58h06.rl Stratagene endothelial cell 937223 Homo sapiens cDNA clone 624443 5' similar to TR G285943 G285943 ORF, COMPLETE CDS), AA301506 (EST14475 Testis tumor Homo sapiens cDNA 5' end similar to hypothetical protein (GB D14659)), D14659 (Human mRNA for KIAA0103 gene, complete cds), and W57328 (ma26d10.rl Life Tech mouse brain Mus musculus cDNA clone). The predicted amino acid sequence disclosed herein for BP163~1 was searched against the GenPept and GeneSeq amino acid sequence databases using the BLASTX search protocol. The predicted BP163~1 protein demonstrated at least some similarity to sequences identified

as D14659 (KIAA0103 [Homo sapiens]). Based upon sequence similarity, BP163~1 proteins and each similar protein or peptide may share at least some activity.

Clone"BZ16 3" A polynucleotide of the present invention has been identified as clone "BZ16~3".

BZ16~3 was isolated from a human fetal kidney cDNA library using methods which are selective for cDNAs encoding secreted proteins (see U.S. Pat. No. 5,536,637), or was identified as encoding a secreted or transmembrane protein on the basis of computer analysis of the amino acid sequence of the encoded protein. BZ16~3 is a full-length clone, including the entire coding sequence of a secreted protein (also referred to herein as "BZ16~3 protein").

The partial nucleotide sequence of By16~3, including its 3' end and any identified polyA tail, as presently determined is reported in SEQ ID NO:16. What applicants presently believe is the proper reading frame for the coding region is indicated in SEQ ID NO:17. The predicted amino acid sequence of the BZ16~3 protein corresponding to the foregoing nucleotide sequence is reported in SEQ ID NO:17. Additional nucleotide sequence from the 5' portion of BZ16~3 is reported in SEQ ID NO:15.

The EcoRI/NotI restriction fragment obtainable from the deposit containing clone BZ16~3 should be approximately 2120 bp.

The nucleotide sequence disclosed herein for BZ16~3 was searched against the GenBank and GeneSeq nucleotide sequence databases using BLASTN/BLASTX and FASTA search protocols. BZ16~3 demonstrated at least some similarity with sequences identified as F06886 (H. sapiens partial cDNA sequence; clone c-lnf02), F06870 (H. sapiens partial cDNA sequence; clone c-lncll), N53511 (yz26b08.sl Homo sapiens cDNA clone 284151 3'), T65313 (yc79g12.sl Homo sapiens cDNA clone 22132 3'), U00084 (Haemophilus influenzae), W44815 (zc21dO1.s1 Soares senescent fibroblasts NbHSF Homo sapiens cDNA clone 322945 3'), and Z49128 (Caenorhabditis elegans cosmid M03C11). The predicted amino acid sequence disclosed herein for BZ16~3 was searched against the GenPept and GeneSeq amino acid sequence databases using the BLASTX search protocol. The predicted BZ16~3 protein demonstrated at least some similarity to sequences identified as D26185 (cell division protein [Bacillus subtilis]), L46096 (HEAHI1465~1 cell division protein [Haemophilus influenzae]), and Z49128 (CEM03C11~5 M03C11.5 [Caenorhabditis elegans]). The BZ16~3 protein demonstrated at least some similarity to ATP-dependent

proteases such as ftsH. Based upon sequence similarity, BZ16~3 proteins and each similar protein or peptide may share at least some activity.

Clone "CC182 1" A polynucleotide of the present invention has been identified as clone "CC182~1".

CC182~1 was isolated from a human adult brain cDNA library using methods which are selective for cDNAs encoding secreted proteins (see U.S. Pat. No. 5,536,637), or was identified as encoding a secreted or transmembrane protein on the basis of computer analysis of the amino acid sequence of the encoded protein. CC182~1 is a full-length clone, including the entire coding sequence of a secreted protein (also referred to herein as "CC182~1 protein").

The nucleotide sequence of CC182~1 as presently determined is reported in SEQ ID NO:18. What applicants presently believe to be the proper reading frame and the predicted amino acid sequence of the CC182~1 protein corresponding to the foregoing nucleotide sequence is reported in SEQ ID NO:19. Amino acids 26 to 38 are a predicted leader/signal sequence, with the predicted mature amino acid sequence beginning at amino acid 39, or are a transmembrane domain.

The EcoRI/NotI restriction fragment obtainable from the deposit containing clone CC182~1 should be approximately 1600 bp.

The nucleotide sequence disclosed herein for CC182~1 was searched against the GenBank and GeneSeq nucleotide sequence databases using BLASTN/BLASTX and FASTA search protocols. CC182~1 demonstrated at least some similarity with sequences identified as H61159 (yu37fO8.sl Homo sapiens cDNA clone 236007 3' similar to contains L1 repetitive element), L09709 (Human lysosomal-associated membrane glycoprotein-2 (LAMP2) gene, 5' end of CDS and flanking region), W44797 (zb98e10.sl Soares parathyroid tumor NbHPA Homo sapiens cDNA clone 320874 3' similar to contains Alu repetitive element), and X62167 (H.sapiens mRNA for P2 protein of peripheral myelin).

Based upon sequence similarity, CC182~1 proteins and each similar protein or peptide may share at least some activity. The nucleotide sequence of CC182~1 indicates that it may contain an L1 repetitive element and a MER42C repetitive element.

Clone "CG109 1" A polynucleotide of the present invention has been identified as clone "CG109~1".

CG109~1 was isolated from a human adult testes cDNA library using methods which are

selective for cDNAs encoding secreted proteins (see U.S. Pat. No. 5,536,637), or was identified as encoding a secreted or transmembrane protein on the basis of computer analysis of the amino acid sequence of the encoded protein. CG109~1 is a full-length clone, including the entire coding sequence of a secreted protein (also referred to herein as "CG109~1 protein").

The nucleotide sequence of CG109~1 as presently determined is reported in SEQ ID NO:20. What applicants presently believe to be the proper reading frame and the predicted amino acid sequence of the CG109~1 protein corresponding to the foregoing nucleotide sequence is reported in SEQ ID NO:21.

The EcoRI/NotI restriction fragment obtainable from the deposit containing clone CG109~1 should be approximately 600 bp.

The nucleotide sequence disclosed herein for CG109~1 was searched against the GenBank and GeneSeq nucleotide sequence databases using BLASTN/BLASTX and FASTA search protocols. No hits were found in the database.

Clone "CT397 1" A polynucleotide of the present invention has been identified as clone "CJ39%1".

CJ397~1 was isolated from a human fetal brain cDNA library using methods which are selective for cDNAs encoding secreted proteins (see U.S. Pat. No. 5,536,637), or was identified as encoding a secreted or transmembrane protein on the basis of computer analysis of the amino acid sequence of the encoded protein. CJ397~1 is a full-length clone, including the entire coding sequence of a secreted protein (also referred to herein as "CJ397~1 protein").

The nucleotide sequence of the 5' portion of CJ3971 as presently determined is reported in SEQ ID NO:22. An additional internal nucleotide sequence from CJ3971 as presently determined is reported in SEQ ID NO:23. What applicants believe is the proper reading frame and the predicted amino acid sequence encoded by such internal sequence is reported in SEQ ID NO:24. Additional nucleotide sequence from the 3' portion of CJ397~1, including the polyA tail, is reported in SEQ ID NO:25.

The EcoRI/NotI restriction fragment obtainable from the deposit containing clone CJ397~1 should be approximately 1900 bp.

The nucleotide sequence disclosed herein for CJ397~1 was searched against the GenBank and GeneSeq nucleotide sequence databases using BLASTN/BLASTX and FASTA search protocols. CJ3971 demonstrated at least some similarity with sequences

identified as H18685 (yn52b08.sl Homo sapiens cDNA clone 172023 3'), H46001 (yo13f06.sl Homo sapiens cDNA clone 177827 3'), and T77612 (yc91f06.rl Homo sapiens cDNA clone 23298 5'). Based upon sequence similarity, CJ397~1 proteins and each similar protein or peptide may share at least some activity.

Deposit of Clones Clones BD441~1, BD441~2, BG102~3, BK158~1, BP163~1, BZ16 3, CC182~1, CG109~1 and CJ397~1 were deposited on November 20, 1996 with the American Type Culture Collection as an original deposit under the Budapest Treaty and were given the accession number ATCC 98264, from which each clone comprising a particular polynucleotide is obtainable. All restrictions on the availability to the public of the deposited material will be irrevocably removed upon the granting of the patent, except for the requirements specified in 37 C.F.R. 1.808(b).

Each clone has been transfected into separate bacterial cells (E. coli) in this composite deposit. Each clone can be removed from the vector in which it was deposited by performing an EcoRI/NotI digestion (5' site, EcoRI; 3' site, NotI) to produce the appropriate fragment for such clone. Each clone was deposited in either the pED6 or pNOTs vector depicted in Fig. 1. The pED6dpc2 vector ("pED6") was derived from pED6dpc1 by insertion of a new polylinker to facilitate cDNA cloning (Kaufman et awl., 1991, Nucleic Acids Res. 19: 4485-4490); the pNOTs vector was derived from pMT2 (Kaufman et al., 1989, Mol. Cell. Biol. 9: 946-958) by deletion of the DHFR sequences, insertion of a new polylinker,and insertion of the M13 origin of replication in the ClaI site.

In some instances, the deposited clone can become "flipped" (i.e., in the reverse orientation) in the deposited isolate. In such instances, the cDNA insert can still be isolated by digestion with EcoRI and Note. However, NotI will then produce the 5' site and EcoRI will produce the 3' site for placement of the cDNA in proper orientation for expression in a suitable vector. The cDNA may also be expressed from the vectors in which they were deposited.

Bacterial cells containing a particular clone can be obtained from the composite deposit as follows: An oligonucleotide probe or probes should be designed to the sequence that is known for that particular clone. This sequence can be derived from the sequences provided herein, or from a combination of those sequences. The sequence of the

oligonucleotide probe that was used to isolate each full-length clone is identified below, and should be most reliable in isolating the clone of interest.

Clone Probe Sequence BD441~1 SEQ ID NO:26 BD441~2 SEQ ID NO:27 BG102~3 SEQ ID NO:28 BK158~1 SEQ ID NO:29 BP163~1 SEQ ID NO:30 BZ16~3 SEQ ID NO:31 CC182~1 SEQ ID NO:32 CG109~1 SEQ ID NO:33 CJ397~1 SEQ ID NO:34 In the sequences listed above which include an N at position 2, that position is occupied in preferred probes/primers by a biotinylated phosphoaramidite residue rather than a nucleotide (such as , for example, that produced by use of biotin phosphoramidite (1- dimethoxytrityloxy-2-(N-biotinyl-4-aminobutyl)-propyl-3-O-(2 -cyanoethyl)- (N,N- diisopropyl)-phosphoramadite) (Glen Research, cat. no. 10-1953)).

The design of the oligonucleotide probe should preferably follow these parameters: (a) It should be designed to an area of the sequence which has the fewest ambiguous bases ("N's"), if any; (b) It should be designed to have a Tm of approx. 80 ° C (assuming 2" for each A or T and 4 degrees for each G or C).

The oligonucleotide should preferably be labeled with g 32p ATP (specific activity 6000 Ci/mmole) and T4 polynucleotide kinase using commonly employed techniques for labeling oligonucleotides. Other labeling techniques can also be used. Unincorporated label should preferably be removed by gel filtration chromatography or other established methods. The amount of radioactivity incorporated into the probe should be quantitated by measurement in a scintillation counter. Preferably, specific activity of the resulting probe should be approximately 4e+6 dpm/pmole.

The bacterial culture containing the pool of full-length clones should preferably be thawed and 100 ,ul of the stock used to inoculate a sterile culture flask containing 25 ml

of sterile L-broth containing ampicillin at 100 ug/ml. The culture should preferably be grown to saturation at 370C, and the saturated culture should preferably be diluted in fresh L-broth. Aliquots of these dilutions should preferably be plated to determine the dilution and volume which will yield approximately 5000 distinct and well-separated colonies on solid bacteriological media containing L-broth containing ampicillin at 100 ,ug/ml and agar at 1.5% in a 150 mm petri dish when grown overnight at 370C. Other known methods of obtaining distinct, well-separated colonies can also be employed.

Standard colony hybridization procedures should then be used to transfer the colonies to nitrocellulose filters and lyse, denature and bake them.

The filter is then preferably incubated at 650C for 1 hour with gentle agitation in 6X SSC (20X stock is 175.3 g NaCl/liter, 88.2 g Na citrate/liter, adjusted to pH 7.0 with NaOH) containing 0.5% SDS, 100 ug/ml of yeast RNA, and 10 mM EDTA (approximately 10 mL per 150 mm filter). Preferably, the probe is then added to the hybridization mix at a concentration greater than or equal to le+6 dpm/mL. The filter is then preferably incubated at 650C with gentle agitation overnight. The filter is then preferably washed in 500 mL of 2X SSC/0.5% SDS at room temperature without agitation, preferably followed by 500 mL of 2X SSC/0.1% SDS at room temperature with gentle shaking for 15 minutes.

A third wash with 0.1X SSC/0.5% SDS at 650C for 30 minutes to 1 hour is optional. The filter is then preferably dried and subjected to autoradiography for sufficient time to visualize the positives on the X-ray film. Other known hybridization methods can also be employed.

The positive colonies are picked, grown in culture, and plasmid DNA isolated using standard procedures. The clones can then be verified by restriction analysis, hybridization analysis, or DNA sequencing.

Fragments of the proteins of the present invention which are capable of exhibiting biological activity are also encompassed by the present invention. Fragments of the protein may be in linear form or they may be cyclized using known methods, for example, as described in H.U. Saragovi, et al., Bio/Technology 10, 773-778 (1992) and in R.S.

McDowell, et al., J. Amer. Chem. Soc. 114,9245-9253 (1992), both of which are incorporated herein by reference. Such fragments may be fused to carrier molecules such as immunoglobulins for many purposes, including increasing the valency of protein binding sites. For example, fragments of the protein may be fused through "linker" sequences to the Fc portion of an immunoglobulin. For a bivalent form of the protein, such a fusion could be to the Fc portion of an IgG molecule. Other immunoglobulin isotypes may also

be used to generate such fusions. For example, a protein - IgM fusion would generate a decavalent form of the protein of the invention.

The present invention also provides both full-length and mature forms of the disclosed proteins. The full-length form of the such proteins is identified in the sequence listing by translation of the nucleotide sequence of each disclosed clone. The mature form of such protein may be obtained by expression of the disclosed full-length polynucleotide (preferably those deposited with ATCC) in a suitable mammalian cell or other host cell.

