CA2382748A1

CA2382748A1 - 50 human secreted proteins

Info

Publication number: CA2382748A1
Application number: CA002382748A
Authority: CA
Inventors: Craig A. Rosen; Steven M. Ruben; George A. Komatsoulis
Original assignee: Individual
Current assignee: Human Genome Sciences Inc
Priority date: 1999-06-11
Filing date: 2000-06-01
Publication date: 2000-12-21
Also published as: EP1185543A1; WO2000077022A1; AU5177000A; JP2003516114A; EP1185543A4

Abstract

The present invention relates to novel human secreted proteins and isolated nucleic acids containing the coding regions of the genes encoding such proteins. Also provided are vectors, host cells, antibodies, and recombinant methods for producing human secreted proteins. The invention further relates to diagnostic and therapeutic methods useful for diagnosing and treating diseases, disorders, and/or conditions related to these novel human secreted proteins.

Description

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2 PCT/US00/15136 50 Human Secreted Proteins Field of the Invention This invention relates to newly identified polynucleotides and the polypeptides encoded by these polynucleotides, uses of such polynucleotides and polypeptides, and their production.
Background of the Invention Unlike bacterium, which exist as a single compartment surrounded by a membrane, human cells and other eucaryotes are subdivided by membranes into many functionally distinct compartments. Each membrane-bounded compartment, or organelle, contains different proteins essential for the function of the organelle. The cell uses "sorting signals," which are amino acid motifs located within the protein, to target proteins to particular cellular organelles.
One type of sorting signal, called a signal sequence, a signal peptide, or a leader sequence, directs a class of proteins to an organelle called the endoplasmic reticulum (ER). The ER separates the membrane-bounded proteins from all other types of proteins. Once localized to the ER, both groups of proteins can be further directed to another organelle called the Golgi apparatus. Here, the Golgi distributes the proteins to vesicles, including secretory vesicles, the cell membrane, lysosomes, and the other organelles.
Proteins targeted to the ER by a signal sequence can be released into the extracellular space as a secreted protein. For example, vesicles containing secreted proteins can fuse with the cell membrane and release their contents into the extracellular space - a process called exocytosis. Exocytosis can occur constitutively or after receipt of a triggering signal. In the latter case, the proteins are stored in secretory vesicles (or secretory granules) until exocytosis is triggered.
Similarly, proteins residing on the cell membrane can also be secreted into the extracellular space by proteolytic cleavage of a "linker" holding the protein to the membrane.
Despite the great progress made in recent years, only a small number of genes encoding human secreted proteins have been identified. These secreted proteins include the commercially valuable human insulin, interferon, Factor VIII, human growth hormone, tissue plasminogen activator, and erythropoeitin. Thus, in light of the pervasive role of secreted proteins in human physiology, a need exists for identifying and characterizing novel human secreted proteins and the genes that encode them. This knowledge will allow one to detect, to treat, and to prevent medical diseases, disorders, and/or conditions by using secreted proteins or the genes that encode them.
Summary of the Invention The present invention relates to novel polynucleotides and the encoded polypeptides. Moreover, the present invention relates to vectors, host cells, antibodies, and recombinant and synthetic methods for producing the polypeptides and polynucleotides. Also provided are diagnostic methods for detecting diseases, disorders, and/or conditions related to the polypeptides and polynucleotides, and therapeutic methods for treating such diseases, disorders, and/or conditions.
The invention further relates to screening methods for identifying binding partners of the polypeptides.
Detailed Description Definitions The following definitions are provided to facilitate understanding of certain terms used throughout this specification.
In the present invention, "isolated" refers to material removed from its original environment (e.g., the natural environment if it is naturally occurring), and thus is altered "by the hand of man" from its natural state. For example, an isolated polynucleotide could be part of a vector or a composition of matter, or could be contained within a cell, and still be "isolated" because that vector, composition of matter, or particular cell is not the original environment of the polynucleotide. The term "isolated" does not refer to genomic or cDNA libraries, whole cell total or mRNA preparations, genomic DNA preparations (including those separated by electrophoresis and transferred onto blots), sheared whole cell genomic DNA
preparations or other compositions where the art demonstrates no distinguishing features of the polynucleotide/sequences of the present invention.
In the present invention, a "secreted" protein refers to those proteins capable of being directed to the ER, secretory vesicles, or the extracellular space as a result of a signal sequence, as well as those proteins released into the extracellular space without necessarily containing a signal sequence. If the secreted protein is released into the extracellular space, the secreted protein can undergo extracellular processing to produce a "mature" protein. Release into the extracellular space can occur by many mechanisms, including exocytosis and proteolytic cleavage.
In specific embodiments, the polynucleotides of the invention are at least 15, at least 30, at least 50, at least 100, at least 125, at least 500, or at least 1000 continuous nucleotides but are less than or equal to 300 kb, 200 kb, 100 kb, 50 kb, 15 kb, 10 kb, 7.5 kb, 5 kb, 2.5 kb, 2.0 kb, or 1 kb, in length. In a further embodiment, polynucleotides of the invention comprise a portion of the coding sequences, as disclosed herein, but do not comprise all or a portion of any intron. In another embodiment, the polynucleotides comprising coding sequences do not contain coding sequences of a genomic flanking gene (i.e., 5' or 3' to the gene of interest in the genome). In other embodiments, the polynucleotides of the invention do not contain the coding sequence of more than 1000, 500, 250, 100, 50, 25, 20, 15, 10, 5, 4, 3, 2, or 1 genomic flanking gene(s).
As used herein, a "polynucleotide" refers to a molecule having a nucleic acid sequence contained in SEQ ID NO:X or the cDNA contained within the clone deposited with the ATCC. For example, the polynucleotide can contain the nucleotide sequence of the full length cDNA sequence, including the 5' and 3' untranslated sequences, the coding region, with or without the signal sequence, the secreted protein coding region, as well as fragments, epitopes, domains, and variants of the nucleic acid sequence. Moreover, as used herein, a "polypeptide" refers to a molecule having the translated amino acid sequence generated from the polynucleotide as broadly defined.
In the present invention, the full length sequence identified as SEQ ID NO:X
was often generated by overlapping sequences contained in multiple clones (contig analysis). A representative clone containing all or most of the sequence for NO:X was deposited with the American Type Culture Collection ("ATCC"). As shown in Table 1, each clone is identified by a cDNA Clone ID (Identifier) and the ATCC Deposit Number. The ATCC is located at 10801 University Boulevard, Manassas, Virginia 20110-2209, USA. The ATCC deposit was made pursuant to the terms of the Budapest Treaty on the international recognition of the deposit of microorganisms for purposes of patent procedure.
A "polynucleotide" of the present invention also includes those polynucleotides capable of hybridizing, under stringent hybridization conditions, to sequences contained in SEQ ID NO:X, the complement thereof, or the cDNA within the clone deposited with the ATCC. "Stringent hybridization conditions" refers to an overnight incubation at 42 degree C in a solution comprising 50% formamide, Sx SSC
(750 mM NaCI, 75 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), Sx Denhardt's solution, 10% dextran sulfate, and 20 y~g/ml denatured, sheared salmon sperm DNA, followed by washing the filters in O.lx SSC at about 65 degree C.
Also contemplated are nucleic acid molecules that hybridize to the polynucleotides of the present invention at lower stringency hybridization conditions.
Changes in the stringency of hybridization and signal detection are primarily accomplished through the manipulation of formamide concentration (lower percentages of formamide result in lowered stringency); salt conditions, or temperature. For example, lower stringency conditions include an overnight incubation at 37 degree C in a solution comprising 6X SSPE (20X SSPE = 3M
NaCI;
0.2M NaH2P04; 0.02M EDTA, pH 7.4), 0.5% SDS, 30% formamide, 100 ug/ml salmon sperm blocking DNA; followed by washes at 50 degree C with 1XSSPE, 0.1 % SDS. In addition, to achieve even lower stringency, washes performed following stringent hybridization can be done at higher salt concentrations (e.g. 5X
SSC).
Note that variations in the above conditions may be accomplished through the inclusion and/or substitution of alternate blocking reagents used to suppress background in hybridization experiments. Typical blocking reagents include Denhardt's reagent, BLOTTO, heparin, denatured salmon sperm DNA, and commercially available proprietary formulations. The inclusion of specific blocking reagents may require modification of the hybridization conditions described above, due to problems with compatibility.

Of course, a polynucleotide which hybridizes only to polyA+ sequences (such as any 3' terminal polyA+ tract of a cDNA shown in the sequence listing), or to a complementary stretch of T (or U) residues, would not be included in the definition of "polynucleotide," since such a polynucleotide would hybridize to any nucleic acid molecule containing a poly (A) stretch or the complement thereof (e.g., practically any double-stranded cDNA clone generated using oligo dT as a primer).
The polynucleotide of the present invention can be composed of any polyribonucleotide or polydeoxribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA. For example, polynucleotides can be composed of single- and double-stranded DNA, DNA that is a mixture of single- and double-stranded regions, single- and double-stranded RNA, and RNA that is mixture of single- and double-stranded regions, hybrid molecules comprising DNA and RNA
that may be single-stranded or, more typically, double-stranded or a mixture of single-and double-stranded regions. In addition, the polynucleotide can be composed of triple-stranded regions comprising RNA or DNA or both RNA and DNA. A
polynucleotide may also contain one or more modified bases or DNA or RNA
backbones modified for stability or for other reasons. "Modified" bases include, for example, tritylated bases and unusual bases such as inosine. A variety of modifications can be made to DNA and RNA; thus, "polynucleotide" embraces chemically, enzymatically, or metabolically modified forms.
The polypeptide of the present invention can be composed of amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres, and may contain amino acids other than the 20 gene-encoded amino acids.
The polypeptides may be modified by either natural processes, such as posttranslational processing, or by chemical modification techniques which are well known in the art. Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature.
Modifications can occur anywhere in a polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. It will be appreciated that the same type of modification may be present in the same or varying degrees at several sites in a given polypeptide. Also, a given polypeptide may contain many types of modifications. Polypeptides may be branched , for example, as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched, and branched cyclic polypeptides may result from posttranslation natural processes or may be made by synthetic methods. Modifications include acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cysteine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, pegylation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA
mediated addition of amino acids to proteins such as arginylation, and ubiquitination.
(See, for instance, PROTEINS - STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E. Creighton, W. H. Freeman and Company, New York (1993);
POSTTRANSLATIONAL COVALENT MODIFICATION OF PROTEINS, B. C.
Johnson, Ed., Academic Press, New York, pgs. 1-12 (1983); Seifter et al., Meth Enzymol 182:626-646 (1990); Rattan et al., Ann NY Acad Sci 663:48-62 (1992).) "SEQ ID NO:X" refers to a polynucleotide sequence while "SEQ ID NO:Y"
refers to a polypeptide sequence, both sequences identified by an integer specified in Table 1.

"A polypeptide having biological activity" refers to polypeptides exhibiting activity similar, but not necessarily identical to, an activity of a polypeptide of the present invention, including mature forms, as measured in a particular biological assay, with or without dose dependency. In the case where dose dependency does exist, it need not be identical to that of the polypeptide, but rather substantially similar to the dose-dependence in a given activity as compared to the polypeptide of the present invention (i.e., the candidate polypeptide will exhibit greater activity or not more than about 25-fold less and, preferably, not more than about tenfold less activity, and most preferably, not more than about three-fold less activity relative to the polypeptide of the present invention.) Many proteins (and translated DNA sequences) contain regions where the amino acid composition is highly biased toward a small subset of the available residues. For example, membrane spanning domains and signal peptides (which are also membrane spanning) typically contain long stretches where Leucine (L), Valine (V), Alanine (A), and Isoleucine (I) predominate. Poly-Adenosine tracts (polyA) at the end of cDNAs appear in forward translations as poly-Lysine (poly-K) and poly-Phenylalanine (poly-F) when the reverse complement is translated. These regions are often referred to as "low complexity" regions.
Such regions can cause database similarity search programs such as BLAST to find high-scoring sequence matches that do not imply true homology. The problem is exacerbated by the fact that most weight matrices (used to score the alignments generated by BLAST) give a match between any of a group of hydrophobic amino acids (L,V and I) that are commonly found in certain low complexity regions almost as high a score as for exact matches.
In order to compensate for this, BLASTX.2 (version 2.Oa5MP-WashU) employs two filters ("seg" and "xnu") which "mask" the low complexity regions in a particular sequence. These filters parse the sequence for such regions, and create a new sequence in which the amino acids in the low complexity region have been replaced with the character "X". This is then used as the input sequence (sometimes referred to herein as "Query" and/or "Q") to the BLASTX program. While this regime helps to ensure that high-scoring matches represent true homology, there is a negative consequence in that the BLASTX program uses the query sequence that has been masked by the filters to draw alignments.
Thus, a stretch of "X"s in an alignment shown in the following application does not necessarily indicate that either the underlying DNA sequence or the translated protein sequence is unknown or uncertain. Nor is the presence of such stretches meant to indicate that the sequence is identical or not identical to the sequence disclosed in the alignment of the present invention. Such stretches may simply indicate that the BLASTX program masked amino acids in that region due to the detection of a low complexity region, as defined above. In all cases, the reference sequences) (sometimes referred to herein as "Subject", "Sbjct", and/or "S") indicated in the specification, sequence table (Table 1), and/or the deposited clone is (are) the definitive embodiments) of the present invention, and should not be construed as limiting the present invention to the partial sequence shown in an alignment, unless specifically noted otherwise herein.
Polyucleotides and Poly~eptides of the Invention FEATURES OF PROTEIN ENCODED BY GENE NO: 1 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.

gi13335148 (all information available through the recited accession number is incorporated herein by reference) which is described therein as "short form transcription factor C-MAF [Homo sapiens]." This transcription factor is thought to play a role in the pathogenesis of multiple myeloma tumors. A partial alignment 5 demonstrating the observed homology is shown immediately below.
>gi~3335148 (AF055376) short form transcription factor C-MAF [Homo Sapiens]
>sp~G3335148~G3335148 SHORT FORM TRANSCRIPTION FACTOR C-MAF.
10 Length = 373 Plus Strand HSPs:
Score = 425 (149.6 bits), Expect = 7.1e-58, Sum P(2) = 7.1e-58 Identities = 85/114 (74~), Positives = 85/114 (74~), Frame = +1 Q: 271 SNSDLPTSPLAMEYVNDFDLMKFEVKKEPVETDRIISQCGRLIAGGXXXXXXXXXXXXXX 450 SNSDLPTSPLAMEYVNDFDLMKFEVKKEPVETDRIISQCGRLIAGG
S: 8 SNSDLPTSPLAMEYVNDFDLMKFEVKKEPVETDRIISQCGRLIAGGSLSSTPMSTPCSSV 67 Q: 451 XXXXXXXXXXXXXXXEQKAHLEDYYWMTGYPQQLNPEALGFSPEDAVEALISNS 612 EQKAHLEDYYWMTGYPQQLNPEALGFSPEDAVEALISNS
S: 68 PPSPSFSAPSPGSGSEQKAHLEDYYWMTGYPQQLNPEALGFSPEDAVEALISNS 121 Score = 210 (73.9 bits), Expect = 7.1e-58, Sum P(2) = 7.1e-58 Identities = 42/43 (97~), Positives = 42/43 (97~), Frame = +2 Q: 719 LNRQLRGVSKEEVIRLKQKRRTLKNRGYAXSCRFKRVQQRHVL 847 LNRQLRGVSKEEVIRLKQKRRTLKNRGYA SCRFKRVQQRHVL
3O S: 274 LNRQLRGVSKEEVIRLKQKRRTLKNRGYAQSCRFKRVQQRHVL 316 The segments of gi13335148 that are shown as "S" above are set out in the sequence listing as SEQ ID NO. 111 and SEQ ID NO. 113 . Based on the structural similarity, these homologous polypeptides are expected to share at least some biological activities. Such activities are known in the art, some of which are described elsewhere herein. Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
Preferred polypeptides of the invention comprise a polypeptide having the amino acid sequence set out in the sequence listing as SEQ 1D NO. 112 and/or SEQ

ID NO. 114 which correspond to the "Q" sequences in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed).
It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Soares melanocyte 2NbHM and to a lesser extent in NCI CGAP_LuS; Soares fetal lung NbHLI9W; Hodgkin's Lymphoma II; Soares placenta Nb2HP; Soares fetal heart_NbHHI9W; Stomach cancer (human),re-excision; NCI CGAP_Kid3; Soares_parathyroid tumor NbHPA;
Soares multiple sclerosis 2NbHMSP; Nine Week Old Early Stage Human;
Activated T-Cells, 8 hrs.; NCI CLAP Pr6; Soares_parathyroid tumor NbHPA;
Hemangiopericytoma; Gessler Wilms tumor; Soares fetal liver spleen_1NFLS S1;
Stratagene lung (#937210); Pancreas Islet Cell Tumor; 12 Week Old Early Stage Human; Soares fetal lung NbHLI9W; Soares_placenta 8to9weeks 2NbHP8to9W;
Soares_pregnant uterus NbHPU; Human Bone Marrow, treated; Human 8 Week Whole Embryo; Human Fetal Liver; Morton Fetal Cochlea; Brain-medulloblastoma;
Human Fetal Spleen; CD40 activated monocyte dendridic cells; HSA 172 Cells;
Soares retina N2b4HR; NCI CGAP_Kid3; Lung Carcinoma A549 TNFalpha activated; Human Tonsils, Lib 2; Healing groin wound - zero hr post-incision (control); NCI CGAP_GC2; Hepatocellular Tumor,re-excision; Healing groin wound, 7.5 hours post incision; Salivary Gland, Lib 2; Healing groin wound, 6.5 hours post incision; Human Manic Depression Tissue; Human Pancreas Tumor;
Stromal cell TF274; Macrophage-oxLDL; Spinal cord; Human Thymus; Soares breast 2NbHBst; NTERA2, control; Soares NhHMPu_S1; Soares_fetal heart_NbHHI9W;
Stratagene schizo brain S11; HepatocellularTumor, re-excision; Fetal Heart;
Human T-Cell Lymphoma; Colon Normal II; Clontech human aorta polyA+ mRNA (#6572);
Colon Tumor II; Dendritic cells, pooled; Primary Dendritic cells,frac 2; Human Adult Pulmonary,re-excision; Activated T-Cell (l2hs)/Thiouridine labelledEco;
Spleen, Chronic lymphocytic leukemia; Activated T-cell(12h)/Thiouridine-re-excision and Primary Dendritic Cells, lib 1.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 61 as residues: Ser-44 to Glu-50, Pro-53 to Gly-60.
Polynucleotides encoding said polypeptides are also provided.
Based upon the homology of this protein to C-MAF, antagonists directed against this protein may be useful in blocking the activity of this protein.
Accordingly, preferred are antibodies which specifically bind a portion of the translation product of this gene. Also provided is a kit for detecting myeloma tumors.
Such a kit comprises in one embodiment an antibody specific for the translation product of this gene bound to a solid support. Also provided is a method of detecting myeloma tumors in an individual which comprises a step of contacting an antibody specific for the translation product of this gene to a bodily fluid from the individual, preferably serum, and ascertaining whether antibody binds to an antigen found in the bodily fluid. Preferably the antibody is bound to a solid support and the bodily fluid is serum. The above embodiments, as well as other treatments and diagnostic tests (kits and methods), are more particularly described elsewhere herein.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:11 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 3336 of SEQ ID
NO:11, b is an integer of 15 to 3350, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:11, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 2 It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Soares total fetus Nb2HF8 9w and to a lesser extent in Human Adipose; H. Frontal cortex,epileptic,re-excision; Soares ovary tumor NbHOT;
Human Amygdala Depression, re-excision; H. Striatum Depression, subtracted;
Smooth muscle, control, re-excision; Human aorta polyA+ (TFujiwara);
NCI CGAP_GCB1; NCI CGAP_Brn23; Soares_parathyroid tumor NbHPA;
Soares senescent fibroblasts_NbHSF; Soares_placenta 8to9weeks_2NbHP8to9W;
Synovial IL-1/TNF stimulated; Human Osteoclastoma, re-excision; Human Prostate;
Soares senescent fibroblasts_NbHSF; Apoptotic T-cell; Hemangiopericytoma;
Human Adrenal Gland Tumor; Human Adult Pulmonary,re-excision; Human 8 Week Whole Embryo and Soares placenta Nb2HP.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:12 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1748 of SEQ ID
N0:12, b is an integer of 15 to 1762, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:12, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 3 It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Human Fetal Brain; Infant brain, Bento Soares and to a lesser extent in Human Fetal Brain; Soares infant brain 1NIB; Soares adult brain N2b4HB55Y; H. Kidney Cortex, subtracted; Human Kidney Cortex, re-rescue;
Human Fetal Brain, random primed; Frontal Lobe, Dementia; Human Cerebellum, subtracted; NCI CGAP_GC3; Stratagene NT2 neuronal precursor 937230;
normalized infant brain cDNA; Human Hypothalamus,schizophrenia, re-excision;
NTERA2 + retinoic acid, 14 days; Human Amygdala,re-excision; Human Manic Depression Tissue; Brain frontal cortex; Endothelial cells-control; Human Amygdala and Smooth muscle,control.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:13 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1461 of SEQ ID
N0:13, b is an integer of 15 to 1475, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:13, and where b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 4 5 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.
gi12S6S069 (all information available through the recited accession number is incorporated herein by reference) which is described therein as "CAGH3 [Homo 10 sapiens]". A partial alignment demonstrating the observed homology is shown immediately below.

>gi~2565069 CAGH3 [Homo sapiens] >sp~015415~015415 CAGH3.
Length = 279 Plus Strand HSPs:
Score = 842 (296.4 bits), Expect = 2.2e-83, P = 2.2e-83 Identities = 159/183 (86~), Positives = 159/183 (86~), Frame = +1 Q: 829 HSNQTSNWSPLGPPSSPYGAAFTAEKPNSPMMYPQAFNNQNPIVPPMANNLQKTTMNNYL 1008 HSNQTSNWSPLGPPSSPYGAAFTAEKPNSPMMYPQAFNNQNPIVPPMANNLQKTTMNNYL
S: 39 HSNQTSNWSPLGPPSSPYGAAFTAEKPNSPMMYPQAFNNQNPIVPPMANNLQKTTMNNYL 98 2S Q: 1009 PQNHMNMINQQPNNLGTNSLNKQHNILTYGNTKPLTHFNADLSQRMTPPVANPNKNPLMP 1188 PQNHMNMINQQPNNLGTNSLNKQHNILTYGNTKPLTHFNADLSQRMTPPVANPNKNPLMP
S: 99 PQNHMNMINQQPNNLGTNSLNKQHNILTYGNTKPLTHFNADLSQRMTPPVANPNKNPLMP 158 Q: 1189 YIXXXXXXXXXXXXXXXXXXPXPSQLQAPXAHLSEDQKRLLXMKQKGVMNQPMAYAALSF 1368 S: 159 YIQQQQQQQQQQQQQQQQQQPPPPQLQAPRAHLSEDQKRLLLMKQKGVMNQPMAYAALPS 218 Q: 1369 HGQ 1377 HGQ
3S S: 219 HGQ 221 The segment of gi12S6S069 that is shown as "S" above is set out in the sequence listing as SEQ ID NO. 115 . Based on the structural similarity, these homologous polypeptides are expected to share at least some biological activities.

Such activities are known in the art, some of which are described elsewhere herein.
Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
Preferred polypeptides of the invention comprise a polypeptide having the amino acid sequence set out in the sequence listing as SEQ ID NO. 116 which corresponds to the "Q" sequence in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed).
It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Human fetal brain S. Meier-Ewert; NCI CGAP_GCB1;
Larynx Normal; Human Bone Marrow, re-excision; Human Pancreas Tumor; Stromal cell TF274; Human Chondrosarcoma; Pancreas Islet Cell Tumor; Neutrophils IL-1 and LPS induced; Human Neutrophil, Activated; Bone Marrow Cell Line (RS4,11);
Human Cerebellum; Soares fetal liver spleen 1NFLS.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:14 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 3043 of SEQ ID
N0:14, b is an integer of 15 to 3057, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:14, and where b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 5 It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Soares fetal liver spleen 1NFLS and to a lesser extent in human pleural cancer; Bone marrow; Soares testis NHT;
Soares fetal liver spleen_1NFLS S1 and Anergic T-cell.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 65 as residues: Asn-28 to Asn-37. Polynucleotides encoding said polypeptides are also provided.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:15 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1107 of SEQ ID
NO:15, b is an integer of 15 to 1121, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:15, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 6 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.

S
gi14091980 (all information available through the recited accession number is incorporated herein by reference) which is described therein as "histone acetyltransferase [Homo Sapiens)". A partial alignment demonstrating the observed homology is shown immediately below.
>gi~4091980 (AF074606) histone acetyltransferase [Homo Sapiens]
>sp~G4091980~G4091980 HISTONE ACETYLTRANSFERASE.
Length = 611 Plus Strand HSPs:
Score = 1536 (540.7 bits), Expect = 6.4e-157, P = 6.4e-157 Identities = 296/348 (85~), Positives = 312/348 (89~), Frame = +2 IS Q: 68 SG*TQEEKKFWTEQRTEREIYG-TQTDLWEHTGTSFRKPDKRV*LGSFPKSTSPGFRGFG 244 SG ++E+K+ + E R + YG T+ L E+ + + D L F ++ +
S: 273 SGLSKEQKEKYMEHR---QTYGNTREPLLENLTSEY---D----LDLFRRAQARASEDLE 322 Q: 245 EVKAASQITEGSNMIKTIAFGRYELDTWYHSPYPEEYARLGRLYMCEFCLKYMKSQTILR 424 ZO +++ QITEGSNMIKTIAFGRYELDTWYHSPYPEEYARLGRLYMCEFCLKYMKSQTILR
S: 323 KLRLQGQITEGSNMIKTIAFGRYELDTWYHSPYPEEYARLGRLYMCEFCLKYMKSQTILR 382 Q: 425 RHMAKCVWKHPPGDEIYRKGSISVFEVDGKKNKIYCQNLCLLAKLFLDHKTLYYDVEPFL 604 RHMAKCVWKHPPGDEIYRKGSISVFEVDGKKNKIYCQNLCLLAKLFLDHKTLYYDVEPFL
ZS S: 383 RHMAKCVWKHPPGDEIYRKGSISVFEVDGKKNKIYCQNLCLLAKLFLDHKTLYYDVEPFL 442 Q: 605 FYVMTEADNTGCHLIGYFSKEKNSFLNYNVSCILTMPQYMRQGYGKMLIDFSYLLSKVEE 784 FYVMTEADNTGCHLIGYFSKEKNSFLNYNVSCILTMPQYMRQGYGKMLIDFSYLLSKVEE
S: 443 FYVMTEADNTGCHLIGYFSKEKNSFLNYNVSCILTMPQYMRQGYGKMLIDFSYLLSKVEE 502 Q: 785 KVGSPERPLSDLGLISYRSYWKEVLLRYLHNFQGKEISIKEISQETAXNPVDIVSTLQAL 964 KVGSPERPLSDLGLISYRSYWKEVLLRYLHNFQGKEISIKEISQETA NPVDIVSTLQAL
S: 503 KVGSPERPLSDLGLISYRSYWKEVLLRYLHNFQGKEISIKEISQETAVNPVDIVSTLQAL 562 3S Q: 965 QMLKYWKGKHLVLKRQDLIDEWIAKEAKRSNSNKTMDPSCLKWTPPKGT 1111 QMLKYWKGKHLVLKRQDLIDEWIAKEAKRSNSNKTMDPSCLKWTPPKGT
S: 563 QMLKYWKGKHLVLKRQDLIDEWIAKEAKRSNSNKTMDPSCLKWTPPKGT 611 The segment of gi14091980 that is shown as "S" above is set out in the sequence listing as SEQ ID NO. 117 . Based on the structural similarity, these homologous polypeptides are expected to share at least some biological activities.
Such activities are known in the art, some of which are described elsewhere herein.

Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
Preferred polypeptides of the invention comprise a polypeptide having the amino acid sequence set out in the sequence listing as SEQ ID NO. 118 which S corresponds to the "Q" sequence in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed).
It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Stratagene NT2 neuronal precursor 937230; Human Cerebellum and to a lesser extent in Soares testis NHT; Soares melanocyte 2NbHM;
Soares placenta Nb2HP; Soares infant brain 1NIB; NCI CGAP_GCBI; Saos2 Cells, Untreated; NCI CGAP_Co3; NCI CGAP_GC4; Soares fetal heart NbHHI9W;
L428; Gessler Wilms tumor; Soares total fetus Nb2HF8 9w; normalized infant brain cDNA; Stratagene ovarian cancer (#937219); Anergic T-cell; human caudate nucleus; Human fetal brain QBoqin2; NCI CGAP_Kid3; NCI CGAP_Pr22;
NCI CGAP_Brn23; Stratagene NT2 neuronal precursor 937230; Colon Tumor;
human colon cancer; NTERA2 teratocarcinoma cell line+retinoic acid (14 days);
Human Normal Breast; Apoptotic T-cell, re-excision; H Female Bladder, Adult;
NTERA2 + retinoic acid, 14 days; Human Amygdala,re-excision; Human Manic Depression Tissue; Human Bone Marrow, re-excision; Breast Cancer Cell line, angiogenic; Human Osteoblasts II; Merkel Cells; Human Ovary; Human Thymus Stromal Cells; Soares breast 2NbHBst; Human Adrenal Gland Tumor; Rejected Kidney, lib 4; Human Whole Six Week Old Embryo; NTERA2, control; HM3; Colon Tumor; Stratagene colon (#937204); Stratagene NT2 neuronal precursor 937230;
Smooth muscle, serum treated; Human Placenta; Human Testes Tumor; Primary Dendritic cells,frac 2; 12 Week Early Stage Human II, Reexcision; Human Testes, Reexcision; Endothelial cells-control; HUMAN B CELL LYMPHOMA; Spleen, Chronic lymphocytic leukemia; Human Testes; Activated T-cell(12h)/Thiouridine-re-excision; Human 8 Week Whole Embryo and Soares fetal liver spleen 1NFLS.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are 5 related to SEQ ID N0:16 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the 10 general formula of a-b, where a is any integer between 1 to 2722 of SEQ ID
N0:16, b is an integer of 15 to 2736, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:16, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 7 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.
gnIIPIDId1021666 (all information available through the recited accession number is incorporated herein by reference) which is described therein as "KIAA0370 [Homo sapiens]". A partial alignment demonstrating the observed homology is shown immediately below.
>gnl~PID~d1021666 (AB002368) KIAA0370 [Homo sapiens] >sp~015076~015076 2l (soe (FRAGMENT). >gi~2981255 (AC003010) KIAA0370 [Homo sapiens]
192-801}
Length = 801 S
Plus Strand HSPS:
Score = 3354 (1180.7 bits), Expect = 0.0, P = 0.0 Identities = 672/732 (91~), Positives = 672/732 (91$), Frame = +3 Q: 348 CL-SCSYIEKFTDFLRLFVSVHLRRIESYSQFPVVEFLTLLFKYTFHQPTHEGYFSCLDI 524 CL S SYIEKFTDFLRLFVSVHLRRIESYSQFPVVEFLTLLFKYTFHQPTHEGYFSCLDI
S: 17 CLVSFSYIEKFTDFLRLFVSVHLRRIESYSQFPVVEFLTLLFKYTFHQPTHEGYFSCLDI 76 IS Q: 525 WTLFLDYLTSKIKSRLGDKEAVLNRYEDALVLLLTEVLNRIQFRYNQAXXXXXXXXXXXX 704 WTLFLDYLTSKIKSRLGDKEAVLNRYEDALVLLLTEVLNRIQFRYNQA
S: 77 WTLFLDYLTSKIKSRLGDKEAVLNRYEDALVLLLTEVLNRIQFRYNQAQLEELDDETLDD 136 Q: 705 XXXXXWQRYLRQSLEWAKVMELLPTHAFSTLFPVLQDNLEVYLGLQQFIVTSGSGHRLN 884 ZO WQRYLRQSLEWAKVMELLPTHAFSTLFPVLQDNLEVYLGLQQFIVTSGSGHRLN
S: 137 DQQTEWQRYLRQSLEWAKVMELLPTHAFSTLFPVLQDNLEVYLGLQQFIVTSGSGHRLN 196 Q: 885 ITAENDCRRLHCSLRDLSSLLQAVGRLAEYFIGDVFAARFNDALTWERLVKVTLYGSQI 1064 ITAENDCRRLHCSLRDLSSLLQAVGRLAEYFIGDVFAARFNDALTVVERLVKVTLYGSQI
Z,S S: 197 ITAENDCRRLHCSLRDLSSLLQAVGRLAEYFIGDVFAARFNDALTWERLVKVTLYGSQI 256 Q: 1065 KLYNIETAVPSVLKPDLIDVHAQSLAALQAYSHWLAQYCSEVHRQNTQQFVTLISTTMDA 1244 KLYNIETAVPSVLKPDLIDVHAQSLAALQAYSHWLAQYCSEVHRQNTQQFVTLISTTMDA
S: 257 KLYNIETAVPSVLKPDLIDVHAQSLAALQAYSHWLAQYCSEVHRQNTQQFVTLISTTMDA 316 Q: 1245 ITPLISTKVQDKXXXXXXXXXXXXXTTVRPVFLISIPAVQKVFNRITDASALRLVDKAQV 1424 ITPLISTKVQDK TTVRPVFLISIPAVQKVFNRITDASALRLVDKAQV
S: 317 ITPLISTKVQDKLLLSACHLLVSLATTVRPVFLISIPAVQKVFNRITDASALRLVDKAQV 376 3S Q: 1425 LVCRAXXXXXXXXXXXXXXXEQQWPVRSINHASLISALSRDYRNLKPSAVAPQRKMPLDD 1604 LVCRA EQQWPVRSINHASLISALSRDYRNLKPSAVAPQRKMPLDD
S: 377 LVCRALSNILLLPWPNLPENEQQWPVRSINHASLISALSRDYRNLKPSAVAPQRKMPLDD 436 Q: 1605 TKLIIHQTLSVLEDIVENISGESTKSRQICYQSLQESVQVSLALFPAFIHQSDVTDEMLS 1784 S: 437 TKLIIHQTLSVLEDIVENISGESTKSRQICYQSLQESVQVSLALFPAFIHQSDVTDEMLS 496 Q: 1785 FFLTLFRGLRVQMGVPFTEQIIQTFLNMFTREQLAESILHEGSTGCRWEKFLKILQVW 1964 FFLTLFRGLRVQMGVPFTEQIIQTFLNMFTREQLAESILHEGSTGCRWEKFLKILQWV
4S S: 497 FFLTLFRGLRVQMGVPFTEQIIQTFLNMFTREQLAESILHEGSTGCRWEKFLKILQWV 556 SO
Q: 1965 QEPGQVFKPFLPSIIALCMEQVYPIIAERPSPDVKAELFELLFRTLHHNWRYFFKSTVLA 2144 QEPGQVFKPFLPSIIALCMEQVYPIIAERPSPDVKAELFELLFRTLHHNWRYFFKSTVLA
S: 557 QEPGQVFKPFLPSIIALCMEQVYPIIAERPSPDVKAELFELLFRTLHHNWRYFFKSTVLA 616 Q: 2145 SVQRGIAEEQMENEPQFSAIMQAFGQSFLQPDIHLFKQNLFYLETLNTKQKLYHKKIFRT 2324 SVQRGIAEEQMENEPQFSAIMQAFGQSFLQPDIHLFKQNLFYLETLNTKQKLYHKKIFRT
S: 617 SVQRGIAEEQMENEPQFSAIMQAFGQSFLQPDIHLFKQNLFYLETLNTKQKLYHKKIFRT 676 SS Q: 2325 AMXXXXXXXXXXXXXHKSHDLLQEEIGIAIYNMASVDFDGFFAAFLPEFLTSCDGVDANQ 2504 AM HKSHDLLQEEIGIAIYNMASVDFDGFFAAFLPEFLTSCDGVDANQ
S: 677 AMLFQFVNVLLQVLVHKSHDLLQEEIGIAIYNMASVDFDGFFAAFLPEFLTSCDGVDANQ 736 Q: 2505 KSVLGRNFKMDR 2540 KSVLGRNFKMDR
S: 737 KSVLGRNFKMDR 748 The segment of gnIIPIDId1021666 that is shown as "S" above is set out in the sequence listing as SEQ ID NO. 119 . Based on the structural similarity, these homologous polypeptides are expected to share at least some biological activities.
Such activities are known in the art, some of which are described elsewhere herein.
Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
Preferred polypeptides of the invention comprise a polypeptide having the amino acid sequence set out in the sequence listing as SEQ ID NO. 120 which corresponds to the "Q" sequence in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed).
It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Human Neutrophil, Activated and to a lesser extent in Activated T-cell(12h)/Thiouridine-re-excision; NCI CGAP_GCB1; Soares adult brain N2b4HB55Y; Soares breast 2NbHBst; Soares breast 3NbHBst; Keratinocyte;
Human Neutrophils, Activated, re-excision; Soares_pregnant uterus NbHPU;
Human Neutrophil; Human Adult Testes, Large Inserts, Reexcision;
Soares fetal liver spleen_1NFLS S1; Human Pancreas Tumor, Reexcision;
Hemangiopericytoma; NTERA2, control; Pancreas Islet Cell Tumor; Fetal Heart;
Soares melanocyte 2NbHM; T Cell helper I; T cell helper II; Primary Dendritic Cells, lib 1; CD34+ cell, I, frac II; NCI CGAP_GC6;
Soares_placenta 8to9weeks 2NbHP8to9W; Healing groin wound - zero hr post-incision (control); Jurkat T-cell G1 phase; Soares testis NHT; Stratagene HeLa cell s3 937216; Soares adult brain N2b5HB55Y; Stratagene liver (#937224); Smooth muscle, serum induced,re-exc; Soares_pregnant uterus NbHPU; HUMAN B CELL
LYMPHOMA; NCI CGAP_LuS; NCI CGAP_Ew 1; Osteoblasts; Adrenal Gland,normal; Human Lung Cancer, subtracted; Kidney cancer; H. hypothalamus, frac A; Ku 812F Basophils Line; Human Colon Cancer, subtracted; HepG2 Cells, lambda library; Resting T-Cell; Frontal Lobe, Dementia; H. Striatum Depression, subt; Human OB HOS control fraction I; Human OB MG63 treated (10 nM E2) fraction I; Adipocytes,re-excision; HSC172 cells; H. Epididiymus, caput &
corpus;
Human Primary Breast Cancer; NCI CGAP_Brn25; Soares NhHMPu_S1;
Soares testis NHT; Soares_pregnant uterus NbHPU; Invasive poorly differentiated lung adenocarcinoma, metastatic; Human Normal Breast; STROMAL -OSTEOCLASTOMA; Hepatocellular Tumor,re-excision; Hepatocellular Tumor;
Smooth muscle, ILIb induced; Salivary Gland, Lib 2; Human endometrial stromal cells; JurkatT-Cell, S phase; H. Meningima, M1; Human Umbilical Vein, Reexcision; KMH2; Human Brain, Striatum; Apoptotic T-cell; Merkel Cells; Human Hypothalmus,Schizophrenia; Gessler Wilms tumor; Human pancreatic islet; Human adult lung 3' directed MboI cDNA; Soares_NhHMPu_S1; Soares NFL T GBC_S1;
Soares fetal heart_NbHHI9W; Soares NSF F8 9W_OT PA P S1;
Soares total fetus Nb2HF8 9w; Soares_parathyroid tumor NbHPA; Liver, Hepatoma; Spinal cord; Human Chondrosarcoma; Soares fetal heart NbHHI9W;
Epithelial-TNFa and INF induced; Macrophage-oxLDL, re-excision; Human Gall Bladder; KGl-a Lambda Zap Express cDNA library; Soares NhHMPu_S1;
Stratagene NT2 neuronal precursor 937230; CHME Cell Line,untreated; Human Eosinophils; breast lymph node CDNA library; Colon Normal II; Human Placenta;
Adipocytes; Human Testes Tumor; 12 Week Early Stage Human 11, Reexcision;
Human Testes, Reexcision; Human Placenta; Human Fetal Heart; Human Primary Breast Cancer Reexcision; CD34 depleted Buffy Coat (Cord Blood), re-excision;