The sequence of the mature form of the protein may also be determinable from the amino acid sequence of the full-length form.

The present invention also provides genes corresponding to the cDNA sequences disclosed herein. "Corresponding genes" are the regions of the genome that are transcribed to produce the mRNAs from which the cDNA sequences are derived and any contiguous regions of the genome necessary for the regulated expression of such genes, including but not limited to coding sequences, 5' and 3' untranslated regions, alternatively spliced exons, introns, promoters, enhancers, and silencer or suppressor elements. The corresponding genes can be isolated in accordance with known methods using the sequence information disclosed herein. Such methods include the preparation of probes or primers from the disclosed sequence information for identification and/or amplification of genes in appropriate genomic libraries or other sources of genomic materials.

Where the protein of the present invention is membrane-bound (e.g., is a receptor), the present invention also provides for soluble forms of such protein. In such forms part or all of the intracellular and transmembrane domains of the protein are deleted such that the protein is fully secreted from the cell in which it is expressed. The intracellular and transmembrane domains of proteins of the invention can be identified in accordance with known techniques for determination of such domains from sequence information.

Proteins and protein fragments of the present invention include proteins with amino acid sequence lengths that are at least 25%(more preferably at least 50%, and most preferably at least 75%) of the length of a disclosed protein and have at least 60% sequence identity (more preferably, at least 75% identity; most preferably at least 90% or 95% identity) with that disclosed protein, where sequence identity is determined by comparing the amino acid sequences of the proteins when aligned so as to maximize overlap and identity while minimizing sequence gaps. Also included in the present invention are proteins and protein fragments that contain a segment preferably comprising 8 or more

(more preferably 20 or more, most preferably 30 or more) contiguous amino acids that shares at least 75% sequence identity (more preferably, at least 85% identity; most preferably at least 95% identity) with any such segment of any of the disclosed proteins.

Species homologs of the disclosed polynucleotides and proteins are also provided by the present invention. As used herein, a "species homologue" is a protein or polynucleotide with a different species of origin from that of a given protein or polynucleotide, but with significant sequence similarity to the given protein or polynucleotide, as determined by those of skill in the art. Species homologs may be isolated and identified by making suitable probes or primers from the sequences provided herein and screening a suitable nucleic acid source from the desired species.

The invention also encompasses allelic variants of the disclosed polynucleotides or proteins; that is, naturally-occurring alternative forms of the isolated polynucleotide which also encode proteins which are identical, homologous, or related to that encoded by the polynucleotides.

The invention also includes polynucleotides with sequences complementary to those of the polynucleotides disclosed herein.

The present invention also includes polynucleotides capable of hybridizing under reduced stringency conditions, more preferably stringent conditions, and most preferably highly stringent conditions, to polynucleotides described herein. Examples of stringency conditions are shown in the table below: highly stringent conditions are those that are at least as stringent as, for example, conditions A-F; stringent conditions are at least as stringent as, for example, conditions G-L; and reduced stringency conditions are at least as stringent as, for example, conditions M-R.

Stringency Polynucleotide Hybrid Hybridization Temperature and Wash Condition Hybrid Length Buffert Temperature (bp)t and Buffert A DNA:DNA # 50 65°C; 1xSSC -or- 65°C; 0.3xSSC 42°C; 1xSSC, 50% formamide B DNA:DNA <50 TB*; 1xSSC T B*; lxSSC C DNA:RNA > 50 67'C; 1xSSC -or- 67°C; 0.3xSSC 45°C; 1xSSC, 50% formamide D DNA:RNA <50 T0*; lxSSC TD*; 1xSSC E RNA:RNA # 50 70°C; 1xSSC -or- 70°C; 0.3xSSC 50°C; 1xSSC, 50% formamide F RNA:RNA <50 T*; 1xSSC TF*; 1xSSC G DNA:DNA # 50 65°C; 4xSSC -or- 65°C; 1xSSC 42°C; 4xSSC, 50% formamide H DNA:DNA <50 TH*; 4xSSC T*; 4xSSC I DNA:RNA 2 50 67°C; 4xSSC -or- 67C; 1xSSC 45°C; 4xSSC, 50% formamide J DNA:RNA <50 T*; 4xSSC T1*; 4xSSC K RNA:RNA # 50 70°C; 4xSSC -or- 67°C; 1xSSC 50°C; 4xSSC, 50% formamide L RNA:RNA <50 TL*; 2xSSC TL*; 2xSSC M DNA:DNA # 50 50°C; 4xSSC -or- 50°C; 2xSSC 40°C; 6xSSC, 50% formamide N DNA:DNA <50 TN*; 6xSSC TN*; 6xSSC O DNA:RNA # 50 55°C; 4xSSC -or- 55°C; 2xSSC 42°C; 6xSSC, 50% formamide P DNA:RNA <50 Tr*; 6xSSC Tr*;6xSSC Q RNA:RNA > 50 60°C; 4xSSC -or- 60°C; 2xSSC 45°C; 6xSSC, 50% formamide R RNA:RNA <50 TR*; 4xSSC TR*; 4xSSC

#: The hybrid length is that anticipated for the hybridized region(s) of the hybridizing polynucleotides. When hybridizing a polynucleotide to a target polynucleotide of unknown sequence, the hybrid length is assumed to be that of the hybridizing polynucleotide. When polynucleotides of known sequence are hybridized, the hybrid length can be determined by aligning the sequences of the polynucleotides and identifying the region or regions of optimal sequence complementarity.

t: SSPE (1xSSPE is 0.15M NaCl, 10mM NaH2PO4, and 1.25mM EDTA, pH 7.4) can be substituted for SSC (1xSSC is 0.15M NaCI and 15mM sodium citrate) in the hybridization and wash buffers; washes are performed for 15 minutes after hybridization is complete.

*TR- - TR: The hybridization temperature for hybrids anticipated to be less than 50 base pairs in length should be 5-10°C less than the melting temperature (Tm) of the hybrid, where Tm is determined according to the following equations. For hybrids less than 18 base pairs in length, Tm(°C) = 2(# of A + T bases) + 4(# of G + C bases). For hybrids between 18 and 49 base pairs in length, Tm(°C) = 81.5 + 16.6(log10[Na+]) + 0.41(%G+C) - (600/N), where N is the number of bases in the hybrid, and [Na+] is the concentration of sodium ions in the hybridization buffer ([Na'] for 1xSSC = 0.165 M).

Additional examples of stringency conditions for polynucleotide hybridization are provided in Sambrook, J., E.F. Fritsch, and T. Maniatis, 1989, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, chapters 9 and 11, and Current Protocols in Molecular Biology, 1995, F.M. Ausubel et al., eds., John Wiley & Sons, Inc., sections 2.10 and 6.3-6.4, incorporated herein by reference.

Preferably, each such hybridizing polynucleotide has a length that is at least 25%(more preferably at least 50%, and most preferably at least 75%) of the length of the polynucleotide of the present invention to which it hybridizes, and has at least 60% sequence identity (more preferably, at least 75% identity; most preferably at least 90% or 95% identity) with the polynucleotide of the present invention to which it hybridizes, where sequence identity is determined by comparing the sequences of the hybridizing polynucleotides when aligned so as to maximize overlap and identity while minimizing sequence gaps.

The isolated polynucleotide of the invention may be operably linked to an expression control sequence such as the pMT2 or pED expression vectors disclosed in Kaufman et al., Nucleic Acids Res. 19, 4485-4490 (1991), in order to produce the protein recombinantly. Many suitable expression control sequences are known in the art. General methods of expressing recombinant proteins are also known and are exemplified in R.

Kaufman, Methods in Enzymology 185 537-566 (1990). As defined herein "operably linked" means that the isolated polynucleotide of the invention and an expression control sequence are situated within a vector or cell in such a way that the protein is expressed by a host cell which has been transformed (transfected) with the ligated polynucleotide/expression control sequence.

A number of types of cells may act as suitable host cells for expression of the protein. Mammalian host cells include, for example, monkey COS cells, Chinese Hamster Ovary (CHO) cells, human kidney 293 cells, human epidermal A431 cells, human Colo205 cells, 3T3 cells, CV-1 cells, other transformed primate cell lines, normal diploid cells, cell strains derived from in vitro culture of primary tissue, primary explants, HeLa cells, mouse L cells, BHK, HL-60, U937, HaK or Jurkat cells.

Alternatively, it may be possible to produce the protein in lower eukaryotes such as yeast or in prokaryotes such as bacteria. Potentially suitable yeast strains include Saccharomyces cerevisiae, Schizosaccharomyces pombe, Kluyveromyces strains, Candida, or any yeast strain capable of expressing heterologous proteins. Potentially suitable bacterial strains include Escherichia coli, Bacillus subtilis, Salmonella typhimurium, or any bacterial

strain capable of expressing heterologous proteins. If the protein is made in yeast or bacteria, it may be necessary to modify the protein produced therein, for example by phosphorylation or glycosylation of the appropriate sites, in order to obtain the functional protein. Such covalent attachments may be accomplished using known chemical or enzymatic methods.

The protein may also be produced by operably linking the isolated polynucleotide of the invention to suitable control sequences in one or more insect expression vectors, and employing an insect expression system. Materials and methods for baculovirus/insect cell expression systems are commercially available in kit form from, e.g., Invitrogen, San Diego, California, U.S.A. (the MaxBac(D kit), and such methods are well known in the art, as described in Summers and Smith, Texas Agricultural Experiment Station Bulletin No. 1555 (1987), incorporated herein by reference. As used herein, an insect cell capable of expressing a polynucleotide of the present invention is "transformed." The protein of the invention may be prepared by culturing transformed host cells under culture conditions suitable to express the recombinant protein. The resulting expressed protein may then be purified from such culture (i.e., from culture medium or cell extracts) using known purification processes, such as gel filtration and ion exchange chromatography. The purification of the protein may also include an affinity column containing agents which will bind to the protein; one or more column steps over such affinity resins as concanavalin A-agarose, heparin-toyopearl8 or Cibacrom blue 3GA SepharoseB; one or more steps involving hydrophobic interaction chromatography using such resins as phenyl ether, butyl ether, or propyl ether; or immunoaffinity chromatography.

Alternatively, the protein of the invention may also be expressed in a form which will facilitate purification. For example, it may be expressed as a fusion protein, such as those of maltose binding protein (MBP), glutathione-S-transferase (GST) or thioredoxin (TRX). Kits for expression and purification of such fusion proteins are commercially available from New England BioLab (Beverly, MA), Pharmacia (Piscataway, NJ) and InVitrogen, respectively. The protein can also be tagged with an epitope and subsequently purified by using a specific antibody directed to such epitope. One such epitope ("Flag") is commercially available from Kodak (New Haven, CT).

Finally, one or more reverse-phase high performance liquid chromatography (RP- HPLC) steps employing hydrophobic RP-HPLC media, e.g., silica gel having pendant

methyl or other aliphatic groups, can be employed to further purify the protein. Some or all of the foregoing purification steps, in various combinations, can also be employed to provide a substantially homogeneous isolated recombinant protein. The protein thus purified is substantially free of other mammalian proteins and is defined in accordance with the present invention as an "isolated protein.

The protein of the invention may also be expressed as a product of transgenic animals, e.g., as a component of the milk of transgenic cows, goats, pigs, or sheep which are characterized by somatic or germ cells containing a nucleotide sequence encoding the protein.

The protein may also be produced by known conventional chemical synthesis.

Methods for constructing the proteins of the present invention by synthetic means are known to those skilled in the art. The synthetically-constructed protein sequences, by virtue of sharing primary, secondary or tertiary structural and/or conformational characteristics with proteins may possess biological properties in common therewith, including protein activity. Thus, they may be employed as biologically active or immunological substitutes for natural, purified proteins in screening of therapeutic compounds and in immunological processes for the development of antibodies.

The proteins provided herein also include proteins characterized by amino acid sequences similar to those of purified proteins but into which modification are naturally provided or deliberately engineered. For example, modifications in the peptide or DNA sequences can be made by those skilled in the art using known techniques. Modifications of interest in the protein sequences may include the alteration, substitution, replacement, insertion or deletion of a selected amino acid residue in the coding sequence. For example, one or more of the cysteine residues may be deleted or replaced with another amino acid to alter the conformation of the molecule. Techniques for such alteration, substitution, replacement, insertion or deletion are well known to those skilled in the art (see, e.g., U.S. Patent No.4,518,584). Preferably, such alteration, substitution, replacement, insertion or deletion retains the desired activity of the protein.

Other fragments and derivatives of the sequences of proteins which would be expected to retain protein activity in whole or in part and may thus be useful for screening or other immunological methodologies may also be easily made by those skilled in the art given the disclosures herein. Such modifications are believed to be encompassed by the present invention.

USES AND BIOLOGICAL ACTIVITY The polynucleotides and proteins of the present invention are expected to exhibit one or more of the uses or biological activities (including those associated with assays cited herein) identified below. Uses or activities described for proteins of the present invention may be provided by administration or use of such proteins or by administration or use of polynucleotides encoding such proteins (such as, for example, in gene therapies or vectors suitable for introduction of DNA).

Research Uses and Utilities The polynucleotides provided by the present invention can be used by the research community for various purposes. The polynucleotides can be used to express recombinant protein for analysis, characterization or therapeutic use; as markers for tissues in which the corresponding protein is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in disease states); as molecular weight markers on Southern gels; as chromosome markers or tags (when labeled) to identify chromosomes or to map related gene positions; to compare with endogenous DNA sequences in patients to identify potential genetic disorders; as probes to hybridize and thus discover novel, related DNA sequences; as a source of information to derive PCR primers for genetic fingerprinting; as a probe to "subtract-out" known sequences in the process of discovering other novel polynucleotides; for selecting and making oligomers for attachment to a "gene chip" or other support, including for examination of expression patterns; to raise anti-protein antibodies using DNA immunization techniques; and as an antigen to raise anti-DNA antibodies or elicit another immune response. Where the polynucleotide encodes a protein which binds or potentially binds to another protein (such as, for example, in a receptor-ligand interaction), the polynucleotide can also be used in interaction trap assays (such as, for example, that described in Gyuris et al., Cell 75:791-803 (1993)) to identify polynucleotides encoding the other protein with which binding occurs or to identify inhibitors of the binding interaction.

The proteins provided by the present invention can similarly be used in assay to determine biological activity, including in a panel of multiple proteins for high- throughput screening; to raise antibodies or to elicit another immune response; as a reagent (including the labeled reagent) in assays designed to quantitatively determine levels of the protein (or its receptor) in biological fluids; as markers for tissues in which

the corresponding protein is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in a disease state); and, of course, to isolate correlative receptors or ligands. Where the protein binds or potentially binds to another protein (such as, for example, in a receptor-ligand interaction), the protein can be used to identify the other protein with which binding occurs or to identify inhibitors of the binding interaction. Proteins involved in these binding interactions can also be used to screen for peptide or small molecule inhibitors or agonists of the binding interaction.

Any or all of these research utilities are capable of being developed into reagent grade or kit format for commercialization as research products.

Methods for performing the uses listed above are well known to those skilled in the art. References disclosing such methods include without limitation "Molecular Cloning: A Laboratory Manual", 2d ed., Cold Spring Harbor Laboratory Press, Sambrook, J., E.F. Fritsch and T. Maniatis eds., 1989, and "Methods in Enzymology: Guide to Molecular Cloning Techniques", Academic Press, Berger, S.L. and A.R. Kimmel eds., 1987.

Nutritional Uses Polynucleotides and proteins of the present invention can also be used as nutritional sources or supplements. Such uses include without limitation use as a protein or amino acid supplement, use as a carbon source, use as a nitrogen source and use as a source of carbohydrate. In such cases the protein or polynucleotide of the invention can be added to the feed of a particular organism or can be administered as a separate solid or liquid preparation, such as in the form of powder, pills, solutions, suspensions or capsules. In the case of microorganisms, the protein or polynucleotide of the invention can be added to the medium in or on which the microorganism is cultured.

Cytokine and Cell Proliferation/Differentiation Activity A protein of the present invention may exhibit cytokine, cell proliferation (either inducing or inhibiting) or cell differentiation (either inducing or inhibiting) activity or may induce production of other cytokines in certain cell populations. Many protein factors discovered to date, including all known cytokines, have exhibited activity in one or more factor dependent cell proliferation assays, and hence the assays serve as a convenient confirmation of cytokine activity. The activity of a protein of the present invention is evidenced by any one of a number of routine factor dependent cell proliferation assays

for cell lines including, without limitation, 32D, DA2, DA1G, T10, B9; B9/11, BaF3, MC9/G, M+ (preB M+), 2E8, RB5, DA1, 123, T1165, HT2, CTLL2, TF-1, Mo7e and CMK.

The activity of a protein of the invention may, among other means, be measured by the following methods: Assays for T-cell or thymocyte proliferation include without limitation those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A.M. Kruisbeek, D.H.

Margulies, E.M. Shevach, W Strober, Pub. Greene Publishing Associates and Wiley- Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies in Humans); Takai et al., J. Immunol. 137:3494-3500, 1986; Bertagnolli et al., J. Immunol. 145:1706-1712, 1990; Bertagnolli et al., Cellular Immunology 133:327-341, 1991; Bertagnolli, et al., J. Immunol. 149:3778-3783, 1992; Bowman et al., J.

Immunol. 152: 1756-1761, 1994.

Assays for cytokine production and/or proliferation of spleen cells, lymph node cells or thymocytes include, without limitation, those described in: Polyclonal T cell stimulation, Kruisbeek, A.M. and Shevach, E.M. In Current Protocols in Immunology. J.E.e.a.

Coligan eds. Vol 1 pp. 3.12.1-3.12.14, John Wiley and Sons, Toronto. 1994; and Measurement of mouse and human Interferon y, Schreiber, R.D. In Current Protocols in Immunology. J.E.e.a. Coligan eds. Vol 1 pp. 6.8.1-6.8.8, John Wiley and Sons, Toronto. 1994.

Assays for proliferation and differentiation of hematopoietic and lymphopoietic cells include, without limitation, those described in: Measurement of Human and Murine Interleukin 2 and Interleukin 4, Bottomly, K., Davis, L.S. and Lipsky, P.E. In Current Protocols in Immunology. J.E.e.a. Coligan eds. Vol 1 pp. 6.3.1-6.3.12, John Wiley and Sons, Toronto. 1991; deVries et al., J. Exp. Med. 173:1205-1211, 1991; Moreau et al., Nature 336:690-692, 1988; Greenberger et al., Proc. Natl. Acad. Sci. U.S.A. 80:2931-2938, 1983; Measurement of mouse and human interleukin 6 - Nordan, R. In Current Protocols in Immunology. J.E.e.a. Coligan eds. Vol 1 pp. 6.6.1-6.6.5, John Wiley and Sons, Toronto. 1991; Smith et al., Proc. Natl. Acad. Sci. U.S.A. 83:1857-1861, 1986; Measurement of human Interleukin 11 - Bennett, F., Giannotti, J., Clark, S.C. and Turner, K. J. In Current Protocols in Immunology. J.E.e.a. Coligan eds. Vol 1 pp. 6.15.1 John Wiley and Sons, Toronto. 1991; Measurement of mouse and human Interleukin 9 - Ciarletta, A., Giannotti, J., Clark, S.C.

and Turner, K.J. In Current Protocols in Immunology. J.E.e.a. Coligan eds. Vol 1 pp. 6.13.1, John Wiley and Sons, Toronto. 1991.

Assays for T-cell clone responses to antigens (which will identify, among others, proteins that affect APC-T cell interactions as well as direct T-cell effects by measuring proliferation and cytokine production) include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A.M. Kruisbeek, D.H. Margulies, E.M. Shevach, W Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function; Chapter 6, Cytokines and their cellular receptors; Chapter 7, Immunologic studies in Humans); Weinberger et al., Proc. Natl. Acad. Sci. USA 77:6091-6095, 1980; Weinberger et al., Eur. J. Immun.

11:405-411, 1981; Takai et al., J. Immunol. 137:3494-3500, 1986; Takai et al., J. Immunol.

140:508-512, 1988.

Immune Stimulating or Suppressing Activity A protein of the present invention may also exhibit immune stimulating or immune suppressing activity, including without limitation the activities for which assays are described herein. A protein may be useful in the treatment of various immune deficiencies and disorders (including severe combined immunodeficiency (SCID)), e.g., in regulating (up or down) growth and proliferation of T and/or B lymphocytes, as well as effecting the cytolytic activity of NK cells and other cell populations. These immune deficiencies may be genetic or be caused by viral (e.g., HIV) as well as bacterial or fungal infections, or may result from autoimmune disorders. More specifically, infectious diseases causes by viral, bacterial, fungal or other infection may be treatable using a protein of the present invention, including infections by HIV, hepatitis viruses, herpesviruses, mycobacteria, Leishmania spp., malaria spp. and various fungal infections such as candidiasis. Of course, in this regard, a protein of the present invention may also be useful where a boost to the immune system generally may be desirable, i.e., in the treatment of cancer.

Autoimmune disorders which may be treated using a protein of the present invention include, for example, connective tissue disease, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, autoimmune pulmonary inflammation, Guillain-Barre syndrome, autoimmune thyroiditis, insulin dependent diabetes mellitis, myasthenia gravis, graft-versus-host disease and autoimmune inflammatory eye disease.

Such a protein of the present invention may also to be useful in the treatment of allergic reactions and conditions, such as asthma (particularly allergic asthma) or other respiratory problems. Other conditions, in which immune suppression is desired (including, for

example, organ transplantation), may also be treatable using a protein bf the present invention.

Using the proteins of the invention it may also be possible to immune responses, in a number of ways. Down regulation may be in the form of inhibiting or blocking an immune response already in progress or may involve preventing the induction of an immune response. The functions of activated T cells may be inhibited by suppressing T cell responses or by inducing specific tolerance in T cells, or both. Immunosuppression of T cell responses is generally an active, non-antigen-specific, process which requires continuous exposure of the T cells to the suppressive agent. Tolerance, which involves inducing non-responsiveness or anergy in T cells, is distinguishable from immunosuppression in that it is generally antigen-specific and persists after exposure to the tolerizing agent has ceased. Operationally, tolerance can be demonstrated by the lack of a T cell response upon reexposure to specific antigen in the absence of the tolerizing agent.

Down regulating or preventing one or more antigen functions (including without limitation B lymphocyte antigen functions (such as, for example, B7)), e.g., preventing high level lymphokine synthesis by activated T cells, will be useful in situations of tissue, skin and organ transplantation and in graft-versus-host disease (GVHD). For example, blockage of T cell function should result in reduced tissue destruction in tissue transplantation. Typically, in tissue transplants, rejection of the transplant is initiated through its recognition as foreign by T cells, followed by an immune reaction that destroys the transplant. The administration of a molecule which inhibits or blocks interaction of a B7 lymphocyte antigen with its natural ligand(s) on immune cells (such as a soluble, monomeric form of a peptide having B7-2 activity alone or in conjunction with a monomeric form of a peptide having an activity of another B lymphocyte antigen (e.g., B7- 1, B7-3) or blocking antibody), prior to transplantation can lead to the binding of the molecule to the natural ligand(s) on the immune cells without transmitting the corresponding costimulatory signal. Blocking B lymphocyte antigen function in this matter prevents cytokine synthesis by immune cells, such as T cells, and thus acts as an immunosuppressant. Moreover, the lack of costimulation may also be sufficient to anergize the T cells, thereby inducing tolerance in a subject. Induction of long-term tolerance by B lymphocyte antigen-blocking reagents may avoid the necessity of repeated administration of these blocking reagents. To achieve sufficient immunosuppression or

tolerance in a subject, it may also be necessary to block the function of a combination of B lymphocyte antigens.

The efficacy of particular blocking reagents in preventing organ transplant rejection or GVHD can be assessed using animal models that are predictive of efficacy in humans. Examples of appropriate systems which can be used include allogeneic cardiac grafts in rats and xenogeneic pancreatic islet cell grafts in mice, both of which have been used to examine the immunosuppressive effects of CTLA4Ig fusion proteins in vivo as described in Lenschow et al., Science 257:789-792 (1992) and Turka et al., Proc. Natl. Acad.

Sci USA, 89:11102-11105 (1992). In addition, murine models of GVHD (see Paul ed., Fundamental Immunology, Raven Press, New York, 1989, pp. 846-847) can be used to determine the effect of blocking B lymphocyte antigen function in vivo on the development of that disease.

Blocking antigen function may also be therapeutically useful for treating autoimmune diseases. Many autoimmune disorders are the result of inappropriate activation of T cells that are reactive against self tissue and which promote the production of cytokines and autoantibodies involved in the pathology of the diseases. Preventing the activation of autoreactive T cells may reduce or eliminate disease symptoms.

Administration of reagents which block costimulation of T cells by disrupting receptor:ligand interactions of B lymphocyte antigens can be used to inhibit T cell activation and prevent production of autoantibodies or T cell-derived cytokines which may be involved in the disease process. Additionally, blocking reagents may induce antigen-specific tolerance of autoreactive T cells which could lead to long-term relief from the disease. The efficacy of blocking reagents in preventing or alleviating autoimmune disorders can be determined using a number of well-characterized animal models of human autoimmune diseases. Examples include murine experimental autoimmune encephalitis, systemic lupus erythmatosis in MRL/lpr/lpr mice or NZB hybrid mice, murine autoimmune collagen arthritis, diabetes mellitus in NOD mice and BB rats, and murine experimental myasthenia gravis (see Paul ed., Fundamental Immunology, Raven Press, New York, 1989, pp. 840-856).

Upregulation of an antigen function (preferably a B lymphocyte antigen function), as a means of up regulating immune responses, may also be useful in therapy.

Upregulation of immune responses may be in the form of enhancing an existing immune response or eliciting an initial immune response. For example, enhancing an immune response through stimulating B lymphocyte antigen function may be useful in cases of

viral infection. In addition, systemic viral diseases such as influenza, the common cold, and encephalitis might be alleviated by the administration of stimulatory forms of B lymphocyte antigens systemically.

Alternatively, anti-viral immune responses may be enhanced in an infected patient by removing T cells from the patient, costimulating the T cells in vitro with viral antigen- pulsed APCs either expressing a peptide of the present invention or together with a stimulatory form of a soluble peptide of the present invention and reintroducing the in vitro activated T cells into the patient. Another method of enhancing anti-viral immune responses would be to isolate infected cells from a patient, transfect them with a nucleic acid encoding a protein of the present invention as described herein such that the cells express all or a portion of the protein on their surface, and reintroduce the transfected cells into the patient. The infected cells would now be capable of delivering a costimulatory signal to, and thereby activate, T cells in vivo.

In another application, up regulation or enhancement of antigen function (preferably B lymphocyte antigen function) may be useful in the induction of tumor immunity. Tumor cells (e.g., sarcoma, melanoma, lymphoma, leukemia, neuroblastoma, carcinoma) transfected with a nucleic acid encoding at least one peptide of the present invention can be administered to a subject to overcome tumor-specific tolerance in the subject. If desired, the tumor cell can be transfected to express a combination of peptides.

For example, tumor cells obtained from a patient can be transfected ex vivo with an expression vector directing the expression of a pep tide having B7-2-like activity alone, or in conjunction with a peptide having B7-1-like activity and/or B7-3-like activity. The transfected tumor cells are returned to the patient to result in expression of the pep tides on the surface of the transfected cell. Alternatively, gene therapy techniques can be used to target a tumor cell for transfection in vivo.

The presence of the pep tide of the present invention having the activity of a B lymphocyte antigen(s) on the surface of the tumor cell provides the necessary costimulation signal to T cells to induce a T cell mediated immune response against the transfected tumor cells. In addition, tumor cells which lack MHC class I or MHC class II molecules, or which fail to reexpress sufficient amounts of MHC class I or MHC class II molecules, can be transfected with nucleic acid encoding all or a portion of (e.g., a cytoplasmic-domain truncated portion) of an MHC class I a chain protein and 2 microglobulin protein or an MHC class II a chain protein and an MHC class II p chain protein to thereby express MHC class I or MHC class II proteins on the cell surface.

Expression of the appropriate class I or class II MHC in conjunction with a peptide having the activity of a B lymphocyte antigen (e.g., B7-1, B7-2, B7-3) induces a T cell mediated immune response against the transfected tumor cell. Optionally, a gene encoding an antisense construct which blocks expression of an MHC class II associated protein, such as the invariant chain, can also be cotransfected with a DNA encoding a peptide having the activity of a B lymphocyte antigen to promote presentation of tumor associated antigens and induce tumor specific immunity. Thus, the induction of a T cell mediated immune response in a human subject may be sufficient to overcome tumor-specific tolerance in the subject.

The activity of a protein of the invention may, among other means, be measured by the following methods: Suitable assays for thymocyte or splenocyte cytotoxicity include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A.M.

Kruisbeek, D.H. Margulies, E.M. Shevach, W Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1- 3.19; Chapter 7, Immunologic studies in Humans); Herrmann et al., Proc. Natl. Acad. Sci.