Anergic T-cell; Soares_pregnant uterus NbHPU; Smooth muscle,control; Human Bone Marrow, treated; NCI CGAP_Ut3; NCI CGAP_Ut4; NCI CGAP_Kid3;
NCI CGAP_Panl; NCI CGAP_Pr28; NCI CGAP_Brn25; H. Frontal cortex,epileptic,re-excision; Human Endometrial Tumor; neutrophils control;
Human fetal brain (TFujiwara); NCl CGAP_Br2; NCI CGAP_GC1; NCI CGAP_Lul;
NCI CGAP_Col2; NCI CGAP_Brl.l; Human 8 Week Whole Embryo; Human Cerebellum; Stratagene pancreas (#937208) and Soares infant brain 1NIB.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 67 as residues: Gly-62 to Gly-69, Pro-96 to Asp-102.
Polynucleotides encoding said polypeptides are also provided.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:17 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 3230 of SEQ ID
N0:17, b is an integer of 15 to 3244, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:17, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 8 It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: normalized infant brain cDNA and to a lesser extent in Soares NFL T_GBC S1; Soares infant brain 1NIB; Human Whole Brain #2 - Oligo dT > I.SKb; Barstead spleen HPLRB2; Human fetal heart, Lambda ZAP Express;
NCI CGAP_Ewl; Human Adult Spleen; Soares_pregnant uterus_NbHPU;
Stratagene neuroepithelium NT2RAMI 937234; Human Fetal Kidney; Stratagene 5 lung (#937210); Human Testes, Reexcision; Bone marrow; Neutrophils IL-1 and LPS
induced; Human Testes; Soares testis NHT; H. Frontal cortex,epileptic,re-excision;
Hodgkin's Lymphoma II; Human 8 Week Whole Embryo and Human Cerebellum.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 68 as residues: Glu-18 to Ser-23. Polynucleotides 10 encoding said polypeptides are also provided.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:18 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically 15 excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 2297 of SEQ ID
N0:18, b is an integer of 15 to 2311, where both a and b correspond to the positions of 20 nucleotide residues shown in SEQ ID N0:18, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 9 25 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.
gi12071947 (all information available through the recited accession number is incorporated herein by reference) which is described therein as "beta-galactosidase [Expression vector pBSII-LUCINT]". A partial alignment demonstrating the observed S homology is shown immediately below.
>gi~2071947 beta-galactosidase [Expression vector pBSII-LUCINT) Length = 69 Plus Strand HSPs:
Score = 342 (120.4 bits), Expect = 1.6e-29, P = 1.6e-29 Identities = 65/69 (94~), Positives = 68/69 (98~), Frame = +2 IS Q: 2075 LAWLQRRDWENPGVTQLNRLAAHPPFASWRNSEEARTDRPSQQLRSLNGEW-QIVSVNI 2251 +AWLQRRDWENPGVTQLNRLAAHPPFASWRNSEEARTDRPSQQLRSLNGEW +IV+VNI
S: 1 MAVVLQRRDWENPGVTQLNRLAAHPPFASWRNSEEARTDRPSQQLRSLNGEWREIVNVNI 60 Q: 2252 LLKFALNFC 2278 S: 61 LLKFALNFC 69 The segment of gi12071947 that is shown as "S" above is set out in the sequence listing as SEQ ID NO. 121 . Based on the structural similarity, these 2S homologous polypeptides are expected to share at least some biological activities.
Such activities are known in the art, some of which are described elsewhere herein.
Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
Preferred polypeptides of the invention comprise a polypeptide having the 30 amino acid sequence set out in the sequence listing as SEQ 1D NO. 122 which corresponds to the "Q" sequence in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed).
It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Neutrophils control, re-excision and to a lesser extent in Soares infant brain 1NIB; Human Cerebellum; Early Stage Human Brain; Human Adult Testes, Large Inserts, Reexcision; Human Testes Tumor, re-excision; 12 Week Early Stage Human II, Reexcision; H. Epididiymus, cauda; normalized infant brain cDNA; Soares placenta Nb2HP; normalized infant brain cDNA; Soares breast 2NbHBst; human tonsils; Soares NFL T GBC_S 1; Osteoblasts; Nine Week Old Early Stage Human; Frontal Lobe, Dementia; Human Cerebellum, subtracted;
Activated T-Cells,l2 hrs,re-excision; Stomach cancer (human),re-excision;
wilm's tumor; Human Umbilical Vein, Reexcision; Apoptotic T-cell; Human Pancreas Tumor; Human Activated T-Cells, re-excision; Soares_pregnant uterus NbHPU;
Stratagene lung carcinoma 937218; NCI CGAP_GC4; Pancreas Islet Cell Tumor; H
Macrophage (GM-CSF treated), re-excision; Human Synovial Sarcoma;
Soares NbHFB; Endothelial cells-control; Soares_pregnant uterus NbHPU;
Soares_parathyroid_tumor NbHPA; Soares fetal liver spleen 1NFLS; Soares ovary tumor NbHOT; Human Uterus, normal; NCI CGAP_Col2; Weizmann Olfactory Epithelium; Human OB MG63 control fraction I; HepG2 Cells, lambda library;
Human Colon; Human Aortic Endothelium; H. Epididiymus, caput & corpus; H.
cerebellum, Enzyme subtracted; Resting T-Cell, re-excision; Human adult small intestine,re-excision; Human Epididymus; Human Hypothalamus,schizophrenia, re-excision; Soares multiple sclerosis 2NbHMSP; H. Kidney Cortex, subtracted;
Human Frontal Cortex, Schizophrenia; LNCAP prostate cell line; Human Osteosarcoma; H. Meningima, M1; H. Lymph node breast Cancer; Brain Frontal Cortex, re-excision; Human Neutrophil; H. Kidney Medulla, re-excision; 12 Week Old Early Stage Human, II; Merkel Cells; Olfactory epithelium,nasalcavity;
NCI CGAP_Ew 1; Human Activated Monocytes; Human Chondrosarcoma;
Ulcerative Colitis; Epithelial-TNFa and INF induced; Soares NhHMPu S1;
Soares testis NHT; Hemangiopericytoma; Fetal Liver, subtraction II;

NCI CGAP_LuS; NCI CGAP_Kids; Fetal Heart; Human T-Cell Lymphoma; Colon Carcinoma; Human Substantia Nigra; breast lymph node CDNA library; Colon Normal II; Soares_pineal_gland_N3HPG; Human Fetal Lung III;
Soares NFL_T GBC_S1; Soares fetal liver spleen_1NFLS S1; Normalized infant brain, Bento Soares; Bone marrow; Human Neutrophil, Activated; Human Adult Pulmonary,re-excision; Soares testis NHT; Activated T-Cell (l2hs)/Thiouridine labelledEco; Human Testes; Activated T-cell(12h)/Thiouridine-re-excision and Keratinocyte.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:19 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 2520 of SEQ ID
N0:19, b is an integer of 15 to 2534, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:19, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 10 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.

gi11872200 (all information available through the recited accession number is incorporated herein by reference) which is described therein as "alternatively spliced product using exon 13A [Homo sapiens]". A partial alignment demonstrating the observed homology is shown immediately below.
S
>gi~1872200 alternatively spliced product using exon 13A [Homo sapiens]
>sp~P78525IP78525 MYB PROTO-ONCOGENE PROTEIN (C-MYB).
Length = 666 Plus Strand HSPs:
Score = 160 (56.3 bits), Expect = 7.3e-14, Sum P(3) = 7.3e-14 Identities Frame = 33/40 = +2 (82$), Positives = 34/40 (85~), 1S Q: 524 FVFLVETGFRHVGQAGLELLTSGDPPTSXSQSAGITGMSH

F FLVETGF HVGQAGLELLTSGD P S
SQSA ITG+SH

S: 608 FEFLVETGFLHVGQAGLELLTSGDLPASASQSARITGVSH

Score 88 (31.0 bits), Expect = 7.3e-14,= 7.3e-14 = Sum P(3) Identities Frame = 15/18 = +3 (83~), Positives = 16/18 (88~), Q: 402 GVQWRNLGSLQPLPPGFK 455 GVQW + GSLQPLPPGFK

S: 568 GVQWHDFGSLQPLPPGFK 585 Score 66 (23.2 bits), Expect .-- 0.080,0.077 = Sum P(2) =

Identities Frame = 10/14 = +1 (71$), Positives = 11/14 (78~), Q: 604 LGLPKCWDYRHEPP 645 3O L LP+ WDYRH PP

S: 590 LSLPRSWDYRHPPP 603 Score 61 (21.5 bits), Expect = 7.3e-14,= 7.3e-14 = Sum P(3) Identities Frame = 10/13 = +1 (76~), Positives = 10/13 (76~), Q: 487 WDCRCPPPHPANF 525 WD R PPP PANF

S: 596 WDYRHPPPRPANF 608 40 Minus Strand HSPs:
Score = 79 (27.8 bits), Expect = 2.4, Sum P(2) = 0.91 Identities = 20/54 (37~), Positives = 25/54 (46g), Frame = -3 4S Q: 1724 TESCSVTQA--AVQWYNHSSLQPQPSEXXXXXXXXXXXXXDYRNAPPCLANFLF 1569 T++ V A VQW++ SLQP P DYR+ PP ANF F
S: 557 TQTSPVADAPTGVQWHDFGSLQPLPPGFKRFSCLSLPRSWDYRHPPPRPANFEF 610 The segments of gi11872200 that are shown as "S" above are set out in the sequence listing as SEQ ID NO. 123,SEQ ID NO. 125,SEQ ID NO. 127,SEQ ID
NO. 129 and SEQ ID NO. 131 . Based on the structural similarity, these homologous polypeptides are expected to share at least some biological activities. Such activities 5 are known in the art, some of which are described elsewhere herein. Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
Preferred polypeptides of the invention comprise a polypeptide having the amino acid sequence set out in the sequence listing as SEQ ID NO. 124,SEQ ID
NO.
10 126,SEQ ID NO. 128,SEQ ID NO. 130 and/or SEQ ID NO. 132 which correspond to the "Q" sequences in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed).
It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Soares total fetus Nb2HF8 9w; Human Cerebellum and to a 15 lesser extent in NCI CGAP_AAl; Hepatocellular Tumor; Human endometrial stromal cells-treated with progesterone; Human Placenta and Activated T-Cell (l2hs)/Thiouridine IabelledEco.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are 20 related to SEQ ID N0:20 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the 25 general formula of a-b, where a is any integer between 1 to 1772 of SEQ ID
N0:20, b is an integer of 15 to 1786, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:20, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 11 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.
gi14050087 (all information available through the recited accession number is incorporated herein by reference) which is described therein as "S164 [Homo Sapiens]". A partial alignment demonstrating the observed homology is shown immediately below.
>gi~4050087 (AF109907) 5164 [Homo Sapiens] >sp~G4050087~G4050087 S164 (FRAGMENT). >bbs~140315 U1 small nuclear ribonucleoprotein homolog [human, thyroid associated ophthalmopathy patient, Peptide Partial, 85 aa] [Homo Sapiens] {SUB 305-389}
Length = 735 Plus Strand HSPs:
Score = 874 (307.7 bits), Expect = 1.3e-95, Sum P(3) = 1.3e-95 Identities = 172/180 (95~), Positives = 172/180 (95~), Frame = +2 Q: 506 KCGLVLSWKRVQGASGKLQAFGFCEYKEPESTLRALRLLHDLQIGEKKLLVKVDAKTKAQ 685 KCGLVLSWKRVQGASGKLQAFGFCEYKEPESTLRALRLLHDLQIGEKKLLVKVDAKTKAQ
~3O S: 1 KCGLVLSWKRVQGASGKLQAFGFCEYKEPESTLRALRLLHDLQIGEKKLLVKVDAKTKAQ 60 Q: 686 LDEWKAKKKASNGNARPETVTNDDEEALDEETKRRDQMIKGAIEVLIREYSSELNAPSQE 865 LDEWKAKKKASNGNARPETVTNDDEEALDEETKRRDQMIKGAIEVLIREYSSELNAPSQE
S: 61 LDEWKAKKKASNGNARPETVTNDDEEALDEETKRRDQMIKGAIEVLIREYSSELNAPSQE 120 Q: 866 SDSHPRXXXXXXXXDIFRRFPVAPLIPYPLITKEDINAIEMEEDKRDLISREISKFRDTH 1045 SDSHPR DIFRRFPVAPLIPYPLITKEDINAIEMEEDKRDLISREISKFRDTH
S: 121 SDSHPRKKKKEKKEDIFRRFPVAPLIPYPLITKEDINAIEMEEDKRDLISREISKFRDTH 180 Score = 60 (21.1 bits), Expect = 1.3e-95, Sum P(3) = 1.3e-95 Identities = 16/47 (34~), Positives = 26/47 (55~), Frame = +1 Q: 982 RNGRRQKRPDISRDQQIQRHT*ETGRRERQKGKRKTGN*ERTERKRE 1122 RN R + + SRD++ +R RER++ + + ER ER+RE
S: 269 RNKDRSRSREKSRDRERERERERERERERERERERERERER-ERERE 314 The segments of gi14050087 that are shown as "S" above are set out in the sequence listing as SEQ ID NO. 133 and SEQ ID NO. 135 . Based on the structural similarity, these homologous polypeptides are expected to share at least some biological activities. Such activities are known in the art, some of which are described elsewhere herein. Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
Preferred polypeptides of the invention comprise a polypeptide having the amino acid sequence set out in the sequence listing as SEQ ID NO. 134 and/or SEQ
ID NO. 136 which correspond to the "Q" sequences in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed).
It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Human T-Cell Lymphoma; Human 8 Week Whole Embryo and to a lesser extent in T cell helper II; Soares placenta Nb2HP; human ovarian cancer; Soares_pregnant uterus NbHPU; Stratagene endothelial cell 937223;
Colon Normal III; Jurkat T-Cell, S phase; Soares total fetus Nb2HF8 9w; Human Ovarian Cancer Reexcision; Soares NFL T GBC_S1; NCI CGAP_Ov26; Human Eosinophils; NCI CGAP_GCB1; CD34 positive cells (Cord Blood); Nine Week Old Early Stage Human; Stratagene HeLa cell s3 937216; Primary Dendritic Cells, lib 1;
Healing Abdomen wound,70&90 min post incision; Soares retina N2b4HR;
Stratagene ovary (#937217); Human adult small intestine,re-excision;
Soares_pregnant uterus NbHPU; Myoloid Progenitor Cell Line;
Soares fetal liver spleen_1NFLS S1; Mo7e Cell Line GM-CSF treated (lng/ml);
Human Adrenal Gland Tumor; Stratagene liver (#937224);

Soares total fetus Nb2HF8 9w; NCI CGAP_Ov2; Soares NhHMPu_S1; multi-tissue normalized short-fragment; Early Stage Human Brain; Normal colon; Human Fetal Lung III; Soares fetal liver spleen_1NFLS S1; Human Testes; Hodgkin's Lymphoma II; Soares fetal liver spleen 1NFLS; Soares NhHMPu_Sl; K562 cells;
Normal lung; Sinus piniformis Tumour; Colon Normal; Messangial cell, frac l;
Larynx Carcinoma; Human osteoarthritic,fraction II; Salivary Gland, Lib 3;
Thymus;
STRIATUM DEPRESSION; Dermatofibrosarcoma Protuberance; H. Striatum Depression, subt; Human Gall Bladder, fraction II; Human Colon Carcinoma (HCC) cell line; H. Atrophic Endometrium; Adipocytes,re-excision; human colon cancer;
Aorta endothelial cells + TNF-a; Activated T-cells; NTERA2 teratocarcinoma cell line+retinoic acid (14 days); Human Normal Breast; Pancreas Tumor PCA4 Tu;
Human Hypothalamus,schizophrenia, re-excision; Human Synovium; Synovial IL-1/TNF stimulated; Human Prostate Cancer, Stage C fraction; Soares NhHMPu_S 1;
pBMC stimulated w/ poly I/C; Human Osteoclastoma Stromal Cells - unamplified;
NTERA2 + retinoic acid, 14 days; Stratagene muscle 937209; Human Adipose Tissue, re-excision; Healing groin wound, 6.5 hours post incision; Synovial Fibroblasts (111/TNF), subt; Prostate BPH; Gessler Wilms tumor; Human pancreatic islet; KG 1-a Lambda Zap Express cDNA library; Soares_pineal_gland N3HPG; H:
Lymph node breast Cancer; Human Adult Small Intestine; KMH2; Apoptotic T-cell;
12 Week Old Early Stage Human, II; Human Fetal Dura Mater; T-Cell PHA 24 hrs;
Human Hypothalmus,Schizophrenia; Human Placenta (re-excision); Human Testes Tumor, re-excision; Human Thymus Stromal Cells; NTERA2, control;
Hepatocellular Tumor, re-excision; Smooth muscle, serum induced,re-exc; Gessler Wilms tumor;
Human promyelocyte; Human pancreatic islet; Soares NSF F8 9W_OT PA P S1;
Colon Tumor; Resting T-Cell Library,II; Human adult (K.Okubo); Human fetal brain (TFujiwara); NCI CGAP_LuS; NCI CGAP_GCB1; NCI CGAP_Lei2;

NCI CGAP_Prl2; Soares breast 3NbHBst; Soares total fetus Nb2HF8 9w; Human Synovial Sarcoma; Human Neutrophil, Activated; Endothelial-induced;
Endothelial cells-control; NCI CGAP_Br2; NCI CGAP_Pr3; Human Osteoclastoma; HUMAN B
CELL LYMPHOMA; Bone Marrow Cell Line (RS4,11); Activated T-cell(12h)/Thiouridine-re-excision and Osteoblasts.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:21 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1757 of SEQ ID
N0:21, b is an integer of 15 to 1771, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:21, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 12 It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Human Neutrophil, Activated and to a lesser extent in Activated T-cell(12h)/Thiouridine-re-excision; Human Neutrophils, Activated, re-excision; Colon Carcinoma; Human Adult Pulmonary,re-excision; Human adult (K.Okubo); Stratagene endothelial cell 937223; Stratagene colon (#937204); H
Female Bladder, Adult; Human Neutrophil; Human Activated T-Cells, re-excision;
NCI CLAP GCB1; Soares_placenta 8to9weeks 2NbHP8to9W; Activated T-Cell (l2hs)/Thiouridine IabelledEco; Soares fetal liver spleen 1NFLS;
Soares fetal heart NbHHI9W; H. hypothalamus, frac A,re-excision; K562 + PMA
(36 hrs); Human Pre-Differentiated Adipocytes; H. Adipose Tissue; K562 + PMA
(36 hrs),re-excision; Hodgkin's Lymphoma I; Human Pituitary, subtracted; Human 5 endometrial stromal cells-treated with estradiol; Stratagene placenta (#937225);
Breast Cancer cell line, MDA 36; Salivary Gland, Lib 2; Human Adipose Tissue, re-excision; Human endometrial stromal cells; Human Prostate; Human Activated T-Cells; Human Adult Testes, Large Inserts, Reexcision; Merkel Cells; Olfactory epithelium,nasalcavity; Human fetal lung; Normalized infant brain, Bento Soares;
10 Soares NSF F8 9W_OT PA P_S1; Soares fetal liver spleen_1NFLS S1; Human Testes Tumor, re-excision; Soares breast 2NbHBst; CHME Cell Line,treated 5 hrs;
Human Liver, normal; CHME Cell Line,untreated; NCI CGAP_GC4;
NCI CGAP_Pr3; NCI CGAP_Pr4.l; Soares senescent fibroblasts_NbHSF; Gessler Wilms tumor; Soares testis NHT; Soares NFL T_GBC S1; Human Fetal Kidney, 15 Reexcision; human tonsils; Endothelial-induced; Human Bone Marrow, treated;
Neutrophils IL-1 and LPS induced; T cell helper II; Primary Dendritic Cells, lib 1 and Soares infant brain 1NIB.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are 20 related to SEQ ID N0:22 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the 25 general formula of a-b, where a is any integer between 1 to 2416 of SEQ ID
N0:22, b is an integer of 15 to 2430, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:22, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 13 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.
gi13002527 (all information available through the recited accession number is incorporated herein by reference) which is described therein as "neuronal thread protein AD7c-NTP [Homo sapiens]". A partial alignment demonstrating the observed homology is shown immediately below.
>gi~3002527 (AF010144) neuronal thread protein AD7c-NTP [Homo Sapiens]
>sp~060448~060448 NEURONAL THREAD PROTEIN AD7C-NTP.
Length = 375 Minus Strand HSPs:
Score = 152 (53.5 bits), Expect = 1.3e-11, Sum P(2) = 1.3e-11 Identities = 38/73 (52~), Positives = 40/73 (54~), Frame = -1 Q: 1824 LRCSFALVAQAGVQWCDLGSLQXXXXXXXXXXXXRLLSGWDYRHPPPCLTNFLYF*KRWG 1645 2S LR S V QAGVQW +LGSLQ LLS WDYR PP L NF F G
S: 202 LRQSLNSVTQAGVQWRNLGSLQPLPPGFKLFSCPSLLSSWDYRRPPR-LANFFVFLVEMG 260 Q: 1644 FTMLARLLLNS*P 1606 FTM ARL+L S P
3O S: 261 FTMFARLILISGP 273 The segment of gi13002527 that is shown as "S" above is set out in the sequence listing as SEQ ID NO. 137 . Based on the structural similarity, these homologous polypeptides are expected to share at least some biological activities.
35 Such activities are known in the art, some of which are described elsewhere herein.

37 .
Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
Preferred polypeptides of the invention comprise a polypeptide having the amino acid sequence set out in the sequence listing as SEQ ID NO. 138 which corresponds to the "Q" sequence in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed).
It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Chromosome 7 Placental cDNA Library; Chromosome 7 Fetal Brain cDNA Library; Human brain cDNA and to a lesser extent in Human Tonsil, Lib 3; Healing groin wound, 7.5 hours post incision; Jurkat T-Cell, S
phase;
Soares testis NHT; Human Activated T-Cells, re-excision; Chromosome 7 HeLa cDNA Library; NCI CGAP_GCB1; NCI CGAP_Lym3; NCI CGAP_Phel; Human Ovarian Cancer Reexcision; human tonsils; Neutrophils IL-1 and LPS induced; H.
Frontal cortex,epileptic,re-excision; Human 8 Week Whole Embryo and T cell helper II.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:23 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1873 of SEQ ID
N0:23, b is an integer of 15 to 1887, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:23, and where b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 14 It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Human Eosinophils; Soares fetal liver spleen 1NFLS;
Soares infant brain 1NIB and to a lesser extent in Human 8 Week Whole Embryo; Human Bone Marrow, treated; Soares fetal heart_NbHHI9W; Soares testis NHT; Nine Week Old Early Stage Human; Smooth muscle,control; 12 Week Old Early Stage Human, II; Fetal Heart; Human Placenta; Colon Normal III; Human Cerebellum;
Monocyte activated, re-excision; Human Adipose; Human Testes Tumor, re-excision;
Gessler Wilms tumor; Human Fetal Heart; Monocyte activated; T Cell helper I;
Human Testes; Hodgkin's Lymphoma II; T cell helper II; Synovial hypoxia;
Synovial Fibroblasts (Il1/TNF), subt; T-Cell PHA 16 hrs; human ovarian cancer; Human Uterine Cancer; Human Placenta (re-excision); Human Chondrosarcoma; NTERA2, control; Human Gall Bladder; Clontech human aorta polyA+ mRNA (#6572); PC3 Prostate cell line; Human Testes Tumor; Colon Tumor II; Dendritic cells, pooled;
Human Fetal Lung III; Human Amygdala; NCl CGAP_Co3; Osteoblasts; Healing groin wound, 6.5 hours post incision; H. Meningima, M1; Human Neutrophil;
Human Prostate; Soares NhHMPu_S1; KMH2; Soares total fetus Nb2HF8 9w; Human Fetal Dura Mater; T-Cell PHA 24 hrs; Human Ovary; Human fetal heart, Lambda ZAP Express; Rejected Kidney, lib 4; Human fetal heart, Lambda ZAP Express;
Human T-Cell Lymphoma; Soares total fetus Nb2HF8 9w; Stratagene schizo brain S11; Soares breast 3NbHBst; 12 Week Early Stage Human II, Reexcision; Human Adult Pulmonary,re-excision; Endothelial cells-control; Human Microvascular Endothelial Cells, fract. A; NCI CGAP_Kid6; Human Fetal Brain; HUMAN
STOMACH; Apoptotic T-cell, re-excision; Human Hypothalamus,schizophrenia, re-excision; STROMAL -OSTEOCLASTOMA; Human Synovium; Hepatocellular Tumor,re-excision; Stratagene placenta (#937225); Synovial hypoxia-RSF
subtracted;
Glioblastoma; Healing groin wound, 7.5 hours post incision; Salivary Gland, Lib 2;
LNCAP prostate cell line; Human endometrial stromal cells;
Soares_pregnant uterus NbHPU; Prostate BPH; Human Infant Brain; Hippocampus, Alzheimer Subtracted; H. Kidney Medulla, re-excision; Gessler Wilms tumor;
Soares fetal heart NbHHI9W; I~28; Human Pancreas Tumor; Human Hypothalmus,Schizophrenia; Pancreatic Islet; Human Rhabdomyosarcoma; Bone Marrow Stromal Cell, untreated; Human Adrenal Gland Tumor; Colon Tumor;
Resting T-Cell Library,II; 12 Week Old Early Stage Human;
Soares multiple sclerosis 2NbHMSP; Soares fetal liver spleen_1NFLS S1;
Stratagene HeLa cell s3 937216; Early Stage Human Brain; Adipocytes; Human Testes, Reexcision; Human Neutrophil, Activated; NCI CGAP_Prl; Clontech human aorta polyA+ mRNA (#6572); Human adult (K.Okubo); Human fetal heart, Lambda ZAP Express; Human Pancreas; Human Testes; Human Eosinophils; PCR, pBMC I/C
treated; Aryepiglottis Normal; Testis, normal; Human Umbilical Vein Endothelial cells, frac B, re-excision; brain stem; Salivary Gland, Lib 3; Human Pre-Differentiated Adipocytes; CD34+cells, II, FRACTION 2; LNCAP + 30nM 81881;
H. Meniingima, M6; Dermatofibrosarcoma Protuberance; Human Adult Liver, subtracted; Human Fetal Brain, random primed; Morton Fetal Cochlea; Human Gall Bladder, fraction II; Human OB HOS control fraction I; metastatic squamous cell lung carcinoma, poorly differentiated; Human (HCC) cell line liver (mouse) metastasis, remake; Human Cerebellum, subtracted; Human Umbilical Vein Endothelial Cells, fract. A; H. Atrophic Endometrium; Human Placenta;
NCI CGAP_Gas4; NCI CGAP_Brn35; Fetal Heart, re-excision; H. cerebellum, Enzyme subtracted; Breast Lymph node cDNA library; Early Stage Human Lung, subtracted; Human T-cell lymphoma,re-excision; NTERA2 teratocarcinoma cell line+retinoic acid (14 days); Soares NhHMPu_S1; Raji Cells, cyclohexamide treated;
CD34 positive cells (cord blood),re-ex; Human Tonsils, Lib 2; Healing groin wound -zero hr post-incision (control); B Cell lymphoma; Human Epididymus; Gessler 5 Wilms tumor; NCI CGAP_GC4; NCI CGAP_LuS; NCI CGAP_Kids; normalized infant brain cDNA; NTERA2 + retinoic acid, 14 days; H. Kidney Cortex, subtracted;
Human Stomach,re-excision; Human Adipose Tissue, re-excision; Human Osteosarcoma; Myoloid Progenitor Cell Line; Jurkat T-Cell, S phase; wilm's tumor;
H. Lymph node breast Cancer; Brain Frontal Cortex, re-excision; ' 10 Soares_placenta 8to9weeks_2NbHP8to9W; Human pancreatic islet;
Soares total fetus Nb2HF8 9w; Mo7e Cell Line GM-CSF treated (lng/ml); TF-1 Cell Line GM-CSF Treated; Human Thymus; NCI CGAP_Br7; NCI CGAP_GC4;
NCI CGAP_LuS; NCI CGAP_GCB1; NCI CGAP_PNS1; WATM1; Human Fetal Kidney; Stratagene fetal spleen (#937205); Human Osteoblasts II; Human Activated 15 T-Cells; Stromal cell TF274; Macrophage-oxLDL; Human Pancreas Tumor, Reexcision; Human Hippocampus; Olfactory epithelium,nasalcavity; Spinal cord;
Stratagene neuroepithelium NT2RAMI 937234; Ulcerative Colitis; PERM TF274;
Soares testis NHT; Soares total fetus Nb2HF8 9w; Hemangiopericytoma; Human Thymus Stromal Cells; Human Whole Six Week Old Embryo; Stratagene liver 20 (#937224); Macrophage-oxLDL, re-excision; Pancreas Islet Cell Tumor;
NCI CGAP_GC3; NCI CGAP_GC4; NCI CGAP_Pr3; NCl CGAP_Brl.l; Human fetal lung; Soares NhHMPu_S1; Soares fetal heart NbHHI9W; Stratagene hNT
neuron (#937233); Stratagene lung carcinoma 937218; normalized infant brain cDNA; Human Substantia Nigra; Colon Normal II; Normal colon; human tonsils;
25 Endothelial-induced; Human Osteoclastoma; Anergic T-cell;
Soares_pregnant uterus NbHPU; Soares fetal lung NbHLI9W;

Soares fetal heart_NbHHI9W; CD34 positive cells (Cord Blood); NCI CGAP_Br2;
NCI CGAP_GC4; NCI CGAP_CLL1; NCI CGAP_Kids; NCI CGAP_Lei2;
Soares testis NHT; Soares total fetus Nb2HF8 9w; Bone Marrow Cell Line (RS4,11); Human Endometrial Tumor; NCI CGAP_Alvl; NCI CGAP_GCB1;
NCI CGAP_HSC1 and Soares fetal lung NbHLI9W.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:24 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 2894 of SEQ ID
N0:24, b is an integer of 15 to 2908, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:24, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 15 It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: NCI CGAP GCB1 and to a lesser extent in Soares NhHMPu_S1; Synovial IL-1/TNF stimulated; Soares NhHMPu_S1;
Soares senescent fibroblasts_NbHSF; Human Bone Marrow, re-excision and Human T-Cell Lymphoma.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:25 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1193 of SEQ ID
N0:25, b is an integer of 15 to 1207, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:25, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 16 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.
gnIIPIDId1014088 (all information available through the recited accession number is incorporated herein by reference) which is described therein as "Similar to Human estrogen-responsive finger protein, efp (A49656) [Homo sapiens]". A partial alignment demonstrating the observed homology is shown immediately below.
>gnl~PID~d1014088 Similar to Human estrogen-responsive finger protein, efp (A49656) [Homo sapiens) >sp~Q92557~Q92557 MYELOBLAST KIAA0268 (FRAGMENT).
Length = 550 Plus Strand HSPs:
Score = 379 (133.4 bits), Expect = 4.9e-32, P = 4.9e-32 Identities = 72/72 (1000 , Positives = 72/72 (1000 , Frame = +3 Q: 3 KQPPLSTVPADGYILELDDGNGGQFREVYVGKETMCTVDGLHFNSTYNARVKAFNKTGVS 182 KQPPLSTVPADGYILELDDGNGGQFREVYVGKETMCTVDGLHFNSTYNARVKAFNKTGVS

S: 349 KQPPLSTVPADGYILELDDGNGGQFREVYVGKETMCTVDGLHFNSTYNARVKAFNKTGVS 408 Q: 183 PYSKTLVLQTSE 218 PYSKTLVLQTSE
S: 409 PYSKTLVLQTSE 420 The segment of gnlIPIDId1014088 that is shown as "S" above is set out in the sequence listing as SEQ ID NO. 139 . Based on the structural similarity, these homologous polypeptides are expected to share at least some biological activities.
Such activities are known in the art, some of which are described elsewhere herein.
Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
Preferred polypeptides of the invention comprise a polypeptide having the amino acid sequence set out in the sequence listing as SEQ ID NO. 140 which corresponds to the "Q" sequence in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed).
It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Soares infant brain 1NIB and to a lesser extent in normalized infant brain cDNA; Early Stage Human Brain; Soares_multiple sclerosis 2NbHMSP;
Human Whole Brain #2 - Oligo dT > I.SKb; Human Manic Depression Tissue;
Smooth muscle, serum induced,re-exc; Human Amygdala and H. Frontal cortex,epileptic,re-excision.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 76 as residues: Met-1 to Cys-7, Leu-21 to Leu-43, Pro-66 to Thr-71. Polynucleotides encoding said polypeptides are also provided.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:26 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 2220 of SEQ ID
N0:26, b is an integer of 15 to 2234, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:26, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 17 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.
gi11196433 (all information available through the recited accession number is incorporated herein by reference) which is described therein as "Homo sapiens protein". A partial alignment demonstrating the observed homology is shown immediately below.
>gi~1196433 unknown protein [Homo Sapiens] >sp~Q14288~Q14288 HYPOTHETICAL
PROTEIN (FRAGMENT).
Length = 641 Minus Strand HSPS:
Score = 447 (157.4 bits), Expect = 1.7e-41, P = 1.7e-41 Identities = 82/86 (95~), Positives = 82/86 (950), Frame = -2 3O Q: 967 KDTCTRMFIXALFTIAKTWNQPKCPTMIDWIKKMWHIYTMEYYAAIKNDEFMSFVGTWMK 788 KDTCTRMFI ALFTIAKTWNQPKCPTMIDWIKKMWHIYTMEYYAAIKNDEFMSFVGTWMK
S: 556 KDTCTRMFIAALFTIAKTWNQPKCPTMIDWIKKMWHIYTMEYYAAIKNDEFMSFVGTWMK 615 Q: 787 LEXIILSKLSQXQKTKHRXFSLIGGN 710 LE IILSKLSQ QKTKHR FSLIGGN
S: 616 LETIILSKLSQEQKTKHRIFSLIGGN 641 The segment of gi11196433 that is shown as "S" above is set out in the 5 sequence listing as SEQ ID NO. 141 . Based on the structural similarity, these homologous polypeptides are expected to share at least some biological activities.
Such activities are known in the art, some of which are described elsewhere herein.
Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
10 Preferred polypeptides of the invention comprise a polypeptide having the amino acid sequence set out in the sequence listing as SEQ ID NO. 142 which corresponds to the "Q" sequence in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed).
It has been discovered that this gene is expressed primarily in the following 15 tissues/cDNA libraries: Soares_parathyroid tumor NbHPA and to a lesser extent in Neutrophils control, re-excision; 12 Week Old Early Stage Human; Stratagene colon (#937204); Soares_parathyroid tumor NbHPA; Neutrophils IL-1 and LPS induced;
neutrophils control; NCI CGAP_GCB1; Human Eosinophils; NCI CGAP_Lu26;
Human Cerebellum; Soares fetal liver spleen 1NFLS; human ovarian cancer; PC3 20 Prostate cell line; Colon Tumor; Colon Normal II; Soares melanocyte 2NbHM;
Human Neutrophil, Activated; Monocyte activated; Human Uterus, normal; SKIN;
Brain-medulloblastoma; Human Fetal Spleen; Fetal Heart, re-excision; Human fetal heart, Lambda ZAP Express; Stomach cancer (human),re-excision; Human Frontal Cortex, Schizophrenia; NCI CGAP_Prl; NCI CGAP_GCB1; NCI CGAP_Pr4.l;
25 Monocyte activated, re-excision; Stromal cell TF274; Soares fetal heart NbHHI9W;
Soares fetal heart_NbHHI9W; Soares_pregnant_uterus NbHPU;
Soares total fetus Nb2HF8 9w; normalized infant brain cDNA; NCI CGAP_Ov2;

NC1 CGAP_Kid3; Neutrophils IL-1 and LPS induced; Stratagene fetal retina 937202; Stratagene lung carcinoma 937218; Brain frontal cortex; HMl;
Soares fetal lung NbHLI9W; Anergic T-cell; Spleen, Chronic lymphocytic leukemia; Nine Week Old Early Stage Human; NCI CLAP Kid3;
NCI CGAP_Ov32; T cell helper II; Bone Cancer, re-excision; Liver, normal;
Whole brain; Soares ovary tumor NbHOT; H. Male bladder, adult; human pleural cancer;
Normal Ovary, Premenopausal; Human Fibrosarcoma; Human Fetal Brain, random primed; prostate-edited; stomach cancer (human); Adipocytes,re-excision; Human Placenta; Human Liver; Clontech human aorta polyA+ mRNA (#6572);
NCI CGAP_Pr22; Soares retina N2b4HR; Soares fetal heart_NbHHI9W;
Stratagene colon (#937204); Stratagene pancreas (#937208); Human Normal Breast;
Human Tonsils, Lib 2; Healing groin wound - zero hr post-incision (control);
Human Synovium; Stratagene placenta (#937225); normalized infant brain cDNA; Human Stomach,re-excision; Human Adipose Tissue, re-excision; Human Osteosarcoma;
Pancreas normal PCA4 No; Prostate BPH; TF-1 Cell Line GM-CSF Treated; KMH2;
NCI CGAP_Br2; NCI CGAP_Co3; NCI CGAP_PrB; NCI CGAP_Col l;
NCI CGAP_Brl.l; Human Fetal Dura Mater; Human Activated T-Cells; Human Pancreas Tumor; Human Hippocampus; Human Chondrosarcoma; PERM TF274;
Soares_parathyroid tumor NbHPA; Human Testes Tumor, re-excision; Atrium cDNA library Human heart; Infant brain, Bento Soares; Soares testis NHT;
Stratagene lung (#937210); Stratagene lung carcinoma 937218; Stratagene liver (#937224); Human Gall Bladder; NCI CGAP_AA1; NCI CGAP_HN3;
NCI CGAP_LuS; NCI CGAP_Lu6; NCI CGAP_Pr3; NCI CGAP_Kids;
NCI CLAP Kid6; NCI CGAP_Ov26; Human Ovarian Cancer Reexcision; Human T-Cell Lymphoma; Stratagene endothelial cell 937223; Stratagene neuroepithelium NT2RAMI 937234; Colon Carcinoma; Human fetal heart, Lambda ZAP Express;

Pancreatic Islet; Soares senescent fibroblasts_NbHSF;
Soares_placenta 8to9weeks 2NbHP8to9W; Human Fetal Heart; Human Microvascular Endothelial Cells, fract. A; T Cell helper I; H. Frontal cortex,epileptic,re-excision; Activated T-cell(12h)/Thiouridine-re-excision;
NCI CGAP_AA1; NCI CGAP_HN4; NCI CGAP_LuS; NCI CGAP_Ut3;
NCI CGAP_Brl6; NCI CGAP_Eso2; NCI CGAP_HSC2; NCI CGAP_Ov3l;
NCI CGAP_Ov34; Soares infant brain 1NIB and Soares_fetal liver spleen_1NFLS S1.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:27 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1008 of SEQ ID
N0:27, b is an integer of 15 to 1022, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:27, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 18 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.