USA 78:2488-2492, 1981; Herrmann et al., J. Immunol. 128:1968-1974, 1982; Handa et al., J. Immunol. 135:1564-1572, 1985; Takai et al., J. Immunol. 137:3494-3500, 1986; Takai et al., J. Immunol. 140:508-512, 1988; Herrmann et al., Proc. Natl. Acad. Sci. USA 78:2488-2492, 1981; Herrmann et al., J. Immunol. 128:1968-1974, 1982; Handa et al., J. Immunol.

135:1564-1572, 1985; Takai et al., J. Immunol. 137:3494-3500, 1986; Bowmanet al., J.

Virology 61:1992-1998; Takai et al., J. Immunol. 140:508-512, 1988; Bertagnolli et al., Cellular Immunology 133:327-341, 1991; Brown et al., J. Immunol. 153:3079-3092, 1994.

Assays for T-cell-dependent immunoglobulin responses and isotype switching (which will identify, among others, proteins that modulate T-cell dependent antibody responses and that affect Thl/Th2 profiles) include, without limitation, those described in: Maliszewski, J. Immunol. 144:3028-3033, 1990; and Assays for B cell function: In vitro antibody production, Mond, J.J. and Brunswick, M. In Current Protocols in Immunology.

J.E.e.a. Coligan eds. Vol 1 pp. 3.8.1-3.8.16, John Wiley and Sons, Toronto. 1994.

Mixed lymphocyte reaction (MLR) assays (which will identify, among others, proteins that generate predominantly Thl and CTh responses) include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A.M. Kruisbeek, D.H. Margulies, E.M. Shevach, W Strober, Pub. Greene Publishing Associates and Wiley- Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter

7, Immunologic studies in Humans); Takai et al., J. Immunol. 137:3494-3500, 1986; Takai et al., J. Immunol. 140:508-512, 1988; Bertagnolli et al., J. Immunol. 149:3778-3783, 1992.

Dendritic cell-dependent assays (which will identify, among others, proteins expressed by dendritic cells that activate naive T-cells) include, without limitation, those described in: Guery et al., J. Immunol. 134:536-544, 1995; Inaba et al., Journal of Experimental Medicine 173:549-559, 1991; Macatonia et al., Journal of Immunology 154:5071-5079, 1995; Porgador et al., Journal of Experimental Medicine 182:255-260, 1995; Nair et al., Journal of Virology 67:4062-4069, 1993; Huang et al., Science 264:961-965, 1994; Macatonia et al., Journal of Experimental Medicine 169:1255-1264, 1989; Bhardwaj et al., Journal of Clinical Investigation 94:797-807, 1994; and Inaba et al., Journal of Experimental Medicine 172:631-640, 1990.

Assays for lymphocyte survival/apoptosis (which will identify, among others, proteins that prevent apoptosis after superantigen induction and proteins that regulate lymphocyte homeostasis) include, without limitation, those described in: Darzynkiewicz et al., Cytometry 13:795-808, 1992; Gorczyca et al., Leukemia 7:659-670, 1993; Gorczyca et al., Cancer Research 53:1945-1951, 1993; Itoh et al., Cell 66:233-243, 1991; Zacharchuk, Journal of Immunology 145:4037-4045, 1990; Zamai et al., Cytometry 14:891-897, 1993; Gorczyca et al., International Journal of Oncology 1:639-648, 1992.

Assays for proteins that influence early steps of T-cell commitment and development include, without limitation, those described in: Antica et al., Blood 84:111-117, 1994; Fine et al., Cellular Immunology 155:111-122, 1994; Galy et al., Blood 85:2770-2778, 1995; Toki et al., Proc. Nat. Acad Sci. USA 88:7548-7551, 1991.

Hematopoiesis Regulating Activitv A protein of the present invention may be useful in regulation of hematopoiesis and, consequently, in the treatment of myeloid or lymphoid cell deficiencies. Even marginal biological activity in support of colony forming cells or of factor-dependent cell lines indicates involvement in regulating hematopoiesis, e.g. in supporting the growth and proliferation of erythroid progenitor cells alone or in combination with other cytokines, thereby indicating utility, for example, in treating various anemias or for use in conjunction with irradiation/chemotherapy to stimulate the production of erythroid precursors and/or erythroid cells; in supporting the growth and proliferation of myeloid cells such as granulocytes and monocytes/macrophages (i.e., traditional CSF activity) useful, for example, in conjunction with chemotherapy to prevent or treat consequent

myelo-suppression; in supporting the growth and proliferation of megakaryocytes and consequently of platelets thereby allowing prevention or treatment of various platelet disorders such as thrombocytopenia, and generally for use in place of or complimentary to platelet transfusions; and/or in supporting the growth and proliferation of hematopoietic stem cells which are capable of maturing to any and all of the above- mentioned hematopoietic cells and therefore find therapeutic utility in various stem cell disorders (such as those usually treated with transplantation, including, without limitation, aplastic anemia and paroxysmal nocturnal hemoglobinuria), as well as in repopulating the stem cell compartment post irradiation/chemotherapy, either in-vivo or ex-vivo (i.e., in conjunction with bone marrow transplantation or with peripheral progenitor cell transplantation (homologous or heterologous)) as normal cells or genetically manipulated for gene therapy.

The activity of a protein of the invention may, among other means, be measured by the following methods: Suitable assays for proliferation and differentiation of various hematopoietic lines are cited above.

Assays for embryonic stem cell differentiation (which will identify, among others, proteins that influence embryonic differentiation hematopoiesis) include, without limitation, those described in: Johansson et al. Cellular Biology 15:141-151, 1995; Keller et al., Molecular and Cellular Biology 13:473-486, 1993; McClanahan et al., Blood 81:2903-2915, 1993.

Assays for stem cell survival and differentiation (which will identify, among others, proteins that regulate lympho-hematopoiesis) include, without limitation, those described in: Methylcellulose colony forming assays, Freshney, M.G. In Culture of Hematopoietic Cells. R.I. Freshney, et al. eds. Vol pp. 265-268, Wiley-Liss, Inc., New York, NY. 1994; Hirayama et al., Proc. Natl. Acad. Sci. USA 89:5907-5911, 1992; Primitive hematopoietic colony forming cells with high proliferative potential, McNiece, I.K. and Briddell, R.A. In Culture of Hematopoietic Cells. R.I. Freshney, et al. eds. Vol pp. 23-39, Wiley-Liss, Inc., New York, NY. 1994; Neben et al., Experimental Hematology 22:353-359, 1994; Cobblestone area forming cell assay, Ploemacher, R.E. In Culture of Hematopoietic Cells. R.I. Freshney, et al. eds. Vol pp. 1-21, Wiley-Liss, Inc.., New York, NY. 1994; Long term bone marrow cultures in the presence of stromal cells, Spooncer, E., Dexter, M. and Allen, T. In Culture of Hematopoietic Cells. R.I. Freshney, et al. eds. Vol pp. 163-179, Wiley-Liss, Inc., New York, NY. 1994; Long term culture initiating cell assay, Sutherland,

H.J. In Culture of Hematopoietic Cells. R.I. Freshney, et al. eds. Vol pp. 139-162, Wiley-Liss, Inc., New York, NY. 1994.

Tissue Growth Activitv A protein of the present invention also may have utility in compositions used for bone, cartilage, tendon, ligament and/or nerve tissue growth or regeneration, as well as for wound healing and tissue repair and replacement, and in the treatment of burns, incisions and ulcers.

A protein of the present invention, which induces cartilage and/or bone growth in circumstances where bone is not normally formed, has application in the healing of bone fractures and cartilage damage or defects in humans and other animals. Such a preparation employing a protein of the invention may have prophylactic use in closed as well as open fracture reduction and also in the improved fixation of artificial joints. De novo bone formation induced by an osteogenic agent contributes to the repair of congenital, trauma induced, or oncologic resection induced craniofacial defects, and also is useful in cosmetic plastic surgery.

A protein of this invention may also be used in the treatment of periodontal disease, and in other tooth repair processes. Such agents may provide an environment to attract bone-forming cells, stimulate growth of bone-forming cells or induce differentiation of progenitors of bone-forming cells. A protein of the invention may also be useful in the treatment of osteoporosis or osteoarthritis, such as through stimulation of bone and/or cartilage repair or by blocking inflammation or processes of tissue destruction (collagenase activity, osteoclast activity, etc.) mediated by inflammatory processes.

Another category of tissue regeneration activity that may be attributable to the protein of the present invention is tendon/ligament formation. A protein of the present invention, which induces tendon/ligament-like tissue or other tissue formation in circumstances where such tissue is not normally formed, has application in the healing of tendon or ligament tears, deformities and other tendon or ligament defects in humans and other animals. Such a preparation employing a tendon/ligament-like tissue inducing protein may have prophylactic use in preventing damage to tendon or ligament tissue, as well as use in the improved fixation of tendon or ligament to bone or other tissues, and in repairing defects to tendon or ligament tissue. De novo tendon/ligament-like tissue formation induced by a composition of the present invention contributes to the repair of

congenital, trauma induced, or other tendon or ligament defects of other origin, and is also useful in cosmetic plastic surgery for attachment or repair of tendons or ligaments. The compositions of the present invention may provide an environment to attract tendon- or ligament-forming cells, stimulate growth of tendon- or ligament-forming cells, induce differentiation of progenitors of tendon- or ligament-forming cells, or induce growth of tendon/ligament cells or progenitors ex vivo for return in vivo to effect tissue repair. The compositions of the invention may also be useful in the treatment of tendinitis, carpal tunnel syndrome and other tendon or ligament defects. The compositions may also include an appropriate matrix and/or sequestering agent as a carrier as is well known in the art.

The protein of the present invention may also be useful for proliferation of neural cells and for regeneration of nerve and brain tissue, i.e. for the treatment of central and peripheral nervous system diseases and neuropathies, as well as mechanical and traumatic disorders, which involve degeneration, death or trauma to neural cells or nerve tissue. More specifically, a protein may be used in the treatment of diseases of the peripheral nervous system, such as peripheral nerve injuries, peripheral neuropathy and localized neuropathies, and central nervous system diseases, such as Alzheimer's, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Shy-Drager syndrome. Further conditions which may be treated in accordance with the present invention include mechanical and traumatic disorders, such as spinal cord disorders, head trauma and cerebrovascular diseases such as stroke. Peripheral neuropathies resulting from chemotherapy or other medical therapies may also be treatable using a protein of the invention.

Proteins of the invention may also be useful to promote better or faster closure of non-healing wounds, including without limitation pressure ulcers, ulcers associated with vascular insufficiency, surgical and traumatic wounds, and the like.

It is expected that a protein of the present invention may also exhibit activity for generation or regeneration of other tissues, such as organs (including, for example, pancreas, liver, intestine, kidney, skin, endothelium), muscle (smooth, skeletal or cardiac) and vascular (including vascular endothelium) tissue, or for promoting the growth of cells comprising such tissues. Part of the desired effects may be by inhibition or modulation of fibrotic scarring to allow normal tissue to regenerate. A protein of the invention may also exhibit angiogenic activity.

A protein of the present invention may also be useful for gut protection or regeneration and treatment of lung or liver fibrosis, reperfusion injury in various tissues, and conditions resulting from systemic cytokine damage.

A protein of the present invention may also be useful for promoting or inhibiting differentiation of tissues described above from precursor tissues or cells; or for inhibiting the growth of tissues described above.

The activity of a protein of the invention may, among other means, be measured by the following methods: Assays for tissue generation activity include, without limitation, those described in: International Patent Publication No. WO95/16035 (bone, cartilage, tendon); International Patent Publication No. W095/05846 (nerve, neuronal); International Patent Publication No. WO91/07491 (skin, endothelium).

Assays for wound healing activity include, without limitation, those described in: Winter, Epidermal Wound Healing, pps. 71-112 (Maibach, HI and Rovee, DT, eds.), Year Book Medical Publishers, Inc., Chicago, as modified by Eaglstein and Mertz, J. Invest.

Dermatol 71:382-84 (1978).

Activin/Inhibin Activity A protein of the present invention may also exhibit activin- or inhibin-related activities. Inhibins are characterized by their ability to inhibit the release of follicle stimulating hormone (FSH), while activins and are characterized by their ability to stimulate the release of follicle stimulating hormone (FSH). Thus, a protein of the present invention, alone or in heterodimers with a member of the inhibin a family, may be useful as a contraceptive based on the ability of inhibins to decrease fertility in female mammals and decrease spermatogenesis in male mammals. Administration of sufficient amounts of other inhibins can induce infertility in these mammals. Alternatively, the protein of the invention, as a homodimer or as a heterodimer with other protein subunits of the inhibin- P group, may be useful as a fertility inducing therapeutic, based upon the ability of activin molecules in stimulating FSH release from cells of the anterior pituitary. See, for example, United States Patent 4,798,885. A protein of the invention may also be useful for advancement of the onset of fertility in sexually immature mammals, so as to increase the lifetime reproductive performance of domestic animals such as cows, sheep and pigs.

The activity of a protein of the invention may, among other means, be measured by the following methods:

Assays for activin/inhibin activity include, without limitation, those described in: Vale et al., Endocrinology 91:562-572, 1972; Ling et al., Nature 321:779-782, 1986; Vale et al., Nature 321:776-779, 1986; Mason et al., Nature 318:659-663, 1985; Forage et al., Proc.

Natl. Acad. Sci. USA 83:3091-3095, 1986.

Chemotactic/Chemokinetic Activity A protein of the present invention may have chemotactic or chemokinetic activity (e.g., act as a chemokine) for mammalian cells, including, for example, monocytes, fibroblasts, neutrophils, T-cells, mast cells, eosinophils, epithelial and/or endothelial cells.

Chemotactic and chemokinetic proteins can be used to mobilize or attract a desired cell population to a desired site of action. Chemotactic or chemokinetic proteins provide particular advantages in treatment of wounds and other trauma to tissues, as well as in treatment of localized infections. For example, attraction of lymphocytes, monocytes or neutrophils to tumors or sites of infection may result in improved immune responses against the tumor or infecting agent.

A protein or peptide has chemotactic activity for a particular cell population if it can stimulate, directly or indirectly, the directed orientation or movement of such cell population. Preferably, the protein or peptide has the ability to directly stimulate directed movement of cells. Whether a particular protein has chemotactic activity for a population of cells can be readily determined by employing such protein or peptide in any known assay for cell chemotaxis.

The activity of a protein of the invention may, among other means, be measured by the following methods: Assays for chemotactic activity (which will identify proteins that induce or prevent chemotaxis) consist of assays that measure the ability of a protein to induce the migration of cells across a membrane as well as the ability of a protein to induce the adhesion of one cell population to another cell population. Suitable assays for movement and adhesion include, without limitation, those described in: Current Protocols in Immunology, Ed by J.E. Coligan, A.M. Kruisbeek, D.H. Margulies, E.M. Shevach, W.Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 6.12, Measurement of alpha and beta Chemokines 6.12.1-6.12.28; Taub et al. J. Clin. Invest. 95:1370-1376, 1995; Lind et al.

APMIS 103:140-146, 1995; Muller et al Eur. J. Immunol. 25: 1744-1748; Gruber et al. J. of Immunol. 152:5860-5867, 1994; Johnston et al. J. of Immunol. 153: 1762-1768, 1994.

Hemostatic and Thrombolytic Activity A protein of the invention may also exhibit hemostatic or thrombolytic activity.

As a result, such a protein is expected to be useful in treatment of various coagulation disorders (including hereditary disorders, such as hemophilias) or to enhance coagulation and other hemostatic events in treating wounds resulting from trauma, surgery or other causes. A protein of the invention may also be useful for dissolving or inhibiting formation of thromboses and for treatment and prevention of conditions resulting therefrom (such as, for example, infarction of cardiac and central nervous system vessels (e.g., stroke).

The activity of a protein of the invention may, among other means, be measured by the following methods: Assay for hemostatic and thrombolytic activity include, without limitation, those described in: Linet et al., J. Clin. Pharmacol. 26:131-140, 1986; Burdick et al., Thrombosis Res. 45:413-419, 1987; Humphrey et al., Fibrinolysis 5:71-79 (1991); Schaub, Prostaglandins 35:467-474, 1988.

Receptor/Ligand Activity A protein of the present invention may also demonstrate activity as receptors, receptor ligands or inhibitors or agonists of receptor/ligand interactions. Examples of such receptors and ligands include, without limitation, cytokine receptors and their ligands, receptor kinases and their ligands, receptor phosphatases and their ligands, receptors involved in cell-cell interactions and their ligands (including without limitation, cellular adhesion molecules (such as selectins, integrins and their ligands) and receptor/ligand pairs involved in antigen presentation, antigen recognition and development of cellular and humoral immune responses). Receptors and ligands are also useful for screening of potential pep tide or small molecule inhibitors of the relevant receptor/ligand interaction. A protein of the present invention (including, without limitation, fragments of receptors and ligands) may themselves be useful as inhibitors of receptor / ligand interactions.

The activity of a protein of the invention may, among other means, be measured by the following methods: Suitable assays for receptor-ligand activity include without limitation those described in:Current Protocols in Immunology, Ed by J.E. Coligan, A.M. Kruisbeek, D.H.

Margulies, E.M. Shevach, W.Strober, Pub. Greene Publishing Associates and

Wiley-Interscience (Chapter 7.28, Measurement of Cellular Adhesion under static conditions 7.28.1-7.28.22), Takai et al., Proc. Natl. Acad. Sci. USA 84:6864-6868, 1987; Bierer et al., J. Exp. Med. 168:1145-1156, 1988; Rosenstein et al., J. Exp. Med. 169:149-160 1989; Stoltenborg et al., J. Immunol. Methods 175:59-68, 1994; Stitt et al., Cell 80:661-670, 1995.

Anti-Inflammatorv Activity Proteins of the present invention may also exhibit anti-inflammatory activity. The anti-inflammatory activity may be achieved by providing a stimulus to cells involved in the inflammatory response, by inhibiting or promoting cell-cell interactions (such as, for example, cell adhesion), by inhibiting or promoting chemotaxis of cells involved in the inflammatory process, inhibiting or promoting cell extravasation, or by stimulating or suppressing production of other factors which more directly inhibit or promote an inflammatory response. Proteins exhibiting such activities can be used to treat inflammatory conditions including chronic or acute conditions), including without limitation inflammation associated with infection (such as septic shock, sepsis or systemic inflammatory response syndrome (SIRS)), ischemia-reperfusion injury, endotoxin lethality, arthritis, complement-mediated hyperacute rejection, nephritis, cytokine or chemokine-induced lung injury, inflammatory bowel disease, Crohn's disease or resulting from over production of cytokines such as TNF or IL-1. Proteins of the invention may also be useful to treat anaphylaxis and hypersensitivity to an antigenic substance or material.

Cadherin/Tumor Invasion Suppressor Activity Cadherins are calcium-dependent adhesion molecules that appear to play major roles during development, particularly in defining specific cell types. Loss or alteration of normal cadherin expression can lead to changes in cell adhesion properties linked to tumor growth and metastasis. Cadherin malfunction is also implicated in other human diseases, such as pemphigus vulgaris and pemphigus foliaceus (auto-immune blistering skin diseases), Crohn's disease, and some developmental abnormalities.

The cadherin superfamily includes well over forty members, each with a distinct pattern of expression. All members of the superfamily have in common conserved extracellular repeats (cadherin domains), but structural differences are found in other parts of the molecule. The cadherin domains bind calcium to form their tertiary structure and thus calcium is required to mediate their adhesion. Only a few amino acids in the

first cadherin domain provide the basis for homophilic adhesion; modification of this recognition site can change the specificity of a cadherin so that instead of recognizing only itself, the mutant molecule can now also bind to a different cadherin. In addition, some cadherins engage in heterophilic adhesion with other cadherins.

E-cadherin, one member of the cadherin superfamily, is expressed in epithelial cell types. Pathologically, if E-cadherin expression is lost in a tumor, the malignant cells become invasive and the cancer metastasizes. Transfection of cancer cell lines with polynucleotides expressing E-cadherin has reversed cancer-associated changes by returning altered cell shapes to normal, restoring cells' adhesiveness to each other and to their substrate, decreasing the cell growth rate, and drastically reducing anchorage- independent cell growth. Thus, reintroducing E-cadherin expression reverts carcinomas to a less advanced stage. It is likely that other cadherins have the same invasion suppressor role in carcinomas derived from other tissue types. Therefore, proteins of the present invention with cadherin activity, and polynucleotides of the present invention encoding such proteins, can be used to treat cancer. Introducing such proteins or polynucleotides into cancer cells can reduce or eliminate the cancerous changes observed in these cells by providing normal cadherin expression.

Cancer cells have also been shown to express cadherins of a different tissue type than their origin, thus allowing these cells to invade and metastasize in a different tissue in the body. Proteins of the present invention with cadherin activity, and polynucleotides of the present invention encoding such proteins, can be substituted in these cells for the inappropriately expressed cadherins, restoring normal cell adhesive properties and reducing or eliminating the tendency of the cells to metastasize.

Additionally, proteins of the present invention with cadherin activity, and polynucleotides of the present invention encoding such proteins, can used to generate antibodies recognizing and binding to cadherins. Such antibodies can be used to block the adhesion of inappropriately expressed tumor-cell cadherins, preventing the cells from forming a tumor elsewhere. Such an anti-cadherin antibody can also be used as a marker for the grade, pathological type, and prognosis of a cancer, i.e. the more progressed the cancer, the less cadherin expression there will be, and this decrease in cadherin expression can be detected by the use of a cadherin-binding antibody.

Fragments of proteins of the present invention with cadherin activity, preferably a polypeptide comprising a decapeptide of the cadherin recognition site, and poly- nucleotides of the present invention encoding such protein fragments, can also be used

to block cadherin function by binding to cadherins and preventing them from binding in ways that produce undesirable effects. Additionally, fragments of proteins of the present invention with cadherin activity, preferably truncated soluble cadherin fragments which have been found to be stable in the circulation of cancer patients, and polynucleotides encoding such protein fragments, can be used to disturb proper cell-cell adhesion.

Assays for cadherin adhesive and invasive suppressor activity include, without limitation, those described in: Hortsch et al. J Biol Chem 270 (32): 18809-18817, 1995; Miyaki et al. Oncogene 11: 2547-2552, 1995; Ozawa et al. Cell 63: 1033-1038, 1990.

Tumor Inhibition Activity In addition to the activities described above for immunological treatment or prevention of tumors, a protein of the invention may exhibit other anti-tumor activities.

A protein may inhibit tumor growth directly or indirectly (such as, for example, via ADCC). A protein may exhibit its tumor inhibitory activity by acting on tumor tissue or tumor precursor tissue, by inhibiting formation of tissues necessary to support tumor growth (such as, for example, by inhibiting angiogenesis), by causing production of other factors, agents or cell types which inhibit tumor growth, or by suppressing, eliminating or inhibiting factors, agents or cell types which promote tumor growth.

Other Activities A protein of the invention may also exhibit one or more of the following additional activities or effects: inhibiting the growth, infection or function of, or killing, infectious agents, including, without limitation, bacteria, viruses, fungi and other parasites; effecting (suppressing or enhancing) bodily characteristics, including, without limitation, height, weight, hair color, eye color, skin, fat to lean ratio or other tissue pigmentation, or organ or body part size or shape (such as, for example, breast augmentation or diminution, change in bone form or shape); effecting biorhythms or caricadic cycles or rhythms; effecting the fertility of male or female subjects; effecting the metabolism, catabolism, anabolism, processing, utilization, storage or elimination of dietary fat, lipid, protein, carbohydrate, vitamins, minerals, cofactors or other nutritional factors or component(s); effecting behavioral characteristics, including, without limitation, appetite, libido, stress, cognition (including cognitive disorders), depression (including depressive disorders) and violent behaviors; providing analgesic effects or other pain reducing effects; promoting differentiation and growth of embryonic stem cells in lineages other than hematopoietic

lineages; hormonal or endocrine activity; in the case of enzymes, correcting deficiencies of the enzyme and treating deficiency-related diseases; treatment of hyperproliferative disorders (such as, for example, psoriasis); immunoglobulin-like activity (such as, for example, the ability to bind antigens or complement); and the ability to act as an antigen in a vaccine composition to raise an immune response against such protein or another material or entity which is cross-reactive with such protein.

ADMINISTRATION AND DOSING A protein of the present invention (from whatever source derived, including without limitation from recombinant and non-recombinant sources) may be used in a pharmaceutical composition when combined with a pharmaceutically acceptable carrier.

Such a composition may also contain (in addition to protein and a carrier) diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The term "pharmaceutically acceptable" means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s). The characteristics of the carrier will depend on the route of administration. The pharmaceutical composition of the invention may also contain cytokines, lymphokines, or other hematopoietic factors such as M-CSF, GM-CSF, TNF, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IFN, TNF0, TNF1, TNF2, G-CSF, Meg-CSF, thrombopoietin, stem cell factor, and erythropoietin. The pharmaceutical composition may further contain other agents which either enhance the activity of the protein or compliment its activity or use in treatment. Such additional factors and/or agents may be included in the pharmaceutical composition to produce a synergistic effect with protein of the invention, or to minimize side effects. Conversely, protein of the present invention may be included in formulations of the particular cytokine, lymphokine, other hematopoietic factor, thrombolytic or anti-thrombotic factor, or anti-inflammatory agent to minimize side effects of the cytokine, lymphokine, other hematopoietic factor, thrombolytic or anti-thrombotic factor, or anti-inflammatory agent.

A protein of the present invention may be active in multimers (e.g., heterodimers or homodimers) or complexes with itself or other proteins. As a result, pharmaceutical compositions of the invention may comprise a protein of the invention in such multimeric or complexed form.

The pharmaceutical composition of the invention may be in the form of a complex of the protein(s) of present invention along with protein or peptide antigens. The protein and/or peptide antigen will deliver a stimulatory signal to both B and T lymphocytes. B lymphocytes will respond to antigen through their surface immunoglobulin receptor. T lymphocytes will respond to antigen through the T cell receptor (TCR) following presentation of the antigen by MHC proteins. MHC and structurally related proteins including those encoded by class I and class II MHC genes on host cells will serve to present the peptide antigen(s) to T lymphocytes. The antigen components could also be supplied as purified MHC-peptide complexes alone or with co-stimulatory molecules that can directly signal T cells. Alternatively antibodies able to bind surface immunolgobulin and other molecules on B cells as well as antibodies able to bind the TCR and other molecules on T cells can be combined with the pharmaceutical composition of the invention.

The pharmaceutical composition of the invention may be in the form of a liposome in which protein of the present invention is combined, in addition to other pharmaceutically acceptable carriers, with amphipathic agents such as lipids which exist in aggregated form as micelles, insoluble monolayers, liquid crystals, or lamellar layers in aqueous solution. Suitable lipids for liposomal formulation include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acids, and the like. Preparation of such liposomal formulations is within the level of skill in the art, as disclosed, for example, in U.S. Patent No. 4,235,871; U.S. Patent No. 4,501,728; U.S.

Patent No. 4,837,028; and U.S. Patent No. 4,737,323, all of which are incorporated herein by reference.

As used herein, the term "therapeutically effective amount" means the total amount of each active component of the pharmaceutical composition or method that is sufficient to show a meaningful patient benefit, i.e., treatment, healing, prevention or amelioration of the relevant medical condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.

In practicing the method of treatment or use of the present invention, a therapeutically effective amount of protein of the present invention is administered to a mammal having a condition to be treated. Protein of the present invention may be

administered in accordance with the method of the invention either- alone or in combination with other therapies such as treatments employing cytokines, lymphokines or other hematopoietic factors. When co-administered with one or more cytokines, lymphokines or other hematopoietic factors, protein of the present invention may be administered either simultaneously with the cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors, or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administering protein of the present invention in combination with cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors.

Administration of protein of the present invention used in the pharmaceutical composition or to practice the method of the present invention can be carried out in a variety of conventional ways, such as oral ingestion, inhalation, topical application or cutaneous, subcutaneous, intraperitoneal, parenteral or intravenous injection.

Intravenous administration to the patient is preferred.

When a therapeutically effective amount of protein of the present invention is administered orally, protein of the present invention will be in the form of a tablet, capsule, powder, solution or elixir. When administered in tablet form, the pharmaceutical composition of the invention may additionally contain a solid carrier such as a gelatin or an adjuvant. The tablet, capsule, and powder contain from about 5 to 95% protein of the present invention, and preferably from about 25 to 90% protein of the present invention.

When administered in liquid form, a liquid carrier such as water, petroleum, oils of animal or plant origin such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils may be added. The liquid form of the pharmaceutical composition may further contain physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol. When administered in liquid form, the pharmaceutical composition contains from about 0.5 to 90% by weight of protein of the present invention, and preferably from about 1 to 50% protein of the present invention.

When a therapeutically effective amount of protein of the present invention is administered by intravenous, cutaneous or subcutaneous injection, protein of the present invention will be in the form of a pyrogen-free, parenterally acceptable aqueous solution.