S
gi1204412 (all information available through the recited accession number is incorporated herein by reference) which is described therein as "glutaminase [Rattus norvegicus]". A partial alignment demonstrating the observed homology is shown immediately below.
>gi~204412 glutaminase [Rattus norvegicus] >sp~P13264~GLSK RAT
GLUTAMINASE, [ swine, KIDNEY ISOFORM PRECURSOR (EC 3.5.1.2) (GLS) (L-GLUTAMINE
AMIDOHYDROLASE). >bbs~174849 glutaminase, GA {C-terminal}
LLC-PK1-F+ cells, Peptide Mitochondrial Partial, 175 aa] [Sus scrofa] {SUB 500-674}
Length = 674 1S Plus Strand HSPS:
Score = 2299 (809.3 bits), Expect = 8.9e-238, P = 8.9e-238 Identities = 433/438 (98~), Positives = 437/438 (99~), Frame = +1 2O Q: 4 DAFGNSEGKELVASGENKIKQGLLPSLEDLLFYTIAEGQEKIPVHKFITALKSTGLRTSD 183 DAFGNSEGKE+VA+G+NK+KQGLLPSLEDLLFYTIAEGQEKIPVHKFITALKSTGLRTSD
S: 118 DAFGNSEGKEMVAAGDNKVKQGLLPSLEDLLFYTIAEGQEKIPVHKFITALKSTGLRTSD 177 Q: 184 PRLKECMDMLRLTLQTTSDGVMLDKDLFKKCVQSNIVLLTQAFRRKFVIPDFMSFTSHID 363 S: 178 PRLKECMDMLRLTLQTTSDGVMLDKDLFKKCVQSNIVLLTQAFRRKFVIPDFMSFTSHID 237 Q: 364 ELYESAKKQSGGKVADYIPQLAKFSPDLWGVSVCTVDGQRHSTGDTKVPFCLQSCVKPLK 543 ELYESAKKQSGGKVADYIPQLAKFSPDLWGVSVCTVDGQRHS GDTKVPFCLQSCVKPLK
3O S: 238 ELYESAKKQSGGKVADYIPQLAKFSPDLWGVSVCTVDGQRHSIGDTKVPFCLQSCVKPLK 297 Q: 544 YAIAVNDLGTEYVHRYVGKEPSGLRFNKLFLNEDDKPHNPMVNAGAIWTSLIKQGVNNA 723 YAIAVNDLGTEYVHRYVGKEPSGLRFNKLFLNEDDKPHNPMVNAGAIWTSLIKQGVNNA
S: 298 YAIAVNDLGTEYVHRYVGKEPSGLRFNKLFLNEDDKPHNPMVNAGAIWTSLIKQGVNNA 357 Q: 724 EKFDYVMQFLNKMAGNEYVGFSNATFQSERESGDRNFAIGYYLKEKKCFPEGTDMVGILD 903 EKFDYVMQFLNKMAGNEYVGFSNATFQSERESGDRNFAIGYYLKEKKCFPEGTDMVGILD
S: 358 EKFDYVMQFLNKMAGNEYVGFSNATFQSERESGDRNFAIGYYLKEKKCFPEGTDMVGILD 417 4O Q: 904 FYFQLCSIEVTCESASVMAATLANGGFCPITGERVLSPEAVRNTLSLMHSCGMYDFSGQF 1083 FYFQLCSIEVTCESASVMAATLANGGFCPITGERVLSPEAVRNTLSLMHSCGMYDFSGQF
S: 418 FYFQLCSIEVTCESASVMAATLANGGFCPITGERVLSPEAVRNTLSLMHSCGMYDFSGQF 477 Q: 1084 AFHVGLPAKSGVAGGILLWPNVMGMMCWSPPLDKMGNSVKGIHFCHDLVSLCNFHNYDN 1263 S: 478 AFHVGLPAKSGVAGGILLWPNVMGMMCWSPPLDKMGNSVKGIHFCHDLVSLCNFHNYDN 537 Q: 1264 LRHFAKKLDPRREGGDQR 1317 LRHFAKKLDPRREGGDQR
SO S: 538 LRHFAKKLDPRREGGDQR 555 The segment of gi1204412 that is shown as "S" above is set out in the sequence listing as SEQ ID NO. 143 . Based on the structural similarity, these homologous polypeptides are expected to share at least some biological activities. Such activities are known in the art, some of which are described elsewhere herein. Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
Preferred polypeptides of the invention comprise a polypeptide having the amino acid sequence set out in the sequence listing as SEQ ID NO. 144 which corresponds to the "Q" sequence in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed).
It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: NCI CGAP GCB 1 and to a lesser extent in T-Cell PHA 24 hrs; 12 Week Old Early Stage Human; Hodgkin's Lymphoma II; Human 8 Week Whole Embryo; Soares placenta Nb2HP; Primary Dendritic Cells, lib 1; Mo7e Cell Line GM-CSF treated (lng/ml); Human Eosinophils; Colon Carcinoma; 12 Week Early Stage Human II, Reexcision; Human T-cell lymphoma,re-excision;
Stratagene endothelial cell 937223; Stratagene NT2 neuronal precursor 937230; Bone Marrow Stromal Cell, untreated; Stratagene lung (#937210);
Soares_pregnant_uterus NbHPU; Human Endometrial Tumor; Human fetal heart, Lambda ZAP Express; Osteoblasts; Human Cerebellum; C7MCF7 cell line, estrogen treated; Soares_placenta 8to9weeks 2NbHP8to9W; Bone Marrow Stroma, TNF&LPS ind; Larynx Normal; Human Microvascular Endothelial Cells, fract. B;
Activated T-Cells, 8 hrs, subtracted; Thymus; Dermatofibrosarcoma Protuberance;
Human Umbilical Vein Endothelial Cells, fract. A; Human Pancreatic Carcinoma;
Human Thyroid; B Cell lymphoma; Human Synovium; pBMC stimulated w/ poly I/C; Synovial hypoxia-RSF subtracted; Healing groin wound, 7.5 hours post incision;

NCI CGAP_GCBI; Human endometrial stromal cells-treated with progesterone;
Soares_pregnant uterus NbHPU; Human Osteoclastoma, re-excision; Jurkat T-cell G1 phase; Healing groin wound, 6.5 hours post incision; Synovial Fibroblasts (Ill/TNF), subt; Human Chronic Synovitis; Soares fetal heart_NbHHI9W; Human 5 Umbilical Vein, Reexcision; Human Bone Marrow, re-excision; TF-1 Cell Line GM-CSF Treated; KMH2; human ovarian cancer; 12 Week Old Early Stage Human, II;
Human Umbilical Vein Endothelial Cells, uninduced;
Soares_placenta 8to9weeks 2NbHP8to9W; Human umbilical vein endothelial cells, IL-4 induced; Human Activated Monocytes; Human fetal heart, Lambda ZAP
10 Express; Human retina cDNA randomly primed sublibrary; NCI CGAP_GCB1;
Human Testes Tumor, re-excision; Human Adrenal Gland Tumor; Rejected Kidney, lib 4; Ovarian Tumor 10-3-95; Soares fetal liver spleen_1NFLS S1; NTERA2, control; Gessler Wilms tumor; Liver HepG2 cell line.; PC3 Prostate cell line;
Resting T-Cell Library,II; Human T-Cell Lymphoma; NCI CGAP_GCB1; Human Substantia 15 Nigra; Colon Tumor II; Human fetal lung; Human Placenta; Human Fetal Heart;
Human Neutrophil, Activated; Endothelial-induced; Anergic T-cell; HUMAN B
CELL LYMPHOMA; Human Bone Marrow, treated; NCI CGAP_Schl and Nine Week Old Early Stage Human.
Many polynucleotide sequences, such as EST sequences, are publicly 20 available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:28 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention 25 are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 3939 of SEQ ID
N0:28, b is an integer of 15 to 3953, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:28, and where b is greater than or equal to a + 14.
S
FEATURES OF PROTEIN ENCODED BY GENE NO: 19 It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Human fetal brain (TFujiwara) and to a lesser extent in Clontech human aorta polyA+ mRNA (#6572); NCI CGAP_GCB1; Fetal Heart;
NCI CGAP_CoB; PC3 Prostate cell line; Soares melanocyte 2NbHM; Soares placenta Nb2HP; Synovial IL-1/TNF stimulated; Prostate BPH; Human Uterine Cancer; Human Heart; Human Ovary; Liver, Hepatoma;
Soares total fetus Nb2HF8 9w; Soares fetal liver spleen_1NFLS S1;
Soares multiple sclerosis 2NbHMSP; Human Amygdala; H. Frontal cortex,epileptic,re-excision and T cell helper II.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:29 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1801 of SEQ ID
N0:29, b is an integer of 15 to 1815, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:29, and where b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 20 It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Macrophage (GM-CSF treated) and to a lesser extent in H
Macrophage (GM-CSF treated), re-excision; Primary Dendritic Cells, lib 1;
Macrophage-oxLDL, re-excision; Human Osteoclastoma; Monocyte activated;
Human Osteoclastoma, excised; Osteoclastoma-normalized A; CD40 activated monocyte dendridic cells; Human Skin Tumor; Human Osteoclastoma, re-excision and Human Adult Pulmonary,re-excision.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ 1D NO: 80 as residues: Asp-229 to Gln-236, Asn-244 to Phe-251. Polynucleotides encoding said polypeptides are also provided.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:30 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1430 of SEQ ID
N0:30, b is an integer of 15 to 1444, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:30, and where b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 21 It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: NCI CGAP_GCB1; Soares testis NHT and to a lesser extent in Soares fetal liver spleen_1NFLS S l; Soares placenta Nb2HP; Soares fetal liver spleen 1NFLS; Human Adult Pulmonary; NCI CGAP_Alvl; Human Colon, re-excision; Spleen metastic melanoma; Spinal Cord, re-excision; Bone Marrow Stromal Cell, untreated; Human Ovarian Cancer Reexcision; Human Osteoclastoma and Soares_parathyroid tumor NbHPA.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:31 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1855 of SEQ ID
N0:31, b is an integer of 15 to 1869, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:31, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 22 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.

gi1288145 (all information available through the recited accession number is incorporated herein by reference) which is described therein as "Homo sapiens protein". A partial alignment demonstrating the observed homology is shown immediately below.
>gi~288145 put. ORF [Homo sapiens] >pir~I38022~I38022 hypothetical protein human >sp~Q29976~Q29976 MAHLAVU HEPATOCELLULAR CARCINOMA HHC(M) DNA.
Length = 196 Plus Strand HSPs:
Score = 286 (100.7 bits), Expect = 5.4e-24, P = 5.4e-24 Identities = 58/99 (58~), Positives = 66/99 (66~), Frame = +1 Q: 1273 HLRSGVQDQPGQHGKTPSLLKISKLARHGGICLQSQLLGRLRWENRLNSRGGECNELRSH 1452 HLRSGVQD PGQHGK PSLLKI +LA HGG CLQSQLL RLR EN LNS G C+E +SH
S: 3 HLRSGVQDYPGQHGKIPSLLKIQELAGHGGRCLQSQLLRRLRQENHLNSGGRGCSEPKSH 62 Q: 1453 HCTPAWATEQESVSKQTNXXXXXXLEGGXRTQSP**CMV 1569 C PAW TE +SVSKQ L + + C++
S: 63 LCIPAWVTEGDSVSKQNKTKNEQHLRNNTKKSNS--CII 99 The segment of gi1288145 that is shown as "S" above is set out in the sequence listing as SEQ ID NO. 145 . Based on the structural similarity, these homologous polypeptides are expected to share at least some biological activities. Such activities are known in the art, some of which are described elsewhere herein. Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
Preferred polypeptides of the invention comprise a polypeptide having the amino acid sequence set out in the sequence listing as SEQ ID NO. 146 which corresponds to the "Q" sequence in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed).
It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Human Testes and to a lesser extent in Activated T-Cell (l2hs)/Thiouridine labelledEco; Soares placenta Nb2HP; Soares fetal liver spleen 1NFLS; Human Primary Breast Cancer; Human Endometrial Tumor; Activated T-cell(12h)/Thiouridine-re-excision; Smooth muscle,control; Raji Cells, cyclohexamide treated; Synovial hypoxia-RSF subtracted;
5 Soares_placenta 8to9weeks 2NbHP8to9W; HUMAN JURKAT MEMBRANE
BOUND POLYSOMES; Infant brain, LLNL array of Dr. M. Soares 1NIB;
NCI CGAP_Pr3; STRATAGENE Human skeletal muscle cDNA library, cat.
#936215.; Human Activated T-Cells, re-excision; Soares breast 2NbHBst; Fetal Liver, subtraction II; Ovarian Tumor 10-3-95; Smooth muscle, serum treated;
10 NCI CGAP_Ov2; T cell helper II; Soares_pregnant uterus NbHPU; Primary Dendritic Cells, lib 1; Leukocyte and Lung, 4 screens; Cem Cells, cyclohexamide treated, subtra; Soares ovary tumor NbHOT; Larynx carcinoma II; Rectum normal;
Pharynx Carcinoma; Human Fetal Heart, Differential (Fetal-Specific); Human Gastrocnemius; Human Placenta, subtracted; H. hypothalamus, frac A; LNCAP +
15 o.3nM 81881; H. Normalized Fetal Liver, II; Soares fetal lung NbHLI9W;
Soares senescent fibroblasts NbHSF; HL-60, RA 4h, Subtracted; HepG2 Cells, lambda library; Human Fetal Brain, random primed; H. Striatum Depression, subt;
Human Fetal Brain; Human Soleus; Pancreas Tumor PCA4 Tu; Human Colon Cancer,re-excision; STROMAL -OSTEOCLASTOMA; Breast Cancer cell line, 20 MDA 36; Smooth muscle, ILIb induced; Human Osteoclastoma Stromal Cells -unamplified; Stratagene HeLa cell s3 937216; HL-60, PMA 4H, re-excision; Human Colon, re-excision; Jurkat T-cell G1 phase; Jurkat T-Cell, S phase; Human Pituitary, subt IX; Human Neutrophil; Human Bone Marrow, re-excision; Breast Cancer Cell line, angiogenic; Human Brain, Striatum; L428; human ovarian cancer; 12 Week Old 25 Early Stage Human, II; Human Uterine Cancer; Liver, Hepatoma;
NCl CGAP_GCB1; NCI CGAP_Pr22; NCI CGAP_Brl.l; Human umbilical vein endothelial cells, IL-4 induced; Human Activated Monocytes; Human epidermal keratinocyte; Infant brain, Bento Soares; Soares_parathyroid tumor NbHPA;
Normal Human Trabecular Bone Cells; Soares testis NHT; Soares NFL T GBC_S1;
Human Testes Tumor, re-excision; CHME Cell Line,treated 5 hrs; NCl CGAP_GC4;
NCI CGAP_Ov35; Soares multiple sclerosis 2NbHMSP; Macrophage-oxLDL, re-excision; PC3 Prostate cell line; Human T-Cell Lymphoma; Colon Normal II;
Soares breast 3NbHBst; Adipocytes; Dendritic cells, pooled; Soares melanocyte 2NbHM;
Human Synovial Sarcoma; Human Fetal Lung III; Human Testes, Reexcision; Bone marrow; Human Neutrophil, Activated; Human Adult Pulmonary,re-excision;
Endothelial cells-control; Human Microvascular Endothelial Cells, fract. A;
Monocyte activated; CD34 positive cells (Cord Blood); Bone Marrow Cell Line (RS4,11); H. Frontal cortex,epileptic,re-excision; Hodgkin's Lymphoma II;
Stratagene HeLa cell s3 937216; Human retina cDNA Tsp5091-cleaved sublibrary;
NCl CGAP_Lym3; Soares fetal lung NbHLI9W; Osteoblasts; Keratinocyte;
Human Cerebellum; Stratagene endothelial cell 937223 and Stratagene neuroepithelium NT2RAMI 937234.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:32 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1558 of SEQ ID
N0:32, b is an integer of 15 to 1572, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:32, and where b is greater than or equal to a + 14.
S FEATURES OF PROTEIN ENCODED BY GENE NO: 23 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.
gi1163086 (all information available through the recited accession number is incorporated herein by reference) which is described therein as "GTP-binding regulatory protein gamma-6 subunit [Bos taurus]". A partial alignment demonstrating the observed homology is shown immediately below.
1S >gi~163086 GTP-binding regulatory protein gamma-6 subunit [Bos taurus]
>gi~163117 G protein gamma-2 subunit [Bos taurus] >pir~B34228~RGBOG2 GTP-binding regulatory protein gamma-2 chain - bovine >sp~P16874~GBG2 BOVIN GUANINE NUCLEOTIDE-BINDING PROTEIN
G(I)/G(S)/G(O) GAMMA-2 SUBUNIT (G GAMMA-I). >sp~G1037115~G1037115 G
PROTEIN GAMMA 2 SUBUNIT. {SUB 2-68} >gi~1353496 G protein gamma 2 subunit [Mus musculus] {SUB 18-52} >pir~D36204~D36204 GTP-binding regulatory protein gamma-2 chain - mouse (fragment) {SUB 22-54}
>gi~2582398 (AF022087) guanine nucleotide binding protein gamma 2 subunit [Rattus norvegicus] {SUB 27-62} >pir~S27048~S27048 2S GTP-binding regulatory protein gamma chain - bovine (fragment) {SUB
43-68}
Length = 71 Plus Strand HSPS:
Score = 356 (125.3 bits), Expect = 1.2e-30, P = 1.2e-30 Identities = 71/71 (100$), Positives = 71/71 (1000 , Frame = +3 Q: 354 MASNNTASIAQARKLVEQLKMEANIDRIKVSKAAADLMAYCEAHAKEDPLLTPVPASENP 533 S: 1 MASNNTASIAQARKLVEQLKMEANIDRIKVSKAAADLMAYCEAHAKEDPLLTPVPASENP 60 Q: 534 FREKKFFCAIL 566 FREKKFFCAIL
S S: 61 FREKKFFCAIL 71 The segment of gi1163086 that is shown as "S" above is set out in the sequence listing as SEQ ID NO. 147 . Based on the structural similarity, these homologous polypeptides are expected to share at least some biological activities. Such activities are known in the art, some of which are described elsewhere herein. Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
Preferred polypeptides of the invention comprise a polypeptide having the amino acid sequence set out in the sequence listing as SEQ ID NO. 148 which corresponds to the "Q" sequence in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed).
It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Human Osteoclastoma and to a lesser extent in Human 8 Week Whole Embryo; Soares infant brain 1NIB; Human Osteoclastoma, re-excision;
Soares testis NHT; normalized infant brain cDNA; Human Activated T-Cells;
Human Pancreas Tumor, Reexcision; Human Activated T-Cells, re-excision; Human Eosinophils; Soares melanocyte 2NbHM; Human Testes, Reexcision; Human Neutrophil, Activated; Human fetal brain (TFujiwara); Human Bone Marrow, treated;
Spleen, Chronic lymphocytic leukemia; Morton Fetal Cochlea; Human Neutrophil;
Mo7e Cell Line GM-CSF treated (lng/ml); Bone Marrow Stromal Cell, untreated;
Brain frontal cortex; NCI CGAP_GCB1; Nine Week Old Early Stage Human; Soares fetal liver spleen 1NFLS; HUman Fetal Brain, normalized 100024F; Brain, normal;
Soares fetal lung NbHLI9W; Human Adult Spleen; Human Neutrophils, Activated, re-excision; Activated T-cells; Human T-cell lymphoma,re-excision; pBMC
stimulated w/ poly I/C; Stratagene hNT neuron (#937233); Spinal Cord, re-excision;
T-Cell PHA 16 hrs; Gessler Wilms tumor; Soares NbHFB;
Soares fetal heart NbHHI9W; Soares total fetus Nb2HF8 9w; Stratagene schizo brain S11; L428; Human Placenta (re-excision); Spinal cord; Human Chondrosarcoma; Clontech human aorta polyA+ mRNA (#6572); Human adult (K.Okubo); Human Testes Tumor, re-excision; Human T-Cell Lymphoma;
Neutrophils 1L-1 and LPS induced; Human Substantia Nigra; Soares breast 3NbHBst;
Human Testes Tumor; Colon Tumor II; Soares total fetus Nb2HF8 9w; Dendritic cells, pooled; NCI CGAP_GC1; NCI CGAP_GC3; NCI CGAP_LuS;
NCl CGAP_Kid6; NCI CGAP_Brn23; Soares fetal lung NbHLI9W;
NCI CLAP GCB1; H. Frontal cortex,epileptic,re-excision; Hodgkin's Lymphoma II
and Primary Dendritic Cells, lib 1.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 83 as residues: Asp-17 to Lys-26. Polynucleotides encoding said polypeptides are also provided.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:33 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 3693 of SEQ ID
N0:33, b is an integer of 15 to 3707, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID I~10:33, and where b is greater than or equal to a + 14.
S FEATURES OF PROTEIN ENCODED BY GENE NO: 24 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.
10 gi11872200 (all information available through the recited accession number is incorporated herein by reference) which is described therein as "alternatively spliced product using exon 13A [Homo sapiens]". A partial alignment demonstrating the observed homology is shown immediately below.
1S >gi~1872200 alternatively spliced product using exon 13A [Homo Sapiens]
>sp~P78525~P78525 MYB PROTO-ONCOGENE PROTEIN (C-MYB).
Length = 666 Minus Strand HSPs:
Score = 191 (67.2 bits), Expect = 7.1e-16, Sum P(2) = 7.1e-16 Identities = 38/67 (56$), Positives = 42/67 (62~), Frame = -3 Q: 831 FXEXXSHSVTQAAMPWRDLGSLQAPPPGFMPFSCLSLPGSWDYRCPPPPPANFFVFLVET 652 2S F + + + W D GSLQ PPGF FSCLSLP SWDYR PPP PANF FLVET
S: 556 FTQTSPVADAPTGVQWHDFGSLQPLPPGFKRFSCLSLPRSWDYRHPPPRPANF-EFLVET 614 Q: 651 GFHCISQ 631 GF + Q
S: 615 GFLHVGQ 621 The segment of gi11872200 that is shown as "S" above is set out in the sequence listing as SEQ ID NO. 149 . Based on the structural similarity, these homologous polypeptides are expected to share at least some biological activities.
3S Such activities are known in the art, some of which are described elsewhere herein.

Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
Preferred polypeptides of the invention comprise a polypeptide having the amino acid sequence set out in the sequence listing as SEQ ID NO. 150 which corresponds to the "Q" sequence in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed).
It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: PERM TF274 and to a lesser extent in Human Umbilical Vein Endothelial Cells, uninduced.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:34 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1143 of SEQ ID
N0:34, b is an integer of 15 to 1157, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:34, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 25 It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Soares retina N2b4HR and to a lesser extent in Activated T-cells, 24 hrs,re-excision; Keratinocyte; Activated T-Cells,l2 hrs,re-excision;
Human Activated T-Cells; Activated T-cell(12h)/Thiouridine-re-excision; Human Neutrophil, Activated; Activated T-Cell (l2hs)/Thiouridine IabelledEco; Epithelial-TNFa and INF induced; Soares retina N2b5HR; Human Neutrophils, Activated, re-excision;
HUMAN JURKAT MEMBRANE BOUND POLYSOMES; Human Pancreas Tumor;
Human Cerebellum; Human Pancreas Tumor, Reexcision; Human Adult Pulmonary,re-excision; Activated T-Cells, 12 hrs, subtracted;
Soares_pregnant_uterus NbHPU; Rejected Kidney, lib 4; Osteoblasts; Human osteoarthritic,fraction II; Human Neutrophil; Bone Marrow Stromal Cell, untreated;
Ovarian Tumor 10-3-95; Human Bone Marrow, treated; Stratagene colon (#937204);
Soares infant brain 1NIB; Activated T-Cells, 24 hrs.; Human osteoarthritis,fraction I;
Brain Frontal Cortex, re-excision; NCI CGAP_GCB1; Human Thymus Stromal Cells; NCI CGAP_Ut3; Soares NhHMPu_S1; Adipocytes; Endothelial-induced;
Human Microvascular Endothelial Cells, fract. A; Smooth muscle,control;
Soares NhHMPu_Sl; NCI CGAP_Kid3; T cell helper II; Activated T-Cells, l2hrs, differentially expressed; Soares testis NHT; Soares ovary tumor NbHOT;
Activated T-Cells, 8 hrs, subtracted; Activated T-Cells, 12 hrs.; NCl CGAP_Utl;
NCI CGAP_Panl; H. Epididiymus, cauda; HEL cell line; HL-60, PMA 4H, re-excision; H. Meningima, M1; Human Infant Brain; T-Cell PHA 16 hrs; Human Umbilical Vein, Reexcision; TF-1 Cell Line GM-CSF Treated; NCI CGAP_ColO;
NCI CLAP Pr25; Human Heart; Soares NhHMPu_Sl; Soares NFL T GBC_S1;
Stratagene lung carcinoma 937218; normalized infant brain cDNA; Olfactory epithelium,nasalcavity; Human Adipose; Human Activated T-Cells, re-excision;
Human Testes Tumor, re-excision; Soares NhHMPu_S1; Stratagene NT2 neuronal precursor 937230; CHME Cell Line,treated 5 hrs; Smooth muscle, serum induced,re-exc; Pancreas Islet Cell Tumor; Colon Tumor; Colon Tumor Il; Endothelial cells-control; Monocyte activated; Spleen, Chronic lymphocytic leukemia; T Cell helper I;

Bone Marrow Cell Line (RS4,11); neutrophils control; HeLa cell line; Human Osteoarthritic Cartilage Fraction IV; Human Normal Cartilage Fraction III;
Larynx normal #10 261-273; human caudate nucleus; Larynx carcinoma II; CD34+ cell, I;
Tongue carcinoma; Human Normal Cartilage Fraction IV; Human Normal Cartilage,Fraction I; Human Normal Cartilage Fraction II; Human B Cell 8866;
Activated T-Cells, 8 hrs., ligation 2; NCI CGAP_Panl; Poorly differentiated adenocarcinoma, Ovary & Fallopian tube - 9809C332; Ku 812F Basophils Line;
Human Hippocampus, subtracted; Soares NhHMPu_S1; B-cells (stimulated); K562 +
PMA (36 hrs),re-excision; Saos2, Dexamethosome Treated; NCI CGAP_Panl;
Normal Ovary - 9805C040R; Human Gall Bladder, fraction II; Human OB HOS
control fraction I; NCI CGAP_Ut3; NCI CGAP_Col4; NCI CGAP_Ov23;
NCI CGAP_Brn23; NCI CGAP_Brn25;
Soares_placenta 8to9weeks_2NbHP8to9W; metastatic squamous cell lung carcinoma, poorly differentiated; Human OB MG63 treated (10 nM E2) fraction I;
Human (HCC) cell line liver (mouse) metastasis, remake; Human White Adipose;
Human Cardiomyopathy, subtracted; Human Pancreatic Carcinoma; Hep G2 Cells, PCR library; Human Pituitary, subtracted; Fetal Heart, re-excision; Smooth muscle, control, re-excision; Smooth muscle-ILb induced; Invasive poorly differentiated lung adenocarcinoma, metastatic; H. cerebellum, Enzyme subtracted; Human Lung;
Human Quadriceps; HTCDL1; NCl CGAP_Pr25; Raji Cells, cyclohexamide treated;
Healing groin wound - zero hr post-incision (control); Pancreas Tumor PCA4 Tu;
pBMC stimulated w/ poly I/C; Smooth muscle, ILlb induced; NTERA2 + retinoic acid, 14 days; Synovial hypoxia-RSF subtracted; Human Adipose Tissue, re-excision;
Jurkat T-cell G1 phase; Myoloid Progenitor Cell Line; Prostate BPH; Human Adult Small Intestine; NCI CGAP_Co3; Monocyte activated, re-excision; L428;
NCI CGAP_AA1; NCI CGAP_Co9; NCI CGAP_GC2; NCI CGAP_GC4;

NCI CGAP_Lul; NCI CGAP_Pr22; NCI CGAP_Pr24; Human Umbilical Vein Endothelial Cells, uninduced; Human Uterine Cancer; Human Hypothalmus,Schizophrenia; HTCDL1; Human pancreatic islet;
Soares total fetus Nb2HF8 9w; Soares_parathyroid tumor NbHPA; Human Hippocampus; Human Activated Monocytes; Hemangiopericytoma;
NCI CGAP_GC4; NCI CGAP_LuS; NCI CGAP_Utl; NCI CGAP_Gas4;
NC1 CGAP_Kids; NCI CGAP_KidB; NCI CGAP_Brn25; Human Gall Bladder;
CHME Cell Line,untreated; Soares NhHMPu_S1; Resting T-Cell Library,II; Colon Carcinoma; Smooth muscle, serum treated; Human Placenta; Human Testes Tumor;
Soares melanocyte 2NbHM; Human Fetal Lung III; Neutrophils control, re-excision;
Human Fetal Heart; Stratagene HeLa cell s3 937216; Human Primary Breast Cancer Reexcision; CD34 depleted Buffy Coat (Cord Blood), re-excision; Neutrophils IL-and LPS induced; Hodgkin's Lymphoma II; Human retina cDNA randomly primed sublibrary; NCl CGAP_GC4; NCI CGAP_Kid3; NCI CGAP_Kid6;
NCI CGAP Brn23 and NCI CGAP Brn25.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 85 as residues: Arg-7 to Ser-32, Ala-37 to Glu-50, Ser-52 to Phe-64, Leu-109 to Ala-115. Polynucleotides encoding said polypeptides are also provided.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ 1D N0:35 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1767 of SEQ ID
N0:35, b is an integer of 15 to 1781, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:35, and where b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 26 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting 10 example, the sequence accessible through the following database accession no.
gi14103490 (all information available through the recited accession number is incorporated herein by reference) which is described therein as "glucocorticoid-induced leucine zipper GILZ protein [Mus musculus]." This protein is thought to protect T lymphocytes from TCR/CD3 activated cell death. A partial alignment 15 demonstrating the observed homology is shown immediately below.
>gi~4103490 (AF024519) glucocorticoid-induced leucine zipper GILZ protein [Mus musculus] >sp~G4103490~G4103490 GLUCOCORTICOID-INDUCED LEUCINE
ZIPPER GILZ PROTEIN.
20 Length = 137 Plus Strand HSPs:
Score = 584 (205.6 bits), Expect = 4.6e-56, P = 4.6e-56 25 Identities = 119/137 (86~), Positives = 124/137 (90~), Frame = +1 Q: 271 MNTEMYQTPMEVAVYQLHNXXXXXXXXLLGGDWSVKLDNSASGASVVAIDNKIEQAMDL 450 MNTEMYQTPMEVAVYQLHN LLGGDWSVKLDNSASGASVVA+DNKIEQAMDL
S: 1 MNTEMYQTPMEVAVYQLHNFSTSFFSSLLGGDWSVKLDNSASGASVVALDNKIEQAMDL 60 Q: 451 VKNHLMYAVREEVEILKEQIRELVEKNSQLERENTLLKTLASPEQLEKFQSCLSPEEPAP 630 VKNHLMYAVREEVE+LKEQIREL+EKNSQLERENTLLKTLASPEQLEKFQS LSPEEPAP
S: 61 VKNHLMYAVREEVEVLKEQIRELLEKNSQLERENTLLKTLASPEQLEKFQSRLSPEEPAP 120 Q: 631 ESPQVPE---APGGSAV 672 E+P+ PE APGGSAV
S: 121 EAPETPETPEAPGGSAV 137 The segment of gi14103490 that is shown as "S" above is set out in the sequence listing as SEQ ID NO. 151 . Based on the structural similarity, these homologous polypeptides are expected to share at least some biological activities.
Such activities are known in the art, some of which are described elsewhere herein.
Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
Preferred polypeptides of the invention comprise a polypeptide having the amino acid sequence set out in the sequence listing as SEQ ID NO. 152 which corresponds to the "Q" sequence in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed).
When tested against sensory neuron cell lines, supernatants removed from cells containing this gene activated the EGR1 assay. Thus, it is likely that this gene activates sensory neuron cells through a signal transduction pathway. Early growth response 1 (EGR1) is a promoter associated with certain genes that induces various tissues and cell types upon activation, leading the cells to undergo differentiation and proliferation.
It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Soares ovary tumor NbHOT; Soares fetal heart NbHHI9W
and to a lesser extent in Human Neutrophil, Activated; Human Neutrophil; Human Thymus; Stratagene lung (#937210); Human Bone Marrow, treated;
Soares multiple sclerosis 2NbHMSP; Human adult small intestine,re-excision;
Human Adult Small Intestine; Rejected Kidney, lib 4; Resting T-Cell Library,II;
Colon Normal II; Neutrophils control, re-excision; Human Cerebellum; Soares infant brain 1NIB; Human osteoarthritic,fraction II; Human osteoarthritis,fraction I;
Soares retina N2b4HR; Human Chronic Synovitis; Human Adrenal Gland Tumor;
normalized infant brain cDNA; Human T-Cell Lymphoma; Human Adult Spleen;

Soares senescent fibroblasts_NbHSF; H. Meningima, M1; Human Uterine Cancer;
NCI CGAP_CLL1; Soares testis NHT; Fetal Heart; NCI CGAP_LuS;
NCI CGAP_GCB1; Soares breast 3NbHBst; NCI CGAP_Co3; Normal colon;
Human Synovial Sarcoma; Human Adult Pulmonary,re-excision; Keratinocyte; T
cell helper II; Human Osteoarthritic Cartilage Fraction IV;
Soares_total fetus Nb2HF8 9w; Human Prostate BPH, re-excision; Human White Fat; Dermatofibrosarcoma Protuberance.; LNCAP untreated; Human Adult Pulmonary; H. Atrophic Endometrium; Human Quadriceps; Human T-cell lymphoma,re-excision; Human Tonsils, Lib 2; Alzheimers, spongy change; Human Adipose Tissue, re-excision; Prostate BPH; Brain Frontal Cortex, re-excision;
Human Infant Brain; Human Bone Marrow, re-excision; Human Hypothalmus,Schizophrenia;
Human Pancreas Tumor, Reexcision; Olfactory epithelium,nasalcavity;
Soares_pregnant uterus NbHPU; Ulcerative Colitis; Fetal Liver, subtraction II;
Soares NFL T GBC_S1; Human Gall Bladder; Colon Tumor;
Soares_pregnant uterus NbHPU; Stratagene colon (#937204);
Soares fetal heart NbHHI9W; Smooth muscle, serum treated; Dendritic cells, pooled; NCI CGAP_Prl; NCI CGAP_GCB1; Human Fetal Kidney, Reexcision;
Human Placenta; human tonsils; CD34 depleted Buffy Coat (Cord Blood), re-excision; Smooth muscle,control; NCI CGAP_CLL1; Spleen, Chronic lymphocytic leukemia; Bone Marrow Cell Line (RS4,11); Activated T-cell(12h)/Thiouridine-re-excision; Soares placenta Nb2HP; Soares fetal liver spleen LNFLS; H.
Leukocytes, normalized cot > SOOA; Human Fetal Kidney; Human Normal Cartilage Fraction III;
Human Lung Cancer, subtracted; Human Osteoarthritic Cartilage Fraction III;
Human Gastrocnemius; Human Placenta, subtracted; Bone marrow stroma,treated; Human Normal Cartilage Fraction II; Human Leukocytes; H. Adipose Tissue; Human White Adipose; Human Pituitary, subtracted; Human Neutrophils, Activated, re-excision;

Smooth Muscle Serum Treated, Norm; Supt Cells, cyclohexamide treated; Smooth muscle, control, re-excision; Smooth muscle-ILb induced; Invasive poorly differentiated lung adenocarcinoma, metastatic; Human Thyroid; Early Stage Human Lung, subtracted; Soares fetal heart_NbHHI9W; Soares_pregnant uterus NbHPU;
Raji Cells, cyclohexamide treated; Human Normal Breast;
Soares multiple sclerosis 2NbHMSP; Human Lung Cancer,re-excision; B Cell lymphoma; Human Epididymus; Human Hypothalamus,schizophrenia, re-excision;
Human Synovium; Human Prostate Cancer, Stage C fraction; pBMC stimulated w/
poly I/C; Smooth muscle, ILIb induced; Human endometrial stromal cells-treated with progesterone; LNCAP prostate cell line; Human Amygdala,re-excision; Human Osteosarcoma; Human Colon, re-excision; Soares_parathyroid tumor NbHPA;
Stratagene HeLa cell s3 937216; Apoptotic T-cell; Human Activated T-Cells;
Human Pancreas Tumor; Human Heart; NCI CGAP_Kid3; Soares_pregnant uterus NbHPU;
Liver, Hepatoma; Human Adipose; NCI CGAP_Kid6; Human Testes Tumor, re-excision; Hemangiopericytoma; Bone Marrow Stromal Cell, untreated; Soares breast 2NbHBst; Barstead spleen HPLRB2; Jia bone marrow stroma;
Soares fetal heart NbHHI9W; Soares fetal liver spleen_1NFLS S1; Stratagene hNT neuron (#937233); Smooth muscle, serum induced,re-exc; Pancreas Islet Cell Tumor; Human adult lung 3' directed MboI cDNA; NCI CGAP_Pr2;
NCI CGAP_Pr22; Soares_pregnant uterus NbHPU;
Soares total fetus Nb2HF8 9w; Soares senescent fibroblasts NbHSF; b4HB3MA;
Stratagene endothelial cell 937223; 12 Week Old Early Stage Human; Infant brain, LLNL array of Dr. M. Soares 1NIB; Neutrophils IL-1 and LPS induced;
NCI CGAP_Kids; Human Eosinophils; breast lymph node CDNA library; Human Testes Tumor; Stratagene endothelial cell 937223; Colon Tumor II; Human adult (K.Okubo); NCI CGAP_Br3; NCI CGAP_Lul; NCI CGAP_Pr2; NCI CGAP_Pr6;

NCI CGAP_Pr9; NCI CGAP_Pr22; NCI CGAP_Pr23; Colon Normal III; Human Amygdala; Human Microvascular Endothelial Cells, fract. A; HUMAN B CELL
LYMPHOMA; Human aorta polyA+ (TFujiwara); Human fetal heart, Lambda ZAP
Express; NCI CGAP_Brn23; Hodgkin's Lymphoma II; Nine Week Old Early Stage Human and Primary Dendritic Cells, lib 1.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 86 as residues: Val-80 to Leu-92, Ser-98 to Lys-104, Pro-111 to Pro-122. Polynucleotides encoding said polypeptides are also provided.
The homology of the protein product of this clone to a leucine-zipper protein thought to protect T-lymphocytes from activated cell death suggests that the translation product of this gene is useful for the diagnosis and treatment of a variety of immune system disorders. This gene product may be involved in the regulation of cytokine production, antigen presentation, or other processes that may also suggest a usefulness in the treatment of cancer (e.g. by boosting immune responses).
Since the gene is expressed in cells of lymphoid origin, the gene or protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Therefore it may be also used as an agent for immunological disorders including arthritis, asthma, immune deficiency diseases such as AIDS, leukemia, rheumatoid arthritis, inflammatory bowel disease, sepsis, acne, and psoriasis. In addition, this gene product may have commercial utility in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types.
Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:36 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention 5 are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1994 of SEQ ID
N0:36, b is an integer of 15 to 2008, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:36, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 27 It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: HEL cell line; Smooth muscle, serum induced,re-exc.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:37 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 946 of SEQ ID
N0:37, b is an integer of 15 to 960, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:37, and where b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 28 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.
gi14097507 (all information available through the recited accession number is incorporated herein by reference) which is described therein as "Tic [Homo Sapiens]".
A partial alignment demonstrating the observed homology is shown immediately below.
>gi~4097507 Tic [Homo Sapiens] >sp~G4097507~G4097507 TIC.
Length = 1056 Plus Strand HSPS:
Score = 725 (255.2 bits), Expect = 3.9e-104, Sum P(2) = 3.9e-104 Identities = 147/202 (72~), Positives = 149/202 (73$), Frame = +2 Q: 185 QEAHVFQLRTADWRLYLFQAPTAKEMSSWIARINLAAATHSAPPFPAAVGSQRRFVRPIL 364 ++ HVFQLRTADWRLYLFQAPTAKEMSSWIARINLAAATHSAPPFPAAVGSQRRFVRPIL
2O S: 855 KKPHVFQLRTADWRLYLFQAPTAKEMSSWIARINLAAATHSAPPFPAAVGSQRRFVRPIL 914 Q: 365 PVGPAQSSLEEQHRSHENCXXXXXXXXXXXQXXXXXXXXXXXXXXXXXXXXXXXXXXKTR 544 PVGPAQSSLEEQHRSHENC Q KTR
S: 915 PVGPAQSSLEEQHRSHENCLDAAADDLLDLQRNLPERRGRGRELEEHRLRKEYLEYEKTR 974 Q: 545 YETYVQLLVARLHCPSDALDLWEEQLGREAGGTREXXXXXXXXXXXXXXXQDEAPTTAKV 724 YETYVQLLVARLHCPSDALDLWEEQLGREAGGTRE QDEAPTTAKV
S: 975 YETYVQLLVARLHCPSDALDLWEEQLGREAGGTREPKLSLKKSHSSPSLHQDEAPTTAKV 1034 3O Q: 725 KRNISERRTYRKIIPKRNRNQL 790 KRNISERRTYRKIIPKRNRNQL
S: 1035 KRNISERRTYRKIIPKRNRNQL 1056 The segment of gi14097507 that is shown as "S" above is set out in the sequence listing as SEQ ID NO. 153 . Based on the structural similarity, these homologous polypeptides are expected to share at least some biological activities.
Such activities are known in the art, some of which are described elsewhere herein.
Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.

Preferred polypeptides of the invention comprise a polypeptide having the amino acid sequence set out in the sequence listing as SEQ ID NO. 154 which corresponds to the "Q" sequence in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed).
It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Soares fetal heart NbHHI9W and to a lesser extent in Activated T-Cells, 12 hrs, subtracted; Human Primary Breast Cancer Reexcision;
Soares fetal liver spleen 1NFLS; Soares fetal liver spleen_1NFLS S1; Colon Carcinoma; human tonsils; Human Colon, differential expression;
Soares_parathyroid tumor NbHPA; Human Fetal Dura Mater; Soares breast 2NbHBst; Human Eosinophils; breast lymph node CDNA library; Colon Normal II;
Anergic T-cell; Activated T-cell(12h)/Thiouridine-re-excision; Primary Dendritic Cells, lib 1; Human Colon, subtraction; NCI CGAP_CoB; NCI CGAP_LuS;
NCI CGAP_Col6; NCI CGAP_Kids; NCI CGAP_Lyml2; Fetal Heart, re-excision;
Dendritic Cells From CD34 Cells; Human Osteosarcoma; Jurkat T-cell G1 phase;
Soares NFL T GBC_S1; Soares NSF F8 9W_OT PA P Sl;
Soares_pregnant uterus NbHPU; Monocyte activated, re-excision; Ulcerative Colitis; Human Thymus; Human Thymus Stromal Cells; Stratagene liver (#937224);
Soares breast 3NbHBst; Dendritic cells, pooled; Human Testes, Reexcision;
Human Fetal Heart; NCI CGAP_Prl2; Human Bone Marrow, treated; Neutrophils 1L-1 and LPS induced; Bone Marrow Cell Line (RS4,11); NCI CGAP_Panl; H. Frontal cortex,epileptic,re-excision; Human Endometrial Tumor; Soares NhHMPu_S1;
Hodgkin's Lymphoma II; Keratinocyte; T cell helper II; NCI CGAP_GCB1 and NCI CGAP Kid3.

Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 88 as residues: Gln-21 to Trp-30. Polynucleotides encoding said polypeptides are also provided.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:38 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 2317 of SEQ ID
N0:38, b is an integer of 15 to 2331, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:38, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 29 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.
gnlIPIDId1014243 (all information available through the recited accession number is incorporated herein by reference) which is described therein as "cytochrome b561 [Sus scrofa]". A partial alignment demonstrating the observed homology is shown immediately below.
>gnl~PID~d1014243 cytochrome b561 [Sus scrofa] >sp~Q95245~C561 PIG
CYTOCHROME
B561 (CYTOCHROME B-561).
Length = 252 Plus Strand HSPS:
S
Score = 293 (103.1 bits), Expect = 8.0e-36, Sum P(2) = 8.0e-36 Identities = 59/124 (47~), Positives = 77/124 (62$), Frame = +3 Q: 186 WMQYWRGGFAWNGSIYMFNWHPVLMVAGMWFYGGASLVYRLPQSWVGPKLPWKLLHAAL 365 W+ +RGG AW ++ FN HP+ M+ G+V G A LVYR+ ++ K K+LH L
S: 35 WLGAYRGGIAWESAL-QFNVHPLCMIIGLVFLQGDALLVYRVFRNEA--KRTTKILHGLL 91 1O Q: 366 HLMAFVLTWGLVAVFTFHNHGRTANLYSLHSWLGITTVFLFACQWFLGFAVFLLPWASM 545 H++AFV+ +VGLVAVF +H A+LYSLHSW GI LF QW +G FL P AS
S: 92 HVLAFVIALVGLVAVFDYHRKKGIADLYSLHSWCGILVFVLFLAQWLVGLGFFLFPGASF 151 Q: 546 WLRS 557 IS LRS
S: 152 SLRS 155 The segment of gnIIPIDId1014243 that is shown as "S" above is set out in the sequence listing as SEQ ID NO. 1SS . Based on the structural similarity, these 20 homologous polypeptides are expected to share at least some biological activities.
Such activities are known in the art, some of which are described elsewhere herein.
Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
Preferred polypeptides of the invention comprise a polypeptide having the 2S amino acid sequence set out in the sequence listing as SEQ ID NO. 1S6 which corresponds to the "Q" sequence in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed).
It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Soares melanocyte 2NbHM and to a lesser extent in 30 NCI CGAP_GCB1; Primary Dendritic Cells, lib l; Soares ovary tumor NbHOT;
Human Rhabdomyosarcoma; human tonsils; Human Cerebellum; Soares infant brain 1NIB; Human endometrial stromal cells-treated with progesterone; Healing groin wound, 6.S hours post incision; Brain Frontal Cortex, re-excision; Macrophage-oxLDL; NCI CGAP_GC6; Soares fetal heart_NbHHI9W; Human Synovial Sarcoma; Soares_pregnant uterus NbHPU; Soares placenta Nb2HP; Soares fetal liver spleen 1NFLS; human adult liver cDNA library; Human Infant Adrenal Gland, subtracted; Soares total fetus Nb2HF8 9w; Soares fetal liver spleen_1NFLS S1;
Soares total fetus Nb2HF8 9w; Palate normal; Normal Prostate; HL-60, RA 4h, 5 Subtracted; Human OB MG63 control fraction I; Smooth muscle-ILb induced;
Activated T-cells; Human Normal Breast; B Cell lymphoma; Human endometrial stromal cells-treated with estradiol; Stratagene endothelial cell 937223;
NCI CGAP_Br2; NCI CGAP_OvB; NCI CGAP_Pr2; NCI CLAP GCBO;
NCI CGAP_Kid6; NCI CGAP_Pr25; Monocyte activated, re-excision; Human 10 Osteoblasts II; Human Uterine Cancer; Human Activated T-Cells; Human retina cell line ARPE-19; Normal Human Trabecular Bone Cells; Soares testis NHT;
Soares_pregnant uterus NbHPU; Soares fetal liver spleen_1NFLS Sl;
Soares senescent fibroblasts_NbHSF; normalized infant brain cDNA; Human Activated T-Cells, re-excision; Human Thymus Stromal Cells; Human Adrenal Gland 15 Tumor; Macrophage (GM-CSF treated); Fetal Liver, subtraction II; NCI
CGAP_LuS;
NCI CGAP_CLL1; NCI CGAP_Brn25; NCI CGAP_Kidll;
Soares fetal lung NbHLI9W; Soares NSF F8 9W_OT PA P S1; Ovarian Tumor 10-3-95; Pancreas Islet Cell Tumor; Human T-Cell Lymphoma; Colon Carcinoma;
breast lymph node CDNA library; H Macrophage (GM-CSF treated), re-excision;
20 Human Fetal Lung III; Human Fetal Heart; Activated T-Cell (l2hs)/Thiouridine IabelledEco; Endothelial cells-control; Smooth muscle,control; Spleen, Chronic lymphocytic leukemia; T Cell helper I; Bone Marrow Cell Line (RS4,11);
Keratinocyte and Stratagene HeLa cell s3 937216.
Preferred polypeptides of the present invention comprise immunogenic 25 epitopes shown in SEQ ID NO: 89 as residues: Gln-79 to Cys-84, Lys-157 to Tyr-163, Ser-195 to Pro-201. Polynucleotides encoding said polypeptides are also provided.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:39 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 2444 of SEQ ID
N0:39, b is an integer of 15 to 2458, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:39, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 30 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.
gnllPIDle236741 (all information available through the recited accession number is incorporated herein by reference) which is described therein as "CMP-sialic acid transporter [Mus musculus]." This murine protein is thought to be a CMP-sialic acid transporter protein, and thus would be involved in the process of transporting nucleotide sugars across the membrane of the Golgi apparatus in order to enable the synthesis of complex carbohydrate structures. A partial alignment demonstrating the observed homology is shown immediately below.
>gnl~PID~e236741 CMP-sialic acid transporter [Mus musculus]

TR).
>sp~Q614201CMST MOUSE CMP-SIALIC ACID TRANSPORTER (CMP-SIA-Length = 336 S Plus Strand HSPs:
Score = 178 (62.7 bits), Expect = 5.6e-10, P = 5.6e-10 Identities = 49/162 (30~), Positives = 85/162 (52~), Frame = +1 1O Q: 91 LGMGHVLIIVQCFISSMANIYNEKILKEGNQLTEGIFIQNSKLYFFGILFNGLTL-GLQR 267 LG G + I V C S A +Y EK+LK + ++++N ++Y GI+ +TL G
S: 176 LGFGAIAIAVLC--SGFAGVYFEKVLKSSDT---SLWVRNIQMYLSGIV---VTLAGTYL 227 Q: 268 SNRDQIKNCGFFYGHSAFSVALIFVTAFQGLSVAFILKFLDNMFHVLMAQXXXXXXXXXX 447 IS S+ +I+ GFFYG++ + +IF+ + GL + ++K+ DN+ A
S: 228 SDGAEIQEKGFFYGYTYYVWFVIFLASVGGLYTSVWKYTDNIMKGFSAAAAIVLSTIAS 287 Q: 448 XLVFDFRPSLEFFLEAPSVLLSIFIYNASKPQ---VPEYAPRQERI 576 L+F + +L F L A V +SI++Y + + + A +ERI
2O S: 288 VLLFGLQITLSFALGALLVCVSIYLYGLPRQDTTSIQQEATSKERI 333 The segment of gnllPIDle236741 that is shown as "S" above is set out in the sequence listing as SEQ ID NO. 1S7 . Based on the structural similarity, these homologous polypeptides are expected to share at least some biological activities.
2S Such activities are known in the art, some of which are described elsewhere herein.
Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
Preferred polypeptides of the invention comprise a polypeptide having the amino acid sequence set out in the sequence listing as SEQ ID NO. 1S8 which 30 corresponds to the "Q" sequence in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed).
It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Soares NhHMPu S1 and to a lesser extent in NCI CGAP_GCB1; Human fetal brain (TFujiwara); Soares fetal heart_NbHHI9W;
3S Stratagene HeLa cell s3 937216; Stratagene ovarian cancer (#937219); Morton Fetal Cochlea; Soares multiple sclerosis 2NbHMSP; NCI CGAP_GC6;

NCI CGAP_LuS; NCI CGAP_Lym 12; Soares testis NHT; Human Hippocampus;
Human Chondrosarcoma; Human fetal heart, Lambda ZAP Express;
Soares NFL T GBC_S1; Soares total fetus Nb2HF8 9w; Human Substantia Nigra; Human Osteoclastoma; Human 8 Week Whole Embryo; Primary Dendritic Cells, lib 1; Soares ovary tumor NbHOT; Breast cancer; H. Adipose Tissue;
Human Fetal Brain; Human Umbilical Vein Endothelial Cells, fract. A; Healing Abdomen wound,70&90 min post incision; Human Liver; Salivary Gland; Apoptotic T-cell, re-excision; Morton Fetal; Human Colon Cancer,re-excision; human corpus colosum;
Human Umbilical Vein, Endo. remake; H Female Bladder, Adult; Healing groin wound, 7.5 hours post incision; LNCAP prostate cell line; T-Cell PHA 16 hrs;
NCI CGAP_Kids; Human Umbilical Vein, Reexcision; human ovarian cancer;
Macrophage-oxLDL; CHME Cell Line,treated 5 hrs; Stratagene lung (#937210);
Macrophage-oxLDL, re-excision; Soares testis NHT; Colon Carcinoma;
NCI CGAP_Co3; NCI CGAP_GC2; NCI CGAP_GC3; NCI CGAP_HN3;
NCI CGAP_LuS; NCI CGAP_Kid3; Colon Normal II; Primary Dendritic cells,frac 2; Human Amygdala; Human Microvascular Endothelial Cells, fract. A; Smooth muscle,control; Spleen, Chronic lymphocytic leukemia and Human Cerebellum.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 90 as residues: Ala-46 to Arg-62, Leu-68 to Thr-94.
Polynucleotides encoding said polypeptides are also provided.
Given the homology to murine CMP-sialic acid transporter proteins, the translation product of this gene is useful for the detection and/or treatment of disorders involving aberrant nucleotide sugar transport, and thus aberrant and/or reduced synthesis of complex carbohydrate structures. Gene therapy or protein therapeutic treatments involving this gene may be useful for the amelioration of defects involving the activity of this gene.

Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:40 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 2106 of SEQ ID
N0:40, b is an integer of 15 to 2120, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:40, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 31 It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Human adult testis, large inserts; Soares infant brain and to a lesser extent in Human Adult Testes, Large Inserts, Reexcision;
breast lymph node CDNA library; Stratagene fetal spleen (#937205); NCI CGAP_Lul; Soares adult brain N2b5HBS5Y; Brain frontal cortex; HUMAN B CELL LYMPHOMA;
Human Cerebellum; Bone Cancer, re-excision; Soares ovary tumor NbHOT; Bone Cancer; H. Whole Brain #2, re-excision; Soares adult brain N2b4HB55Y;
Stratagene placenta (#937225); NTERA2 + retinoic acid, 14 days; Human Frontal Cortex, Schizophrenia; NCI CGAP_CoB; Soares testis NHT;
Soares fetal liver spleen_1NFLS S1; normalized infant brain cDNA; Human Infant Brain; Soares fetal liver spleen_1NFLS S1; Human Fetal Kidney; Human retina cDNA randomly primed sublibrary; NCI CGAP_Kids; Human Umbilical Vein Endothelial Cells, uninduced; Human umbilical vein endothelial cells, IL-4 induced;

NCI CGAP_GCB1; Stratagene colon (#937204); Rejected Kidney, lib 4;
Soares_senescent fibroblasts NbHSF; Human Synovial Sarcoma; Human Fetal Lung III; NCI CGAP_GCB1; Spleen, Chronic lymphocytic leukemia; Human Endometrial Tumor; Keratinocyte; Soares fetal liver spleen 1NFLS; Human Uterine Cancer, 5 subtracted; Gessler Wilms tumor; Soares testis NHT; Human Pituitary; Larynx Normal; Human Colon, subtraction; Human Colon; Human Adult Retina; Smooth Muscle Serum Treated, Norm; Smooth muscle, control, re-excision; Human Primary Breast Cancer; Human Soleus; Soares total fetus Nb2HF8 9w; Human Adult Heart,re-excision; Cem cells cyclohexamide treated; Raji Cells, cyclohexamide 10 treated; Human Normal Breast; Human Tonsils, Lib 2; Human Lung Cancer,re-excision; Jurkat T-cell G1 phase; Jurkat T-Cell, S phase; H. Meningima, M1;
Human Manic Depression Tissue; Spleen metastic melanoma; 1-NIB; Gessler Wilms tumor;
Human epidermal keratinocyte; Infant brain, Bento Soares; NCI CGAP_Kids;
NCI CGAP_Brn25; Soares NFL T GBC_Sl; Soares_parathyroid tumor NbHPA;
15 Soares senescent fibroblasts NbHSF; H. Lymph node breast Cancer; Human Bone Marrow, re-excision; Human Brain, Striatum; Human heart cDNA (YNakamura);
NCI CGAP_Co2; NCI CGAP_Co3; NCI CGAP_Co4; NCI CGAP_GC4;
NCI CGAP_LuS; NCI CGAP_ColO; NCI CGAP_Prl2; Human Fetal Dura Mater;
Macrophage-oxLDL; Human Adipose; Bone Marrow Stromal Cell, untreated; Human 20 Fetal Brain; Soares breast 2NbHBst; Stratagene liver (#937224); Fetal Heart; Human Substantia Nigra; Soares fetal lung NbHLI9W; NCI CGAP_ColO;
Soares testis NHT; Colon Tumor II; Soares testis NHT;
Soares total fetus Nb2HF8 9w; Human Fetal Kidney, Reexcision; Human Testes, Reexcision; Bone marrow; Human Adult Pulmonary,re-excision; Anergic T-cell;
25 Human Microvascular Endothelial Cells, fract. A; Monocyte activated; Human Testes; Hodgkin's Lymphoma II; Nine Week Old Early Stage Human; Primary Dendritic Cells, lib 1 and Infant brain, LLNL array of Dr. M. Soares 1NIB.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:41 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 2226 of SEQ ID
N0:41, b is an integer of 15 to 2240, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:41, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 32 It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Human Testes, Reexcision; Human Testes and to a lesser extent in Human Adult Testes, Large Inserts, Reexcision; Soares testis NHT;
Human adult testis, large inserts; NCI CGAP_GC4; H Female Bladder, Adult;
Soares NFL T GBC_S1; Testis, normal; Human testis (C. De Smet) and Testis 1.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 92 as residues: Phe-30 to Lys-37, Pro-43 to Lys-75.
Polynucleotides encoding said polypeptides are also provided.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:42 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the S general formula of a-b, where a is any integer between 1 to 1067 of SEQ ID
N0:42, b is an integer of 1S to 1081, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:42, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 33 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.
giI5S3S33 (all information available through the recited accession number is incorporated herein by reference) which is described therein as "MHC HLA-BS 1 [Homo Sapiens]". A partial alignment demonstrating the observed homology is shown immediately below.
>gi~553533 MHC HLA-B51 [Homo Sapiens]
Length = 365 Plus Strand HSPs:
Score = 836 (294.3 bits), Expect = 3.8e-113, Sum P(3) = 3.8e-113 2S Identities = 155/194 (79~), Positives = 156/194 (80~), Frame = +3 Q: 282 AYDGKDYIALNEDLXSWTAADTAAQITQRKWXXXXXXXXXXXYLEGXCVEWLRRYLENGK 461 AYDGKDYIALNEDL SWTAADTAAQITQRKW YLEG CVEWLRR+LENGK
S: 141 AYDGKDYIALNEDLSSWTAADTAAQITQRKWEAAREAEQLRAYLEGLCVEWLRRHLENGK 200 Q: 462 ETLQRADPPKTHVTHHPXSDHEATLRCWALGFYPAEITLTWQRDGEDQTQDTELVETRPA 641 ETLQRADPPKTHVTHHP SDHEATLRCWALGFYPAEITLTWQRDGEDQTQDTELVETRPA
S: 201 ETLQRADPPKTHVTHHPVSDHEATLRCWALGFYPAEITLTWQRDGEDQTQDTELVETRPA 260 3S Q: 642 GDRTFQKWAAVVVPSGEEQRYTCHVQHEGLPKPLTLRWEPSSQSTXPXXXXXXXXXXXXX 821 GDRTFQKWAAWVPSGEEQRYTCHVQHEGLPKPLTLRWEPSSQST P

S: 261 GDRTFQKWAAWVPSGEEQRYTCHVQHEGLPKPLTLRWEPSSQSTIPIVGIVAGLAVLAV 320 Q: 822 XXXXXXXXXXMCRR 863 MCRR
S S: 321 WIGAWATVMCRR 334 Score = 257 (90.5 bits), Expect = 3.8e-113, Sum P(3) = 3.8e-113 Identities = 50/64 (78~), Positives = 50/64 (78~), Frame = +2 1O Q: 65 MRVXAPRTXXXXXXXXXXXTETWAGSHSMRYFYTAXSRPGRGEPRFIAVGYVDDTQFVXF 244 MRV APRT TETWAGSHSMRYFYTA SRPGRGEPRFIAVGYVDDTQFV F
S: 1 MRVTAPRTVLLLLWGAVALTETWAGSHSMRYFYTAMSRPGRGEPRFIAVGYVDDTQFVRF 60 Q: 245 DSDA 256 IS DSDA
S: 61 DSDA 64 Score = 64 (22.5 bits), Expect = 3.8e-113, Sum P(3) = 3.8e-113 Identities = 13/13 (100$), Positives = 13/13 (1000 , Frame = +1 Q: 910 ATVPRALMCLSQL 948 ATVPRALMCLSQL
S: 353 ATVPRALMCLSQL 365 2S The segments of giISS3S33 that are shown as "S" above are set out in the sequence listing as SEQ ID NO. 1S9,SEQ ID NO. 161 and SEQ ID NO. 163 .
Based on the structural similarity, these homologous polypeptides are expected to share at least some biological activities. Such activities are known in the art, some of which are described elsewhere herein. Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
Preferred polypeptides of the invention comprise a polypeptide having the amino acid sequence set out in the sequence listing as SEQ ID NO. 160,SEQ ID
NO.
162 and/or SEQ ID NO. 164 which correspond to the "Q" sequences in the alignment shown above (gaps introduced in a sequence by the computer are, of course, 3S removed).
When tested against sensory neuron cell lines, supernatants removed from cells containing this gene activated the EGR1 assay. Thus, it is likely that this gene activates sensory neuron cells through a signal transduction pathway. Early growth response 1 (EGRI) is a promoter associated with certain genes that induces various tissues and cell types upon activation, leading the cells to undergo differentiation and proliferation.
It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Primary Dendritic Cells, lib 1 and to a lesser extent in Activated T-cell(12h)/Thiouridine-re-excision; Macrophage-oxLDL, re-excision;
Human Bone Marrow, treated; H Macrophage (GM-CSF treated), re-excision; Human Neutrophil, Activated; Human Endometrial Tumor; Spleen, Chronic lymphocytic leukemia; Macrophage (GM-CSF treated); Macrophage-oxLDL; Human T-Cell Lymphoma; Colon Tumor II; Primary Dendritic cells,frac 2; Activated T-Cell (l2hs)/Thiouridine labelledEco; Human Activated Monocytes; T cell helper II;
Human Pancreas Tumor, Reexcision; Epithelial-TNFa and INF induced; Larynx carcinoma III; Rejected Kidney, lib 4; Soares ovary tumor NbHOT; Human Testes Tumor, re-excision; HUMAN B CELL LYMPHOMA; Activated T-Cells,l2 hrs,re-excision; breast lymph node CDNA library; Hodgkin's Lymphoma II; Human Pancreas Tumor; Soares fetal liver spleen 1NFLS; Liver, Hepatoma; Bone marrow;
Osteoblasts; Human Activated T-Cells; Human Activated T-Cells, re-excision;
Resting T-Cell Library,II; Human Primary Breast Cancer Reexcision; T-Cell PHA

hrs; Neutrophils control, re-excision; Colon Normal III; T Cell helper I;
Human Colon, re-excision; Stratagene lung (#937210); Monocyte activated; T-Cell PHA

hrs; Colon Normal II; Human Placenta; Stratagene pancreas (#937208); Human Adult Pulmonary,re-excision; Soares placenta Nb2HP; Weizmann Olfactory Epithelium;
Activated T-cells; Human Neutrophil; Ulcerative Colitis; Human Eosinophils;
Anergic T-cell; neutrophils control; Human Epididymus; pBMC stimulated w/ poly I/C; Apoptotic T-cell; Colon Tumor; Normal colon; Prostate BPH; Human Thymus;
CD34 depleted Buffy Coat (Cord Blood), re-excision; Resting T-Cell, re-excision;

Human endometrial stromal cells-treated with progesterone; Stromal cell TF274;
NCI CGAP_Lul; Siebben Polyposis; Apoptotic T-cell, re-excision; Human Placenta (re-excision); Bone Marrow Stromal Cell, untreated; Activated T-Cells, 12 hrs.;
prostate-edited; CD40 activated monocyte dendridic cells; Aorta endothelial cells +
5 TNF-a; LPS activated derived dendritic cells; Human Normal Breast; Human Osteoclastoma Stromal Cells - unamplified; Human endometrial stromal cells;
Human Thymus; Human Gall Bladder; Fetal Heart; NCI CGAP_Lul; Human T-cell lymphoma,re-excision; Human Adult Small Intestine; Human Adipose; Human Rhabdomyosarcoma; Human Liver, normal; Colon Carcinoma; Soares melanocyte 10 2NbHM; Human Osteoclastoma; Bone Marrow Cell Line (RS4,11); Soares infant brain 1NIB; Human Colon; B Cell lymphoma; Human Colon Cancer,re-excision;
Human endometrial stromal cells-treated with estradiol; normalized infant brain cDNA; Human Testes Tumor; Human Synovial Sarcoma; Human Fetal Lung III;
Resting T-Cell; Human Adult Spleen; Human White Adipose; Human Neutrophils, 15 Activated, re-excision; Human Tonsils, Lib 2; Stratagene colon (#937204);
NCI CGAP_Co2; Monocyte activated, re-excision; Stratagene colon (#937204);
Ovarian Tumor 10-3-95; Neutrophils IL-1 and LPS induced; Smooth muscle, serum treated; Dendritic cells, pooled; human tonsils; NCI CGAP_Co2; eosinophil-ILS
induced; Human Pituitary, subtracted; Breast Lymph node cDNA library; Human 20 Pineal Gland; Healing groin wound, 7.5 hours post incision; L428;
Hepatocellular Tumor, re-excision; Human Fetal Heart; NCI CGAP_GCS; Activated T-Cells, l2hrs, differentially expressed; Rectum normal; Human Colon Cancer, subtracted; human colon cancer; Human Primary Breast Cancer; Activated T-cells, 24 hrs,re-excision;
Hepatocellular Tumor,re-excision; Human Prostate Cancer, Stage C fraction; HL-60, 25 PMA 4H, re-excision; Human Osteoclastoma, re-excision; Healing groin wound, 6.5 hours post incision; Stratagene fetal spleen (#937205); Spinal cord; Human Chondrosarcoma; Stratagene colon (#937204); Soares breast 3NbHBst; Adipocytes;
Endothelial-induced; Neutrophils IL-1 and LPS induced; H. Frontal cortex,epileptic,re-excision; NCI CGAP_AA1; Crohn's Disease; Human Leukocytes;
Human epithelioid sarcoma; Human Colon, subtraction; NCl CGAP_Kids; A-14 cell line; HUMAN STOMACH; Human Lung; Human adult small intestine,re-excision;
STROMAL -OSTEOCLASTOMA; Human Stomach,re-excision; H. Meningima, M1;
Spleen metastic melanoma; H. Kidney Medulla, re-excision; Human Umbilical Vein, Reexcision; Human Adult Testes, Large Inserts, Reexcision; Human Hypothalmus,Schizophrenia; Barstead spleen HPLRB2;
Soares senescent fibroblasts_NbHSF; Human Whole Six Week Old Embryo;
Stratagene liver (#937224); Smooth muscle, serum induced,re-exc; Human Testes, Reexcision; Human Microvascular Endothelial Cells, fract. A;
Soares_fetal lung NbHLI9W; NCI CGAP_Pr25; NCI CGAP_Brl.l; Human Leukocytes,normalized control #4; Human Membrane Bound Polysomes; Human Macrophage; Stomach Tumour; CD34+cells, II, FRACTION 2; NCI CGAP_GC3;
NCI CGAP_Kid6; Human Primary Breast Cancer,re-excision; Human Pancreatic Carcinoma; H. Epididiymus, caput & corpus; H. Epididiymus, cauda; HSA 172 Cells;
HEL cell line; normalized infant brain cDNA; Stratagene placenta (#937225); H
Female Bladder, Adult; Myoloid Progenitor Cell Line; Human Pituitary, subt IX;
CD34 depleted Buffy Coat (Cord Blood); Human Bone Marrow, re-excision;
NCI CGAP_Lul; NCI CGAP_Prl; Human Uterine Cancer; Human Heart; Barstead spleen HPLRB2; Human pancreatic islet; Human Thymus Stromal Cells; Soares breast 2NbHBst; Human adult testis, large inserts; Human Placenta; Endothelial cells-control; NCI CGAP_Col2; Human Testes; NCI CGAP_Col2; NCI CGAP_Kid6;
NCI CGAP_Pr2l; NCI CGAP_Brl.l; Keratinocyte; NCI CGAP_Col2; Activated T-Cells, 24 hrs., ligation 2; Prostate-BPH subtracted II; Human Leukocyte, control #2; Human Primary Breast Cancer; Human Rejected Kidney, 704 re-excision; Human Activated Macrophage (LPS), thiour; Human colon cancer, metaticized to liver, subtraction; Rectum tumour; Human Bone Marrow; Colon, tumour; Larynx tumor;
Thyroid Tumour; Adenocarcinoma; Stomach Normal; Liver Normal MetSNo; Human Placenta, subtracted; Tongue Normal; Human Membrane Bound Polysomes- Enzyme Subtraction; Human Whole 6 Week Old Embryo (II), subt; Human Uterus, normal;
Human Fetal Lung; HL-60, RA 4h, Subtracted; Human Pituitary, re-excision;
NCI CGAP_HN3; Human Gall Bladder, fraction II; metastatic squamous cell lung carcinoma, poorly differentiated; stomach cancer (human); Human Adult Pulmonary;
Hodgkin's Lymphoma I; Healing Abdomen wound,70&90 min post incision; Human Placenta; Smooth Muscle Serum Treated, Norm; Invasive poorly differentiated lung adenocarcinoma, metastatic; Liver HepG2 cell line.; Stratagene pancreas (#937208);
Stratagene ovary (#937217); Healing groin wound - zero hr post-incision (control);
Stomach cancer (human),re-excision; Human Synovium; STRATAGENE Human skeletal muscle cDNA library, cat. #936215.; Human Fetal Epithelium (Skin);
Glioblastoma; Pancreas normal PCA4 No; Synovial hypoxia; Jurkat T-cell G1 phase;
H. Lymph node breast Cancer; Spinal Cord, re-excision; Human Prostate; Mo7e Cell Line GM-CSF treated (lng/ml); Soares senescent fibroblasts_NbHSF;
NCI CGAP_Pr2; NCI CGAP_Pr3; NC1 CGAP_PrlO; NCI CGAP_Prl l;
NCI CGAP_Pr25; Human Fetal Dura Mater; HTCDL1;
Soares total fetus Nb2HF8 9w; Soares_parathyroid tumor NbHPA; Human umbilical vein endothelial cells, IL-4 induced; Soares_parathyroid tumor NbHPA;
Soares adult brain N2bSHB55Y; Soares fetal lung NbHLI9W;
Soares_parathyroid tumor NbHPA; Soares senescent fibroblasts NbHSF;
Stratagene hNT neuron (#937233); Synovial Fibroblasts (control);
Soares_parathyroid tumor NbHPA; Brain frontal cortex; HTCDL1; Human Fetal Kidney, Reexcision; NCI CGAP_AA1; Pancreatic Islet;
Soares senescent fibroblasts_NbHSF; NCI CGAP_GC3; NCI CGAP_GC4;
NCI CGAP_Kid6; NCI CGAP_Pr22; Soares_multiple sclerosis 2NbHMSP;
Stratagene HeLa cell s3 937216; Stratagene endothelial cell 937223;
NCI CGAP_Lul; NC1 CGAP_Ov2; NCI CGAP_PrS; NCI CGAP_PrB; Nine Week Old Early Stage Human; NCI CGAP_Col; NCI CGAP_ColO;
Soares multiple_sclerosis 2NbHMSP; Stratagene ovarian cancer (#937219); Human Hippocampus, prescreened; Human Fetal Brain; Activated T-Cells, 4 hrs.; TH2 cells;
Human Adult Kidney; Human Cornea; Human Cornea, subtracted; human colon cancer, metastatic to liver, differentially expressed; Human Colon Cancer, metasticized to live; H. Leukocytes, control; H. Striatum Depression, subt II;
Human Adult Lymph Node; Human Primary Breast Cancer; Human Testes; CD34 positive cells (Cord Blood); human adult liver cDNA library; Human Eosinophils;
Pericardium; Larynx normal #10 261-273; Human Adult Spleen, fractionlI; Human Macrophage, subtracted; Human Infant Adrenal Gland, Subtracted; HTCDL1;
Prostate,BPH, Lib 2; Spleen/normal; Larynx carcinoma II; Sinus piniformis Tumour;
Prostate BPH,Lib 2, subtracted; Larynx carcinoma IV; Colon Normal; Pharynx Carcinoma; Palate normal; Osteoclastoma-normalized A; Colon Tumor; Liver Tumour Met 5 Tu; Colon, normal; Activated T-Cells, 12 hrs, subtracted; Human rejected kidney; Healing Abdomen Wound,21&29 days post incision; Human Tonsils, lib I; Larynx Tumor; Normal Prostate; Activated T-Cells, 8 hrs.;
Human Infant Adrenal Gland; Human Normal Cartilage,Fraction I; Human Umbilical Vein Endothelial cells, frac B, re-excision; Human Prostate Cancer, Stage B2; Human Pre-Differentiated Adipocytes; Human Prostate BPH, re-excision; H. Striatum Depression, subtracted; Normal Ovary, Premenopausal; Normal Lung; Activated T-Cells, 8 hrs., ligation 2; Human 7 Weeks Old Embryo, subtracted; Human Prostate, subtracted; Poorly differentiated adenocarcinoma, Ovary & Fallopian tube -9809C332; Thymus; Ku 812F Basophils Line; B-cells (stimulated); H Umbilical Vein Endothelial Cells, frac A, re-excision; STRIATUM DEPRESSION; Human OB HOS
treated (1 nM E2) fraction I; Soares_placenta 8to9weeks 2NbHP8to9W; Weizmann Olfactory; Human OB MG63 control fraction I; Saos2 Cells, Untreated; Human pancreatic cancer cell line Patu 8988t; Morton Fetal Cochlea; HL-60, PMA 4H;
NCI CGAP_LuS; NCI CGAP_Col2; H. Striatum Depression, subt; A1-CELL
LINE; L1 Cell line; Human OB MG63 treated (10 nM E2) fraction I; Human Cardiomyopathy, subtracted; Human Adult Retina; Human Umbilical Vein Endothelial Cells, fract. A; H. Atrophic Endometrium; Adipocytes,re-excision;
Human Fetal Spleen; Hep G2 Cells, PCR library; Soares_pregnant uterus NbHPU;
Frontal lobe,dementia,re-excision; Smooth muscle-ILb induced; Human Thyroid;
Human Liver; Amniotic Cells - TNF induced; Early Stage Human Lung, subtracted;
Human Quadriceps; Human Soleus; NCI CGAP_Panl; Human Skin Tumor;
Soares fetal heart NbHHI9W; Stratagene colon (#937204); Smooth Muscle-HASTE normalized; Cem cells cyclohexamide treated; Raji Cells, cyclohexamide treated; Pancreas Tumor PCA4 Tu; Hepatocellular Tumor; Synovial IL-1/TNF
stimulated; Salivary Gland, Lib 2; Human Adipose Tissue, re-excision; Human Osteosarcoma; Soares_pregnant uterus NbHPU; Stratagene colon (#937204);
Stratagene pancreas (#937208); Stratagene NT2 neuronal precursor 937230; Human placenta cDNA (TFujiwara); Brain Frontal Cortex, re-excision; Human Chronic Synovitis; HM3; Soares fetal liver spleen_1NFLS S1; KMH2; Human Brain, Striatum; NCI CGAP_AA1; NCI CGAP_Br2; NCI CGAP_Alvl;
NCI CGAP_Pr2l; NCI CGAP_Pr22; Human Fetal Kidney; human ovarian cancer;
Human Osteoblasts II; HUMAN JURKAT MEMBRANE BOUND POLYSOMES;
Soares testis NHT; Human Hippocampus; Human colon mucosa; Human promyelocyte; Human pancreatic islet; Soares testis NHT;
Soares fetal heart NbHHI9W; Soares_pregnant uterus NbHPU;
Soares total fetus Nb2HF8 9w; Soares_pregnant uterus NbHPU; Stratagene pancreas (#937208); Pancreatic Islet; Soares fetal heart_NbHHI9W; Human adult 5 (K.Okubo); Pancreatic Islet; Soares senescent fibroblasts NbHSF;
Hemangiopericytoma; Stratagene endothelial cell 937223; Stratagene ovarian cancer (#937219); Fetal Liver, subtraction II; NCl CGAP_Ut4; NTERA2, control;
Soares_pineal_gland N3HPG; Human Ovarian Cancer Reexcision; Human fetal heart, Lambda ZAP Express; KG1-a Lambda Zap Express cDNA library;
10 Soares testis NHT; Soares_pineal_gland_N3HPG; Stratagene muscle 937209;
Stratagene colon (#937204); Stratagene hNT neuron (#937233); Human Substantia Nigra; NCI CGAP_BrS; NCI CGAP_GC4; NCI CGAP_HN3; NCI CGAP_Col2;
NCI CGAP_Kids; Stratagene colon (#937204); Stratagene hNT neuron (#937233);
Stratagene ovarian cancer (#937219); Soares_placenta 8to9weeks 2NbHP8to9W;
15 Pancreatic Islet; Soares fetal heart NbHHI9W;
Soares senescent fibroblasts NbHSF; NCI CGAP_GCB1; NCI CGAP_Pr24;
Soares NhHMPu S1; Stratagene NT2 neuronal precursor 937230; NCI CGAP_Ut4;
Human Amygdala; NCI CGAP_Br2; NCI CGAP_Br7; NCI CGAP_CoB;
NCI CGAP_Ew 1; NCI CGAP_Pr3; NCI CGAP_Kid3; NCI CGAP_Kids;
20 NCI CGAP_Prl8; Soares NhHMPu_S1; Stratagene NT2 neuronal precursor 937230;
NCI CGAP_Co4; NCI CGAP_Pr6; NCI CGAP_CNSI;
Soares senescent fibroblasts_NbHSF; Stratagene pancreas (#937208); Human 8 Week Whole Embryo; NCI CGAP_AAI; NCI CGAP_Br2; NCI CGAP_GCS;
NCI CGAP_Prl; NCI CGAP_Pr2; NCI CGAP_Col l; NCI CGAP_Col2;
25 NCI CGAP_Prl l; NCI CGAP_Pr24; Human Cerebellum; HMI; NCI CGAP_Br3;
NCI CGAP_Ovl; NCI CGAP_Pr2; NCI CGAP_Kid6; NCI CLAP Pr23;

NCI CGAP_Pr4.l; Stratagene pancreas (#937208) and Stratagene hNT neuron (#937233).
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:43 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1427 of SEQ ID
N0:43, b is an integer of 15 to 1441, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:43, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 34 It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Soares placenta Nb2HP and to a lesser extent in Soares_pregnant uterus NbHPU; Soares infant brain 1NIB; Soares NhHMPu_S1;
Soares testis NHT; Stratagene lung carcinoma 937218; Soares NFL T GBC_S1;
Morton Fetal Cochlea; Soares NhHMPu_S 1; Salivary Gland, Lib 2; Temporal cortex-Alzheizmer, subtracted; NCI CGAP_GCB 1; T-Cell PHA 24 hrs;
Soares fetal heart_NbHHI9W; Soares total fetus Nb2HF8 9w; Human Thymus Stromal Cells; Soares fetal heart_NbHHI9W; Soares_pregnant uterus NbHPU;
normalized infant brain cDNA; Normal colon; Soares melanocyte 2NbHM;
Stratagene hNT neuron (#937233); Human Testes; Hodgkin's Lymphoma II; Tongue Normal; Human osteoarthritic,fraction II; Colorectal Tumor; Human Kidney;

Soares_parathyroid tumor NbHPA; Frontal Lobe, Dementia; Human colon carcinoma (HCC) cell line, remake; Hodgkin's Lymphoma I; NCI CGAP_GCB1;
Soares retina N2b4HR; Stratagene HeLa cell s3 937216; Stratagene hNT neuron (#937233); NTERA2 teratocarcinoma cell line+retinoic acid (14 days); Human Pineal Gland; Human Epididymus; STROMAL -OSTEOCLASTOMA; Human Synovium;
Synovial hypoxia-RSF subtracted; Pancreas normal PCA4 No; Human Infant Brain;
Human adult (K.Okubo); Human fetal heart, Lambda ZAP Express;
NCI CGAP_Br2; NCI CGAP_Ewl; NCI CGAP_GC3; NCI CGAP_Kid3;
NCI CGAP_Pr22; Monocyte activated, re-excision; Human Pancreas Tumor;
Soares multiple sclerosis 2NbHMSP; Soares_placenta 8to9weeks 2NbHP8to9W;
Soares_parathyroid tumor NbHPA; Human Ovary; Human Chondrosarcoma;
Ulcerative Colitis; Bone Marrow Stromal Cell, untreated; Rejected Kidney, lib 4;
CHME Cell Line,treated 5 hrs; Pancreas Islet Cell Tumor;
Soares_parathyroid tumor NbHPA; normalized infant brain cDNA; Fetal Heart;
Colon Tumor; Soares total fetus Nb2HF8 9w; Stratagene lung carcinoma 937218;
Endothelial-induced; Human Osteoclastoma; Anergic T-cell; Human Microvascular Endothelial Cells, fract. A; HUMAN B CELL LYMPHOMA; Spleen, Chronic lymphocytic leukemia; Human 8 Week Whole Embryo; Nine Week Old Early Stage Human and T cell helper II.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:44 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the S
general formula of a-b, where a is any integer between 1 to 2870 of SEQ ID
N0:44, b is an integer of 1S to 2884, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:44, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 35 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.
gnIIPIDle1343479 (all information available through the recited accession number is incorporated herein by reference) which is described therein as "similar to diphthine synthase [Caenorhabditis elegans]". A partial alignment demonstrating the observed homology is shown immediately below.
1S >gnl~PID~e1343479 similar to diphthine synthase [Caenorhabditis elegans]
>sp~Q17514~Q17514 B0491.7 PROTEIN.
Length = 274 Plus Strand HSPs:
Score = 895 (315.1 bits), Expect = 5.2e-89, P = 5.2e-89 Identities = 170/267 (63~), Positives = 214/267 (80~), Frame = +3 Q: 75 IGLGLGDAKDITVKGLEWRRCSRVYLEAYTSVLTVG--KEALEEFYGRKLVVADREEVE 248 2S IGLGLGD +DITVKGL +V+ C+RV+LEAYTS+L G K LE+FYGR+++ ADR VE
S: 6 IGLGLGDVEDITVKGLNIVKNCARVHLEAYTSILCYGLDKTNLEKFYGREIIEADRTWE 65 Q: 249 QEADNILKDADISDVAFLWGDPFGATTHSDLVLRATKLGIPYRVIHNASIMNAVGCCGL 428 QE+D IL AD DVA LWGDPFGATTH+DLVLRA + IP +VIHNASIMNAVGCCGL
3O S: 66 QESDAILNGADKEDVALLWGDPFGATTHADLVLRAKQQNIPVKVIHNASIMNAVGCCGL 125 Q: 429 QLYKFGETVSIVFWTDTWRPESFFDKVKKNRQNGMHTLCLLDIKVKEQSLENLIKGRKIY 608 QLY FGETVSIV WTD W+PES++DK+ NR+ GMHTLCLLDIK KEQ++EN+++GRKI+
S: 126 QLYNFGETVSIVMWTDEWQPESYYDKIALNRKRGMHTLCLLDIKTKEQTVENMMRGRKIF 185 Q: 609 EPPRYMSVNQAAQQLLEIVQNQRIRGEEPAVTEETLCVGLARVGADDQKIAAGTLRQMCT 788 EP RY ++AA+QLL I + ++ +GEE A E T+ VGLARVG D+QKI +++ M
S: 186 EPARYQKCSEAARQLLTIYERRKAKGEECAYDENTMWGLARVGWDNQKIVYASMKDMSE 245 4O Q: 789 VDLGEPLHSLIITGGSIHPMEMEMLSLF 872 +++GEPLHSLII G + HP+E++ML F

S': 246 MEMGEPLHSLIIPGET-HPLEVDMLETF 272 The segment of gnllPIDle1343479 that is shown as "S" above is set out in the sequence listing as SEQ ID NO. 165 . Based on the structural similarity, these homologous polypeptides are expected to share at least some biological activities.
Such activities are known in the art, some of which are described elsewhere herein.
Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
Preferred polypeptides of the invention comprise a polypeptide having the amino acid sequence set out in the sequence listing as SEQ ID NO. 166 which corresponds to the "Q" sequence in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed).
It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Resting T-Cell Library,II and to a lesser extent in Soares fetal liver spleen 1NFLS; Human Whole Six Week Old Embryo;
Soares fetal lung NbHLI9W; Human Pancreatic Carcinoma; Human Thyroid; Bone Marrow Stromal Cell, untreated; Human Fetal Brain; Ovarian Tumor 10-3-95;
Human Fetal Lung Ill and Endothelial-induced.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:45 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1337 of SEQ ID
N0:45, b is an integer of 1S to 1351, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:4S, and where b is greater than or equal to a + 14.
S FEATURES OF PROTEIN ENCODED BY GENE NO: 36 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.
gi13449376 (all information available through the recited accession number is 10 incorporated herein by reference) which is described therein as "anti-death protein [Homo sapiens]". A partial alignment demonstrating the observed homology is shown immediately below.
>gi~3449376 (AF039067) anti-death protein [Homo Sapiens] >gi~3851532 1S (AF071596) apoptosis inhibitor [Homo Sapiens] >sp~075353~075353 ANTI-DEATH
PROTEIN. >sp~G3851532~G3851532 APOPTOSIS INHIBITOR.
Length = 193 Plus Strand HSPs:
Score = 422 (148.6 bits), Expect = 1.4e-64, Sum P(2) = 1.4e-64 Identities = 82/83 (98~), Positives = 83/83 (100$), Frame = +1 Q: 250 WRRQLPVEEPNPAKRLLFLLLTIVFCQILMAEEGVPAPLPPEDAPNAASLAPTPVSPVL 429 2S +VRRQLPVEEPNPAKRLLFLLLTIVFCQILMAEEGVPAPLPPEDAPNAASLAPTPVSPVL
S: 107 LVRRQLPVEEPNPAKRLLFLLLTIVFCQILMAEEGVPAPLPPEDAPNAASLAPTPVSPVL 166 Q: 430 EPFNLTSEPSDYALDLSTFLQQH 498 EPFNLTSEPSDYALDLSTFLQQH
3O S: 167 EPFNLTSEPSDYALDLSTFLQQH 189 Score = 260 (91.5 bits), Expect = 1.4e-64, Sum P(2) = 1.4e-64 Identities = 52/72 (72~), Positives = 52/72 (72$), Frame = +2 3S Q: 44 MCHSRSCHPTMTILQAPTPAPSTIPGPRRGSGPEIFTFDPLPEXXXXXXXXXXXXXXHRK 223 MCHSRSCHPTMTILQAPTPAPSTIPGPRRGSGPEIFTFDPLPE HRK
S: 1 MCHSRSCHPTMTILQAPTPAPSTIPGPRRGSGPEIFTFDPLPEPAAAPAGRPSASRGHRK 60 Q: 224 RSAGFSTLEWSG 259 S: 61 RSRRVS-LPSSG 71 The segments of gi13449376 that are shown as "S" above are set out in the sequence listing as SEQ ID NO. 167 and SEQ ID NO. 169 . Based on the structural similarity, these homologous polypeptides are expected to share at least some biological activities. Such activities are known in the art, some of which are described elsewhere herein. Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
Preferred polypeptides of the invention comprise a polypeptide having the amino acid sequence set out in the sequence listing as SEQ ID NO. 168 and/or SEQ
ID NO. 170 which correspond to the "Q" sequences in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed).
It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Human Neutrophil, Activated and to a lesser extent in Human Activated Monocytes; Colon Carcinoma; Human Neutrophils, Activated, re-excision;
Amniotic Cells - Primary Culture; Human Thymus Stromal Cells; Primary Dendritic Cells, lib l; Activated T-Cells,l2 hrs,re-excision; Primary Dendritic cells,frac 2;
Amniotic Cells - TNF induced; Activated T-cell(12h)/Thiouridine-re-excision;
Soares_pregnant uterus NbHPU; Neutrophils IL-1 and LPS induced;
Soares_placenta 8to9weeks 2NbHP8to9W; Epithelial-TNFa and INF induced;
Endothelial-induced; Keratinocyte; Human endometrial stromal cells-treated with estradiol; Synovial IL-1/TNF stimulated; Human Neutrophil; NCI CGAP_Co3;
HUMAN JURKAT MEMBRANE BOUND POLYSOMES; Colon Tumor II;
Activated T-Cell (l2hs)/Thiouridine labelledEco;
Soares senescent fibroblasts NbHSF; Osteoblasts; Human epithelioid sarcoma;
Human OB HOS control fraction I; Messangial cell, frac 2; NCI CGAP_ColO;
Human umbilical vein endothelial cells, IL-4 induced; Ulcerative Colitis;
Neutrophils control, re-excision; Pancreatic Islet; Resting T-Cell, re-excision; B Cell lymphoma;

Stratagene placenta (#937225); H Female Bladder, Adult; Stratagene pancreas (#937208); Human endometrial stromal cells-treated with progesterone; Salivary Gland, Lib 2; Human endometrial stromal cells; Synovial Fibroblasts (Ill/TNF), subt;
Breast Cancer Cell line, angiogenic; NCI CGAP_Br2; NCI CGAP_Co9; Human Umbilical Vein Endothelial Cells, uninduced; Stratagene colon (#937204);
Stratagene pancreas (#937208); NCI CGAP_Co4; Smooth muscle, serum induced,re-exc; Colon Normal II; Soares melanocyte 2NbHM; Human Fetal Lung III; Endothelial cells-control; Colon Normal III; Spleen, Chronic lymphocytic leukemia; Activated T-Cell;
Human Activated Macrophage (LPS); Human Resting Macrophage; Human Colon Cancer; Human Astrocyte; Osteoarthritis (OA-4); Human Osteoarthritic Cartilage Fraction III; Rectum normal; Larynx Carcinoma; Liver Tumour Met 5 Tu; Human Pancreatic Langerhans; H. Striatum Depression, subtracted; Colorectal Tumor;
Weizmann Olfactory Epithelium; Activated T-Cells, 12 hrs.; Human Pituitary, re-excision; Human Colon, subtraction; Human Aortic Endothelium; Human Primary Breast Cancer,re-excision; Human Primary Breast Cancer; Human Adult Heart,re-excision; Human Normal Breast; Healing groin wound - zero hr post-incision (control); Human Colon Cancer,re-excision; pBMC stimulated w/ poly I/C; Smooth muscle, ILIb induced; Synovial hypoxia-RSF subtracted; Healing groin wound, 7.5 hours post incision; Healing groin wound, 6.5 hours post incision; Human Chronic Synovitis; KMH2; NCI CGAP_Brl.l; Human Dermal Endothelial Cells,untreated;
Human Brain, Striatum; human ovarian cancer; NCI CGAP_Col;
NCI CGAP_Col2; NCI CGAP_Kid3; NCI CGAP_Larl; NCI CGAP_Lei2;
NCI CGAP_Pr22; NCI CGAP_Pr24; NCI CLAP Pr25; Merkel Cells; Human Adipose; Human Testes Tumor, re-excision; Synovial Fibroblasts (control); Bone Marrow Stromal Cell, untreated; Human Adrenal Gland Tumor; CHME Cell Line,untreated; Colon Tumor; Neutrophils IL-1 and LPS induced; Human Substantia Nigra; breast lymph node CDNA library; Human Placenta; Adipocytes;
NCI CGAP_Pr25; Bone marrow; human tonsils; Human Primary Breast Cancer Reexcision; CD34 depleted Buffy Coat (Cord Blood), re-excision; Hodgkin's Lymphoma II; neutrophils control and NCI CGAP_Br2.
This clone is the human ortholog of the g1y96 cDNA cloned from a serum-induced mouse fibroblast library. It is a 153 amino acid glycoprotein with a short half-life. This clone has an interesting cell-type distribution in that we find this group (46 members +) in white blood, endothelial, and smooth muscle cells. This gene may be involved in inflammation or normal vascular function. According to hydropathy analysis it does not have an amino-terminal hydrophobic region, thus may have no signal peptide. It does have a single hydrophobic region towards the carboxy-terminus indicating that it is membrane bound.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 96 as residues: Glu-4 to Ala-9, Leu-35 to Ala-40.
Polynucleotides encoding said polypeptides are also provided.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:46 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1294 of SEQ ID
N0:46, b is an integer of 15 to 1308, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:46, and where b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 37 It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Soares infant brain 1NIB and to a lesser extent in Human Cerebellum; Soares adult brain N2b4HB55Y; Human Hypothalmus,Schizophrenia;
Human Substantia Nigra; H. cerebellum, Enzyme subtracted; Merkel Cells;
Soares senescent fibroblasts NbHSF; HUMAN B CELL LYMPHOMA; Human Activated T-Cells (II); H. Striatum Depression, subt; Human Cerebellum, subtracted;
Supt Cells, cyclohexamide treated; Human Pineal Gland; Human Lung Cancer,re-excision; STROMAL -OSTEOCLASTOMA; Human Whole Brain #2 - Oligo dT >
l.SKb; Human Frontal Cortex, Schizophrenia; HL-60, PMA 4H, re-excision; Human endometrial stromal cells; Prostate BPH; Brain Frontal Cortex, re-excision;
Human Fetal Kidney; HUMAN JURKAT MEMBRANE BOUND POLYSOMES; Soares adult brain N2b5HB55Y; Human Thymus; Macrophage (GM-CSF treated); Human adult testis, large inserts; Activated T-Cell (l2hs)/Thiouridine labelledEco;
Endothelial cells-control; Stratagene neuroepithelium (#937231); H. Frontal cortex,epileptic,re-excision and Soares fetal liver spleen 1NFLS.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:47 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1753 of SEQ ID
N0:47, b is an integer of 15 to 1767, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:47, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 38 It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Soares fetal heart NbHHI9W; Soares infant brain 1NIB
and to a lesser extent in Soares_pregnant_uterus NbHPU; Soares testis NHT;
Soares total fetus Nb2HF8 9w; Soares placenta Nb2HP; Soares fetal liver spleen 1NFLS; Soares fetal heart NbHHI9W; Infant brain, Bento Soares; Early Stage Human Brain; Colon Tumor II; Stratagene neuroepithelium NT2RAMI 937234;
Stratagene hNT neuron (#937233); Stratagene lung carcinoma 937218; Human Pancreas Tumor, Reexcision; Soares retina N2b4HR; Stratagene muscle 937209;
Glioblastoma; Soares_pregnant uterus NbHPU; Brain frontal cortex;
NCI CGAP_Co3; NCI CGAP_Brn25; Soares melanocyte 2NbHM;
Soares_placenta 8to9weeks 2NbHP8to9W; Smooth muscle,control; Monocyte activated; Nine Week Old Early Stage Human; H. hypothalamus, frac A,re-excision;
Thyroid Thyroiditis; Osteoclastoma-normalized B; Normal Prostate; H.
hypothalamus, frac A; Human 8 Week Whole Embryo, subtracted; H. Striatum Depression, subt; Human Adult Spleen; Human Fetal Brain; Human Soleus; Human Hypothalamus,schizophrenia, re-excision; Human endometrial stromal cells-treated with estradiol; Stratagene fetal retina 937202; H Female Bladder, Adult; H.
Kidney Cortex, subtracted; Prostate BPH; Brain Frontal Cortex, re-excision; Human Prostate;
Stromal cell TF274; Human epidermal keratinocyte;
Soares_pregnant uterus NbHPU; Stratagene fetal retina 937202; Human Ovary;
Human umbilical vein endothelial cells, IL-4 induced; Human Rhabdomyosarcoma;
Stratagene neuroepithelium NT2RAMI 937234; Human Fetal Brain; Human Thymus Stromal Cells; Human Whole Six Week Old Embryo; Macrophage-oxLDL, re-excision; Smooth muscle, serum treated; Human adult (K.Okubo); Human fetal heart, Lambda ZAP Express; NCI CGAP_Ew 1; NCI CGAP_GC4; NCI CGAP_ColO;
NCI CGAP_Col2; NCI CGAP_Kidl; NCI CGAP_Kid3; NCI CGAP_Pr22;
Soares multiple sclerosis 2NbHMSP; Human Osteoclastoma; Human Amygdala;
HUMAN B CELL LYMPHOMA; Osteoblasts and Human 8 Week Whole Embryo.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:48 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1241 of SEQ ID
N0:48, b is an integer of 15 to 1255, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:48, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 39 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.
gi1486369 (all information available through the recited accession number is incorporated herein by reference) which is described therein as "ORF YKL207w [Saccharomyces cerevisiae]". A partial alignment demonstrating the observed homology is shown immediately below.

S
>gi~486369 ORF YKL207w [Saccharomyces cerevisiae] >pir~S38045~538045 hypothetical protein YKL207w - yeast (Saccharomyces cerevisiae) Length = 260 Plus Strand HSPs:
1~
Score = 283 (99.6 bits), Expect = 3.7e-24, P = 3.7e-24 Identities = 66/203 (32~), Positives = 107/203 (52~), Frame = +1 Q: 181 SVKMA-GPELLLDSNIRLWVVLPIVIITFFVGMIRHYVSILLQ-SDKKLTQEQV--SDSQ 348 S++ A P++LLD ++ WV+LPI I+ G+++ Y+ L+ S Q +V ++ Q
S: 21 SIQQARAPQMLLDDQLKYWVLLPISIVMVLTGVLKQYIMTLITGSSANEAQPRVKLTEWQ 80 IS Q: 349 VLIRSRVLRENGKYIPKQSFLTRKYYF--NNPEDGFFKKTKRKVVXXXXX--------XX 498 L +++L NG + +F +K + + E+ K K++
S: 81 YLQWAQLLIGNGGNLSSDAFAAKKEFLVKDLTEERHLAKAKQQDGSQAGEVPNPFNDPSM 140 Q: 499 XXXXXXXXKGNVTNVLPMILIGGWINMTFSGFVTTKVPFPLTLRFKPMLQQGIELLTLDA 678 2O KGN+ + +P +I W+N F+GF+ ++PFPLT +FK MLQ GI LD
S: 141 SNAMMNMAKGNMASFIPQTIIMWWVNHFFAGFILMQLPFPLTAKFKEMLQTGIICQDLDV 200 Q: 679 SWVSSASWYFLNVFGLRSIYSLI 747 WVSS SWYF++V GL +Y+LI
ZS S: 201 RWVSSISWYFISVLGLNPVYNLI 223 The segment of gi1486369 that is shown as "S" above is set out in the sequence listing as SEQ ID NO. 171 . Based on the structural similarity, these homologous polypeptides are expected to share at least some biological activities. Such activities 30 are known in the art, some of which are described elsewhere herein. Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
Preferred polypeptides of the invention comprise a polypeptide having the amino acid sequence set out in the sequence listing as SEQ ID NO. 172 which 3S corresponds to the "Q" sequence in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed).
It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Soares fetal liver spleen 1NFLS and to a lesser extent in Soares melanocyte 2NbHM; Soares ovary tumor NbHOT; Soares infant brain 1NIB;

Stratagene colon (#937204); Stratagene muscle 937209;
Soares_pregnant uterus NbHPU; normalized infant brain cDNA; Human Testes;
Primary Dendritic Cells, lib 1; Soares_parathyroid_tumor NbHPA;
NCI CGAP_GCBI; Synovial hypoxia-RSF subtracted;
Soares multiple sclerosis 2NbHMSP; Primary Dendritic cells,frac 2; Human Testes, Reexcision; Nine Week Old Early Stage Human; Soares fetal lung NbHLI9W;
Soares testis_NHT; NCI CGAP_Br2; NCI CGAP_GC4; NCI CGAP_Pr3;
NCI CGAP_Kids; NCI CGAP_Pr22; Human Aortic Endothelium; Smooth Muscle Serum Treated, Norm; human corpus colosum; Human Osteoclastoma, re-excision;
Human Rhabdomyosarcoma; Stratagene liver (#937224);
Soares total fetus Nb2HF8 9w; Human Endometrial Tumor; Human Cerebellum;
Keratinocyte, lib 3; H.Leukocytes, normalized cot SB; Soares NFL T GBC_S1;
Soares_pineal_gland N3HPG; brain stem; Human B Cell 8866; LNCAP + o.3nM
81881; Human 8 Week Whole Embryo, subtracted; Human adult (K.Okubo);
NCI CGAP_AA1; NCI CGAP_Co3; NCI CGAP_GC2; NCI CGAP_LuS;
NCI CGAP_ColO; NCI CGAP_HSC1; NCl CGAP_Kid3; NCI CGAP_Prl2;
Saos2, Dexamethosome Treated; Human Kidney; Human Prostate Cancer, Stage B2 fraction; H. Normalized Fetal Liver, II; Human Cerebellum, subtracted; Human Adult Pulmonary; Human Adult Retina; Adipocytes,re-excision; Frontal lobe,dementia,re-excision; Human Soleus; HSA 172 Cells; HEL cell line; Pancreas Tumor PCA4 Tu;
Stratagene pancreas (#937208); Stratagene ovarian cancer (#937219); H. Kidney Cortex, subtracted; Human endometrial stromal cells; Human Adult Small Intestine;
Human Bone Marrow, re-excision; Human pancreatic islet; Normalized infant brain, Bento Soares; Soares testis NHT; Soares_pregnant uterus NbHPU;
Soares senescent fibroblasts NbHSF; TF-1 Cell Line GM-CSF Treated; HUMAN
JURKAT MEMBRANE BOUND POLYSOMES; Human Pancreas Tumor; T-Cell PHA 24 hrs; Human Heart; Stromal cell TF274; Human Placenta (re-excision);
Human Activated Monocytes; Human Adrenal Gland Tumor;
Soares_parathyroid tumor NbHPA; Macrophage (GM-CSF treated); Fetal Liver, subtraction II; Ovarian Tumor 10-3-95; Hepatocellular Tumor, re-excision;
Macrophage-oxLDL, re-excision; PC3 Prostate cell line; Colon Tumor; Colon Carcinoma; Smooth muscle, serum treated; Colon Normal II; Soares breast 3NbHBst;
Adipocytes; H Macrophage (GM-CSF treated), re-excision; Dendritic cells, pooled;
Stratagene ovarian cancer (#937219); Normal colon; Neutrophils control, re-excision;
Human Placenta; Bone marrow; Human Adult Pulmonary,re-excision; Endothelial cells-control; Soares testis NHT; Colon Normal III; Human Osteoclastoma; Human Amygdala; Smooth muscle,control; H. Frontal cortex,epileptic,re-excision;
Keratinocyte; T cell helper II and Pancreatic Islet.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 99 as residues: Asp-85 to Arg-92, Ala-107 to Glu-116. Polynucleotides encoding said polypeptides are also provided.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:49 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1099 of SEQ ID
N0:49, b is an integer of 15 to 1113, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:49, and where b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 40 It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Stratagene NT2 neuronal precursor 937230; Human Cerebellum and to a lesser extent in Soares testis NHT; Soares melanocyte 2NbHM;
Soares placenta Nb2HP; Soares infant brain 1NIB; NCI CGAP_GCB1; Saos2 Cells, Untreated; NCI CGAP_Co3; NCI CGAP_GC4; Soares fetal heart_NbHHI9W;
L428; Gessler Wilms tumor; Soares total fetus Nb2HF8 9w; normalized infant brain cDNA; Stratagene ovarian cancer (#937219); Anergic T-cell; human caudate nucleus; Human fetal brain QBoqin2; NCI CGAP_Kid3; NCI CGAP_Pr22;
NCI CGAP_Brn23; Stratagene NT2 neuronal precursor 937230; Colon Tumor;
human colon cancer; NTERA2 teratocarcinoma cell line+retinoic acid (14 days);
Human Normal Breast; Apoptotic T-cell, re-excision; H Female Bladder, Adult;
NTERA2 + retinoic acid, 14 days; Human Amygdala,re-excision; Human Manic Depression Tissue; Human Bone Marrow, re-excision; Breast Cancer Cell line, angiogenic; Human Osteoblasts II; Merkel Cells; Human Ovary; Human Thymus Stromal Cells; Soares breast 2NbHBst; Human Adrenal Gland Tumor; Rejected Kidney, lib 4; Human Whole Six Week Old Embryo; NTERA2, control; HM3; Colon Tumor; Stratagene colon (#937204); Stratagene NT2 neuronal precursor 937230;
Smooth muscle, serum treated; Human Placenta; Human Testes Tumor; Primary Dendritic cells,frac 2; 12 Week Early Stage Human II, Reexcision; Human Testes, Reexcision; Endothelial cells-control; HUMAN B CELL LYMPHOMA; Spleen, Chronic lymphocytic leukemia; Human Testes; Activated T-cell(12h)/Thiouridine-re-excision; Human 8 Week Whole Embryo and Soares fetal liver spleen 1NFLS.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:SO and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention S are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 2722 of SEQ ID
NO:SO, b is an integer of 1S to 2736, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:SO, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 41 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.
1S gnlIPIDIe13S6777 (all information available through the recited accession number is incorporated herein by reference) which is described therein as "conserved hypothetical PFAM UPF0031 containing protein [Schizosaccharomyces pombe]". A
partial alignment demonstrating the observed homology is shown immediately below.
>gnl~PID~e1356777 (AL034381) conserved hypothetical PFAM UPF0031 containing protein [Schizosaccharomyces pombe] >sp~E1356777~E1356777 CONSERVED HYPOTHETICAL PFAM UPF0031 CONTAINING PROTEIN.
Length = 327 Plus Strand HSPs:
Score = 371 (130.6 bits), Expect = 9.3e-55, Sum P(3) = 9.3e-55 Identities = 84/205 (40~), Positives = 124/205 (60~), Frame = +3 Q: 333 SPIFCRISALKVGADLSHVFCASAAAPVIKAYSPELIVHPVL---------DSPNAVHEV 485 +P + +S++ G+D SH+FC AA VIK+YSP+LIVHP L DS + E+
S: 46 APYYSSMSSMLFGSDQSHIFCEKEAANVIKSYSPDLIVHPFLREKDKAGPEDSVDKCFEL 105 3S Q: 486 EK-WLPRLHALWGPGLGRDDALLRNVQGILEVSKARDIPWIDADGLWXVAQQPALIHG 662 K + RLHA+V+GPGLGRD+ + + ++E ++ D+P+VIDADGLW + Q+P L+ G
S: 106 IKPMMGRLHAIVIGPGLGRDEWMQEIMAKVIEYARKNDMPMVIDADGLWLIQQRPELVSG 165 Q: 663 YRKAVLTPNHVEFSRLYDAVLRGPMDSDDSHGSVLRLSQALGNVTWQKGERDILSNGQQ 842 S Y +LTPN +EF RL D L D D+ +L+ L N+ ++QKG+ DI+S+G
S: 166 YHNVILTPNVIEFKRLCDK-LDIKSDGPDACN---QLAGKL-NLLIIQKGQSDIISDGAT 220 Q: 843 VLVCSQEGSSAGVEGKG---TSCRAPWASW 923 CS G G+G T A + +W
1O S: 221 AYACSVPGGLKRCGGQGDILTGILATFLAW 250 The segment of gnIIPIDIe13S6777 that is shown as "S" above is set out in the sequence listing as SEQ ID NO. 173 . Based on the structural similarity, these homologous polypeptides are expected to share at least some biological activities.
1S Such activities are known in the art, some of which are described elsewhere herein.
Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
Preferred polypeptides of the invention comprise a polypeptide having the amino acid sequence set out in the sequence listing as SEQ ID NO. 174 which 20 corresponds to the "Q" sequence in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed).
It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Soares fetal liver spleen 1NFLS and to a lesser extent in NCI CGAP_GCB1; Soares total fetus Nb2HF8 9w;
2S Soares fetal heart_NbHHI9W; NCI CGAP_LuS; Soares_pregnant uterus NbHPU;
Soares adult brain N2b4HBSSY; Soares_parathyroid_tumor NbHPA; Human Endometrial Tumor; Human Cerebellum; Human Pituitary, subt IX; Human Brain, Striatum; Soares NhHMPu_S1; NCI CGAP_Kids; Nine Week Old Early Stage Human; NCl CGAP_CoB; NCI CGAP_Col4; Human Infant Brain;
30 Soares fetal heart NbHHI9W; Soares fetal liver spleen_1NFLS S1; Human umbilical vein endothelial cells, IL-4 induced; Soares melanocyte 2NbHM;

NCI CGAP_Co3; NCI CGAP_CoB; Stratagene schizo brain 511; Activated T-cell(12h)/Thiouridine-re-excision; Soares fetal_lung NbHLI9W; Human Cerebellum; Human Colon Cancer, metasticized to live; Kidney medulla;
Soares fetal liver spleen_1NFLS S1; Stratagene colon (#937204); Stratagene lung carcinoma 937218; H. hypothalamus, frac A,re-excision; Human Lung Cancer, subtracted; Human Gastrocnemius; Human Adult Liver, subtracted; Human Gall Bladder, fraction II; Fetal Heart, re-excision; H. Epididiymus, cauda; Human Pineal Gland; NCI CGAP_Utl; NCI CGAP_Ut2; NCI CGAP_CLL1; NCI CGAP_Kids;
NCI CGAP_Lym6; NCI CGAP_Ov36; Dendritic Cells From CD34 Cells; Human Colon Cancer,re-excision; Soares fetal liver spleen_1NFLS S1; normalized infant brain cDNA; Hepatocellular Tumor,re-excision; Synovial hypoxia; H. Meningima, M1; Human Prostate; H. Kidney Medulla, re-excision; Human Thymus; Human Pancreas Tumor; Human Adult Testes, Large Inserts, Reexcision; Stromal cell TF274; Macrophage-oxLDL; Soares fetal lung NbHLI9W;
Soares senescent fibroblasts_NbHSF; Human Ovary; Olfactory epithelium,nasalcavity; Soares adult brain N2b5HB55Y; Hemangiopericytoma; PC3 Prostate cell line; NCI CGAP_GCBl; Resting T-Cell Library,II; Adipocytes;
Human Testes Tumor; Human Fetal Heart; Soares NhHMPu_S 1;
Soares_placenta_8to9weeks 2NbHP8to9W; Human Primary Breast Cancer Reexcision; Gessler Wilms tumor; Human retina cDNA randomly primed sublibrary;
Jia bone marrow stroma; NCI CGAP_Br2; NCl CGAP_Lul; NCI CGAP_LuS;
NCI CGAP_Kid6; NCI CGAP_Larl; NCI CGAP_Thyl; NCI CGAP_Brn23;
Soares testis NHT; Soares fetal liver spleen_1NFLS S 1; Stratagene hNT neuron (#937233); Colon Normal III; Human Amygdala; Spleen, Chronic lymphocytic leukemia; Osteoblasts; Human 8 Week Whole Embryo and T cell helper II.

[09 Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:S1 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically S excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 2622 of SEQ ID
NO:S1, b is an integer of 1S to 2636, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:S1, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 42 The computer algorithm BLASTX has been used to determine that the 1S translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.
gi1307311 (all information available through the recited accession number is incorporated herein by reference) which is described therein as "nueroendocrine-specific protein C [Homo sapiens]". A partial alignment demonstrating the observed homology is shown immediately below.
>gi~307311 nueroendocrine-specific protein C [Homo Sapiens]
>pir~I60904~I60904 neuroendocrine-specific protein C - human >sp~Q16801~Q16801 2S NEUROENDOCRINE-SPECIFIC PROTEIN C.
Length = 208 Plus Strand HSPS:
Score = 274 (96.5 bits), Expect = 3.8e-36, Sum P(2) = 3.8e-36 Identities = 53/103 (51~), Positives = 68/103 (66~), Frame = +2 Q: 782 SVWDLLYWRDIKKTGXXXXXXXXXXXXXXXXXXXXXTAYIALALLSVTISFRIYKGVIQ 961 S +DLLYWRDIK+TG AY+ALA LS TISFRIYK V+Q
S: 19 SQAIDLLYWRDIKQTGIVFGSFLLLLFSLTQFSVVSVVAYLALAALSATISFRIYKSVLQ 78 Q: 962 AIQKSDEGHPFRAYLESEVAISEELVQKYSNSALGHVNCTIKE 1090 S A+QK+DEGHPF+AYLE E+ +S+E +QKY++ +VN T+KE
S: 79 AVQKTDEGHPFKAYLELEITLSQEQIQKYTDCLQFYVNSTLKE 121 Score = 138 (48.6 bits), Expect = 3.8e-36, Sum P(2) = 3.8e-36 Identities = 26/42 (61~), Positives = 32/42 (76~), Frame = +1 Q: 1156 VPVIYERHQAQIDHYLGLANKNVKDAMAKIQAKIPGLKRKAE 1281 +pV+Y +HQAQID YLGL ++ +AKIQAKIpG KR AE
S: 167 LPWYVKHQAQIDQYLGLVRTHINAWAKIQAKIPGAKRHAE 208 1S The segments of gi1307311 that are shown as "S" above are set out in the sequence listing as SEQ ID NO. 17S and SEQ ID NO. 177 . Based on the structural similarity, these homologous polypeptides are expected to share at least some biological activities. Such activities are known in the art, some of which are described elsewhere herein. Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
Preferred polypeptides of the invention comprise a polypeptide having the amino acid sequence set out in the sequence listing as SEQ ID NO. 176 and/or SEQ
ID NO. 178 which correspond to the "Q" sequences in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed).
2S Additionally, the translation product of this gene shares sequence homology with Rattus norvegicus NogoB (see, e.g., Genbank accession CAB71028; all references available through this accession are hereby incorporated by reference herein) which is thought to be important in neurological development, axon growth and regeneration.
Based on the sequence similarity, the translation product of this clone is expected to share at least some biological activities with Nogo proteins. Such activities are known in the art, some of which are described elsewhere herein.

In specific embodiments, polypeptides of the invention comprise, or alternatively consists of, the following amino acid sequences:
VPRLSRPSPSQSSPTPTTARGSETRPRRRRQQLQHHLHPPAMEDLDQSPLVSSS
DSPPRPQPAFKYQFV REPEDEEEEEEEEEEDEDEDLEELEV LERKPAAGLSAAP
VPTAPAAGAPLMDFGNDFVPPAPRGPLPAAPPVAPERQPSWDPSPVSSTVPAP
SPLSAAAVSPSKLPEDDEPPARPPPPPPASVSPQAEPV WTPPAPAPAAPPSTPA
APKRRGSSGSVVVDLLYWRDIKKTGVVFGASLFLLLSLTVFSIVSVTAYIALA
LLS VTISFRIYKGV IQAIQKSDEGHPFRAYLESEV AISEELV QKY SNSALGHV N
CTIKELRRLFLVDDLVDSLKLSFHSSVFLLFMNGIRHR (SEQ ID N0:189 ), VPRLSRPSPSQSSPTPTTARGSETRPRRRRQQLQHHLHPPA (SEQ ID NO: 190), MEDLDQSPLVSSSDSPPRPQPAFKYQFVREPED (SEQ ID NO: 191), PV PTAPAAGAPLMDFGNDFV PPAPRGPLPAAPPVAPERQPS WDPSPV S STV PA
(SEQ ID NO: 192), PSPLSAAAVSPSKLPEDDEPP (SEQ ID NO: 193), VSPQAEPVWTPPAPAPAAPPSTPAAPKRRGSSGSVVVDLLY (SEQ ID N0:194 ), WRDIKKTGVVFGASLFLLLSLTVFSIVSVTAYIALAL (SEQ ID N0:195 ), LSVTISFRIYKGVIQAIQKSDEGHPF (SEQ ID NO: 196), FRAYLESEVAISEELVQKYSNSALGHVNCTI (SEQ ID N0:197 ), and KELRRLFLVDDLVDSLKLSFHSSVFLLFMNGIRHR (SEQ ID N0:198 ).
Moreover, fragments and variants of these polypeptides (such as, for example, fragments as described herein, polypeptides at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to these polypeptides and polypeptides encoded by the polynucleotide which hybridizes, under stringent conditions, to the polynucleotide encoding these polypeptides ) are encompassed by the invention.
Polynucleotides encoding these polypeptides are also encompassed by the invention. Fragments with activity are most preferred. Activity includes, but is not limited to, enhancing or inhibiting neuronal growth, neuronal development, axonal regeneration.

It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Osteoblasts and to a lesser extent in Soares placenta Nb2HP;
Soares senescent fibroblasts_NbHSF; Human Amygdala; Primary Dendritic Cells, lib 1; Human Thymus Stromal Cells; Morton Fetal Cochlea; Smooth muscle, serum treated; Keratinocyte; Nine Week Old Early Stage Human; Stratagene fetal spleen (#937205); Bone Marrow Stromal Cell, untreated; Smooth muscle, serum induced,re-exc; Soares melanocyte 2NbHM; Soares fetal liver spleen 1NFLS; Stratagene muscle 937209; Synovial Fibroblasts (control); Stratagene lung (#937210);
NCI CGAP_Kids; Stromal cell TF274; Human Eosinophils; Soares infant brain 1NIB; Stratagene pancreas (#937208); Human Umbilical Vein Endothelial Cells, uninduced; Soares_senescent fibroblasts NbHSF; Epithelial-TNFa and INF
induced;
Fetal Liver, subtraction II; H Macrophage (GM-CSF treated), re-excision; Colon Tumor II; Normal colon; Soares fetal heart_NbHH 19W; Human Microvascular Endothelial Cells, fract. A; NCI CGAP_LuS; Hodgkin's Lymphoma II;
Soares_pregnant uterus NbHPU; Soares fetal lung NbHLI9W; Smooth muscle, control, re-excision; Synovial IL-1/TNF stimulated; Human Whole Brain #2 -Oligo dT > I.SKb; Human Amygdala,re-excision; Synovial hypoxia; Healing groin wound, 6.5 hours post incision; Temporal cortex-Alzheizmer, subtracted; Macrophage-oxLDL; Soares_parathyroid tumor NbHPA; Human umbilical vein endothelial cells, IL-4 induced; Human Adrenal Gland Tumor; CHME Cell Line,treated 5 hrs;
Macrophage-oxLDL, re-excision; CHME Cell Line,untreated; Adipocytes; Human Osteoclastoma; Stratagene muscle 937209; Human 8 Week Whole Embryo;
Soares_parathyroid tumor NbHPA; NCI CGAP_GCB l ; H. Adipose Tissue; Smooth Muscle Serum Treated, Norm; Soares retina N2b4HR; Human endometrial stromal cells-treated with estradiol; Amniotic Cells - Primary Culture; Healing groin wound, 7.5 hours post incision; Human Osteoclastoma, re-excision;

Soares_pregnant uterus NbHPU; Synovial Fibroblasts (I11/TNF), subt;
STRATAGENE Human skeletal muscle cDNA library, cat. #936215.; Human Umbilical Vein, Reexcision; Soares total fetus Nb2HF8 9w; human ovarian cancer;
12 Week Old Early Stage Human, II; Human Osteoblasts II; Human Adipose;
Soares_fetal heart_NbHHI9W; Human Testes Tumor, re-excision;
Soares_pineal_gland_N3HPG; Pancreas Islet Cell Tumor; 12 Week Old Early Stage Human; Human Substantia Nigra; Soares_pregnant uterus NbHPU; Dendritic cells, pooled; Human Fetal Kidney, Reexcision; Human Placenta; CD34 depleted Buffy Coat (Cord Blood), re-excision; Colon Normal III; Stratagene muscle 937209;
Smooth muscle,control; Stratagene pancreas (#937208); T Cell helper I; H.
Frontal cortex,epileptic,re-excision; Stratagene neuroepithelium NT2RAMI 937234;
Soares fetal heart NbHHI9W; Soares_pregnant uterus NbHPU; Human Cerebellum; Human Placenta, subtracted; NCl CGAP_Prl; Human Aortic Endothelium; Human Cerebellum, subtracted; Adipocytes,re-excision; H.
Epididiymus, cauda; Human Pineal Gland; H. Whole Brain #2, re-excision; Morton Fetal; Human Synovium; Stratagene hNT neuron (#937233); Hepatocellular Tumor;
Human Prostate Cancer, Stage C fraction; H Female Bladder, Adult; NTERA2 +
retinoic acid, 14 days; H. Kidney Cortex, subtracted; Glioblastoma; Stratagene endothelial cell 937223; Prostate BPH; Spinal Cord, re-excision; Human Prostate;
NCI CGAP_GCB1; L428; Human Fetal Kidney; HUMAN JURKAT MEMBRANE
BOUND POLYSOMES; NCI CGAP_Br2; Human Hypothalmus,Schizophrenia;
Soares testis NHT; Human Pancreas Tumor, Reexcision; Human Hippocampus;
NCI CGAP_GCB1; Rejected Kidney, lib 4; Soares_parathyroid tumor NbHPA;
Stratagene liver (#937224); Colon Tumor; Soares fetal lung NbHLI9W; Colon Normal II; Soares breast 3NbHBst; Early Stage Human Brain; normalized infant brain cDNA; Primary Dendritic cells,frac 2; 12 Week Early Stage Human II, Reexcision; Endothelial cells-control; Stratagene colon HT29 (#937221);
Stratagene ovarian cancer (#937219); Neutrophils IL-1 and LPS induced; NCI CGAP_CoB;
NCI CGAP_Brn23; Human fetal heart, Lambda ZAP Express; NCI CGAP_GC4;
NCI CGAP_LuS; NCI CGAP_Alvl; NCI CGAP_Kid3; NCI CGAP_Kids;
NCI CGAP_Pr22; NCI CGAP_Brn23; Stratagene colon (#937204); Human Old Ovary, subtracted; Human Fetal Kidney; Human Prostate,differential expression;
Uterus, normal; Human Astrocyte; Human Infant Adrenal Gland, subtracted; Human Old Ovary; Early Stage Human Brain, random primed; Soares ovary tumor NbHOT;
Colon Normal; Human Amygdala Depression, re-excision; Human rejected kidney;
NCI CGAP_Alvl; NCI CGAP_GCB1; Larynx Tumor; Human Umbilical Vein Endothelial cells, frac B, re-excision; H. hypothalamus, frac A; H. Striatum Depression, subtracted; Ku 812F Basophils Line; Human 8 Week Whole Embryo, subtracted; Hypothalamus; Soares_multiple sclerosis 2NbHMSP; Soares retina N2b5HR; Human OB HOS treated (10 nM E2) fraction I; Human colon carcinoma (HCC) cell line, remake; H. Atrophic Endometrium; HSC172 cells; Healing Abdomen wound,70&90 min post incision; Frontal lobe,dementia,re-excision; Supt Cells, cyclohexamide treated; Human Fetal Bone; H. Epididiymus, caput &
corpus;
Aorta endothelial cells + TNF-a; Invasive poorly differentiated lung adenocarcinoma, metastatic; H. cerebellum, Enzyme subtracted; Amniotic Cells - TNF induced;
Human Lung; HSA 172 Cells; Stratagene pancreas (#937208); NTERA2 teratocarcinoma cell line+retinoic acid (14 days); Human Normal Breast;
Messangial cell, frac 2; Stomach cancer (human),re-excision; Human Colon Cancer,re-excision;
STROMAL -OSTEOCLASTOMA; Soares_pregnant uterus NbHPU; pBMC
stimulated w/ poly I/C; Smooth muscle, ILlb induced; Alzheimers, spongy change;
Soares fetal lung NbHLI9W; Human Adipose Tissue, re-excision; Human Osteosarcoma; Human endometrial stromal cells; Stratagene fetal retina 937202;

Stratagene ovarian cancer (#937219); Stratagene neuroepithelium (#937231);
Stratagene colon (#937204); Stratagene neuroepithelium NT2RAMI 937234;
Myoloid Progenitor Cell Line; Spleen metastic melanoma; Brain Frontal Cortex, re-excision; Human Adult Small Intestine; Human Infant Brain; Human Chronic Synovitis; H. Kidney Medulla, re-excision; Human promyelocyte; normalized infant brain cDNA; Human Bone Marrow, re-excision; KMH2; Human Brain, Striatum;
NCl CGAP_Alvl; NCI CGAP_Kids; NCI CGAP_Pr22; Monocyte activated, re-excision; NCI CGAP_GC2; NCI CGAP_Col l; Human Activated T-Cells; T-Cell PHA 24 hrs; Barstead spleen HPLRB2; Gessler Wilms tumor; Human pancreatic islet; Soares_pregnant uterus NbHPU; Soares total fetus Nb2HF8 9w; Olfactory epithelium,nasalcavity; Soares multiple sclerosis 2NbHMSP; Spinal cord; Human Activated T-Cells, re-excision; Human Chondrosarcoma; PERM TF274;
Soares fetal lung NbHLI9W; Stratagene neuroepithelium (#937231);
NCI CGAP_Ewl; NCI CGAP_PrlO; Soares breast 2NbHBst; NTERA2, control;
STRATAGENE Human skeletal muscle cDNA library, cat. #936215.;
Soares testis NHT; Soares fetal heart NbHHI9W;
Soares total fetus Nb2HF8 9w; Stratagene fetal retina 937202; Stratagene hNT
neuron (#937233); Human Liver, normal; Human Gall Bladder; NCI CGAP_GC4;
PC3 Prostate cell line; Resting T-Cell Library,II; Human T-Cell Lymphoma;
Human pancreatic islet; Jia bone marrow stroma; Soares testis NHT;
Soares total fetus Nb2HF8 9w; Stratagene lung carcinoma 937218; Colon Carcinoma; Human Placenta; NCI CGAP_Pr25;
Soares multiple sclerosis 2NbHMSP; Stratagene cat#937212 (1992); Stratagene fetal retina 937202; Stratagene hNT neuron (#937233); Neutrophils control, re-excision; Human Testes, Reexcision; Endothelial-induced; Human Adult Pulmonary,re-excision; NCI CGAP_LuS; NCl CGAP_Kids; NCI CGAP_Kid6;

Monocyte activated; Spleen, Chronic lymphocytic leukemia; Stratagene neuroepithelium (#937231); NCI CGAP_Utl; NCI CGAP_Ov36;
NCI CGAP_Brn35; NCI CGAP_Kidl2; Activated T-cell(12h)/Thiouridine-re-excision; neutrophils control; Clontech human aorta polyA+ mRNA (#6572); HMI;
NCI CGAP_AA1; NCI CGAP_Br3; NCI CGAP_Ewl; NCI CGAP_HN4;
NCI CGAP_Kid6; NCI CGAP_Larl; NCI CGAP_PNS1; NCI CGAP_Prl2;
NCI CGAP_Pr24; NCI CGAP_Brn25; Stratagene pancreas (#937208);
Soares fetal lung NbHLI9W; Soares multiple sclerosis 2NbHMSP and NCI CGAP GCB 1.
Based on the sequence similarity to Rattus norvegicus NogoB and the tissue distribution indicates that polynucleotides and polypeptides of the invention would be useful for the detection, treatment, and/or prevention of neurodegenerative disease states, behavioral disorders, or inflammatory conditions. Representative uses are described in the "Regeneration" and "Hyperproliferative Disorders" sections below, in Example 11, 15, and 18, and elsewhere herein. Briefly, the uses include, but are not limited to the detection, treatment, and/or prevention of Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Tourette Syndrome, meningitis, encephalitis, demyelinating diseases, peripheral neuropathies, neoplasia, trauma, congenital malformations, spinal cord injuries, ischemia and infarction, aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, depression, panic disorder, learning disabilities, ALS, psychoses, autism, and altered behaviors, including disorders in feeding, sleep patterns, balance, and perception. In addition, elevated expression of this gene product in regions of the brain indicates it plays a role in normal neural function. Potentially, this gene product is involved in synapse formation, neurotransmission, learning, cognition, homeostasis, or neuronal differentiation or survival. Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Additionally it is contemplated that nervous system diseases, disorders, and/or conditions, which can be treated with the compositions of the invention (e.g., polypeptides, polynucleotides, and/or agonists or antagonists), include, but are not limited to, nervous system injuries, and diseases, disorders, and/or conditions which result in either a disconnection of axons, a diminution or degeneration of neurons, or demyelination. Nervous system lesions which may be treated in a patient (including human and non-human mammalian patients) according to the invention, include but are not limited to, the following lesions of either the central (including spinal cord, brain) or peripheral nervous systems: (1) ischemic lesions, in which a lack of oxygen in a portion of the nervous system results in neuronal injury or death, including cerebral infarction or ischemia, or spinal cord infarction or ischemia; (2) traumatic lesions, including lesions caused by physical injury or associated with surgery, for example, lesions which sever a portion of the nervous system, or compression injuries; (3) malignant lesions, in which a portion of the nervous system is destroyed or injured by malignant tissue which is either a nervous system associated malignancy or a malignancy derived from non-nervous system tissue; (4) infectious lesions, in which a portion of the nervous system is destroyed or injured as a result of infection, for example, by an abscess or associated with infection by human immunodeficiency virus, herpes zoster, or herpes simplex virus or with Lyme disease, tuberculosis, syphilis; (5) degenerative lesions, in which a portion of the nervous system is destroyed or injured as a result of a degenerative process including but not limited to degeneration associated with Parkinson's disease, Alzheimer's disease, Huntington's chorea, or amyotrophic lateral sclerosis (ALS); (6) lesions associated with nutritional diseases, disorders, and/or conditions, in which a portion of the nervous system is destroyed or injured by a nutritional disorder or disorder of metabolism including but not limited to, vitamin B12 deficiency, folic acid deficiency, Wernicke disease, tobacco-alcohol amblyopia, Marchiafava-Bignami disease (primary degeneration of the corpus callosum), and alcoholic cerebellar degeneration; (7) neurological lesions associated with systemic diseases including, but not limited to, diabetes (diabetic neuropathy, Bell's palsy), systemic lupus erythematosus, carcinoma, or sarcoidosis;
(8) lesions caused by toxic substances including alcohol, lead, or particular neurotoxins; and (9) demyelinated lesions in which a portion of the nervous system is destroyed or injured by a demyelinating disease including, but not limited to, multiple sclerosis, human immunodeficiency virus-associated myelopathy, transverse myelopathy or various etiologies, progressive multifocal leukoencephalopathy, and central pontine myelinolysis.
In a preferred embodiment, the polypeptides, polynucleotides, or agonists or antagonists of the invention are used to protect neural cells from the damaging effects of cerebral hypoxia. According to this embodiment, the compositions of the invention are used to treat, prevent, and/or diagnose neural cell injury associated with cerebral hypoxia. In one aspect of this embodiment, the polypeptides, polynucleotides, or agonists or antagonists of the invention are used to treat, prevent, and/or diagnose neural cell injury associated with cerebral ischemia. In another aspect of this embodiment, the polypeptides, polynucleotides, or agonists or antagonists of the invention are used to treat, prevent, and/or diagnose neural cell injury associated with cerebral infarction. In another aspect of this embodiment, the polypeptides, polynucleotides, or agonists or antagonists of the invention are used to 1l9 treat, prevent, and/or diagnose neural cell injury associated with a stroke.
In a further aspect of this embodiment, the polypeptides, polynucleotides, or agonists or antagonists of the invention are used to treat, prevent, and/or diagnose neural cell injury associated with a heart attack.
The compositions of the invention which are useful for treating, preventing, and/or diagnosing a nervous system disorder may be selected by testing for biological activity in promoting the survival or differentiation of neurons. For example, and not by way of limitation, compositions of the invention which elicit any of the following effects may be useful according to the invention: (1) increased survival time of neurons in culture; (2) increased sprouting of neurons in culture or in vivo;

(3) increased production of a neuron-associated molecule in culture or in vivo, e.g., choline acetyltransferase or acetylcholinesterase with respect to motor neurons; or (4) decreased symptoms of neuron dysfunction in vivo. Such effects may be measured by any method known in the art. In preferred, non-limiting embodiments, increased survival of neurons may routinely be measured using a method set forth herein or otherwise known in the art, such as, for example, the method set forth in Arakawa et al. (J. Neurosci. 10:3507-3515 (1990)); increased sprouting of neurons may be detected by methods known in the art, such as, for example, the methods set forth in Pestronk et al. (Exp. Neurol. 70:65-82 (1980)) or Brown et al. (Ann. Rev.
Neurosci.