The preparation of such parenterally acceptable protein solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art. A preferred

pharmaceutical composition for intravenous, cutaneous, or subcutaneous injection should contain, in addition to protein of the present invention, an isotonic vehicle such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer's Injection, or other vehicle as known in the art. The pharmaceutical composition of the present invention may also contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those of skill in the art.

The amount of protein of the present invention in the pharmaceutical composition of the present invention will depend upon the nature and severity of the condition being treated, and on the nature of prior treatments which the patient has undergone.

Ultimately, the attending physician will decide the amount of protein of the present invention with which to treat each individual patient. Initially, the attending physician will administer low doses of protein of the present invention and observe the patient's response. Larger doses of protein of the present invention may be administered until the optimal therapeutic effect is obtained for the patient, and at that point the dosage is not increased further. It is contemplated that the various pharmaceutical compositions used to practice the method of the present invention should contain about 0.01 pg to about 100 mg (preferably about 0.lng to about 10 mg, more preferably about 0.1 pg to about 1 mg) of protein of the present invention per kg body weight.

The duration of intravenous therapy using the pharmaceutical composition of the present invention will vary, depending on the severity of the disease being treated and the condition and potential idiosyncratic response of each individual patient. It is contemplated that the duration of each application of the protein of the present invention will be in the range of 12 to 24 hours of continuous intravenous administration.

Ultimately the attending physician will decide on the appropriate duration of intravenous therapy using the pharmaceutical composition of the present invention.

Protein of the invention may also be used to immunize animals to obtain polyclonal and monoclonal antibodies which specifically react with the protein. Such antibodies may be obtained using either the entire protein or fragments thereof as an immunogen. The peptide immunogens additionally may contain a cysteine residue at the carboxyl terminus, and are conjugated to a hasten such as keyhole limpet hemocyanin (KLH). Methods for synthesizing such peptides are known in the art, for example, as in R.P. Merrifield, J. Amer.Chem.Soc. 85, 2149-2154 (1963); J.L. Krstenansky, et al., FEBS Lett.

, 10 (1987). Monoclonal antibodies binding to the protein of the invention may be useful diagnostic agents for the immunodetection of the protein. Neutralizing monoclonal

antibodies binding to the protein may also be useful therapeutics for both conditions associated with the protein and also in the treatment of some forms of cancer where abnormal expression of the protein is involved. In the case of cancerous cells or leukemic cells, neutralizing monoclonal antibodies against the protein may be useful in detecting and preventing the metastatic spread of the cancerous cells, which may be mediated by the protein.

For compositions of the present invention which are useful for bone, cartilage, tendon or ligament regeneration, the therapeutic method includes administering the composition topically, systematically, or locally as an implant or device. When administered, the therapeutic composition for use in this invention is, of course, in a pyrogen-free, physiologically acceptable form. Further, the composition may desirably be encapsulated or injected in a viscous form for delivery to the site of bone, cartilage or tissue damage. Topical administration may be suitable for wound healing and tissue repair. Therapeutically useful agents other than a protein of the invention which may also optionally be included in the composition as described above, may alternatively or additionally, be administered simultaneously or sequentially with the composition in the methods of the invention. Preferably for bone and/or cartilage formation, the composition would include a matrix capable of delivering the protein-containing composition to the site of bone and/or cartilage damage, providing a structure for the developing bone and cartilage and optimally capable of being resorbed into the body.

Such matrices may be formed of materials presently in use for other implanted medical applications.

The choice of matrix material is based on biocompatibility, biodegradability, mechanical properties, cosmetic appearance and interface properties. The particular application of the compositions will define the appropriate formulation. Potential matrices for the compositions may be biodegradable and chemically defined calcium sulfate, tricalciumphosphate, hydroxyapatite, polylactic acid, polyglycolic acid and polyanhydrides. Other potential materials are biodegradable and biologically well- defined, such as bone or dermal collagen. Further matrices are comprised of pure proteins or extracellular matrix components. Other potential matrices are nonbiodegradable and chemically defined, such as sintered hydroxapatite, bioglass, aluminates, or other ceramics. Matrices may be comprised of combinations of any of the above mentioned types of material, such as polylactic acid and hydroxyapatite or collagen and tricalciumphosphate. The bioceramics may be altered in composition, such as in calcium-

aluminate-phosphate and processing to alter pore size, particle size, particle shape, and biodegradability.

Presently preferred is a 50:50 (mole weight) copolymer of lactic acid and glycolic acid in the form of porous particles having diameters ranging from 150 to 800 microns.

In some applications, it will be useful to utilize a sequestering agent, such as carboxymethyl cellulose or autologous blood clot, to prevent the protein compositions from disassociating from the matrix.

A preferred family of sequestering agents is cellulosic materials such as alkylcelluloses (including hydroxyalkylcelluloses), including methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl- methylcellulose, and carboxymethylcellulose, the most preferred being cationic salts of carboxymethylcellulose (CMC). Other preferred sequestering agents include hyaluronic acid, sodium alginate, poly(ethylene glycol), polyoxyethylene oxide, carboxyvinyl polymer and poly(vinyl alcohol). The amount of sequestering agent useful herein is 0.5-20 wt%, preferably 1-10 wt% based on total formulation weight, which represents the amount necessary to prevent desorbtion of the protein from the polymer matrix and to provide appropriate handling of the composition, yet not so much that the progenitor cells are prevented from infiltrating the matrix, thereby providing the protein the opportunity to assist the osteogenic activity of the progenitor cells.

In further compositions, proteins of the invention may be combined with other agents beneficial to the treatment of the bone and/or cartilage defect, wound, or tissue in question. These agents include various growth factors such as epidermal growth factor (EGF), platelet derived growth factor (PDGF), transforming growth factors (TGF-a and TGF-,), and insulin-like growth factor (IGF).

The therapeutic compositions are also presently valuable for veterinary applications. Particularly domestic animals and thoroughbred horses, in addition to humans, are desired patients for such treatment with proteins of the present invention.

The dosage regimen of a protein-containing pharmaceutical composition to be used in tissue regeneration will be determined by the attending physician considering various factors which modify the action of the proteins, e.g., amount of tissue weight desired to be formed, the site of damage, the condition of the damaged tissue, the size of a wound, type of damaged tissue (e.g., bone), the patient's age, sex, and diet, the severity of any infection, time of administration and other clinical factors. The dosage may vary with the type of matrix used in the reconstitution and with inclusion of other proteins in

the pharmaceutical composition. For example, the addition of other known growth factors, such as IGF I (insulin like growth factor I), to the final composition, may also effect the dosage. Progress can be monitored by periodic assessment of tissue/bone growth and/or repair, for example, X-rays, histomorphometric determinations and tetracycline labeling.

Polynucleotides of the present invention can also be used for gene therapy. Such polynucleotides can be introduced either in vivo or ex vivo into cells for expression in a mammalian subject. Polynucleotides of the invention may also be administered by other known methods for introduction of nucleic acid into a cell or organism (including, without limitation, in the form of viral vectors or naked DNA).

Cells may also be cultured ex vivo in the presence of proteins of the present invention in order to proliferate or to produce a desired effect on or activity in such cells.

Treated cells can then be introduced in vivo for therapeutic purposes.

Patent and literature references cited herein are incorporated by reference as if fully set forth.

SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: Jacobs, Kenneth McCoy, John M.

LaVallie, Edward R.

Racie, Lisa A.

Merberg, David Treacy, Maurice Spaulding, Vikki Agostino, Michael J.

(ii) TITLE OF INVENTION: SECRETED PROTEINS AND POLYNUCLEOTIDES ENCODING THEM (iii) NUMBER OF SEQUENCES: 34 (iv) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: Genetics Institute, Inc.

(B) STREET: 87 CambridgePark Drive (C) CITY: Cambridge (D) STATE: MA (E) COUNTRY: U.S.A.

(F) ZIP: 02140 (v) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS (D) SOFTWARE: PatentIn Release #1.0, Version #1.30 (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: (B) FILING DATE: (C) CLASSIFICATION: (viii) ATTORNEY/AGENT INFORMATION: (A) NAME: Sprunger, Suzanne A.