4:17-42 (1981)); increased production of neuron-associated molecules may be measured by bioassay, enzymatic assay, antibody binding, Northern blot assay, etc., using techniques known in the art and depending on the molecule to be measured; and motor neuron dysfunction may be measured by assessing the physical manifestation of motor neuron disorder, e.g., weakness, motor neuron conduction velocity, or functional disability.

In specific embodiments, motor neuron diseases, disorders, and/or conditions that may be treated according to the invention include, but are not limited to, diseases, disorders, and/or conditions such as infarction, infection, exposure to toxin, trauma, surgical damage, degenerative disease or malignancy that may affect motor neurons as well as other components of the nervous system, as well as diseases, disorders, and/or conditions that selectively affect neurons such as amyotrophic lateral sclerosis, and including, but not limited to, progressive spinal muscular atrophy, progressive bulbar palsy, primary lateral sclerosis, infantile and juvenile muscular atrophy, progressive bulbar paralysis of childhood (Fazio-Londe syndrome), poliomyelitis and the post polio syndrome, and Hereditary Motorsensory Neuropathy (Charcot-Marie-Tooth Disease).
Additional examples of neurologic diseases which can be treated, prevented, and/or diagnosed with polynucleotides, polypeptides, agonists, and/or antagonists of the present invention include brain diseases, such as metabolic brain diseases which includes phenylketonuria such as maternal phenylketonuria, pyruvate carboxylase deficiency, pyruvate dehydrogenase complex deficiency, Wernicke's Encephalopathy, brain edema, brain neoplasms such as cerebellar neoplasms which include infratentorial neoplasms, cerebral ventricle neoplasms such as choroid plexus neoplasms, hypothalamic neoplasms, supratentorial neoplasms, canavan disease, cerebellar diseases such as cerebellar ataxia which include spinocerebellar degeneration such as ataxia telangiectasia, cerebellar dyssynergia, Friederich's Ataxia, Machado-Joseph Disease, olivopontocerebellar atrophy, cerebellar neoplasms such as infratentorial neoplasms, diffuse cerebral sclerosis such as encephalitis periaxialis, globoid cell leukodystrophy, metachromatic leukodystrophy and subacute sclerosing panencephalitis, cerebrovascular diseases, disorders, and/or conditions (such as carotid artery diseases which include carotid artery thrombosis, carotid stenosis and Moyamoya Disease, cerebral amyloid angiopathy, cerebral aneurysm, cerebral anoxia, cerebral arteriosclerosis, cerebral arteriovenous malformations, cerebral artery diseases, cerebral embolism and thrombosis such as carotid artery thrombosis, sinus thrombosis and Wallenberg's Syndrome, cerebral hemorrhage such as epidural hematoma, subdural hematoma and subarachnoid hemorrhage, cerebral infarction, cerebral ischemia such as transient cerebral ischemia, Subclavian Steal Syndrome and vertebrobasilar insufficiency, vascular dementia such as multi-infarct dementia, periventricular leukomalacia, vascular headache such as cluster headache, migraine, dementia such as AIDS Dementia Complex, presenile dementia such as Alzheimer's Disease and Creutzfeldt-Jakob Syndrome, senile dementia such as Alzheimer's Disease and progressive supranuclear palsy, vascular dementia such as multi-infarct dementia, encephalitis which include encephalitis periaxialis, viral encephalitis such as epidemic encephalitis, Japanese Encephalitis, St. Louis Encephalitis, tick-borne encephalitis and West l~lile Fever, acute disseminated encephalomyelitis, meningoencephalitis such as uveomeningoencephalitic syndrome, Postencephalitic Parkinson Disease and subacute sclerosing panencephalitis, encephalomalacia such as periventricular leukomalacia, epilepsy such as generalized epilepsy which includes infantile spasms, absence epilepsy, myoclonic epilepsy which includes MERRF
Syndrome, tonic-clonic epilepsy, partial epilepsy such as complex partial epilepsy, frontal lobe epilepsy and temporal lobe epilepsy, post-traumatic epilepsy, status epilepticus such as Epilepsia Partialis Continua, Hallervorden-Spatz Syndrome, hydrocephalus such as Dandy-Walker Syndrome and normal pressure hydrocephalus, hypothalamic diseases such as hypothalamic neoplasms, cerebral malaria, narcolepsy which includes cataplexy, bulbar poliomyelitis, cerebri pseudotumor, Rett Syndrome, Reye's Syndrome, thalamic diseases, cerebral toxoplasmosis, intracranial tuberculoma and Zellweger Syndrome, central nervous system infections such as AIDS
Dementia Complex, Brain Abscess, subdural empyema, encephalomyelitis such as Equine Encephalomyelitis, Venezuelan Equine Encephalomyelitis, Necrotizing Hemorrhagic Encephalomyelitis, Visna, cerebral malaria, meningitis such as arachnoiditis, aseptic meningtitis such as viral meningtitis which includes lymphocytic choriomeningitis.
Bacterial meningtitis which includes Haemophilus Meningtitis, Listeria Meningtitis, Meningococcal Meningtitis such as Waterhouse-Friderichsen Syndrome, Pneumococcal Meningtitis and meningeal tuberculosis, fungal meningitis such as Cryptococcal Meningtitis, subdural effusion, meningoencephalitis such as uvemeningoencephalitic syndrome, myelitis such as transverse myelitis, neurosyphilis such as tabes dorsalis, poliomyelitis which includes bulbar poliomyelitis and postpoliomyelitis syndrome, prion diseases (such as Creutzfeldt-Jakob Syndrome, Bovine Spongiform Encephalopathy, Gerstmann-Straussler Syndrome, Kuru, Scrapie) cerebral toxoplasmosis, central nervous system neoplasms such as brain neoplasms that include cerebellear neoplasms such as infratentorial neoplasms, cerebral ventricle neoplasms such as choroid plexus neoplasms, hypothalamic neoplasms and supratentorial neoplasms, meningeal neoplasms, spinal cord neoplasms which include epidural neoplasms, demyelinating diseases such as Canavan Diseases, diffuse cerebral sceloris which includes adrenoleukodystrophy, encephalitis periaxialis, globoid cell leukodystrophy, diffuse cerebral sclerosis such as metachromatic leukodystrophy, allergic encephalomyelitis, necrotizing hemorrhagic encephalomyelitis, progressive multifocal leukoencephalopathy, multiple sclerosis, central pontine myelinolysis, transverse myelitis, neuromyelitis optica, Scrapie, Swayback, Chronic Fatigue Syndrome, Visna, High Pressure Nervous Syndrome, Meningism, spinal cord diseases such as amyotonia congenita, amyotrophic lateral sclerosis, spinal muscular atrophy such as Werdnig-Hoffmann Disease, spinal cord compression, spinal cord neoplasms such as epidural neoplasms, syringomyelia, Tabes Dorsalis, Stiff-Man Syndrome, mental retardation such as Angelman Syndrome, Cri-du-Chat Syndrome, De Lange's Syndrome, Down Syndrome, Gangliosidoses such as gangliosidoses G(M1), Sandhoff Disease, Tay-Sachs Disease, Hartnup Disease, homocystinuria, Laurence-Moon- Biedl Syndrome, Lesch-Nyhan Syndrome, Maple Syrup Urine Disease, mucolipidosis such as fucosidosis, neuronal ceroid-lipofuscinosis, oculocerebrorenal syndrome, phenylketonuria such as maternal phenylketonuria, Prader-Willi Syndrome, Rett Syndrome, Rubinstein-Taybi Syndrome, Tuberous Sclerosis, WAGR Syndrome, nervous system abnormalities such as holoprosencephaly, neural tube defects such as anencephaly which includes hydrangencephaly, Arnold-Chairi Deformity, encephalocele, meningocele, meningomyelocele, spinal dysraphism such as spina bifida cystica and spina bifida occulta, hereditary motor and sensory neuropathies which include Charcot-Marie Disease, Hereditary optic atrophy, Refsum's Disease, hereditary spastic paraplegia, Werdnig-Hoffmann Disease, Hereditary Sensory and Autonomic Neuropathies such as Congenital Analgesia and Familial Dysautonomia, Neurologic manifestations (such as agnosia that include Gerstmann's Syndrome, Amnesia such as retrograde amnesia, apraxia, neurogenic bladder, cataplexy, communicative diseases, disorders, and/or conditions such as hearing diseases, disorders, and/or conditions that includes deafness, partial hearing loss, loudness recruitment and tinnitus, language diseases, disorders, and/or conditions such as aphasia which include agraphia, anomia, broca aphasia, and Wernicke Aphasia, Dyslexia such as Acquired Dyslexia, language development diseases, disorders, and/or conditions, speech diseases, disorders, and/or conditions such as aphasia which includes anomia, broca aphasia and Wernicke Aphasia, articulation diseases, disorders, and/or conditions, communicative diseases, disorders, and/or conditions such as speech disorders which include dysarthria, echolalia, mutism and stuttering, voice diseases, disorders, and/or conditions such as aphonia and hoarseness, decerebrate state, delirium, fasciculation, hallucinations, meningism, movement diseases, disorders, and/or conditions such as angelman syndrome, ataxia, athetosis, chorea, dystonia, hypokinesia, muscle hypotonia, myoclonus, tic, torticollis and tremor, muscle hypertonia such as muscle rigidity such as stiff-man syndrome, muscle spasticity, paralysis such as facial paralysis which includes Herpes Zoster Oticus, Gastroparesis, Hemiplegia, ophthalmoplegia such as diplopia, Duane's Syndrome, Horner's Syndrome, Chronic progressive external ophthalmoplegia such as Kearns Syndrome, Bulbar Paralysis, Tropical Spastic Paraparesis, Paraplegia such as Brown-Seqm-'1 Syndrome, quadriplegia, respiratory paralysis and vocal cord paralysis, paresis, phantom limb, taste diseases, disorders, and/or conditions such as ageusia and dysgeusia, vision diseases, disorders, and/or conditions such as amblyopia, blindness, color vision defects, diplopia, hemianopsia, scotoma and subnormal vision, sleep diseases, disorders, and/or conditions such as hypersomnia which includes Kleine-Levin Syndrome, insomnia, and somnambulism, spasm such as trismus, unconsciousness such as coma, persistent vegetative state and syncope and vertigo, neuromuscular diseases such as amyotonia congenita, amyotrophic lateral sclerosis, Lambert-Eaton Myasthenic Syndrome, motor neuron disease, muscular atrophy such as spinal muscular atrophy, Charcot-Marie Disease and Werdnig-Hoffmann Disease, Postpoliomyelitis Syndrome, Muscular Dystrophy, Myasthenia Gravis, Myotonia Atrophica, Myotonia Confenita, Nemaline Myopathy, Familial Periodic Paralysis, Multiplex Paramyloclonus, Tropical Spastic Paraparesis and Stiff-Man Syndrome, peripheral nervous system diseases such as acrodynia, amyloid neuropathies, autonomic nervous system diseases such as Adie's Syndrome, Barre-Lieou Syndrome, Familial Dysautonomia, Homer's Syndrome, Reflex Sympathetic Dystrophy and Shy-Drager Syndrome, Cranial Nerve Diseases such as Acoustic Nerve Diseases such as Acoustic Neuroma which includes Neurofibromatosis 2, Facial Nerve Diseases such as Facial Neuralgia,Melkersson-Rosenthal Syndrome, ocular motility diseases, disorders, and/or conditions which includes amblyopia, nystagmus, oculomotor nerve paralysis, ophthalmoplegia such as Duane's Syndrome, Homer's Syndrome, Chronic Progressive External Ophthalmoplegia which includes Kearns Syndrome, Strabismus such as Esotropia and Exotropia, Oculomotor Nerve Paralysis, Optic Nerve Diseases such as Optic Atrophy which includes Hereditary Optic Atrophy, Optic Disk Drusen, Optic Neuritis such as Neuromyelitis Optica, Papilledema, Trigeminal Neuralgia, Vocal Cord Paralysis, Demyelinating Diseases such as Neuromyelitis Optica and Swayback, Diabetic neuropathies such as diabetic foot, nerve compression syndromes such as carpal tunnel syndrome, tarsal tunnel syndrome, thoracic outlet syndrome such as cervical rib syndrome, ulnar nerve compression syndrome, neuralgia such as causalgia, cervico-brachial neuralgia, facial neuralgia and trigeminal neuralgia, neuritis such as experimental allergic neuritis, optic neuritis, polyneuritis, polyradiculoneuritis and radiculities such as polyradiculitis, hereditary motor and sensory neuropathies such as Charcot-Marie Disease, Hereditary Optic Atrophy, Refsum's Disease, Hereditary Spastic Paraplegia and Werdnig-Hoffmann Disease, Hereditary Sensory and Autonomic Neuropathies which include Congenital Analgesia and Familial Dysautonomia, POEMS Syndrome, Sciatica, Gustatory Sweating and Tetany).
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 102 as residues: Gln-47 to Gly-52.
Polynucleotides encoding said polypeptides are also provided. Antibodies that bind epitopes and/or fragments with activity are also preferred embodiments of the invention.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:52 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1669 of SEQ ID
N0:52, b is an integer of 15 to 1683, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:52, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 43 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.
gnlIPIDIe229590 (all information available through the recited accession number is incorporated herein by reference) which is described therein as "novel stromal cell protein (Mus musculus]." The murine novel stromal cell protein is thought to be facilitate the activation and expression of recombination activation genes (RAGs) in lymphoid progenitors. A partial alignment demonstrating the observed homology is shown immediately below.
>gnl~PID~e229590 novel stromal cell protein [Mus musculus]
>pir~JC4761~JC4761 recombination activating gene 1 inducing protein - human >sp~Q62275~Q62275 RECOMBINATION ACTIVATING PROTEIN 1 PROTEIN
2S ACTIVATION (NOVEL STROMAL CELL PROTEIN).
Length = 221 Minus Strand HSPs:
Score = 777 (273.5 bits), Expect = 1.6e-76, P = 1.6e-76 Identities = 154/221 (69~), Positives = 168/221 (76~), Frame = -1 Q: 1278 MEAGGFLDSLIYGACWFTLGMFSAGLSDLRHMRMTRSVDNVQFLPFLTTEVNNLGWLSY 1099 MEAGG DS + ACV+FTLGMFS GLSDLRHM+ TRSVDN+QFLPFLTT+VNNL WLSY

S: 1 MEAGGVADSFLSSACVLFTLGMFSTGLSDLRHMQRTRSVDNIQFLPFLTTDVNNLSWLSY 60 Q: 1098 GALKGDGILIVVNTVGAALQTLYILAYLHYCPRKRXXXXXXXXXXXXXXXXXXXXXXXXP 919 G LKGDG LI+VN+VGA LQTLYILAYLHY P+K P
S S: 61 GVLKGDGTLIIVNSVGAVLQTLYILAYLHYSPQKHGVLLQTATLLAVLLLGYGYFWLLVP 120 Q: 918 NPEARLQQLGLFCSVFTISMYLSPLADLAKVIQTKSTQCLSYPLTIATLLTSASWCLYGF 739 + EARLQQLGLFCSVFTISMYLSPLADLAK++QTKSTQ LS+ LTIATL SASW +YGF
S: 121 DLEARLQQLGLFCSVFTISMYLSPLADLAKIVQTKSTQRLSFSLTIATLFCSASWSIYGF 180 Q: 738 RLRDPYIMVSNFPGIVTSFIRFWLFWKYPQEQDRNYWLLQT 616 RLRDPYI V N PGI+TS IR LF KYP EQDR Y LLQT
S: 181 RLRDPYIAVPNLPGILTSLIRLGLFCKYPPEQDRKYRLLQT 221 1S The segment of gnlIPIDIe229S90 that is shown as "S" above is set out in the sequence listing as SEQ ID NO. 179 . Based on the structural similarity, these homologous polypeptides are expected to share at least some biological activities.
Such activities are known in the art, some of which are described elsewhere herein.
Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
Preferred polypeptides of the invention comprise a polypeptide having the amino acid sequence set out in the sequence listing as SEQ ID NO. 180 which corresponds to the "Q" sequence in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed). Fragments and variants of SEQ
2S ID NO. 180 are also preferred.
It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Colon Normal II and to a lesser extent in Keratinocyte;
KMH2; NTERA2, control; Colon Normal III; Soares placenta Nb2HP; Soares ovary tumor NbHOT; Human Adult Pulmonary; H. Epididiymus, caput & corpus; Breast Cancer cell line, MDA 36; Breast Cancer Cell line, angiogenic; HUMAN JURKAT
MEMBRANE BOUND POLYSOMES; Smooth muscle, serum induced,re-exc;
Soares total fetus Nb2HF8 9w; Fetal Heart; Colon Tumor; 12 Week Old Early Stage Human; breast lymph node CDNA library; Adipocytes; NCI CGAP_Pr24;

Normal colon; Endothelial-induced; NCl CGAP_Co9; NCI CGAP_Prl; Anergic T-cell; Human Bone Marrow, treated; Activated T-cell(12h)/Thiouridine-re-excision;
Stratagene HeLa cell s3 937216; T cell helper II; Human Cerebellum and Primary Dendritic Cells, lib 1.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 103 as residues: Asn-47 to Leu-52, Tyr-134 to Trp-143. Polynucleotides encoding said polypeptides are also provided. Antibodies that bind immunogenic epitopes/and or fragments of the invention (with or without activity) are also preferred.
The homology of this gene product to the novel stromal-cell protein suggests a role in the regulation of the proliferation; survival; differentiation; and/or activation of potentially all hematopoietic cell lineages, including blood stem cells.
Polynucleotides and polypeptides of the invention may be useful in treating and/or diagnosing B-cell development related disorders. This gene product may be involved in the regulation of cytokine production, antigen presentation, or other processes that may also suggest a usefulness in the treatment of cancer (e.g. by boosting immune responses). Since the gene is expressed in cells of lymphoid origin, the gene or protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Therefore it may be also used as an agent for immunological disorders including arthritis, asthma, immune deficiency diseases such as AIDS, leukemia, rheumatoid arthritis, inflammatory bowel disease, sepsis, acne, and psoriasis. In addition, this gene product may have commercial utility in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.

Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:53 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1345 of SEQ ID
N0:53, b is an integer of 15 to 1359, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:53, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 44 It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Soares melanocyte 2NbHM and to a lesser extent in Human Cerebellum; Soares_parathyroid tumor NbHPA; Soares fetal liver spleen 1NFLS;
Soares retina N2b5HR; Soares ovary tumor NbHOT; Osteoblasts;
Soares_pineal_gland N3HPG; Stratagene placenta (#937225); Synovial hypoxia-RSF
subtracted; Human Adrenal Gland Tumor; Stratagene lung (#937210); Smooth muscle, serum induced,re-exc; Human fetal heart, Lambda ZAP Express;
Soares_pregnant uterus NbHPU; Soares_senescent fibroblasts_NbHSF; Human Thyroid; Soares retina N2b4HR; Smooth Muscle- HASTE normalized; Synovial hypoxia; Human Manic Depression Tissue; Human Fetal Dura Mater; Stromal cell TF274; Human Hypothalmus,Schizophrenia; Human Hippocampus;
Soares_pregnant uterus NIiHPU; Human Placenta; Human Fetal Heart; Human Osteoclastoma; Soares fetal heart_NbHHI9W; Human Amygdala; Human Testes;

Soares_pineal_gland N3HPG; Soares placenta Nb2HP; STRATAGENE Human skeletal muscle cDNA library, cat. #936215.; Human Kidney Cortex, re-rescue;
Human Pre-Differentiated Adipocytes; Human Hippocampus, subtracted; H.
Striatum Depression, subt; HSC172 cells; Smooth muscle-ILb induced;
Soares fetal heart_NbHHI9W; Human Lung Cancer,re-excision; Human endometrial stromal cells-treated with estradiol; Smooth muscle, ILlb induced;
H
Female Bladder, Adult; Soares total fetus Nb2HF8 9w; Human endometrial stromal cells-treated with progesterone; Human endometrial stromal cells; Human Fetal Kidney; Human Ovary; Soares testis NHT; Bone Marrow Stromal Cell, untreated;
Soares breast 2NbHBst; NCI CGAP_Pr9; Soares_senescent fibroblasts_NbHSF;
Colon Tumor; Human T-Cell Lymphoma; Smooth muscle, serum treated; Soares breast 3NbHBst; Early Stage Human Brain; Human Testes, Reexcision; Human Adult Pulmonary,re-excision; Human heart cDNA (YNakamura); NCl CGAP_Col2;
NCI CGAP_Kids; NCI CGAP_Brn25; Activated T-cell(12h)/Thiouridine-re-excision; NCI CGAP_LuS; Stratagene fibroblast (#937212); Stratagene neuroepithelium NT2RAMI 937234; Nine Week Old Early Stage Human; Soares infant brain 1NIB; Neuroblastoma; Soares testis NHT;
Soares_pregnant uterus NbHPU; Soares total fetus Nb2HF8 9w;
Soares fetal liver spleen_1NFLS S1; Stratagene schizo brain 511; Stratagene lung carcinoma 937218; normalized infant brain cDNA; Stomach,normal; Larynx tumor;
Human Adult Spleen; Human Aortic Endothelium; Human Cardiomyopathy, subtracted; Human Adult Retina; Human Fetal Spleen; Smooth Muscle Serum Treated, Norm; Human Soleus; HSA 172 Cells; Human Adult Heart,re-excision;
Soares_pineal_gland_N3HPG; Soares_parathyroid tumor NbHPA; Human Pineal Gland; Messangial cell, frac 2; Pancreas Tumor PCA4 Tu; STROMAL -OSTEOCLASTOMA; Alzheimers, spongy change; Human Osteoclastoma Stromal Cells - unamplified; Glioblastoma; Healing groin wound, 7.5 hours post incision;
Human Frontal Cortex, Schizophrenia; Human Osteosarcoma; Human Osteoclastoma, re-excision; Jurkat T-cell G1 phase; Soares NhHMPu_S1; Prostate BPH; Human Thymus; Apoptotic T-cell; human ovarian cancer; 12 Week Old Early Stage Human, II; Human Osteoblasts II; Human Uterine Cancer; Soares testis NHT;
Soares total fetus Nb2HF8 9w; Human Pancreas Tumor, Reexcision;
Soares fetal lung NbHLI9W; Soares_parathyroid tumor NbHPA;
Soares senescent fibroblasts NbHSF; Liver, Hepatoma; Human Rhabdomyosarcoma; Soares fetal heart_NbHHI9W; Human Thymus; Epithelial-TNFa and INF induced; Hemangiopericytoma; Soares total fetus Nb2HF8 9w;
Human Fetal Brain; Human Whole Six Week Old Embryo; Hepatocellular Tumor, re-excision; NCI CGAP_AAl; NCI CGAP_PrS; NCI CGAP_HSC1;
NCl CGAP_Larl; NCI CGAP_Lip2; 12 Week Old Early Stage Human; Adipocytes;
Soares fetal lung NbHLI9W; Soares_placenta 8to9weeks 2NbHP8to9W;
Soares testis NHT; Human Fetal Kidney, Reexcision; Human Synovial Sarcoma;
Human Fetal Lung III; Endothelial-induced; Soares NhHMPu S1; CD34 depleted Buffy Coat (Cord Blood), re-excision; Colon Normal III; Human retina cDNA
randomly primed sublibrary; NCI CGAP_Br3; NCI CGAP_Ewl; NCI CGAP_GC4;
NCI CGAP_LuS; NCl CGAP_Alvl; NCI CGAP_Brn23;
Soares_pregnant_uterus NbHPU; Anergic T-cell; Human Microvascular Endothelial Cells, fract. A; Smooth muscle,control; HUMAN B CELL LYMPHOMA; Spleen, Chronic lymphocytic leukemia; NCI CLAP CoB; NCI CGAP_GC4;
NCI CGAP_ColO; NCI CGAP_Col2; NCI CGAP_GCB1; NCI CGAP_Kids and Keratinocyte.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:54 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1574 of SEQ 1D
N0:54, b is an integer of 15 to 1588, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:54, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 45 It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Soares melanocyte 2NbHM and to a lesser extent in Soares infant brain 1NIB; Soares_pregnant uterus NbHPU; Human retina cDNA randomly primed sublibrary; normalized infant brain cDNA; Human 8 Week Whole Embryo;
Soares retina N2b4HR; Bone Marrow Stromal Cell, untreated; Human Testes, Reexcision; Human Amygdala; Soares_fetal heart NbHHI9W; Synovial hypoxia;
Myoloid Progenitor Cell Line; Soares NFL T GBC_S1; Soares fetal liver spleen 1NFLS; B Cell lymphoma; Human Infant Brain;
Soares fetal liver spleen_1NFLS S1; Human Pancreas Tumor; Spinal cord; Human Rhabdomyosarcoma; Soares_pregnant uterus NbHPU; Ulcerative Colitis; Human Adrenal Gland Tumor; Soares total fetus Nb2HF8 9w; Normal Human Trabecular Bone Cells; Stratagene fetal retina 937202; Human T-Cell Lymphoma;
NCI CGAP_LuS; NCI CGAP_Ov2; Soares_pregnant uterus NbHPU; Human Endometrial Tumor; Osteoblasts; Nine Week Old Early Stage Human; Human Colon, differential expression; H.Leukocytes, normalized cot 5B; Human Umbilical Vein Endothelial Cells, fract. B; stomach cancer (human); H. Atrophic Endometrium;
Hodgkin's Lymphoma I; HSC172 cells; Human Thyroid; Human Liver; Human T-cell lymphoma,re-excision; Human Normal Breast; Messangial cell, frac 2; Human Tonsils, Lib 2; Stomach cancer (human),re-excision; H Female Bladder, Adult;
Synovial hypoxia-RSF subtracted; Human Amygdala,re-excision; Human Osteoclastoma, re-excision; Human Colon, re-excision; Jurkat T-Cell, S phase;
Synovial Fibroblasts (Ill/TNF), subt; Prostate BPH; Infant brain, Bento Soares;
Human Umbilical Vein, Reexcision; Temporal cortex-Alzheizmer, subtracted;
KMH2; human ovarian cancer; 12 Week Old Early Stage Human, II; Human Osteoblasts II; T-Cell PHA 24 hrs; Stromal cell TF274; Human Hypothalmus,Schizophrenia; Human Adipose; Epithelial-TNFa and INF induced;
Hemangiopericytoma; Human Thymus Stromal Cells; Rejected Kidney, lib 4;
HTCDL1; Soares NhHMPu_S1; Soares senescent fibroblasts NbHSF; Stratagene lung (#937210); Human fetal heart, Lambda ZAP Express; Stratagene ovarian cancer (#937219); Smooth muscle, serum induced,re-exc; Macrophage-oxLDL, re-excision;
Human Gall Bladder; Fetal Heart; Human Ovarian Cancer Reexcision; Soares breast 3NbHBst; Human Placenta; Colon Tumor II; Normal colon;
Soares multiple sclerosis 2NbHMSP; Primary Dendritic cells,frac 2; Endothelial cells-control; NCI CGAP_Kids; Human Osteoclastoma; Smooth muscle,control;
Human Testes and Primary Dendritic Cells, lib 1.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:55 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 3267 of SEQ ID
NO:55, b is an integer of 15 to 3281, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:55, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 46 It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Soares fetal liver spleen 1NFLS and to a lesser extent in NCI CGAP_GCB1; Soares multiple sclerosis 2NbHMSP; NCI CGAP_GCB1;
Colon Tumor II; Human Colon Cancer,re-excision; human ovarian cancer; Stromal cell TF274; Human Bone Marrow, treated; Human Fetal Brain, normalized 50021F;
Adipose tissue (human); LNCAP untreated; stomach cancer (human); CD34 positive cells (cord blood),re-ex; Human Epididymus; Stomach cancer (human),re-excision;
Hepatocellular Tumor,re-excision; Salivary Gland, Lib 2; Myoloid Progenitor Cell Line; Human Adult Small Intestine; Spinal Cord, re-excision; CD34 depleted Buffy Coat (Cord Blood); Soares NhHMPu_S1; TF-1 Cell Line GM-CSFTreated;
Soares_parathyroid tumor NbHPA; Macrophage-oxLDL; Human Chondrosarcoma;
Hepatocellular Tumor, re-excision; Pancreas Islet Cell Tumor; 12 Week Old Early Stage Human; Human T-Cell Lymphoma; Soares breast 3NbHBst; Early Stage Human Brain; Soares testis NHT; Soares NFL T_GBC S1;
Soares_pineal_gland N3HPG; Primary Dendritic cells,frac 2; Human Fetal Heart;
Soares_placenta 8to9weeks 2NbHP8to9W; CD34 depleted Buffy Coat (Cord Blood), re-excision; NCI CLAP GC4; Soares_parathyroid tumor NbHPA;
Soares multiple sclerosis 2NbHMSP; Human Osteoclastoma;
Soares_parathyroid tumor NbHPA; Human Amygdala; CD34 positive cells (Cord Blood); HUMAN B CELL LYMPHOMA; Spleen, Chronic lymphocytic leukemia;
Human Testes; NCI CGAP_Pr9; Activated T-cell(12h)/Thiouridine-re-excision;
Osteoblasts; Human 8 Week Whole Embryo; Human Cerebellum; Soares placenta Nb2HP and Primary Dendritic Cells, lib 1.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:56 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 2152 of SEQ ID
N0:56, b is an integer of 15 to 2166, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:56, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 47 It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Soares_parathyroid_tumor NbHPA and to a lesser extent in Human Prostate Cancer, Stage B2 fraction; H. Kidney Medulla, re-excision;
NCI CGAP_Kid3; NCI CGAP_Brl.l; Soares testis NHT; Soares placenta Nb2HP;
Human Macrophage, subtracted; Soares ovary tumor NbHOT; Colon, normal; Human Adult Pulmonary; Human Colon Cancer,re-excision; Hepatocellular Tumor; Human Prostate Cancer, Stage C fraction; Salivary Gland, Lib 2; Human Colon, re-excision;
Human Adult Small Intestine; CD34 depleted Buffy Coat (Cord Blood);
NCI CGAP_Co3; NCI CGAP_Prl; NCI CGAP_Pr9; NCI CGAP_Kids;

NCI CGAP_Pr4.l; Stratagene pancreas (#937208); Monocyte activated, re-excision;
Human Fetal Kidney; NTERA2, control; Stratagene lung (#937210); Hepatocellular Tumor, re-excision; Human Liver, normal; Colon Carcinoma; Colon Normal II;
Normal colon; Soares NhHMPu_S1; Soares testis NHT;
Soares NSF F8 9W OT PA P Sl; Soares_parathyroid tumor NbHPA; Human Fetal Kidney, Reexcision; Stratagene pancreas (#937208); Primary Dendritic cells,frac 2; Soares_pineal_gland N3HPG and Soares fetal liver spleen 1NFLS.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:57 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1915 of SEQ ID
N0:57, b is an integer of 15 to 1929, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:57, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 48 It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Soares multiple sclerosis 2NbHMSP and to a lesser extent in Soares NhHMPu_S1; Soares placenta Nb2HP; Soares fetal liver spleen 1NFLS;
NCI CGAP_GCB1; Soares breast 3NbHBst; Soares fetal liver spleen_1NFLS S1;
NCI CGAP_Kids; Soares senescent fibroblasts NbHSF; normalized infant brain cDNA; Human Fetal Kidney, Reexcision; Spleen, Chronic lymphocytic leukemia;

Soares fetal liver spleen_1NFLS S1; Soares senescent fibroblasts NbHSF; Soares infant brain 1NIB; Rectum normal; Rectum tumour; NCI CGAP_Br2;
NCI CGAP_Co3; NCI CGAP_LuS; Saos2 Cells, Vitamin D3 Treated; Human Tonsils, Lib 2; HEL cell line; Human Colon Cancer,re-excision; Human Synovium;
Human Stomach,re-excision; Human Fetal Kidney; Human umbilical vein endothelial cells, IL-4 induced; Human Placenta (re-excision); Rejected Kidney, lib 4;
NCI CGAP_Co3; Colon Carcinoma; Normal colon; Soares melanocyte 2NbHM;
Human placenta cDNA (TFujiwara); NCl CGAP_Lym3; STRATAGENE Human skeletal muscle cDNA library, cat. #936215.; Soares fetal lung NbHLI9W; Human Fetal Lung III; Bone marrow; human tonsils; Human Primary Breast Cancer Reexcision; Human Amygdala; NCI CGAP_Ut3; H. Frontal cortex,epileptic,re-excision; T cell helper II; Soares fetal lung NbHLI9W and Soares multiple sclerosis 2NbHMSP.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:58 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1400 of SEQ ID
N0:58, b is an integer of 15 to 1414, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:58, and where b is greater than or equal toga + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 49 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.
gi12746788 (all information available through the recited accession number is S incorporated herein by reference) which is described therein as " contains similarity to transacylases [Caenorhabditis elegans]". A partial alignment demonstrating the observed homology is shown immediately below.
>gi~2746788 (AF040642) contains similarity to transacylases [Caenorhabditis elegans] >sp~044793~044793 C50D2.7 PROTEIN.
Length = 895 Plus Strand HSPs:
Score = 603 (212.3 bits), Expect = 1.0e-57, P = 1.0e-57 Identities = 144/408 (35~), Positives = 228/408 (55~), Frame = +1 Q: 310 LSGVKLLQALGLSPGNGKDHSILHSRNDLEEAFIHFMGKGAAAERFFSDKETFHDIAQVA 489 ZO +SGV+++ AL + GKD L + DL + F HF +GAAAER+ S ++ F+ + +
S: 79 VSGVRWDALNTTCSEGKDQETLETLADLHQTFAHFFQRGAAAERYMSSEDQFNLLVAES 138 Q: 490 SEFPGAQHYVGGNAALIGQKFAAN-SDLKVLLCGPVGPKLHELLDDNVFVPPESLQEVDE 666 + H++GGNAAL+ + AAN +V L GP+GP+ LL +V + DE
ZS S: 139 EASTRSHHHIGGNAALMADRIAANFPSTEVYLVGPIGPRSQALLHPSVKRTNSTRILKDE 198 Q: 667 FHLILEYQAGEEWGQLKAPHANRFIFSHDLSNGAMNMLEVFVSSLEEFQPDLWLSGLHM 846 H+ILEY+ GE G AP ++RFI SHD +G+M ++E+F ++ +F+PDLW++G+H+
S: 199 LHVILEYKQGEILGDWVAPSSSRFITSHDHFSGSMWMEMFFKAIAQFRPDLWITGVHL 258 Q: 847 MEGQSKELQRKRLLEWTSISDIPTGIPVHLELASMTNRELMSSIVHQQVFPAVTSLGLN 1026 +E QSKE++++++ + ++ IP +P+HLEL S+ + E+ S+ V ++ p V SLG+N
S:' 259 LEFQSKEMRQEKMRLIKRNLLQIPPKVPIHLELGSLAD-EIFSTDVINKILPYVDSLGIN 317 3S Q: 1027 EQELLFLTQSASGPH-SSLSSWNGVPDVGMVSDILFWILKEHGRSKSR--ASD----LTR 1185 EQEL FL+ A+GPH G V V ++L W+LK +GR + AS L+R
S: 318 EQELTFLSHIANGPHMEEYPVQAGTVHVHKWEMLHWLLKTYGRDPTGQIASKTGYRLSR 377 Q: 1186 IHFHTLVYHILATVDGHWXXXXXXXXXXXXXXXXXX--XXTETIDTSRVSLRAPQEFMTS 1359 4O IHFH L YHI+ + W T+D+ + +R P F+
S: 378 IHFHCLTYHIMVSSGTDWSNLAAGLAAGARIAGRLSCNIGANTMDSELLEIRTPANFVLD 437 Q: 1360 HSEAGSRIVLNPNKPWEWHREGISFHFTPVLVCKDPIRTVGL---GDAISAEGLFYSEV 1530 +I N E H+ + TP + + R + G I EG+ +S+V
4S S: 438 -----KKIEKNYQ---FEAHK----YMLTPFNIARCSTRLIRRKPPGGGILDEGVTFSDV 485 Q: 1531 H 1533 H

S: 486 H 486 The segment of gi12746788 that is shown as "S" above is set out in the sequence listing as SEQ ID NO. 181 . Based on the structural similarity, these homologous polypeptides are expected to share at least some biological activities.
Such activities are known in the art, some of which are described elsewhere herein.
Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
Preferred polypeptides of the invention comprise a polypeptide having the amino acid sequence set out in the sequence listing as SEQ ID NO. 182 which corresponds to the "Q" sequence in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed).
It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Human Endometrial Tumor and to a lesser extent in Primary Dendritic Cells, lib 1; Soares fetal liver spleen 1NFLS; Monocyte activated;
normalized infant brain cDNA; Activated T-cell(12h)/Thiouridine-re-excision;
Soares infant brain 1NIB; Soares fetal heart NbHHI9W; Human Testes Tumor; Human 8 Week Whole Embryo; Nine Week Old Early Stage Human; Human Skin Tumor;
NCI CGAP_Co3; 12 Week Old Early Stage Human, II; HUMAN JURKAT
MEMBRANE BOUND POLYSOMES; NCI CGAP_Kid3; Soares testis NHT;
Soares_parathyroid tumor NbHPA; Soares fetal liver spleen_1NFLS S1;
Stratagene liver (#937224); Soares melanocyte 2NbHM; human tonsils; Human Bone Marrow, treated; Soares fetal lung NbHLI9W; Soares fetal heart_NbHHI9W;
Soares_pregnant_uterus NbHPU; LNCAP untreated; prostate-edited; Human Adult Spleen; NCI CGAP_GC6; NCI CGAP_Utl; NCI CGAP_Panl;
NCI CGAP_Brn23; NCI CGAP_Brn25; NCI CGAP_Kidl l; NCl CGAP_Lyml2;

l40 Soares_placenta 8to9weeks 2NbHP8to9W; Papillary serous cystic neoplasm of low malignant potential (ovary); Human Lung Cancer,re-excision; Apoptotic T-cell, re-excision; pBMC stimulated w/ poly I/C; Human Umbilical Vein, Endo. remake;
Jurkat T-Cell, S phase; Synovial Fibroblasts (Il1/TNF), subt; H. Lymph node breast Cancer; Mo7e Cell Line GM-CSF treated (lng/ml); NCI CGAP_PrB; Monocyte activated, re-excision; L428; Human adult (K.Okubo); NCI CGAP_Br2;
NC1 CGAP_GC3; NCI CGAP_GC4; NCI CGAP_GCS; NCI CGAP_LuS;
NCI CLAP Pr2; NCI CGAP_CLL1; NCl CGAP_GCB 1; NCI CGAP_Brn23;
Human Umbilical Vein Endothelial Cells, uninduced;
Soares total fetus Nb2HF8 9w; Human Pancreas Tumor, Reexcision; Human umbilical vein endothelial cells, IL-4 induced; Human Testes Tumor, re-excision;
Bone Marrow Stromal Cell, untreated; Rejected Kidney, lib 4; Stratagene lung (#937210); Soares_pineal_gland_N3HPG; Human Synovial Sarcoma; Primary Dendritic cells,frac 2; Human Testes, Reexcision; Human Placenta; Human Neutrophil, Activated; Endothelial-induced; Colon Normal III;
Soares_parathyroid tumor NbHPA; Human Microvascular Endothelial Cells, fract.
A; Spleen, Chronic lymphocytic leukemia; Soares_parathyroid tumor NbHPA;
Neutrophils IL-1 and LPS induced; Hodgkin's Lymphoma II; NCl CGAP_GC4;
NCI CGAP_Ut2; NCI CGAP_Panl; NCI CGAP_Kidl l; Human fetal heart, Lambda ZAP Express; Osteoblasts; Keratinocyte; Human Cerebellum and NCI CGAP GCB 1.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ 1D NO: 109 as residues: Trp-1 to Ser-15. Polynucleotides encoding said polypeptides are also provided.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:59 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 2594 of SEQ ID
N0:59, b is an integer of 15 to 2608, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:59, and where b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 50 The computer algorithm BLASTX has been used to determine that the translation product of this gene shares sequence homology with, as a non-limiting example, the sequence accessible through the following database accession no.
gnlIPIDIe1355127 (all information available through the recited accession number is incorporated herein by reference) which is described therein as "matrilin-4 [Homo sapiens]". A partial alignment demonstrating the observed homology is shown immediately below.
>gnl~PID~e1355127 (AJ007581) matrilin-4 [Homo sapiensl >sp~E1355127~E1355127 MATRILIN-4.
Length = 581 Plus Strand HSPs:
Score = 1464 (515.4 bits), Expect = 1.0e-230, Sum P(2) = 1.0e-230 Identities = 284/287 (98$), Positives = 284/287 (98~), Frame = +2 Q: 782 CXVRDLCNGVDHGCEFQCVSEGLSYRCLCPEGRQLQADGKSCNRCREGHVDLVLLVDGSK 961 S: 295 CQVRDLCNGVDHGCEFQCVSEGLSYRCLCPEGRQLQADGKSCNRCREGHVDLVLLVDGSK 354 Q: 962 SVRPQNFELVKRFVNQIVDFLDVSPEGTRVGLVQFSSRVRTEFPLGRYGTAAEVKQAVLA 1141 SVRPQNFELVKRFVNQIVDFLDVSPEGTRVGLVQFSSRVRTEFPLGRYGTAAEVKQAVLA
3S S: 355 SVRPQNFELVKRFVNQIVDFLDVSPEGTRVGLVQFSSRVRTEFPLGRYGTAAEVKQAVLA 414 S
Q: 1142 VEYMERGTMTGLALRHMVEHSFSEAQGARPRALNVPRVGLVFTDGRSQDDISVWAARAKE 1321 VEYMERGTMTGLALRHMVEHSFSEAQGARPRALNVPRVGLVFTDGRSQDDISVWAARAKE
S: 415 VEYMERGTMTGLALRHMVEHSFSEAQGARPRALNVPRVGLVFTDGRSQDDISVWAARAKE 474 Q: 1322 EGIVMYAXGVGKAVEAELREIASEPAELHVSYAPDFGTMTHLLENLRSSICPEEGISAGT 1501 EGIVMYA GVGKAVEAELREIASEPAELHVSYAPDFGTMTHLLENLR SICPEEGISAGT
S: 475 EGIVMYAVGVGKAVEAELREIASEPAELHVSYAPDFGTMTHLLENLRGSICPEEGISAGT 534 1O Q: 1502 ELRSPCECESLVEFQGRTLGALESLTLNLAQLTARLEDLENQLANQK 1642 ELRSPCECESLVEFQGRTLGALESLTLNLAQLTARLEDLENQLANQK
S: 535 ELRSPCECESLVEFQGRTLGALESLTLNLAQLTARLEDLENQLANQK 581 Score = 791 (278.4 bits), Expect = 1.0e-230, Sum P(2) = 1.0e-230 1S Identities = 166/213 (77~), Positives = 166/213 (77~), Frame = +1 Q: 145 MRGXXXXXXXXXXXQPWETQLQLTGPRCHTXXLDLVXVIDSSRSVRPFEFETMRQFLMGL 324 MRG QPWETQLQLTGPRCHT LDLV VIDSSRSVRPFEFETMRQFLMGL
S: 1 MRGLLCWPVLLLLLQPWETQLQLTGPRCHTGPLDLVFVIDSSRSVRPFEFETMRQFLMGL 60 Q: 325 LRGLNVGPNATRVGVIQYSSQVQSVFPLRAFSRREDMERAIRDLVPLAQGTMTGLAIQYA 504 LRGLNVGPNATRVGVIQYSSQVQSVFPLRAFSRREDMERAIRDLVPLAQGTMTGLAIQYA
S: 61 LRGLNVGPNATRVGVIQYSSQVQSVFPLRAFSRREDMERAIRDLVPLAQGTMTGLAIQYA 120 2S Q: 505 MNVAFSXXXXXXXXXXXXXXXXXIVTDGXXXXXXXXXXXXXXXXGIEIYAVGVQRADVGS 684 MNVAFS IVTDG GIEIYAVGVQRADVGS
S: 121 MNVAFSVAEGARPPEERVPRVAVIVTDGRPQDRVAEVAAQARASGIEIYAVGVQRADVGS 180 Q: 685 LRAMASPPLDEHVFLVESFDLIQEFGLQFQSRL 783 S: 181 LRAMASPPLDEHVFLVESFDLIQEFGLQFQSRL 213 Score = 374 (131.7 bits), Expect = 3.6e-32, P = 3.6e-32 Identities = 82/213 (38$), Positives = 129/213 (60$), Frame = +2 Q: 863 LCPEGRQLQADGKSCNRCREGHVDLVLLVDGSKSVRPQNFELVKRFVNQIVDFLDVSPEG 1042 L P QLQ G RC G +DLV ++D S+SVRP FE +++F+ ++ L+V P
S: 14 LQPWETQLQLTGP---RCHTGPLDLVFVIDSSRSVRPFEFETMRQFLMGLLRGLNVGPNA 70 4O Q: 1043 TRVGLVQFSSRVRTEFPLGRYGTAAEVKQAVLAVEYMERGTMTGLALRHMVEHSFSEAQG 1222 TRVG++Q+SS+V++ FPL + ++++A+ + + +GTMTGLA+++ + +FS A+G
S: 71 TRVGVIQYSSQVQSVFPLRAFSRREDMERAIRDLVPLAQGTMTGLAIQYAMNVAFSVAEG 130 Q: 1223 ARPRALNVPRVGLVFTDGRSQDDISVWAARAKEEGIVMYAXGVGKAVEAELREIASEPAE 1402 4S ARP VPRV ++ TDGR QD ++ AA+A+ GI +YA GV +A LR +AS P +
S: 131 ARPPEERVPRVAVIVTDGRPQDRVAEVAAQARASGIEIYAVGVQRADVGSLRAMASPPLD 190 Q: 1403 LHVSYAPDFGTMTHLLENLRSSICPEEGISAGT 1501 HV F + +S +C + + GT
SO S: 191 EHVFLVESFDLIQEFGLQFQSRLCAIDLCAEGT 223 The segments of gnlIPIDIe13SS127 that are shown as "S" above are set out in the sequence listing as SEQ ID NO. 183,SEQ ID NO. 18S and SEQ ID NO.