(B) REGISTRATION NUMBER: 41,323 (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: (617) 498-8284 (B) TELEFAX: (617) 876-5851 (2) INFORMATION FOR SEQ ID NO:1: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 349 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1: ACTTCGCANC CCATCCCGGC TGGACGCGAC CGGGGAGTGC AGCAGCCCGT TCCCCTCCTC 60 GGTGCCGCCT CTGCCCAGCG TTTGCTTGGC TGGGCTACCA CCTGCGCTCG GACGGCGCTC 120 GGAGGGTCCT CGCCCCCGGC CTGCCTACCT GAAAACCANA ACTGATGGCT CTATTTGCAG 180 TCTTTCANAC AACATTCTTC TTAACATTGC TGTCCTTGAG GACTTACCAN ANTGAAGTCT 240 TGGCTGAACG TTTACCATTG ACTCCTGTTN TCACTTAAAG TTTCCACCAA TTCTACGCGT 300 CAGAGTTTGC ACTTACAATG GACTGTCCAC AACCTTCCTT ATCATCAGG 349 (2) INFORMATION FOR SEQ ID NO:2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 563 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: TCCATTCCAG CACCAGCCAA CAGCACAAAA TTAATCCTTG ACAGGTGTTC CTACCAAATT 60 TGNGTCATAG CCAACAACAG TGNGGGTGCT TCTCCTGCTT CTGTAATAGT CATTTNTGCA 120 GACCCCGAAA ACAAAGAGGT TGAGGAAGAA AGAATTGCAG GCACAGAGGG TGGATTNTTT 180 TTNTTTTGGA AACCCCAACC TGGAGATGTT ATAGGTTATG TTGTGGANTG GTGTGACCAN 240 ACCCAGGATG TGCCTCGGTG ATTTCCAGTG GAAGAATGTA GGTCCCAATA CCACAAGCAC 300 AGTCATTAGC ACAGATGCTT TTAGGCCAGG AGTTCGATAT GACTTCAGAA TTTATGGGTT 360 ATCTACAAAA AGGATTGCTT GTTTATTAGA GAAAAAAAAC AGGATACTCT CAGGAACTTG 420 CTCCTTCAGA CAACCCTCAC GTGCTGGTGG ATACATTGAC ATCCCACTCC TTCACTCTGA 480 GTTGGAAAGA TTACTCTACT GAATCTCAAC CTGGTTTTAT ACAAGGGTAC CATGTCTATC 540 TGAAATCCAA GGCGAGGCAG TGC 563 (2) INFORMATION FOR SEQ ID NO:3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 58 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: Arg Lys Lys Thr Gly Tyr Ser Gln Glu Leu Ala Pro Ser Asp Asn Pro 1 5 10 15 His Val Leu Val Asp Thr Leu Thr Ser His Ser Phe Thr Leu Ser Trp 20 25 30 Lys Asp Tyr Ser Thr Glu Ser Gln Pro Gly Phe Ile Gln Gly Tyr His 35 40 45 Val Tyr Leu Lys Ser Lys Ala Arg Gln Cys 50 55 (2) INFORMATION FOR SEQ ID NO:4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 361 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: GAAAAGGCAG TTCTTTCAGA TGGTTCAGAA TGTTGCAAAT ACAAAATTGA CAACCCGGAA 60 GAAAAGGCAT TGATTGTGGA CAACCTAAAG CCAGAATCCT TNTANGAGTT TTTCATCACT 120 CCATTCACTA GTGCTGGTGA AGGCCCCAGT GCNACGTTCA CGAAGGTCAC GACTCCGGAT 180 GAACANTCCT NGATGCTGAT TCATATCCTA CTGCCCATGG TTTTCTGCGT CTTGCTCATC 240 ATGGTCATGT GNNACTTGAA AAGTCAGTGG ATCAAGGAGA CCTGTTATCC TGACATCCCT 300 GACCCTTACA AGAGCAGCAT CCTGTCATTA ATAAAATTCA AGGTAAAAAA AAAAAAAAAA 360 A 361 (2) INFORMATION FOR SEQ ID NO:5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 756 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5: ATTGAATTCT AGACCTGCGG CCGCTGCTCC CTCAGANGCC CCTGATGTCT GGANAATTGT 60 GAGCTTGGAG CCAGGAAATC ATACTGTGAC CTTATTCTGG AAGCCATTAT CAAAACTGCA 120 TGCCAATGGA AAGATCCTGT TCTATAATGT AGTTGTAGAA AACCTAGACA AACCATCCAG 180 TTCAGAGCTC CATTCCATTC CAGCACCAGC CAACAGCACA AAACTAATCC TTGACAGGTG 240 TTCCTACCAA ATCTGCGTCA TAGCCAACAA CAGTGTGGGT GCTTCTCCTG CTTCTGTAAT 300 AGTCATYTCT GCAGACCCCG AAAACAAAGA GGTTGAGGAA GAAAGAATTG CAGGCACAGA 360 GGGTGGATTT TTTTTNTTTT GGAAACCCCA ACCTGGAGAT GTTATAGGTT ATGTTGTGGA 420 CTGGTGTGAC CANACCCAGG ATGTGCCTCG GTGATTTCCA GTGGAAGAAT GTAGGTCCCA 480 ATACCACAAG CACAGTCATT AGCACAGATG CTTTTAGGCC AGGAGTTCGA TATGACTTCA 540 GAATTTATGG GTTATCTACA AAAAGGATTG CTTGTTTATT AGAGAAAAAA AACAGGATAC 600 TCTCAGGAAC TTGCTCCTTC AGACAACCCT CACGTGCTGG TGGATACATT GACATCCCAC 660 TCCTTCACTC TGAGTTGGAA AGATTACTCT ACTGAATCTC AACCTGGTTT TATACAAGGG 720 TACCATGTCT ATCTGAAATC CAAGGCGAGG CAGTGC 756 (2) INFORMATION FOR SEQ ID NO:6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 58 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: Arg Lys Lys Thr Gly Tyr Ser Gln Glu Leu Ala Pro Ser Asp Asn Pro 1 5 10 15 His Val Leu Val Asp Thr Leu Thr Ser His Ser Phe Thr Leu Ser Trp 20 25 30 Lys Asp Tyr Ser Thr Glu Ser Gln Pro Gly Phe Ile Gln Gly Tyr His 35 40 45 Val Tyr Leu Lys Ser Lys Ala Arg Gln Cys 50 55 (2) INFORMATION FOR SEQ ID NO:7: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 79 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7: <BR> <BR> <BR> <BR> <BR> TCATTAATAA AATTCAAGGT AAATGTTAAA AAAAAAAA A AAAAAAAAAA AAAAAAAA A 60 AAAAAAAAAA AAAAAAAAA 79 (2) INFORMATION FOR SEQ ID NO:8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1939 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8: ATTGGTTTTC AAATATTAAA CCAGCATTTT ATTTTAAAAT AAACCCCACT TAGTTATGAT 60 ATTTTATCTT TTTTATATAA TGTGGGATTT GATTTGCCGA TATTTTATTA AAGATTTTTG 120 CATCATGTTC TTTTTCTGAA ATTTTATTTT GTTCTAATGT CATAAAATAA GTTGGAAATT 180 ATCCTCTCTA TCTCTACTTT GTGAAAGAAT TTATATTACA TTGGTATTAT TTCTTCCTTG 240 AATGTTTGAT AGACTATACT AGTGAAAGCA TCTGGGCCTA GGGTTTTCTC TGTGGAAGAT 300 TTTCAGTTAC AAATTCAATT TTACTGAGTC AGGTTTGATA AGTTACATTT CTCAAGGAAT 360 TTATCTATTT AATCATTGAA TGTATTGAAC ATTCATTTGT TTATAATTTT GTTTTGTTAT 420 TGAAAATGTC TGTAAGATTT ATAGTGATGT TCCCTTTTCT ATTCCTGACA TTGTTAATTT 480 GTGTTCTCTC TCCCTCCATC CCTCTCTCAC TCTCTCTTGT CAGCTGGTCT GTGGGATTAT 540 CACCTTTATT AATCTTTTCA GAGAACCACT TTTTATTTCT TTGATTTCCT TTATTGTTTG 600 TTAACTTTTT AGTTTATTGA TTCCCTCTCT TAGCTTTATT ACTTCCTTCC TTCTACTTAG 660 TAAGAGTTTA ATTTGCCCTC ATTTTTTTAG CTTCTTAAGG TAGGAAATTT GATTATATTT 720 TAAACTTAAA AAAACTTAAA GCTATAAAAT TCCCTTTAAG CACTGTTTTA GCTGAATTCT 780 ACATATTTTG ATTGGGTATG TTTTCATCAT TCAATTAAAA ACATAGTTTC TAATTTTTTC 840 TTGCAATTTC TTCTTTAACC CATAGGTTAT TTGGCAGTTT GCTGCTGAAT TTCAAAGTGC 900 TTGGGAGGTT TTATAGCTAT CTTGTTAAAA ATTGATTTCT AATTTAATTT TGTCAGAGAA 960 CATACTTTGT ATGACTTAAA TCTTTTAAAA TACGTTCAGA CTGATTTAGG GTCCAGCATA 1020 TGGTACGTCT TAGTGAATGT AATATATGCC ATTGGAAATG ATGCACATTC TGCAATTGTT 1080 GGTTGTAATG TGCTATAAAT GTCAACCAGG TTAACTTGGT TGATAGTATT GTTGAATTCC 1140 TGTGTTCCAA ATGATATTTT TTGTCTGTTT ATTCTATCAA TTAATGAGAA AGGTTTATTA 1200 AAATCTCCAA CCATTGTTGT GCATTTATTT CTATTTCTTT AGTTCTGTTG ATTTTTGTTT 1260 TATATATTTT GAAGCTCTGA GTACATCTCC CTGATGAGTT GACCCTTTTA TCATTATGAA 1320 ATGTCATTCT TTCTCTGTAA TGCTTATCTT AAAATCTACT TTGTTTGATA TGAATGTAGC 1380 CACTTAAGCT TTCTTATGCA TACTGTTTGC AAAGTGTGTG TGTGTGTGTG TGTGTGTGTG 1440 TGTATCTATC TCAATCCTTT AGTTTCCGCC TATCTCTGTC TTTTTATTTA AAGTGTGTTT 1500 TTGCAGGTAG TGTATAACTT GGATCTTGTT TTTATATTCA GTCTGACAAT TTATGCTTCT 1560 TGATTATTGT GTTTAGTTTA TTTGCATAGT GTGTAGTCCA TTGACATTTG GCATAATATT 1620 GATAATTTGT GTTGGAGCGT ATTGTCTTCA TTTCTGATTG TCCCATCTGG TTTTGTTGCT 1680 GTTTTGTTGT TCCTCTGTTC CACACTTTTT GTCTTCTTTT GGGTTAATCA AATATTCTTT 1740 GGCTTTGCAT CTTATGTCTT CTGTTGGATT TTTATCTATA CCTTGTCGTA TTTTTCTTTA 1800 GTGGTTTCTC TAGGGGTTAC ACTATACATT ATTAATTAAT CATAGTCCAT TTAGAATTAA 1860 TATTGTACAC TTTACATAAA ATGTAAAACA TTTGTCACAG TATAAAGTCT ATTCCTTCCA 1920 AAAAAAAAAA AAAAAAAAA 1939 (2) INFORMATION FOR SEQ ID NO:9: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 52 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9: Met Ser Val Arg Phe Ile Val Met Phe Pro Phe Leu Phe Leu Thr Leu 1 5 10 15 Leu Ile Cys Val Leu Ser Pro Ser Ile Pro Leu Ser Leu Ser Leu Val 20 25 30 Ser Trp Ser Val Gly Leu Ser Pro Leu Leu Ile Phe Ser Glu Asn His 35 40 45 Phe Leu Phe Leu 50 (2) INFORMATION FOR SEQ ID NO:10: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1252 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10: GTAGAAATCC CAAAAAGATT TGGACAGAGG CAGAGCCTAT GTCACTACAC CTTAAAGGAT 60 AACAAGGTTT ATATCAAGAC TCATGGTGAA CATGTAGGTT TTAGAATTTT CATGGATGCC 120 ATACTACTTT CTTTGACTAG AAAGGTGAAG ATGCCAGATG TGGAGCTCTT TGTTAATTTG 180 GGAGACTGGC CTTTGGAAAA AAAGAAATCC AATTCAAACA TCCATCCGAT CTTTTCCTGG 240 TGTGGCTCCA CAGATTCCAA GGATATCGTG ATGCCTACGT ACGATTTGAC TGATTCTGTT 300 CTGGAAACCA TGGGCCGGGT AAGTCTGGAT ATGATGTCCG TGCAAGCTAA CACGGGTCCT 360 CCCTGGGAAA GCAAAAATTC CACTGCCGTC TGGAGAGGGC GAGACAGCCG CAAAGAGAGA 420 CTCGAGCTGG TTAAACTCAG TAGAAAACAC CCAGAACTCA TAGACGCTGC TTTCACCAAC 480 TTTTTCTTCT TTAAACACGA TGAAAACCTG TATGGTCCCA TTGTGAAACA TATTTCATTT 540 TTTGATTTCT TCAAGCATAA GTATCAAATA AATATCGATG GCACTGTAGC AGCTTATCGC 600 CTGCCATATT TGCTAGTTGG TGACAGTGTT GTGCTGAAGC AGGATTCCAT CTACTATGAA 660 CATTTTTACA ATGAGCTGCA GCCCTGGAAA CACTACATTC CAGTTAAGAG CAACCTGAGC 720 GATCTGCTAG AAAAACTTAA ATGGGCGAAA GATCACGATG AAGAGGCCAA AAAGATAGCA 780 AAAGCAGGAC AAGAATTTGC AAGAAATAAT CTCATGGGCG ATGACATATT CTGTTATTAT 840 TTCAAACTTT TCCAGGAATA TGCCAATTTA CAAGTGAGTG AGCCCCAAAT CCGAGAGGGC 900 ATGAAAAGGG TAGAACCACA GACTGAGGAC GACCTCTTCC CTTGTACTTG CCATAGGAAA 960 AAGACCAAAG ATGAACTCTG ATATGCAAAA TAACTTCTAT TAGAATAATG GTGCTCTGAA 1020 GACTCTTCTT AACTAAAAAG AAGAATTTTT TTAAGTATTA ATTCCATGGA CAATATAAAA 1080 TCTGTGTGAT TGTTTGCAGT ATGAAGACAC ATTTCTACTT ATGCAGTATT CTCATGACTG 1140 TACTTTAAAG TACATTTTTA GAATTTTATA ATAAAACCAC CTTTATTTTA AAGGAAAAAA 1200 AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AA 1252 (2) INFORMATION FOR SEQ ID NO:ll: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 289 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 11: Met Asp Ala Ile Leu Leu Ser Leu Thr Arg Lys Val Lys Met Pro Asp 1 5 10 15 Val Glu Leu Phe Val Asn Leu Gly Asp Trp Pro Leu Glu Lys Lys Lys 20 25 30 Ser Asn Ser Asn Ile His Pro Ile Phe Ser Trp Cys Gly Ser Thr Asp 35 40 45 Ser Lys Asp Ile Val Met Pro Thr Tyr Asp Leu Thr Asp Ser Val Leu 50 55 60 Glu Thr Met Gly Arg Val Ser Leu Asp Met Met Ser Val Gln Ala Asn 65 70 75 80 Thr Gly Pro Pro Trp Glu Ser Lys Asn Ser Thr Ala Val Trp Arg Gly 85 90 95 Arg Asp Ser Arg Lys Glu Arg Leu Glu Leu Val Lys Leu Ser Arg Lys 100 105 110 His Pro Glu Leu Ile Asp Ala Ala Phe Thr Asn Phe Phe Phe Phe Lys 115 120 125 His Asp Glu Asn Leu Tyr Gly Pro Ile Val Lys His Ile Ser Phe Phe 130 135 140 Asp Phe Phe Lys His Lys Tyr Gln Ile Asn Ile Asp Gly Thr Val Ala 145 150 155 160 Ala Tyr Arg Leu Pro Tyr Leu Leu Val Gly Asp Ser Val Val Leu Lys 165 170 175 Gin Asp Ser Ile Tyr Tyr Glu His Phe Tyr Asn Glu Leu Gln Pro Trp 180 185 190 Lys His Tyr Ile Pro Val Lys Ser Asn Leu Ser Asp Leu Leu Glu Lys 195 200 205 Leu Lys Trp Ala Lys Asp His Asp Glu Glu Ala Lys Lys Ile Ala Lys 210 215 220 Ala Gly Gln Glu Phe Ala Arg Asn Asn Leu Met Gly Asp Asp Ile Phe 225 230 235 240 Cys Tyr Tyr Phe Lys Leu Phe Gln Glu Tyr Ala Asn Leu Gln Val Ser 245 250 255 Glu Pro Gln Ile Arg Glu Gly Met Lys Arg Val Glu Pro Gln Thr Glu 260 265 270 Asp Asp Leu Phe Pro Cys Thr Cys His Arg Lys Lys Thr Lys Asp Glu 275 280 285 Leu (2) INFORMATION FOR SEQ ID NO:12: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 492 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12: CTAGGTTCTG GGAAGATGGC GAAGGTCTCA GAGCTTTACG ATGTCACTTG GGAAGAAATG 60 AGAGATAAAA TGAGAAAATG GAGAGAAGAA AACTCAAGAA ATAGTGAGCA AATTGTGGAA 120 GTTGGAGAAG AATTAATTAA TGAATATGCT TCTAAGCTGG GAGATGATAT TTGGATCATA 180 TATGAACAGG TGATGATTGC AGCACTAGAC TATGGTCGGG ATGACTTGGC ATTGTTTTGT 240 CTTCAAGAGC TGAGAAGACA GTTCCCTGGC AGTCACAGAG TCAAGCGATT AACAGGCATG 300 AGATTTGAAG CCATGGAAAG ATATGATGAT GCTATACAGC TATATGATAG GATTTTACAA 360 GAAGATCCAA CTAACACTGC TGCAAGAAAG CGTAAGATTG CCATTCGAAA AGCCCAGGGG 420 AAAAATGTGG AGGCCATTCG GGAGCTGAAT GAGTATCTGG AACAATTTGT TGGAGACCAA 480 GAAGCCTGGC AT 492 (2) INFORMATION FOR SEQ ID NO:13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 159 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13: Met Ala Lys Val Ser Glu Leu Tyr Asp Val Thr Trp Glu Glu Met Arg 1 5 10 15 Asp Lys Met Arg Lys Trp Arg Glu Glu Asn Ser Arg Asn Ser Glu Gln 20 25 30 Ile Val Glu Val Gly Glu Glu Leu Ile Asn Glu Tyr Ala Ser Lys Leu 35 40 45 Gly Asp Asp Ile Trp Ile Ile Tyr Glu Gln Val Met Ile Ala Ala Leu 50 55 60 Asp Tyr Gly Arg Asp Asp Leu Ala Leu Phe Cys Leu Gln Glu Leu Arg 65 70 75 80 Arg Gln Phe Pro Gly Ser His Arg Val Lys Arg Leu Thr Gly Met Arg 85 90 95 Phe Glu Ala Met Glu Arg Tyr Asp Asp Ala Ile Gln Leu Tyr Asp Arg 100 105 110 Ile Leu Gln Glu Asp Pro Thr Asn Thr Ala Ala Arg Lys Arg Lys Ile 115 120 125 Ala Ile Arg Lys Ala Gln Gly Lys Asn Val Glu Ala Ile Arg Glu Leu 130 135 140 Asn Glu Tyr Leu Glu Gln Phe Val Gly Asp Gln Glu Ala Trp His 145 150 155 (2) INFORMATION FOR SEQ ID NO:14: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 85 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14: CCTTGTTAAA TAAACCATGN TGATTTNTTA AACTTGCCAA AAAAAAAAA AAAA AAAA 60 <BR> <BR> <BR> <BR> AAAAAAAAAA A AAAAAA A AAAAA 85 (2) INFORMATION FOR SEQ ID NO:15: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 313 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15: CCTTGGATTA TCTGAACTAA AAATTGGACA GATTGATCAG CTGGTAAAAA ATCTACTTCC 60 TGGATTTNGT AAAGGCAAAA ACATTTCTTC CCATTGGCAT ACATCCCNTG TCTCTGCACA 120 ATCCTTCTTT GAAAATNAAT ATGGTAACTT AAATATATTT AGTACATTAC GTTCCTCTTG 180 CTTGTATCGA CATCATTCAA AAGCTCTTCA AAGCATTTGT TCAAATCTTC AGTACTGGCC 240 AGTTTTCATA CAGTCTCGGG GTTTTAAAAC TTTGAAATCA AGGACACNAC GTCTCCAGTC 300 TACCTCCGAG AGA 313 (2) INFORMATION FOR SEQ ID NO:16: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 964 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16: GCTTTTCCGG AGCAGAGTTG GAGAATCTTG TGAACCAGGC TGCATTAAAA GCAGCTGTTG 60 ATGGAAAAGA AATGGTTACC ATGAAGGAGC TGGAGTTTTC CAAAGACAAA ATTCTAATGG 120 GGCCTGAAAG AAGAAGTGTG GAAATTGATA ACAAAAACAA AACCATCACA GCATATCATG 180 AATCTGGTCA TGCCATTATT GCATATTACA CAAAAGATGC AATGCCTATC AACAAAGCTA 240 CAATCATGCC ACGGGGGCCA ACACTTGGAC ATGTGTCCCT GTTACCTGAG AATGACAGAT 300 GGAATGAAAC TAGAGCCCAG CTGCTTGCAC AAATGGATGT TAGTATGGGA GGAAGAGTGG 360 CAGAGGAGCT TATATTTGGA ACCGACCATA TTACNACAGG TGCTTCCAGT GATTTTGATA 420 ATGCCACTAA AATAGCAAAG CGGATRGYTA CCAAATTTGG AATGAGTGAA AAGCTTGGAG 480 TTATGACCTA CAGTGATACA GGGGAAACTA AGTCCAGAAA CCCAATCTGC CATCGAACAA 540 GAAATAAGAA TCCTTCTAAG GGACTCATAT GAACGAGCAA AACATATCTT GAAAACTCAT 600 GCAAAGGAGC ATAAGAATCT CGCAGAAGCT TTATTGACCT ATGAGACTTT GGATGCCAAA 660 GAGATTCAAA TTGTTCTKGA GGGGAAAAAG TTGGAAGTGA GATGATAACT CTCTKGATAT 720 GGATGCTTGC TGGTTTTATT GCAAGAATAT AAGTAGCATT GCAGTAGTCT ACTTTTACAA 780 CGCTTTCCCC TCATTCTTGA TGTGGTGTAA TTGAAGGGTG TGAAATGCTT TGTCAATCAT 840 TTGTCACATT TATCCAGTTT GGGTTATTCT CATTAGGACA CCTATTGCAA ATTAGCATCC 900 CATGGCAAAT ATATTTTGAA AAAATAAAGA ACTATCAGGA TTGAAAAAAA AAAAAAAAAA 960 AAAA 964 (2) INFORMATION FOR SEQ ID NO:17: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 166 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17: Met Val Thr Met Lys Glu Leu Glu Phe Ser Lys Asp Lys Ile Leu Met 1 5 10 15 Gly Pro Glu Arg Arg Ser Val Glu Ile Asp Asn Lys Asn Lys Thr Ile 20 25 30 Thr Ala Tyr His Glu Ser Gly His Ala Ile Ile Ala Tyr Tyr Thr Lys 35 40 45 Asp Ala Met Pro Ile Asn Lys Ala Thr Ile Met Pro Arg Gly Pro Thr 50 55 60 Leu Gly His Val Ser Leu Leu Pro Glu Asn Asp Arg Trp Asn Glu Thr 65 70 75 80 Arg Ala Gln Leu Leu Ala Gln Met Asp Val Ser Met Gly Gly Arg Val 85 90 95 Ala Glu Glu Leu Ile Phe Gly Thr Asp His Ile Thr Thr Gly Ala Ser 100 105 110 Ser Asp Phe Asp Asn Ala Thr Lys Ile Ala Lys Arg Xaa Xaa Thr Lys 115 120 125 Phe Gly Met Ser Glu Lys Leu Gly Val Met Thr Tyr Ser Asp Thr Gly 130 135 140 Glu Thr Lys Ser Arg Asn Pro Ile Cys His Arg Thr Arg Asn Lys Asn 145 150 155 160 Pro Ser Lys Gly Leu Ile 165 (2) INFORMATION FOR SEQ ID NO:18: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1362 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18: CTTTTCATAT CCTTTTATTT TCCCAATTCA TATAGGAAAG ATAAGTATTT TCCCTTTCAT 60 TTTCAAAATT GATTGGTACA CTAACCTCCT CCATAGTAAC TAATTTGTAT TTTTTTATTA 120 TGAACTCATG AATTTAAACA TTTGATGTTG TTTCAGTCCA TTGCAGTCAT TATCCTTATT 180 GATTCTCAAA GTGTTTTATT TTTGACAAAT AAGTTCTTCA AATTAGTTAG TTATTTTGAT 240 AGTGACCTTA ATAGTCTTTG CTAGCTTCCA TCCCTGTATG GCATAACAAA ACATTCCAGG 300 CCCCTTTAGT ACATTTCCTG TCCCAGACCT GGTATTAGTC ATCTAATCTG GAAGCCCTGC 360 TTTCTTTCTG TGGGAAACAT TATTTCAAGA CATTAGGGAT AAGAATGCCA GTTGCTACTG 420 AGTTGGTTAT TGTTTCAAGG ATTTATCAAT ACATAGAGCA AATAATTATG TTTTGCTTTG 480 TCTTATTTTT ATTTCTTTAC TTTAGAAACA GTACAGCTAC TTACAAATCA AGTTTAGAAC 540 TCTCAGGTTA TCTTAAATCT GAAGCTTCTA CCTTCCTAAG AACAAAACAC CGGAATGATG 600 AGATGTCATA TAAATATCCA TTTATTTTAT TTCACAATAC ATACATTGAC CTATTGTATG 660 TATGATTAGT ACAAATGGTT TAAATTGGCT TGTTGTGCTT TGTTTTGTTT TTGCAGTTTT 720 TTTTTGTCAT TAGATTTTAT CTCACTAGAA ATGTATAGTC AAATTTCTGT GTTCTAAAGT 780 CACTTGAAGT AGTTTTTCTG TTTGTAGTAA TGTTACCAGT TGGACACATT AGGTTCATTT 840 ATTTTTGGGA ATTGCTTTTG TTCCCATTTA AATTTTTATT TATCTTGCGT ATCTTGGATT 900 AACGGTAATA GACCATATAC AATTTTCTCT ACTTTTTTTC ATTKGAGAGT TTCCTCATTT 960 ATTTTGTTTT CGGATGCAAA GTATTTCATT GTATGAATTA CCAGTTTGTT CAATTAGTTT 1020 TCTTTGATAA CATTTGGGTT GCTTCTAGTC TTTTGTTATW ACAGAGTCTT GCAATGAATA 1080 GTCTTATGCT TATATGTTTT GTGGTTTCTG GCAAGGATTT CAACGTAATT TAAGGCTATC 1140 CTCTACTTAA GTTATGGCCA ATTAAGTGTC TGATTAAATG TCTGTAATAA TTTAAAAATA 1200 ACAATACTTA ATTTAAAAGA GCTTATAATA CATAATTATT CATTAGAGAG ATGCAGCAAA 1260 CCACCATGGC AAATGTATTC CTATGTAACA AACCTGCACG TTCAGCAAGT GTATCCCAGC 1320 ACTGAAAGTA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AA 1362 (2) INFORMATION FOR SEQ ID NO:19: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 86 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19: Met Pro Val Ala Thr Glu Leu Val Ile Val Ser Arg Ile Tyr Gln Tyr 1 5 10 15 Ile Glu Gln Ile Ile Met Phe Cys Phe Val Leu Phe Leu Phe Leu Tyr 20 25 30 Phe Arg Asn Ser Thr Ala Thr Tyr Lys Ser Ser Leu Glu Leu Ser Gly 35 40 45 Tyr Leu Lys Ser Glu Ala Ser Thr Phe Leu Arg Thr Lys His Arg Asn 50 55 60 Asp Glu Met Ser Tyr Lys Tyr Pro Phe Ile Leu Phe His Asn Thr Tyr 65 70 75 80 Ile Asp Leu Leu Tyr Val 85 (2) INFORMATION FOR SEQ ID NO:20: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 479 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20: CTGGCTTCTT CGGAGCTGTG TAKTCTTAAT TTGCTTTGCT GCTGGCTGGC TGACAGCTGA 60 TGGGGGACTC CTCAGGACGG ACTCCCTTCC AGATGCACCC ATCTCCATCC TTCTCAACTC 120 CCCAACCTTT GTCCTCCCCA CTCTTCGCTC GCGCGGCGGT CTGAGACCAC CAGGACCAGT 180 TTCAGGGGTT TCCTTCTCCA GCGAGACTTG GCAGAACAGG CTTTAAAAGC AAAGGAGGCA 240 GCGGAAGACT GTGAATTCCT TTGGACAATT GATGATATTT ATCATTGTGC CCAGTTTCTA 300 CAAATAAAAG ATGGGTGGAT TATTTTCTCG ATGGAGGACA AAACCTTCAA CTGTAGAAGT 360 TCTAGAAAGT ATAGATAAGG AAATTCAAGC ATTGGAAGAA TTTAGGGAAA AAAAAAAAAA 420 A A AAAA A AAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAA4 479 (2) INFORMATION FOR SEQ ID NO:21: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 33 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21: Met Gly Gly Leu Phe Ser Arg Trp Arg Thr Lys Pro Ser Thr Val Glu 1 5 10 15 Val Leu Glu Ser Ile Asp Lys Glu Ile Gln Ala Leu Glu Glu Phe Arg 20 25 30 Glu (2) INFORMATION FOR SEQ ID NO:22: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 333 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22: CTGACTTACT AATACTAAAG AAGTGGGGGG AGCTCGAGAG CCAGACGGCC AGACAGGCAG 60 ACCCCTCCAN AGGCCCGCCA GGTGGGCATG GTCCCCCATT TTCTTTAAGG CAGCACCTGG 120 AGTGGAGAGA GGCCACTCCC TCTCCAGCCC CCGATNTGGA CCCGGGGGAG GGGAGGCTGA 180 TGCNTTTGGC CCCGGCCTGG CCAAAANAGC CCATCCCCAG GGCAGTTTCA GGTGCCGGCT 240 GGGCCCTGAA TGTCAAGGAT AATATATAGC CCGCTCCTGG GTCCTGGAGC TGTGGCCCTT 300 TGTACTCNTG TTGTGTCCAT TGTGTGTGTG COT 333 (2) INFORMATION FOR SEQ ID NO:23: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 611 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23: GTCCATTGTG TGTGTGCGTG GGGACAGAGG CCTGGAAATG CGGAGGACTA TACAGAGAAG 60 GNAGGTTTTG TGAAGGCCAG GCAGGGTTGG AGGCCGGGGG TGTGAGAGGA GAGGCCCATA 120 GGGCTGAGTG GGGTCGGGTG AGGCAGAGGT CAGAAACAGA AGAGCTGCAG TTGCTGGAGC 180 TGGGNTGAGA ANTGGGCTGC CTCCTGCCAT CCCCCCGTCT CCTCCCCTTC TCCCCTTGGT 240 GCCCCCCTNT GCTCAGAATC TGAAGTAGTT CCCTCCTCAG CAATTTCATN TCTTGAACAC 300 TGACTCACAC CTTTTAGGCA CCTACTGTGT GCATAGCATT CCACCAGGAC TCATCTCCCT 360 TCCTTCTCAG GGGGTCCCGA GCCCCGACTA GCTTTGCCCT AACTCCTTCA TCAAAAGACC 420 CCCCGCCAGC TTCCCACACC TCATACGCAG CCACATCTGC CCTATTCTCC ATGCTTTCCA 480 GCTTGCCTGC CCTTCCTCAT CTCTCCCTGC CTGTGCAGAC CTCCACCCTT CTTTCCTCCA 540 CCCCTCCATC CCCCAATGCT TGTAGACCTT CCATTCATTC CGTCTCATCG TGCGTGGTCT 600 CTGATCGTCC A 611 (2) INFORMATION FOR SEQ ID NO:24: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 47 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24: Met Leu Ser Ser Leu Pro Ala Leu Pro His Leu Ser Leu Pro Val Gln 1 5 10 15 Thr Ser Thr Leu Leu Ser Ser Thr Pro Pro Ser Pro Asn Ala Cys Arg 20 25 30 Pro Ser Ile His Ser Val Ser Ser Cys Val Val Ser Asp Arg Pro 35 40 45 (2) INFORMATION FOR SEQ ID NO:25: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 274 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25: ATCCAGGGCG TGGGGAGACC ATTGGCATTT GGGAACCATT TTCCTTCGAA CGGCTTCCCC 60 TTGAGCTGAG CATTCTGCTT GCTGCAGTAG ACGGGTCGCC TTTTGCCCAT ACCGAAATTT 120 TCTGAAATTA AATCGCACAC CCCCACCATT TCCTCTCCCC TGGGATCTGG AGGAACATCA 180 TACATAGTAG GTGAATCGTT TTGTAGAGTG AAGAATGCTA ATGTAAAGCA AATAGTCACC 240 CACGTTCCCT TGTAAATCCA AAAAAAAAAA AAAA 274 (2) INFORMATION FOR SEQ ID NO:26: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 29 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (A) DESCRIPTION: /desc = "oligonucleotide" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26: ANGGAGCAAGT TCCTGAGAGT ATCCTGTT 29 (2) INFORMATION FOR SEQ ID NO:27: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 29 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (A) DESCRIPTION: /desc = "oligonucleotide" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27: ANGGAGCAAGT TCCTGAGAGT ATCCTGTT 29 (2) INFORMATION FOR SEQ ID NO:28: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 29 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (A) DESCRIPTION: /desc = "oligonucleotide" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28: GNATGGAGGGA GAGAGAACAC AAATTAAC 29 (2) INFORMATION FOR SEQ ID NO:29: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 29 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (A) DESCRIPTION: /desc = "oligonucleotide" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29: GNGACAGTGTT GTGCTGAAGC AGGATTCC 29 (2) INFORMATION FOR SEQ ID NO:30: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 29 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (A) DESCRIPTION: /desc = "oligonucleotide" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30: CNTCTCCAACT TCCACAATTT GCTCACTA 29 (2) INFORMATION FOR SEQ ID NO:31: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 29 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (A) DESCRIPTION: /desc = "oligonucleotide" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31: TNGGAGGAAGA GTGGCAGAGG AGCTTATA 29 (2) INFORMATION FOR SEQ ID NO:32: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 29 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (A) DESCRIPTION: /desc = "oligonucleotide" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32: CNGTGTTTTGT TCTTAGGAAG GTAGAAGC 29 (2) INFORMATION FOR SEQ ID NO:33: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 29 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (A) DESCRIPTION: /desc = "oligonucleotide" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33: CNGCCAGCCAG CAGCAAAGCA AATTAAGA 29 (2) INFORMATION FOR SEQ ID NO:34: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 29 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (A) DESCRIPTION: /desc = "oligonucleotide" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34: TNGAGGAAAGA AGGGTGGAGG TCTGCACA 29