187 . Based on the structural similarity, these homologous polypeptides are expected to share at least some biological activities. Such activities are known in the art, some of which are described elsewhere herein. Assays for determining such activities are also known in the art, some of which have been described elsewhere herein.
Preferred polypeptides of the invention comprise a polypeptide having the amino acid sequence set out in the sequence listing as SEQ ID NO. 184,SEQ ID
NO.
186 and/or SEQ ID NO. 188 which correspond to the "Q" sequences in the alignment shown above (gaps introduced in a sequence by the computer are, of course, removed).
It has been discovered that this gene is expressed primarily in the following tissues/cDNA libraries: Human Fetal Dura Mater; Human Whole Six Week Old Embryo; Human Fetal Lung III.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:60 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence would be cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1986 of SEQ ID
N0:60, b is an integer of 15 to 2000, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:60, and where b is greater than or equal to a + 14.

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x x x x x x Table 1 summarizes the information corresponding to each "Gene No." described above. The nucleotide sequence identified as "NT SEQ ID NO:X" was assembled from partially homologous ("overlapping") sequences obtained from the "cDNA
clone ID" identified in Table 1 and, in some cases, from additional related DNA
clones. The overlapping sequences were assembled into a single contiguous sequence of high redundancy (usually three to five overlapping sequences at each nucleotide position), resulting in a final sequence identified as SEQ ID NO:X.
The cDNA Clone ID was deposited on the date and given the corresponding deposit number listed in "ATCC Deposit No:Z and Date." Some of the deposits contain multiple different clones corresponding to the same gene. "Vector"
refers to the type of vector contained in the cDNA Clone ID.
"Total NT Seq." refers to the total number of nucleotides in the contig identified by "Gene No." The deposited clone may contain all or most of these sequences, reflected by the nucleotide position indicated as "5' NT of Clone Seq."
and the "3' NT of Clone Seq." of SEQ ID NO:X. The nucleotide position of SEQ
ID
NO:X of the putative start codon (methionine) is identified as "5' NT of Start Codon."
Similarly , the nucleotide position of SEQ ID NO:X of the predicted signal sequence is identified as "5' NT of First AA of Signal Pep."
The translated amino acid sequence, beginning with the methionine, is identified as "AA SEQ ID NO:Y," although other reading frames can also be easily translated using known molecular biology techniques. The polypeptides produced by these alternative open reading frames are specifically contemplated by the present invention.
The first and last amino acid position of SEQ ID NO:Y of the predicted signal peptide is identified as "First AA of Sig Pep" and "Last AA of Sig Pep." The predicted first amino acid position of SEQ ID NO:Y of the secreted portion is identified as "Predicted First AA of Secreted Portion." Finally, the amino acid position of SEQ ID NO:Y of the last amino acid in the open reading frame is identified as "Last AA of ORF."
SEQ ID NO:X (where X may be any of the polynucleotide sequences disclosed in the sequence listing) and the translated SEQ ID NO:Y (where Y may be any of the polypeptide sequences disclosed in the sequence listing) are sufficiently accurate and otherwise suitable for a variety of uses well known in the art and described further below. For instance, SEQ ID NO:X is useful for designing nucleic acid hybridization probes that will detect nucleic acid sequences contained in SEQ ID
NO:X or the cDNA contained in the deposited clone. These probes will also hybridize to nucleic acid molecules in biological samples, thereby enabling a variety of forensic and diagnostic methods of the invention. Similarly, polypeptides identified from SEQ ID NO:Y may be used, for example, to generate antibodies which bind specifically to proteins containing the polypeptides and the secreted proteins encoded by the cDNA clones identified in Table 1.
Nevertheless, DNA sequences generated by sequencing reactions can contain sequencing errors. The errors exist as misidentified nucleotides, or as insertions or deletions of nucleotides in the generated DNA sequence. The erroneously inserted or deleted nucleotides cause frame shifts in the reading frames of the predicted amino acid sequence. In these cases, the predicted amino acid sequence diverges from the actual amino acid sequence, even though the generated DNA sequence may be greater than 99.9% identical to the actual DNA sequence (for example, one base insertion or deletion in an open reading frame of over 1000 bases).
Accordingly, for those applications requiring precision in the nucleotide sequence or the amino acid sequence, the present invention provides not only the generated nucleotide sequence identified as SEQ ID NO:X and the predicted translated amino acid sequence identified as SEQ ID NO:Y, but also a sample of plasmid DNA containing a human cDNA of the invention deposited with the ATCC, as set forth in Table 1. The nucleotide sequence of each deposited clone can readily be determined by sequencing the deposited clone in accordance with known methods.
The predicted amino acid sequence can then be verified from such deposits.
Moreover, the amino acid sequence of the protein encoded by a particular clone can also be directly determined by peptide sequencing or by expressing the protein in a suitable host cell containing the deposited human cDNA, collecting the protein, and determining its sequence.
The present invention also relates to the genes corresponding to SEQ ID
NO:X, SEQ ID NO:Y, or the deposited clone. The corresponding gene can be isolated in accordance with known methods using the sequence information disclosed herein. Such methods include preparing probes or primers from the disclosed sequence and identifying or amplifying the corresponding gene from appropriate sources of genomic material.
Also provided in the present invention are allelic variants, orthologs, and/or species homologs. Procedures known in the art can be used to obtain full-length genes, allelic variants, splice variants, full-length coding portions, orthologs, and/or species homologs of genes corresponding to SEQ ID NO:X, SEQ ID NO:Y, or a deposited clone, using information from the sequences disclosed herein or the clones deposited with the ATCC. For example, allelic variants and/or 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 for allelic variants and/or the desired homologue.
The polypeptides of the invention can be prepared in any suitable manner.
Such polypeptides include isolated naturally occurring polypeptides, recombinantly produced polypeptides, synthetically produced polypeptides, or polypeptides produced by a combination of these methods. Means for preparing such polypeptides are well understood in the art.
The polypeptides may be in the form of the secreted protein, including the mature form, or may be a part of a larger protein, such as a fusion protein (see below).
It is often advantageous to include an additional amino acid sequence which contains secretory or leader sequences, pro-sequences, sequences which aid in purification , such as multiple histidine residues, or an additional sequence for stability during recombinant production.
The polypeptides of the present invention are preferably provided in an isolated form, and preferably are substantially purified. A recombinantly produced version of a polypeptide, including the secreted polypeptide, can be substantially purified using techniques described herein or otherwise known in the art, such as, for example, by the one-step method described in Smith and Johnson, Gene 67:31-40 (1988). Polypeptides of the invention also can be purified from natural, synthetic or recombinant sources using techniques described herein or otherwise known in the art, such as, for example, antibodies of the invention raised against the secreted protein.
The present invention provides a polynucleotide comprising, or alternatively consisting of, the nucleic acid sequence of SEQ ID NO:X, and/or a cDNA
contained in ATCC deposit Z. The present invention also provides a polypeptide comprising, or alternatively, consisting of, the polypeptide sequence of SEQ ID NO:Y and/or a polypeptide encoded by the cDNA contained in ATCC deposit Z. Polynucleotides encoding a polypeptide comprising, or alternatively consisting of the polypeptide sequence of SEQ ID NO:Y and/or a polypeptide sequence encoded by the cDNA
contained in ATCC deposit Z are also encompassed by the invention.
Signal Sequences The present invention also encompasses mature forms of the polypeptide having the polypeptide sequence of SEQ ID NO:Y and/or the polypeptide sequence encoded by the cDNA in a deposited clone. Polynucleotides encoding the mature forms (such as, for example, the polynucleotide sequence in SEQ ID NO:X and/or the polynucleotide sequence contained in the cDNA of a deposited clone) are also encompassed by the invention. According to the signal hypothesis, proteins secreted by mammalian cells have a signal or secretary leader sequence which is cleaved from the mature protein once export of the growing protein chain across the rough endoplasmic reticulum has been initiated. Most mammalian cells and even insect cells cleave secreted proteins with the same specificity. However, in some cases, cleavage of a secreted protein is not entirely uniform, which results in two or more mature species of the protein. Further, it has long been known that cleavage specificity of a secreted protein is ultimately determined by the primary structure of the complete protein, that is, it is inherent in the amino acid sequence of the polypeptide.
Methods for predicting whether a protein has a signal sequence, as well as the cleavage point for that sequence, are available. For instance, the method of McGeoch, Virus Res. 3:271-286 (1985), uses the information from a short N-terminal charged region and a subsequent uncharged region of the complete (uncleaved) protein. The method of von Heinje, Nucleic Acids Res. 14:4683-4690 (1986) uses the information from the residues surrounding the cleavage site, typically residues -13 to +2, where +1 indicates the amino terminus of the secreted protein. The accuracy of predicting the cleavage points of known mammalian secretory proteins for each of these methods is in the range of 75-80%. (von Heinje, supra.) However, the two methods do not always produce the same predicted cleavage points) for a given protein.

In the present case, the deduced amino acid sequence of the secreted polypeptide was analyzed by a computer program called SignalP (Henrik Nielsen et al., Protein Engineering 10:1-6 (1997)), which predicts the cellular location of a protein based on the amino acid sequence. As part of this computational prediction of localization, the methods of McGeoch and von Heinje are incorporated. The analysis of the amino acid sequences of the secreted proteins described herein by this program provided the results shown in Table 1.
As one of ordinary skill would appreciate, however, cleavage sites sometimes vary from organism to organism and cannot be predicted with absolute certainty.
Accordingly, the present invention provides secreted polypeptides having a sequence shown in SEQ ID NO:Y which have an N-terminus beginning within 5 residues (i.e., + or - 5 residues) of the predicted cleavage point. Similarly, it is also recognized that in some cases, cleavage of the signal sequence from a secreted protein is not entirely uniform, resulting in more than one secreted species. These polypeptides, and the polynucleotides encoding such polypeptides, are contemplated by the present invention.
Moreover, the signal sequence identified by the above analysis may not necessarily predict the naturally occurring signal sequence. For example, the naturally occurring signal sequence may be further upstream from the predicted signal sequence. However, it is likely that the predicted signal sequence will be capable of directing the secreted protein to the ER. Nonetheless, the present invention provides the mature protein produced by expression of the polynucleotide sequence of SEQ ID
NO:X and/or the polynucleotide sequence contained in the cDNA of a deposited clone, in a mammalian cell (e.g., COS cells, as desribed below). These polypeptides, and the polynucleotides encoding such polypeptides, are contemplated by the present invention.

Polynucleotide and Polype_ptide Variants The present invention is directed to variants of the polynucleotide sequence disclosed in SEQ ID NO:X, the complementary strand thereto, and/or the cDNA
sequence contained in a deposited clone.
The present invention also encompasses variants of the polypeptide sequence disclosed in SEQ ID NO:Y and/or encoded by a deposited clone.
"Variant" refers to a polynucleotide or polypeptide differing from the polynucleotide or polypeptide of the present invention, but retaining essential properties thereof. Generally, variants are overall closely similar, and, in many regions, identical to the polynucleotide or polypeptide of the present invention.
The present invention is also directed to nucleic acid molecules which comprise, or alternatively consist of, a nucleotide sequence which is at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to, for example, the nucleotide coding sequence in SEQ ID NO:X or the complementary strand thereto, the nucleotide coding sequence contained in a deposited cDNA clone or the complementary strand thereto, a nucleotide sequence encoding the polypeptide of SEQ ID NO:Y, a nucleotide sequence encoding the polypeptide encoded by the cDNA contained in a deposited clone, and/or polynucleotide fragments of any of these nucleic acid molecules (e.g., those fragments described herein).
Polynucleotides which hybridize to these nucleic acid molecules under stringent hybridization conditions or lower stringency conditions are also encompassed by the invention, as are polypeptides encoded by these polynucleotides.
The present invention is also directed to polypeptides which comprise, or alternatively consist of, an amino acid sequence which is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to, for example, the polypeptide sequence shown in SEQ ID NO:Y, the polypeptide sequence encoded by the cDNA contained in a deposited clone, and/or polypeptide fragments of any of these polypeptides (e.g., those fragments described herein).
By a nucleic acid having a nucleotide sequence at least, for example, 95%
"identical" to a reference nucleotide sequence of the present invention, it is intended that the nucleotide sequence of the nucleic acid is identical to the reference sequence except that the nucleotide sequence may include up to five point mutations per each 100 nucleotides of the reference nucleotide sequence encoding the polypeptide.
In other words, to obtain a nucleic acid having a nucleotide sequence at least 95%
identical to a reference nucleotide sequence, up to 5% of the nucleotides in the reference sequence may be deleted or substituted with another nucleotide, or a number of nucleotides up to 5% of the total nucleotides in the reference sequence may be inserted into the reference sequence. The query sequence may be an entire sequence shown inTable l, the ORF (open reading frame), or any fragment specified as described herein.
As a practical matter, whether any particular nucleic acid molecule or polypeptide is at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to a nucleotide sequence of the presence invention can be determined conventionally using known computer programs. A preferred method for determining the best overall match between a query sequence (a sequence of the present invention) and a subject sequence, also referred to as a global sequence alignment, can be determined using the FASTDB computer program based on the algorithm of Brutlag et al.
(Comp.
App. Biosci. 6:237-245(1990)). In a sequence alignment the query and subject sequences are both DNA sequences. An RNA sequence can be compared by converting U's to T's. The result of said global sequence alignment is in percent identity. Preferred parameters used in a FASTDB alignment of DNA sequences to calculate percent identiy are: Matrix=Unitary, k-tuple=4, Mismatch Penalty=1, Joining Penalty=30, Randomization Group Length=0, Cutoff Score=1, Gap Penalty=5, Gap Size Penalty 0.05, Window Size=500 or the lenght of the subject nucleotide sequence, whichever is shorter.
If the subject sequence is shorter than the query sequence because of 5' or 3' deletions, not because of internal deletions, a manual correction must be made to the results. This is because the FASTDB program does not account for 5' and 3' truncations of the subject sequence when calculating percent identity. For subject sequences truncated at the 5' or 3' ends, relative to the query sequence, the percent identity is corrected by calculating the number of bases of the query sequence that are

5' and 3' of the subject sequence, which are not matched/aligned, as a percent of the total bases of the query sequence. Whether a nucleotide is matched/aligned is determined by results of the FASTDB sequence alignment. This percentage is then subtracted from the percent identity, calculated by the above FASTDB program using the specified parameters, to arrive at a final percent identity score. This corrected score is what is used for the purposes of the present invention. Only bases outside the 5' and 3' bases of the subject sequence, as displayed by the FASTDB alignment, which are not matched/aligned with the query sequence, are calculated for the purposes of manually adjusting the percent identity score.
For example, a 90 base subject sequence is aligned to a 100 base query sequence to determine percent identity. The deletions occur at the 5' end of the subject sequence and therefore, the FASTDB alignment does not show a matched/alignment of the first 10 bases at 5' end. The 10 unpaired bases represent 10% of the sequence (number of bases at the 5' and 3' ends not matched/total number of bases in the query sequence) so 10% is subtracted from the percent identity score calculated by the FASTDB program. If the remaining 90 bases were perfectly matched the final percent identity would be 90%. In another example, a 90 base subject sequence is compared with a 100 base query sequence. This time the deletions are internal deletions so that there are no bases on the 5' or 3' of the subject sequence which are not matched/aligned with the query. In this case the percent identity calculated by FASTDB is not manually corrected. Once again, only bases 5' and 3' of the subject sequence which are not matched/aligned with the query sequence are manually corrected for. No other manual corrections are to made for the purposes of the present invention.
By a polypeptide having an amino acid sequence at least, for example, 95%
"identical" to a query amino acid sequence of the present invention, it is intended that the amino acid sequence of the subject polypeptide is identical to the query sequence except that the subject polypeptide sequence may include up to five amino acid alterations per each 100 amino acids of the query amino acid sequence. In other words, to obtain a polypeptide having an amino acid sequence at least 95%
identical to a query amino acid sequence, up to 5% of the amino acid residues in the subject sequence may be inserted, deleted, (indels) or substituted with another amino acid.
These alterations of the reference sequence may occur at the amino or carboxy terminal positions of the reference amino acid sequence or anywhere between those terminal positions, interspersed either individually among residues in the reference sequence or in one or more contiguous groups within the reference sequence.
As a practical matter, whether any particular polypeptide is at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to, for instance, an amino acid sequences shown in Table 1 (SEQ ID NO:Y) or to the amino acid sequence encoded by cDNA contained in a deposited clone can be determined conventionally using known computer programs. A preferred method for determing the best overall match between a query sequence (a sequence of the present invention) and a subject sequence, also referred to as a global sequence alignment, can be determined using the FASTDB computer program based on the algorithm of Brutlag et al. (Comp.
App.
Biosci. 6:237-245(1990)). In a sequence alignment the query and subject sequences are either both nucleotide sequences or both amino acid sequences. The result of said S global sequence alignment is in percent identity. Preferred parameters used in a FASTDB amino acid alignment are: Matrix=PAM 0, k-tuple=2, Mismatch Penalty=1, Joining Penalty=20, Randomization Group Length=0, Cutoff Score=1, Window Size=sequence length, Gap Penalty=5, Gap Size Penalty=0.05, Window Size=500 or the length of the subject amino acid sequence, whichever is shorter.
if the subject sequence is shorter than the query sequence due to N- or C-terminal deletions, not because of internal deletions, a manual correction must be made to the results. This is because the FASTDB program does not account for N-and C-terminal truncations of the subject sequence when calculating global percent identity. For subject sequences truncated at the N- and C-termini, relative to the query sequence, the percent identity is corrected by calculating the number of residues of the query sequence that are N- and C-terminal of the subject sequence, which are not matched/aligned with a corresponding subject residue, as a percent of the total bases of the query sequence. Whether a residue is matched/aligned is determined by results of the FASTDB sequence alignment. This percentage is then subtracted from the percent identity, calculated by the above FASTDB program using the specified parameters, to arrive at a final percent identity score. This final percent identity score is what is used for the purposes of the present invention. Only residues to the N- and C-termini of the subject sequence, which are not matched/aligned with the query sequence, are considered for the purposes of manually adjusting the percent identity score. That is, only query residue positions outside the farthest N- and C-terminal residues of the subject sequence.

For example, a 90 amino acid residue subject sequence is aligned with a 100 residue query sequence to determine percent identity. The deletion occurs at the N-terminus of the subject sequence and therefore, the FASTDB alignment does not show a matching/alignment of the first 10 residues at the N-terminus. The 10 unpaired residues represent 10% of the sequence (number of residues at the N-and C-termini not matched/total number of residues in the query sequence) so 10% is subtracted from the percent identity score calculated by the FASTDB program.
If the remaining 90 residues were perfectly matched the final percent identity would be 90%. In another example, a 90 residue subject sequence is compared with a 100 residue query sequence. This time the deletions are internal deletions so there are no residues at the N- or C-termini of the subject sequence which are not matched/aligned with the query. In this case the percent identity calculated by FASTDB is not manually corrected. Once again, only residue positions outside the N- and C-terminal ends of the subject sequence, as displayed in the FASTDB alignment, which are not matched/aligned with the query sequnce are manually corrected for. No other manual corrections are to made for the purposes of the present invention.
The variants may contain alterations in the coding regions, non-coding regions, or both. Especially preferred are polynucleotide variants containing alterations which produce silent substitutions, additions, or deletions, but do not alter the properties or activities of the encoded polypeptide. Nucleotide variants produced by silent substitutions due to the degeneracy of the genetic code are preferred.
Moreover, variants in which 5-10, 1-5, or 1-2 amino acids are substituted, deleted, or added in any combination are also preferred. Polynucleotide variants can be produced for a variety of reasons, e.g., to optimize codon expression for a particular host (change codons in the human mRNA to those preferred by a bacterial host such as E.
coli).

Naturally occurring variants are called "allelic variants," and refer to one of several alternate forms of a gene occupying a given locus on a chromosome of an organism. (Genes II, Lewin, B., ed., John Wiley & Sons, New York (1985).) These allelic variants can vary at either the polynucleotide and/or polypeptide level and are included in the present invention. Alternatively, non-naturally occurring variants may be produced by mutagenesis techniques or by direct synthesis.
Using known methods of protein engineering and recombinant DNA
technology, variants may be generated to improve or alter the characteristics of the polypeptides of the present invention. For instance, one or more amino acids can be deleted from the N-terminus or C-terminus of the secreted protein without substantial loss of biological function. The authors of Ron et al., J. Biol. Chem. 268:

(1993), reported variant KGF proteins having heparin binding activity even after deleting 3, 8, or 27 amino-terminal amino acid residues. Similarly, Interferon gamma exhibited up to ten times higher activity after deleting 8-10 amino acid residues from the carboxy terminus of this protein. (Dobeli et al., J. Biotechnology 7:199-(1988).) Moreover, ample evidence demonstrates that variants often retain a biological activity similar to that of the naturally occurring protein. For example, Gayle and coworkers (J. Biol. Chem 268:22105-22111 (1993)) conducted extensive mutational analysis of human cytokine IL-la. They used random mutagenesis to generate over 3,500 individual IL-la mutants that averaged 2.5 amino acid changes per variant over the entire length of the molecule. Multiple mutations were examined at every possible amino acid position. The investigators found that "[m]ost of the molecule could be altered with little effect on either [binding or biological activity]." (See, Abstract.) In fact, only 23 unique amino acid sequences, out of more than 3,500 nucleotide sequences examined, produced a protein that significantly differed in activity from wild-type.
Furthermore, even if deleting one or more amino acids from the N-terminus or C-terminus of a polypeptide results in modification or loss of one or more biological functions, other biological activities may still be retained. For example, the ability of a deletion variant to induce and/or to bind antibodies which recognize the secreted form will likely be retained when less than the majority of the residues of the secreted form are removed from the N-terminus or C-terminus. Whether a particular polypeptide lacking N- or C-terminal residues of a protein retains such immunogenic activities can readily be determined by routine methods described herein and otherwise known in the art.
Thus, the invention further includes polypeptide variants which show substantial biological activity. Such variants include deletions, insertions, inversions, repeats, and substitutions selected according to general rules known in the art so as have little effect on activity. For example, guidance concerning how to make phenotypically silent amino acid substitutions is provided in Bowie et al., Science 247:1306-1310 (1990), wherein the authors indicate that there are two main strategies for studying the tolerance of an amino acid sequence to change.
The first strategy exploits the tolerance of amino acid substitutions by natural selection during the process of evolution. By comparing amino acid sequences in different species, conserved amino acids can be identified. These conserved amino acids are likely important for protein function. In contrast, the amino acid positions where substitutions have been tolerated by natural selection indicates that these positions are not critical for protein function. Thus, positions tolerating amino acid substitution could be modified while still maintaining biological activity of the protein.

The second strategy uses genetic engineering to introduce amino acid changes at specific positions of a cloned gene to identify regions critical for protein function.
For example, site directed mutagenesis or alanine-scanning mutagenesis (introduction of single alanine mutations at every residue in the molecule) can be used.
(Cunningham and Wells, Science 244:1081-1085 (1989).) The resulting mutant molecules can then be tested for biological activity.
As the authors state, these two strategies have revealed that proteins are surprisingly tolerant of amino acid substitutions. The authors further indicate which amino acid changes are likely to be permissive at certain amino acid positions in the protein. For example, most buried (within the tertiary structure of the protein) amino acid residues require nonpolar side chains, whereas few features of surface side chains are generally conserved. Moreover, tolerated conservative amino acid substitutions involve replacement of the aliphatic or hydrophobic amino acids Ala, Val, Leu and Ile; replacement of the hydroxyl residues Ser and Thr; replacement of the acidic residues Asp and Glu; replacement of the amide residues Asn and Gln, replacement of the basic residues Lys, Arg, and His; replacement of the aromatic residues Phe, Tyr, and Trp, and replacement of the small-sized amino acids Ala, Ser, Thr, Met, and Gly.
Besides conservative amino acid substitution, variants of the present invention include (i) substitutions with one or more of the non-conserved amino acid residues, where the substituted amino acid residues may or may not be one encoded by the genetic code, or (ii) substitution with one or more of amino acid residues having a substituent group, or (iii) fusion of the mature polypeptide with another compound, such as a compound to increase the stability and/or solubility of the polypeptide (for example, polyethylene glycol), or (iv) fusion of the polypeptide with additional amino acids, such as, for example, an IgG Fc fusion region peptide, or leader or secretory sequence, or a sequence facilitating purification. Such variant polypeptides are deemed to be within the scope of those skilled in the art from the teachings herein.
For example, polypeptide variants containing amino acid substitutions of charged amino acids with other charged or neutral amino acids may produce proteins with improved characteristics, such as less aggregation. Aggregation of pharmaceutical formulations both reduces activity and increases clearance due to the aggregate's immunogenic activity. (Pinckard et al., Clin. Exp. Immunol. 2:331-(1967); Robbins et al., Diabetes 36: 838-845 (1987); Cleland et al., Crit.
Rev.
Therapeutic Drug Carrier Systems 10:307-377 (1993).) A further embodiment of the invention relates to a polypeptide which comprises the amino acid sequence of the present invention having an amino acid sequence which contains at least one amino acid substitution, but not more than 50 amino acid substitutions, even more preferably, not more than 40 amino acid substitutions, still more preferably, not more than 30 amino acid substitutions, and still even more preferably, not more than 20 amino acid substitutions. Of course, in order of ever-increasing preference, it is highly preferable for a peptide or polypeptide to have an amino acid sequence which comprises the amino acid sequence of the present invention, which contains at least one, but not more than 10, 9, 8, 7,

6, 5, 4, 3, 2 or 1 amino acid substitutions. In specific embodiments, the number of additions, substitutions, and/or deletions in the amino acid sequence of the present invention or fragments thereof (e.g., the mature form and/or other fragments described herein), is 1-5, 5-10, 5-25, 5-50, 10-50 or 50-150, conservative amino acid substitutions are preferable.
Polynucleotide and Polvneptide Fragments The present invention is also directed to polynucleotide fragments of the polynucleotides of the invention.
In the present invention, a "polynucleotide fragment" refers to a short polynucleotide having a nucleic acid sequence which: is a portion of that contained in a deposited clone, or encoding the polypeptide encoded by the cDNA in a deposited clone; is a portion of that shown in SEQ ID NO:X or the complementary strand thereto, or is a portion of a polynucleotide sequence encoding the polypeptide of SEQ
ID NO:Y. The nucleotide fragments of the invention are preferably at least about 15 nt, and more preferably at least about 20 nt, still more preferably at least about 30 nt, and even more preferably, at least about 40 nt, at least about 50 nt, at least about 75 nt, or at least about 150 nt in length. A fragment "at least 20 nt in length,"
for example, is intended to include 20 or more contiguous bases from the cDNA
sequence contained in a deposited clone or the nucleotide sequence shown in SEQ ID
NO:X. In this context "about" includes the particularly recited value, a value larger or smaller by several (5, 4, 3, 2, or 1) nucleotides, at either terminus or at both termini. These nucleotide fragments have uses that include, but are not limited to, as diagnostic probes and primers as discussed herein. Of course, larger fragments (e.g., 50, 150, 500, 600, 2000 nucleotides) are preferred.
Moreover, representative examples of polynucleotide fragments of the invention, include, for example, fragments comprising, or alternatively consisting of, a sequence from about nucleotide number 1-50, 51-100, 101-150, 151-200, 201-250, 251-300, 301-350, 351-400, 401-450, 451-500, 501-550, 551-600, 651-700, 701-750, 751-800, 800-850, 851-900, 901-950, 951-1000, 1001-1050, 1051-1100, 1101-1150, 1151-1200, 1201-1250, 1251-1300, 1301-1350, 1351-1400, 1401-1450, 1451-1500, 1501-1550, 1551-1600, 1601-1650, 1651-1700, 1701-1750, 1751-1800, 1801-1850, 1851-1900, 1901-1950, 1951-2000, or 2001 to the end of SEQ ID NO:X, or the complementary strand thereto, or the cDNA contained in a deposited clone. In this context "about" includes the particularly recited ranges, and ranges larger or smaller by several (5, 4, 3, 2, or 1) nucleotides, at either terminus or at both termini.
Preferably, these fragments encode a polypeptide which has biological activity. More preferably, these polynucleotides can be used as probes or primers as discussed herein. Polynucleotides which hybridize to these nucleic acid molecules under stringent hybridization conditions or lower stringency conditions are also encompassed by the invention, as are polypeptides encoded by these polynucleotides.
In the present invention, a "polypeptide fragment" refers to an amino acid sequence which is a portion of that contained in SEQ ID NO:Y or encoded by the cDNA contained in a deposited clone. Protein (polypeptide) fragments may be "free-standing," or comprised within a larger polypeptide of which the fragment forms a part or region, most preferably as a single continuous region. Representative examples of polypeptide fragments of the invention, include, for example, fragments comprising, or alternatively consisting of, from about amino acid number 1-20, 21-40, 41-60, 61-80, 81-100, 102-120, 121-140, 141-160, or 161 to the end of the coding region. Moreover, polypeptide fragments can be about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150 amino acids in length. In this context "about"
includes the particularly recited ranges or values, and ranges or values larger or smaller by several (5, 4, 3, 2, or 1) amino acids, at either extreme or at both extremes.
Polynucleotides encoding these polypeptides are also encompassed by the invention.
Preferred polypeptide fragments include the secreted protein as well as the mature form. Further preferred polypeptide fragments include the secreted protein or the mature form having a continuous series of deleted residues from the amino or the carboxy terminus, or both. For example, any number of amino acids, ranging from 1 60, can be deleted from the amino terminus of either the secreted polypeptide or the mature form. Similarly, any number of amino acids, ranging from 1-30, can be deleted from the carboxy terminus of the secreted protein or mature form.
Furthermore, any combination of the above amino and carboxy terminus deletions are preferred. Similarly, polynucleotides encoding these polypeptide fragments are also preferred.
Also preferred are polypeptide and polynucleotide fragments characterized by structural or functional domains, such as fragments that comprise alpha-helix and alpha-helix forming regions, beta-sheet and beta-sheet-forming regions, turn and turn-forming regions, coil and coil-forming regions, hydrophilic regions, hydrophobic regions, alpha amphipathic regions, beta amphipathic regions, flexible regions, surface-forming regions, substrate binding region, and high antigenic index regions.
Polypeptide fragments of SEQ ID NO:Y falling within conserved domains are specifically contemplated by the present invention. Moreover, polynucleotides encoding these domains are also contemplated.
Other preferred polypeptide fragments are biologically active fragments.
Biologically active fragments are those exhibiting activity similar, but not necessarily identical, to an activity of the polypeptide of the present invention. The biological activity of the fragments may include an improved desired activity, or a decreased undesirable activity. Polynucleotides encoding these polypeptide fragments are also encompassed by the invention.
Preferably, the polynucleotide fragments of the invention encode a polypeptide which demonstrates a functional activity. By a polypeptide demonstrating a "functional activity" is meant, a polypeptide capable of displaying one or more known functional activities associated with a full-length (complete) polypeptide of invention protein. Such functional activities include, but are not limited to, biological activity, antigenicity [ability to bind (or compete with a polypeptide of the invention for binding) to an antibody to the polypeptide of the invention], immunogenicity (ability to generate antibody which binds to a polypeptide of the invention), ability to form multimers with polypeptides of the invention, and ability to bind to a receptor or ligand for a polypeptide of the invention.
The functional activity of polypeptides of the invention, and fragments, variants derivatives, and analogs thereof, can be assayed by various methods.
For example, in one embodiment where one is assaying for the ability to bind or compete with full-length polypeptide of the invention for binding to an antibody of the polypeptide of the invention, various immunoassays known in the art can be used, including but not limited to, competitive and non-competitive assay systems using techniques such as radioimmunoassays, ELISA (enzyme linked immunosorbent assay), "sandwich" immunoassays, immunoradiometric assays, gel diffusion precipitation reactions, immunodiffusion assays, in situ immunoassays (using colloidal gold, enzyme or radioisotope labels, for example), western blots, precipitation reactions, agglutination assays (e.g., gel agglutination assays, hemagglutination assays), complement fixation assays, immunofluorescence assays, protein A assays, and immunoelectrophoresis assays, etc. In one embodiment, antibody binding is detected by detecting a label on the primary antibody. In another embodiment, the primary antibody is detected by detecting binding of a secondary antibody or reagent to the primary antibody. In a further embodiment, the secondary antibody is labeled. Many means are known in the art for detecting binding in an immunoassay and are within the scope of the present invention.
In another embodiment, where a ligand for a polypeptide of the invention identified, or the ability of a polypeptide fragment, variant or derivative of the invention to multimerize is being evaluated, binding can be assayed, e.g., by means well-known in the art, such as, for example, reducing and non-reducing gel chromatography, protein affinity chromatography, and affinity blotting. See generally, Phizicky, E., et al., 1995, Microbiol. Rev. 59:94-123. In another embodiment, physiological correlates of binding of a polypeptide of the invention to its substrates (signal transduction) can be assayed.
In addition, assays described herein (see Examples) and otherwise known in the art may routinely be applied to measure the ability of polypeptides of the invention and fragments, variants derivatives and analogs thereof to elicit related biological activity related to that of the polypeptide of the invention (either in vitro or in vivo). Other methods will be known to the skilled artisan and are within the scope of the invention.
Epitopes and Antibodies The present invention encompasses polypeptides comprising, or alternatively consisting of, an epitope of the polypeptide having an amino acid sequence of SEQ ID
NO:Y, or an epitope of the polypeptide sequence encoded by a polynucleotide sequence contained in ATCC deposit No. Z or encoded by a polynucleotide that hybridizes to the complement of the sequence of SEQ ID NO:X or contained in ATCC deposit No. Z under stringent hybridization conditions or lower stringency hybridization conditions as defined supra. The present invention further encompasses polynucleotide sequences encoding an epitope of a polypeptide sequence of the invention (such as, for example, the sequence disclosed in SEQ ID NO:X), polynucleotide sequences of the complementary strand of a polynucleotide sequence encoding an epitope of the invention, and polynucleotide sequences which hybridize to the complementary strand under stringent hybridization conditions or lower stringency hybridization conditions defined supra.

The term "epitopes," as used herein, refers to portions of a polypeptide having antigenic or immunogenic activity in an animal, preferably a mammal, and most preferably in a human. In a preferred embodiment, the present invention encompasses a polypeptide comprising an epitope, as well as the polynucleotide encoding this polypeptide. An "immunogenic epitope," as used herein, is defined as a portion of a protein that elicits an antibody response in an animal, as determined by any method known in the art, for example, by the methods for generating antibodies described infra. (See, for example, Geysen et al., Proc. Natl. Acad. Sci. USA
81:3998- 4002 (1983)). The term "antigenic epitope," as used herein, is defined as a portion of a protein to which an antibody can immunospecifically bind its antigen as determined by any method well known in the art, for example, by the immunoassays described herein. Immunospecific binding excludes non-specific binding but does not necessarily exclude cross- reactivity with other antigens. Antigenic epitopes need not necessarily be immunogenic.
Fragments which function as epitopes may be produced by any conventional means. (See, e.g., Houghten; Proc. Natl. Acad. Sci. USA 82:5131-5135 (1985), further described in U.S. Patent No. 4,631,211).
In the present invention, antigenic epitopes preferably contain a sequence of at least 4, at least 5, at least 6, at least 7, more preferably at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 25, at least 30, at least 40, at least 50, and, most preferably, between about 15 to about 30 amino acids. Preferred polypeptides comprising immunogenic or antigenic epitopes are at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 amino acid residues in length. Additional non-exclusive preferred antigenic epitopes include the antigenic epitopes disclosed herein, as well as portions thereof.
Antigenic epitopes are useful, for example, to raise antibodies, including monoclonal antibodies, that specifically bind the epitope. Preferred antigenic epitopes include the antigenic epitopes disclosed herein, as well as any combination of two, three, four, five or more of these antigenic epitopes. Antigenic epitopes can be used as the target molecules in immunoassays. (See, for instance, Wilson et al., Cell 37:767-778 (1984);
Sutcliffe et al., Science 219:660-666 (1983)).
Similarly, immunogenic epitopes can be used, for example, to induce antibodies according to methods well known in the art. (See, for instance, Sutcliffe et al., supra; Wilson et al., supra; Chow et al., Proc. Natl. Acad. Sci. USA
82:910-914; and Bittle et al., J. Gen. Virol. 66:2347-2354 (1985). Preferred immunogenic epitopes include the immunogenic epitopes disclosed herein, as well as any combination of two, three, four, five or more of these immunogenic epitopes.
The polypeptides comprising one or more immunogenic epitopes may be presented for eliciting an antibody response together with a carrier protein, such as an albumin, to an animal system (such as rabbit or mouse), or, if the polypeptide is of sufficient length (at least about 25 amino acids), the polypeptide may be presented without a carrier. However, immunogenic epitopes comprising as few as 8 to 10 amino acids have been shown to be sufficient to raise antibodies capable of binding to, at the very least, linear epitopes in a denatured polypeptide (e.g., in Western blotting).
Epitope-bearing polypeptides of the present invention may be used to induce antibodies according to methods well known in the art including, but not limited to, in vivo immunization, in vitro immunization, and phage display methods. See, e.g., Sutcliffe et al., supra; Wilson et al., supra, and Bittle et al., J. Gen.
Virol., 66:2347-2354 (1985). If in vivo immunization is used, animals may be immunized with free peptide; however, anti-peptide antibody titer may be boosted by coupling the peptide to a macromolecular carrier, such as keyhole limpet hemacyanin (KLH) or tetanus toxoid. For instance, peptides containing cysteine residues may be coupled to a carrier using a linker such as maleimidobenzoyl- N-hydroxysuccinimide ester (MBS), while other peptides may be coupled to carriers using a more general linking agent such as glutaraldehyde. Animals such as rabbits, rats and mice are immunized with either free or carrier- coupled peptides, for instance, by intraperitoneal and/or intradermal injection of emulsions containing about 100 ycg of peptide or carrier protein and Freund's adjuvant or any other adjuvant known for stimulating an immune response. Several booster injections may be needed, for instance, at intervals of about two weeks, to provide a useful titer of anti-peptide antibody which can be detected, for example, by ELISA assay using free peptide adsorbed to a solid surface. The titer of anti-peptide antibodies in serum from an immunized animal may be increased by selection of anti-peptide antibodies, for instance, by adsorption to the peptide on a solid support and elution of the selected antibodies according to methods well known in the art.
As one of skill in the art will appreciate, and as discussed above, the polypeptides of the present invention comprising an immunogenic or antigenic epitope can be fused to other polypeptide sequences. For example, the polypeptides of the present invention may be fused with the constant domain of immunoglobulins (IgA, IgE, IgG, IgM), or portions thereof (CH1, CH2, CH3, or any combination thereof and portions thereof) resulting in chimeric polypeptides. Such fusion proteins may facilitate purification and may increase half-life in vivo. This has been shown for chimeric proteins consisting of the first two domains of the human CD4-polypeptide and various domains of the constant regions of the heavy or light chains of mammalian immunoglobulins. See, e.g., EP 394,827; Traunecker et al., Nature, 331:84-86 (1988). Enhanced delivery of an antigen across the epithelial barrier to the immune system has been demonstrated for antigens (e.g., insulin) conjugated to an FcRn binding partner such as IgG or Fc fragments (see, e.g., PCT Publications WO

96/22024 and WO 99/04813). IgG Fusion proteins that have a disulfide-linked dimeric structure due to the IgG portion desulfide bonds have also been found to be more efficient in binding and neutralizing other molecules than monomeric polypeptides or fragments thereof alone. See, e.g., Fountoulakis et al., J.
Biochem., 270:3958-3964 (1995). Nucleic acids encoding the above epitopes can also be recombined with a gene of interest as an epitope tag (e.g., the hemagglutinin ("HA") tag or flag tag) to aid in detection and purification of the expressed polypeptide. For example, a system described by Janknecht et al. allows for the ready purification of non-denatured fusion proteins expressed in human cell lines (Janknecht et al., 1991, Proc. Natl. Acad. Sci. USA 88:8972- 897). In this system, the gene of interest is subcloned into a vaccinia recombination plasmid such that the open reading frame of the gene is translationally fused to an amino-terminal tag consisting of six histidine residues. The tag serves as a matrix binding domain for the fusion protein.
Extracts from cells infected with the recombinant vaccinia virus are loaded onto Ni2+
nitriloaceti~c acid-agarose column and histidine-tagged proteins can be selectively eluted with imidazole-containing buffers.
Additional fusion proteins of the invention may be generated through the techniques of gene-shuffling, motif-shuffling, exon-shuffling, and/or codon-shuffling (collectively referred to as "DNA shuffling"). DNA shuffling may be employed to modulate the activities of polypeptides of the invention, such methods can be used to generate polypeptides with altered activity, as well as agonists and antagonists of the polypeptides. See, generally, U.S. Patent Nos. 5,605,793; 5,811,238;
5,830,721;
5,834,252; and 5,837,458, and Patten et al., Curr. Opinion Biotechnol. 8:724-(1997); Harayama, Trends Biotechnol. 16(2):76-82 (1998); Hansson, et al., J.
Mol.
Biol. 287:265-76 (1999); and Lorenzo and Blasco, Biotechniques 24(2):308- 13 (1998) (each of these patents and publications are hereby incorporated by reference in its entirety). In one embodiment, alteration of polynucleotides corresponding to SEQ
ID NO:X and the polypeptides encoded by these polynucleotides may be achieved by DNA shuffling. DNA shuffling involves the assembly of two or more DNA
segments by homologous or site-specific recombination to generate variation in the polynucleotide sequence. In another embodiment, polynucleotides of the invention, or the encoded polypeptides, may be altered by being subjected to random mutagenesis by error-prone PCR, random nucleotide insertion or other methods prior to recombination. In another embodiment, one or more components, motifs, sections, parts, domains, fragments, etc., of a polynucleotide encoding a polypeptide of the invention may be recombined'with one or more components, motifs, sections, parts, domains, fragments, etc. of one or more heterologous molecules.
Antibodies Further polypeptides of the invention relate to antibodies and T-cell antigen receptors (TCR) which immunospecifically bind a polypeptide, polypeptide fragment, or variant of SEQ ID NO:Y, and/or an epitope, of the present invention (as determined by immunoassays well known in the art for assaying specific antibody-antigen binding). Antibodies of the invention include, but are not limited to, polyclonal, monoclonal, multispecific, human, humanized or chimeric antibodies, single chain antibodies, Fab fragments, F(ab') fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Id antibodies to antibodies of the invention), and epitope-binding fragments of any of the above. The term "antibody," as used herein, refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that immunospecifically binds an antigen.
The immunoglobulin molecules of the invention can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgGI, IgG2, IgG3, IgG4, IgAI and IgA2) or subclass of immunoglobulin molecule.
Most preferably the antibodies are human antigen-binding antibody fragments of the present invention and include, but are not limited to, Fab, Fab' and F(ab')2, Fd, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv) and fragments comprising either a VL or VH domain. Antigen-binding antibody fragments, including single-chain antibodies, may comprise the variable regions) alone or in combination with the entirety or a portion of the following: hinge region, CH1, CH2, and CH3 domains. Also included in the invention are antigen-binding fragments also comprising any combination of variable regions) with a hinge region, CH1, CH2, and CH3 domains. The antibodies of the invention may be from any animal origin including birds and mammals. Preferably, the antibodies are human, murine (e.g., mouse and rat), donkey, ship rabbit, goat, guinea pig, camel, horse, or chicken. As used herein, "human" antibodies include antibodies having the amino acid sequence of a human immunoglobulin and include antibodies isolated from human immunoglobulin libraries or from animals transgenic for one or more human immunoglobulin and that do not express endogenous immunoglobulins, as described infra and, for example in, U.S. Patent No. 5,939,598 by Kucherlapati et al.
The antibodies of the present invention may be monospecific, bispecific, trispecific or of greater multispecificity. Multispecific antibodies may be specific for different epitopes of a polypeptide of the present invention or may be specific for both a polypeptide of the present invention as well as for a heterologous epitope, such as a heterologous polypeptide or solid support material. See, e.g., PCT
publications WO
93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt, et al., J. Immunol.
147:60-69 (1991); U.S. Patent Nos. 4,474,893; 4,714,681; 4,925,648; 5,573,920;
5,601,819; Kostelny et al., J. Immunol. 148:1547-1553 (1992).

Antibodies of the present invention may be described or specified in terms of the epitope(s) or portions) of a polypeptide of the present invention which they recognize or specifically bind. The epitope(s) or polypeptide portions) may be specified as described herein, e.g., by N-terminal and C-terminal positions, by size in contiguous amino acid residues, or listed in the Tables and Figures.
Antibodies which specifically bind any epitope or polypeptide of the present invention may also be excluded. Therefore, the present invention includes antibodies that specifically bind polypeptides of the present invention, and allows for the exclusion of the same.
Antibodies of the present invention may also be described or specified in terms of their cross-reactivity. Antibodies that do not bind any other analog, ortholog, or homolog of a polypeptide of the present invention are included.
Antibodies that bind polypeptides with at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 65%, at least 60%, at least 55%, and at least 50% identity (as calculated using methods known in the art and described herein) to a polypeptide of the present invention are also included in the present invention. In specific embodiments, antibodies of the present invention cross-react with murine, rat and/or rabbit homologs of human proteins and the corresponding epitopes thereof. Antibodies that do not bind polypeptides with less than 95%, less than 90%, less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, and less than 50% identity (as calculated using methods known in the art and described herein) to a polypeptide of the present invention are also included in the present invention. In a specific embodiment, the above-described cross-reactivity is with respect to any single specific antigenic or immunogenic polypeptide, or combinations) of 2, 3, 4, 5, or more of the specific antigenic and/or immunogenic polypeptides disclosed herein. Further included in the present invention are antibodies which bind polypeptides encoded by polynucleotides which hybridize to a polynucleotide of the present invention under stringent hybridization conditions (as described herein). Antibodies of the present invention may also be described or specified in terms of their binding affinity to a polypeptide of the invention. Preferred binding affinities include those with a dissociation constant or Kd less than 5 X 10-z M, 10-z M, 5 X 10-3 M, 10-3 M, 5 X 10-4 M, 10-4 M, 5 X 10-5 M, 10-5 M, 5 X 10-6 M, 10-6M, 5 X 10-' M, 10' M, 5 X 10-8 M, 10-g M, 5 M, 10-9 M, 5 X 10-'° M, 10-'° M, 5 X 10-" M, 10-" M, 5 X 10-'z M,'°-'z M, 5 X 10-'3 M, 10-'3 M, 5 X 10-'4 M, 10-'4 M, 5 X 10-'5 M, or 10-'S M.
The invention also provides antibodies that competitively inhibit binding of an antibody to an epitope of the invention as determined by any method known in the art for determining competitive binding, for example, the immunoassays described herein. In preferred embodiments, the antibody competitively inhibits binding to the epitope by at least 95%, at least 90%, at least 85 %, at least 80%, at least 75%, at least 70%, at least 60%, or at least 50%.
Antibodies of the present invention may act as agonists or antagonists of the polypeptides of the present invention. For example, the present invention includes antibodies which disrupt the receptor/ligand interactions with the polypeptides of the invention either partially or fully. Preferrably, antibodies of the present invention bind an antigenic epitope disclosed herein, or a portion thereof. The invention features both receptor-specific antibodies and ligand-specific antibodies. The invention also features receptor-specific antibodies which do not prevent ligand binding but prevent receptor activation. Receptor activation (i.e., signaling) may be determined by techniques described herein or otherwise known in the art. For example, receptor activation can be determined by detecting the phosphorylation (e.g., tyrosine or serine/threonine) of the receptor or its substrate by immunoprecipitation followed by western blot analysis (for example, as described supra). In specific embodiments, antibodies are provided that inhibit ligand activity or receptor activity by at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 60%, or at least 50% of the activity in absence of the antibody.
The invention also features receptor-specific antibodies which both prevent ligand binding and receptor activation as well as antibodies that recognize the receptor-ligand complex, and, preferably, do not specifically recognize the unbound receptor or the unbound ligand. Likewise, included in the invention are neutralizing antibodies which bind the ligand and prevent binding of the ligand to the receptor, as well as antibodies which bind the ligand, thereby preventing receptor activation, but do not prevent the ligand from binding the receptor. Further included in the invention are antibodies which activate the receptor. These antibodies may act as receptor agonists, i.e., potentiate or activate either all or a subset of the biological activities of the ligand-mediated receptor activation, for example, by inducing dimerization of the receptor. The antibodies may be specified as agonists, antagonists or inverse agonists for biological activities comprising the specific biological activities of the peptides of the invention disclosed herein. The above antibody agonists can be made using methods known in the art. See, e.g., PCT publication WO 96/40281; U.S. Patent No.
5,811,097; Deng et al., Blood 92(6):1981-1988 (1998); Chen et al., Cancer Res.
58(16):3668-3678 (1998); Harrop et al., J. Immunol. 161(4):1786-1794 (1998);
Zhu et al., Cancer Res. 58(15):3209-3214 (1998); Yoon et al., J. Immunol.
160(7):3170-3179 (1998); Prat et al., J. Cell. Sci. 111(Pt2):237-247 (1998); Pitard et al., J.
Immunol. Methods 205(2):177-190 (1997); Liautard et al., Cytokine 9(4):233-241 (1997); Carlson et al., J. Biol. Chem. 272(17):11295-11301 (1997); Taryman et al., Neuron 14(4):755-762 (1995); Muller et al., Structure 6(9):1153-1167 (1998);

Bartunek et al., Cytokine 8(1):14-20 (1996) (which are all incorporated by reference herein in their entireties).
Antibodies of the present invention may be used, for example, but not limited to, to purify, detect, and target the polypeptides of the present invention, including both in vitro and in vivo diagnostic and therapeutic methods. For example, the antibodies have use in immunoassays for qualitatively and quantitatively measuring levels of the polypeptides of the present invention in biological samples.
See, e.g., Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988) (incorporated by reference herein in its entirety).
As discussed in more detail below, the antibodies of the present invention may be used either alone or in combination with other compositions. The antibodies may further be recombinantly fused to a heterologous polypeptide at the N- or C-terminus or chemically conjugated (including covalently and non-covalently conjugations) to polypeptides or other compositions. For example, antibodies of the present invention may be recombinantly fused or conjugated to molecules useful as labels in detection assays and effector molecules such as heterologous polypeptides, drugs, radionuclides, or toxins. See, e.g., PCT publications WO 92/08495; WO
91/14438;
WO 89/12624; U.S. Patent No. 5,314,995; and EP 396,387.
The antibodies of the invention include derivatives that are modified, i.e, by the covalent attachment of any type of molecule to the antibody such that covalent attachment does not prevent the antibody from generating an anti-idiotypic response.
For example, but not by way of limitation, the antibody derivatives include antibodies that have been modified, e.g., by glycosylation, acetylation, pegylation, phosphylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, etc. Any of numerous chemical modifications may be carried out by known techniques, including, but not limited to specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, etc. Additionally, the derivative may contain one or more non-classical amino acids.
The antibodies of the present invention may be generated by any suitable method known in the art. Polyclonal antibodies to an antigen-of- interest can be produced by various procedures well known in the art. For example, a polypeptide of the invention can be administered to various host animals including, but not limited to, rabbits, mice, rats, etc. to induce the production of sera containing polyclonal antibodies specific for the antigen. Various adjuvants may be used to increase the immunological response, depending on the host species, and include but are not limited to, Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanins, dinitrophenol, and potentially useful human adjuvants such as BCG (bacille Calmette-Guerin) and corynebacterium parvum. Such adjuvants are also well known in the art.
Monoclonal antibodies can be prepared using a wide variety of techniques known in the art including the use of hybridoma, recombinant, and phage display technologies, or a combination thereof. For example, monoclonal antibodies can be produced using hybridoma techniques including those known in the art and taught, for example, in Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); Hammerling, et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563-681 (Elsevier, N.Y., 1981 ) (said references incorporated by reference in their entireties). The term "monoclonal antibody" as used herein is not limited to antibodies produced through hybridoma technology. The term "monoclonal antibody" refers to an antibody that is derived from a single clone, including any eukaryotic, prokaryotic, or phage clone, and not the method by which it is produced.
Methods for producing and screening for specific antibodies using hybridoma technology are routine and well known in the art and are discussed in detail in the Examples (e.g., Example 16). In a non-limiting example, mice can be immunized with a polypeptide of the invention or a cell expressing such peptide. Once an immune response is detected, e.g., antibodies specific for the antigen are detected in the mouse serum, the mouse spleen is harvested and splenocytes isolated. The splenocytes are then fused by well known techniques to any suitable myeloma cells, for example cells from cell line SP20 available from the ATCC. Hybridomas are selected and cloned by limited dilution. The hybridoma clones are then assayed by methods known in the art for cells that secrete antibodies capable of binding a polypeptide of the invention. Ascites fluid, which generally contains high levels of antibodies, can be generated by immunizing mice with positive hybridoma clones.
Accordingly, the present invention provides methods of generating monoclonal antibodies as well as antibodies produced by the method comprising culturing a hybridoma cell secreting an antibody of the invention wherein, preferably, the hybridoma is generated by fusing splenocytes isolated from a mouse immunized with an antigen of the invention with myeloma cells and then screening the hybridomas resulting from the fusion for hybridoma clones that secrete an antibody able to bind a polypeptide of the invention.
Antibody fragments which recognize specific epitopes may be generated by known techniques. For example, Fab and F(ab')2 fragments of the invention may be produced by proteolytic cleavage of immunoglobulin molecules, using enzymes such as papain (to produce Fab fragments) or pepsin (to produce F(ab')2 fragments).

F(ab')2 fragments contain the variable region, the light chain constant region and the CH1 domain of the heavy chain.
For example, the antibodies of the present invention can also be generated using various phage display methods known in the art. In phage display methods, functional antibody domains are displayed on the surface of phage particles which carry the polynucleotide sequences encoding them. In a particular embodiment, such phage can be utilized to display antigen binding domains expressed from a repertoire or combinatorial antibody library (e.g., human or murine). Phage expressing an antigen binding domain that binds the antigen of interest can be selected or identified with antigen, e.g., using labeled antigen or antigen bound or captured to a solid surface or bead. Phage used in these methods are typically filamentous phage including fd and M13 binding domains expressed from phage with Fab, Fv or disulfide stabilized Fv antibody domains recombinantly fused to either the phage gene lII or gene VIII protein. Examples of phage display methods that can be used to make the antibodies of the present invention include those disclosed in Brinkman et al., J. lmmunol. Methods 182:41-50 (1995); Ames et al., J. Immunol. Methods 184:177-186 (1995); Kettleborough et al., Eur. J. Immunol. 24:952-958 (1994);
Persic et al., Gene 187 9-18 (1997); Burton et al., Advances in Immunology 57:191-280 (1994); PCT application No. PCT/GB91/01134; PCT publications WO 90/02809;

7; WO 92/01047; WO 92/18619; WO 93/11236; WO 95/15982; WO
95/20401; and U.S. Patent Nos. 5,698,426; 5,223,409; 5,403,484; 5,580,717;
5,427,908; 5,750,753; 5,821,047; 5,571,698; 5,427,908; 5,516,637; 5,780,225;
5,658,727; 5,733,743 and 5,969,108; each of which is incorporated herein by reference in its entirety.
As described in the above references, after phage selection, the antibody coding regions from the phage can be isolated and used to generate whole antibodies, including human antibodies, or any other desired antigen binding fragment, and expressed in any desired host, including mammalian cells, insect cells, plant cells, yeast, and bacteria, e.g., as described in detail below. For example, techniques to recombinantly produce Fab, Fab' and F(ab')2 fragments can also be employed using methods known in the art such as those disclosed in PCT publication WO
92/22324;
Mullinax et al., BioTechniques 12(6):864-869 (1992); and Sawai et al., AJRI
34:26-34 (1995); and Better et al., Science 240:1041-1043 (1988) (said references incorporated by reference in their entireties).
Examples of techniques which can be used to produce single-chain Fvs and antibodies include those described in U.S. Patents 4,946,778 and 5,258,498;
Huston et al., Methods in Enzymology 203:46-88 (1991); Shu et al., PNAS 90:7995-7999 (1993); and Skerra et al., Science 240:1038-1040 (1988). For some uses, including in vivo use of antibodies in humans and in vitro detection assays, it may be preferable to use chimeric, humanized, or human antibodies. A chimeric antibody is a molecule in which different portions of the antibody are derived from different animal species, such as antibodies having a variable region derived from a marine monoclonal antibody and a human immunoglobulin constant region. Methods for producing chimeric antibodies are known in the art. See e.g., Morrison, Science 229:1202 (1985); Oi et al., BioTechniques 4:214 (1986); Gillies et al., (1989) J.
lmmunol.
Methods 125:191-202; U.S. Patent Nos. 5,807,715; 4,816,567; and 4,816397, which are incorporated herein by reference in their entirety. ' Humanized antibodies are antibody molecules from non-human species antibody that binds the desired antigen having one or more complementarity determining regions (CDRs) from the non-human species and a framework regions from a human immunoglobulin molecule.
Often, framework residues in the human framework regions will be substituted with the corresponding residue from the CDR donor antibody to alter, preferably improve, antigen binding. These framework substitutions are identified by methods well known in the art, e.g., by modeling of the interactions of the CDR and framework residues to identify framework residues important for antigen binding and sequence comparison to identify unusual framework residues at particular positions.
(See, e.g., Queen et al., U.S. Patent No. 5,585,089; Riechmann et al., Nature 332:323 (1988), which are incorporated herein by reference in their entireties.) Antibodies can be humanized using a variety of techniques known in the art including, for example, CDR-grafting (EP 239,400; PCT publication WO 91/09967; U.S. Patent Nos.
5,225,539; 5,530,101; and 5,585,089), veneering or resurfacing (EP 592,106; EP
519,596; Padlan, Molecular Immunology 28(4/5):489-498 (1991); Studnicka et al., Protein Engineering 7(6):805-814 (1994); Roguska. et al., PNAS 91:969-973 (1994)), and chain shuffling (U.S. Patent No. 5,565,332).
Completely human antibodies are particularly desirable for therapeutic treatment of human patients. Human antibodies can be made by a variety of methods known in the art including phage display methods described above using antibody libraries derived from human immunoglobulin sequences. See also, U.S. Patent Nos.
4,444,887 and 4,716,111; and PCT publications WO 98/46645, WO 98/50433, WO
98/24893, WO 98/16654, WO 96/34096, WO 96/33735, and WO 91/10741; each of which is incorporated herein by reference in its entirety.
Human antibodies can also be produced using transgenic mice which are incapable of expressing functional endogenous immunoglobulins, but which can express human immunoglobulin genes. For example, the human heavy and light chain immunoglobulin gene complexes may be introduced randomly or by homologous recombination into mouse embryonic stem cells. Alternatively, the human variable region, constant region, and diversity region may be introduced into mouse embryonic stem cells in addition to the human heavy and light chain genes.

The mouse heavy and light chain immunoglobulin genes may be rendered non-functional separately or simultaneously with the introduction of human immunoglobulin loci by homologous recombination. In particular, homozygous deletion of the JH~region prevents endogenous antibody production. The modified embryonic stem cells are expanded and microinjected into blastocysts to produce chimeric mice. The chimeric mice are then bred to produce homozygous offspring which express human antibodies. The transgenic mice are immunized in the normal fashion with a selected antigen, e.g., all or a portion of a polypeptide of the invention.
Monoclonal antibodies directed against the antigen can be obtained from the immunized, transgenic mice using conventional hybridoma technology. The human immunoglobulin transgenes harbored by the transgenic mice rearrange during B
cell differentiation, and subsequently undergo class switching and somatic mutation.
Thus, using such a technique, it is possible to produce therapeutically useful IgG, IgA, IgM and IgE antibodies. For an overview of this technology for producing human antibodies, see Lonberg and Huszar, Int. Rev. Immunol. 13:65-93 (1995). For a detailed discussion of this technology for producing human antibodies and human monoclonal antibodies and protocols for producing such antibodies, see, e.g., PCT
publications WO 98/24893; WO 92/01047; WO 96/34096; WO 96/33735; European Patent No. 0 598 877; U.S. Patent Nos. 5,413,923; 5,625,126; 5,633,425;
5,569,825;
5,661,016; 5,545,806; 5,814,318; 5,885,793; 5,916,771; and 5,939,598, which are incorporated by reference herein in their entirety. In addition, companies such as Abgenix, Inc. (Freemont, CA) and Genpharm (San Jose, CA) can be engaged to provide human antibodies directed against a selected antigen using technology similar to that described above.
Completely human antibodies which recognize a selected epitope can be generated using a technique referred to as "guided selection." In this approach a selected non-human monoclonal antibody, e.g., a mouse antibody, is used to guide the selection of a completely human antibody recognizing the same epitope.
(Jespers et al., Biotechnology 12:899-903 (1988)).
Further, antibodies to the polypeptides of the invention can, in turn, be utilized to generate anti-idiotype antibodies that "mimic" polypeptides of the invention using techniques well known to those skilled in the art. (See, e.g., Greenspan &
Bona, FASEB J. 7(5):437-444; (1989) and Nissinoff, J. Immunol. 147(8):2429-2438 (1991)). For example, antibodies which bind to and competitively inhibit polypeptide multimerization and/or binding of a polypeptide of the invention to a ligand can be used to generate anti-idiotypes that "mimic" the polypeptide multimerization and/or binding domain and, as a consequence, bind to and neutralize polypeptide and/or its ligand. Such neutralizing anti-idiotypes or Fab fragments of such anti-idiotypes can be used in therapeutic regimens to neutralize polypeptide ligand. For example, such anti-idiotypic antibodies can be used to bind a polypeptide of the invention and/or to bind its ligands/receptors, and thereby block its biological activity.
Polvnucleotides Encoding Antibodies The invention further provides polynucleotides comprising a nucleotide sequence encoding an antibody of the invention and fragments thereof. The invention also encompasses polynucleotides that hybridize under stringent or lower stringency hybridization conditions, e.g., as defined supra, to polynucleotides that encode an antibody, preferably, that specifically binds to a polypeptide of the invention, preferably, an antibody that binds to a polypeptide having the amino acid sequence of SEQ ID NO:Y.
The polynucleotides may be obtained, and the nucleotide sequence of the polynucleotides determined, by any method known in the art. For example, if the nucleotide sequence of the antibody is known, a polynucleotide encoding the antibody may be assembled from chemically synthesized oligonucleotides (e.g., as described in Kutmeier et al., BioTechniques 17:242 (1994)), which, briefly, involves the synthesis of overlapping oligonucleotides containing portions of the sequence encoding the antibody, annealing and ligating of those oligonucleotides, and then amplification of the ligated oligonucleotides by PCR.
Alternatively, a polynucleotide encoding an antibody may be generated from nucleic acid from a suitable source. If a clone containing a nucleic acid encoding a particular antibody is not available, but the sequence of the antibody molecule is known, a nucleic acid encoding the immunoglobulin may be chemically synthesized or obtained from a suitable source (e.g., an antibody cDNA library, or a cDNA
library generated from, or nucleic acid, preferably poly A+ RNA, isolated from, any tissue or cells expressing the antibody, such as hybridoma cells selected to express an antibody of the invention) by PCR amplification using synthetic primers hybridizable to the 3' and 5' ends of the sequence or by cloning using an oligonucleotide probe specific for the particular gene sequence to identify, e.g., a cDNA clone from a cDNA library that encodes the antibody. Amplified nucleic acids generated by PCR
may then be cloned into replicable cloning vectors using any method well known in the art.
Once the nucleotide sequence and corresponding amino acid sequence of the antibody is determined, the nucleotide sequence of the antibody may be manipulated using methods well known in the art for the manipulation of nucleotide sequences, e.g., recombinant DNA techniques, site directed mutagenesis, PCR, etc. (see, for example, the techniques described in Sambrook et al., 1990, Molecular Cloning, A
Laboratory Manual, 2d Ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, NY and Ausubel et al., eds., 1998, Current Protocols in Molecular Biology, John Wiley & Sons, NY, which are both incorporated by reference herein in their entireties ), to generate antibodies having a different amino acid sequence, for example to create amino acid substitutions, deletions, and/or insertions.
In a specific embodiment, the amino acid sequence of the heavy and/or light chain variable domains may be inspected to identify the sequences of the complementarity determining regions (CDRs) by methods that are well know in the art, e.g., by comparison to known amino acid sequences of other heavy and light chain variable regions to determine the regions of sequence hypervariability.
Using routine recombinant DNA techniques, one or more of the CDRs may be inserted within framework regions, e.g., into human framework regions to humanize a non-human antibody, as described supra. The framework regions may be naturally occurring or consensus framework regions, and preferably human framework regions (see, e.g., Chothia et al., J. Mol. Biol. 278: 457-479 (1998) for a listing of human framework regions). Preferably, the polynucleotide generated by the combination of the framework regions and CDRs encodes an antibody that specifically binds a polypeptide of the invention. Preferably, as discussed supra, one or more amino acid substitutions may be made within the framework regions, and, preferably, the amino acid substitutions improve binding of the antibody to its antigen.
Additionally, such methods may be used to make amino acid substitutions or deletions of one or more variable region cysteine residues participating in an intrachain disulfide bond to generate antibody molecules lacking one or more intrachain disulfide bonds.
Other alterations to the polynucleotide are encompassed by the present invention and within the skill of the art.
In addition, techniques developed for the production of "chimeric antibodies"
(Morrison et al., Proc. Natl. Acad. Sci. 81:851-855 (1984); Neuberger et al., Nature 312:604-608 (1984); Takeda et al., Nature 314:452-454 (1985)) by splicing genes from a mouse antibody molecule of appropriate antigen specificity together with genes from a human antibody molecule of appropriate biological activity can be used.
As described supra, a chimeric antibody is a molecule in which different portions are derived from different animal species, such as those having a variable region derived from a murine mAb and a human immunoglobulin constant region, e.g., humanized antibodies.
Alternatively, techniques described for the production of single chain antibodies (U.S. Patent No. 4,946,778; Bird, Science 242:423- 42 (1988);
Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988); and Ward et al., Nature 334:544-54 (1989)) can be adapted to produce single chain antibodies. Single chain antibodies are formed by linking the heavy and light chain fragments of the Fv region via an amino acid bridge, resulting in a single chain polypeptide. Techniques for the assembly of functional Fv fragments in E. coli may also be used (Skerra et al., Science 242:1038- 1041 (1988)).
Methods of Producing Antibodies The antibodies of the invention can be produced by any method known in the art for the synthesis of antibodies, in particular, by chemical synthesis or preferably, by recombinant expression techniques.
Recombinant expression of an antibody of the invention, or fragment, derivative or analog thereof, (e.g., a heavy or light chain of an antibody of the invention or a single chain antibody of the invention), requires construction of an expression vector containing a polynucleotide that encodes the antibody. Once a polynucleotide encoding an antibody molecule or a heavy or light chain of an antibody, or portion thereof (preferably containing the heavy or light chain variable domain), of the invention has been obtained, the vector for the production of the antibody molecule may be produced by recombinant DNA technology using techniques well known in the art. Thus, methods for preparing a protein by expressing a polynucleotide containing an antibody encoding nucleotide sequence are described herein. Methods which are well known to those skilled in the art can be used to construct expression vectors containing antibody coding sequences and appropriate transcriptional and translational control signals. These methods include, for example, in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. The invention, thus, provides replicable vectors comprising a nucleotide sequence encoding an antibody molecule of the invention, or a heavy or light chain thereof, or a heavy or light chain variable domain, operably linked to a promoter. Such vectors may include the nucleotide sequence encoding the constant region of the antibody molecule (see, e.g., PCT Publication WO 86/05807; PCT
Publication WO 89/01036; and U.S. Patent No. 5,122,464) and the variable domain of the antibody may be cloned into such a vector for expression of the entire heavy or light chain.
The expression vector is transferred to a host cell by conventional techniques and the transfected cells are then cultured by conventional techniques to produce an antibody of the invention. Thus, the invention includes host cells containing a polynucleotide encoding an antibody of the invention, or a heavy or light chain thereof, or a single chain antibody of the invention, operably linked to a heterologous promoter. In preferred embodiments for the expression of double-chained antibodies, vectors encoding both the heavy and light chains may be co-expressed in the host cell for expression of the entire immunoglobulin molecule, as detailed below.
A variety of host-expression vector systems may be utilized to express the antibody molecules of the invention. Such host-expression systems represent vehicles by which the coding sequences of interest may be produced and subsequently purified, but also represent cells which may, when transformed or transfected with the appropriate nucleotide coding sequences, express an antibody molecule of the invention in situ. These include but are not limited to microorganisms such as bacteria (e.g., E. coli, B. subtilis) transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing antibody coding sequences; yeast (e.g., Saccharomyces, Pichia) transformed with recombinant yeast expression vectors containing antibody coding sequences; insect cell systems infected with recombinant virus expression vectors (e.g., baculovirus) containing antibody coding sequences; plant cell systems infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid) containing antibody coding sequences; or mammalian cell systems (e.g., COS, CHO, BHK, 293, 3T3 cells) harboring recombinant expression constructs containing promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or from mammalian viruses (e.g., the adenovirus late promoter; the vaccinia virus 7.5K promoter). Preferably, bacterial cells such as Escherichia coli, and more preferably, eukaryotic cells, especially for the expression of whole recombinant antibody molecule, are used for the expression of a recombinant antibody molecule. For example, mammalian cells such as Chinese hamster ovary cells (CHO), in conjunction with a vector such as the major intermediate early gene promoter element from human cytomegalovirus is an effective expression system for antibodies (Foecking et al., Gene 45:101 (1986); Cockett et al., Bio/Technology 8:2 ( 1990) ).
In bacterial systems, a number of expression vectors may be advantageously selected depending upon the use intended for the antibody molecule being expressed.
For example, when a large quantity of such a protein is to be produced, for the generation of pharmaceutical compositions of an antibody molecule, vectors which direct the expression of high levels of fusion protein products that are readily purified may be desirable. Such vectors include, but are not limited, to the E. coli expression vector pUR278 (Ruther et al., EMBO J. 2:1791 (1983)), in which the antibody coding sequence may be ligated individually into the vector in frame with the lac Z
coding region so that a fusion protein is produced; pIN vectors (lnouye & Inouye, Nucleic Acids Res. 13:3101-3109 (1985); Van Heeke & Schuster, J. Biol. Chem. 24:5503-5509 (1989)); and the like. pGEX vectors may also be used to express foreign polypeptides as fusion proteins with glutathione S-transferase (GST). In general, such fusion proteins are soluble and can easily be purified from lysed cells by adsorption and binding to matrix glutathione-agarose beads followed by elution in the presence of free glutathione. The pGEX vectors are designed to include thrombin or factor Xa protease cleavage sites so that the cloned target gene product can be released from the GST moiety.
In an insect system, Autographa californica nuclear polyhedrosis virus (AcNPV) is used as a vector to express foreign genes. The virus grows in Spodoptera frugiperda cells. The antibody coding sequence may be cloned individually into non-essential regions (for example the polyhedrin gene) of the virus and placed under control of an AcNPV promoter (for example the polyhedrin promoter).
In mammalian host cells, a number of viral-based expression systems may be utilized. In cases where an adenovirus is used as an expression vector, the antibody coding sequence of interest may be ligated to an adenovirus transcription/translation control complex, e.g., the late promoter and tripartite leader sequence. This chimeric gene may then be inserted in the adenovirus genome by in vitro or in vivo recombination. Insertion in a non- essential region of the viral genome (e.g., region E1 or E3) will result in a recombinant virus that is viable and capable of expressing the antibody molecule in infected hosts. (e.g., see Logan & Shenk, Proc. Natl.
Acad.
Sci. USA 81:355-359 (1984)). Specific initiation signals may also be required for efficient translation of inserted antibody coding sequences. These signals include the S ATG initiation codon and adjacent sequences. Furthermore, the initiation codon must be in phase with the reading frame of the desired coding sequence to ensure translation of the entire insert. These exogenous translational control signals and initiation codons can be of a variety of origins, both natural and synthetic.
The efficiency of expression may be enhanced by the inclusion of appropriate transcription enhancer elements, transcription terminators, etc. (see Bittner et al., Methods in Enzymol. 153:51-544 (1987)).
In addition, a host cell strain may be chosen which modulates the expression of the inserted sequences, or modifies and processes the gene product in the specific fashion desired. Such modifications (e.g., glycosylation) and processing (e.g., cleavage) of protein products may be important for the function of the protein.
Different host cells have characteristic and specific mechanisms for the post-translational processing and modification of proteins and gene products.
Appropriate cell lines or host systems can be chosen to ensure the correct modification and processing of the foreign protein expressed. To this end, eukaryotic host cells which possess the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the gene product may be used. Such mammalian host cells include but are not limited to CHO, VERY, BHK, Hela, COS, MDCK, 293, 3T3, WI38, and in particular, breast cancer cell lines such as, for example, BT483, Hs578T, HTB2, BT20 and T47D, and normal mammary gland cell line such as, for example, CRL7030 and Hs578Bst.

For long-term, high-yield production of recombinant proteins, stable expression is preferred. For example, cell lines which stably express the antibody molecule may be engineered. Rather than using expression vectors which contain viral origins of replication, host cells can be transformed with DNA
controlled by appropriate expression control elements (e.g., promoter, enhancer, sequences, transcription terminators, polyadenylation sites, etc.), and a selectable marker.
Following the introduction of the foreign DNA, engineered cells may be allowed to grow for 1-2 days in an enriched media, and then are switched to a selective media.
The selectable marker in the recombinant plasmid confers resistance to the selection and allows cells to stably integrate the plasmid into their chromosomes and grow to form foci which in turn can be cloned and expanded into cell lines. This method may advantageously be used to engineer cell lines which express the antibody molecule.
Such engineered cell lines may be particularly useful in screening and evaluation of compounds that interact directly or indirectly with the antibody molecule.
A number of selection systems may be used, including but not limited to the herpes simplex virus thymidine kinase (Wigler et al., Cell 11:223 (1977)), hypoxanthine-guanine phosphoribosyltransferase (Szybalska & Szybalski, Proc.
Natl.
Acad. Sci. USA 48:202 (1992)), and adenine phosphoribosyltransferase (Lowy et al., Cell 22:817 ( 1980)) genes can be employed in tk-, hgprt- or aprt- cells, respectively.
Also, antimetabolite resistance can be used as the basis of selection for the following genes: dhfr, which confers resistance to methotrexate (Wigler et al., Natl.
Acad. Sci.
USA 77:357 (1980); O'Hare et al., Proc. Natl. Acad. Sci. USA 78:1527 (1981));
gpt, which confers resistance to mycophenolic acid (Mulligan & Berg, Proc. Natl.
Acad.
Sci. USA 78:2072 (1981)); neo, which confers resistance to the aminoglycoside G-418 Clinical Pharmacy 12:488-505; Wu and Wu, Biotherapy 3:87-95 (1991);
Tolstoshev, Ann. Rev. Pharmacol. Toxico(. 32:573-596 (1993); Mulligan, Science 260:926-932 (1993); and Morgan and Anderson, Ann. Rev. Biochem. 62:191-217 (1993); May, 1993, TIB TECH 11_(5):155-215); and hygro, which confers resistance to hygromycin (Santerre et al., Gene 30:147 (1984)). Methods commonly known in the art of recombinant DNA technology may be routinely applied to select the desired recombinant clone, and such methods are described, for example, in Ausubel et al.
(eds.), Current Protocols in Molecular Biology, John Wiley & Sons, NY (1993);
Kriegler, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY
(1990); and in Chapters 12 and 13, Dracopoli et al. (eds), Current Protocols in Human Genetics, John Wiley & Sons, NY ( 1994); Colberre-Garapin et al., J.
Mol.
Biol. 150:1 (1981), which are incorporated by reference herein in their entireties.
The expression levels of an antibody molecule can be increased by vector amplification (for a review, see Bebbington and Hentschel, The use of vectors based on gene amplification for the expression of cloned genes in mammalian cells in DNA
cloning, Vol.3. (Academic Press, New York, 1987)). When a marker in the vector system expressing antibody is amplifiable, increase in the level of inhibitor present in culture of host cell will increase the number of copies of the marker gene.
Since the amplified region is associated with the antibody gene, production of the antibody will also increase (Grouse et al., Mol. Cell. Biol. 3:257 (1983)).
The host cell may be co-transfected with two expression vectors of the invention, the first vector encoding a heavy chain derived polypeptide and the second vector encoding a light chain derived polypeptide. The two vectors may contain identical selectable markers which enable equal expression of heavy and light chain polypeptides. Alternatively, a single vector may be used which encodes, and is capable of expressing, both heavy and light chain polypeptides. In such situations, the light chain should be placed before the heavy chain to avoid an excess of toxic free heavy chain (Proudfoot, Nature 322:52 (1986); Kohler, Proc. Natl. Acad.
Sci.

USA 77:2197 (1980)). The coding sequences for the heavy and light chains may comprise cDNA or genomic DNA.
Once an antibody molecule of the invention has been produced by an animal, chemically synthesized, or recombinantly expressed, it may be purified by any method known in the art for purification of an immunoglobulin molecule, for example, by chromatography (e.g., ion exchange, affinity, particularly by affinity for the specific antigen after Protein A, and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique for the purification of proteins. In addition, the antibodies of the present invention or fragments thereof can be fused to heterologous polypeptide sequences described herein or otherwise known in the art, to facilitate purification.
The present invention encompasses antibodies recombinantly fused or chemically conjugated (including both covalently and non-covalently conjugations) to a polypeptide (or portion thereof, preferably at least 10, 20, 30, 40, S0, 60, 70, 80, 90 or 100 amino acids of the polypeptide) of the present invention to generate fusion proteins. The fusion does not necessarily need to be direct, but may occur through linker sequences. The antibodies may be specific for antigens other than polypeptides (or portion thereof, preferably at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 amino acids of the polypeptide) of the present invention. For example, antibodies may be used to target the polypeptides of the present invention to particular cell types, either in vitro or in vivo, by fusing or conjugating the polypeptides of the present invention to antibodies specific for particular cell surface receptors. Antibodies fused or conjugated to the polypeptides of the present invention may also be used in in vitro immunoassays and purification methods using methods known in the art. See e.g., Harbor et al., supra, and PCT publication WO 93/21232; EP 439,095; Naramura et al., Immunol. Lett. 39:91-99 (1994); U.S. Patent 5,474,981; Gillies et al., PNAS

89:1428-1432 (1992); Fell et al., J. Immunol. 146:2446-2452(1991), which are incorporated by reference in their entireties.
The present invention further includes compositions comprising the polypeptides of the present invention fused or conjugated to antibody domains other than the variable regions. For example, the polypeptides of the present invention may be fused or conjugated to an antibody Fc region, or portion thereof. The antibody portion fused to a polypeptide of the present invention may comprise the constant region, hinge region, CH1 domain, CH2 domain, and CH3 domain or any combination of whole domains or portions thereof. The polypeptides may also be fused or conjugated to the above antibody portions to form multimers. For example, Fc portions fused to the polypeptides of the present invention can form dimers through disulfide bonding between the Fc portions. Higher multimeric forms can be made by fusing the polypeptides to portions of IgA and IgM. Methods for fusing or conjugating the polypeptides of the present invention to antibody portions are known in the art. See, e.g., U.S. Patent Nos. 5,336,603; 5,622,929; 5,359,046;
5,349,053;
5,447,851; 5,112,946; EP 307,434; EP 367,166; PCT publications WO 96/04388; WO
91/06570; Ashkenazi et al., Proc. Natl. Acad. Sci. USA 88:10535-10539 (1991);
Zheng et al., J. Immunol. 154:5590-5600 (1995); and Vil et al., Proc. Natl.
Acad. Sci.
USA 89:11337- 11341(1992) (said references incorporated by reference in their entireties).
As discussed, supra, the polypeptides corresponding to a polypeptide, polypeptide fragment, or a variant of SEQ ID NO:Y may be fused or conjugated to the above antibody portions to increase the in vivo half life of the polypeptides or for use in immunoassays using methods known in the art. Further, the polypeptides corresponding to SEQ ID NO:Y may be fused or conjugated to the above antibody portions to facilitate purification. One reported example describes chimeric proteins consisting of the first two domains of the human CD4-polypeptide and various domains of the constant regions of the heavy or light chains of mammalian immunoglobulins. (EP 394,827; Traunecker et al., Nature 331:84-86 (1988). The polypeptides of the present invention fused or conjugated to an antibody having disulfide- linked dimeric structures (due to the IgG) may also be more efficient in binding and neutralizing other molecules, than the monomeric secreted protein or protein fragment alone. (Fountoulakis et al., J. Biochem. 270:3958-3964 (1995)). In many cases, the Fc part in a fusion protein is beneficial in therapy and diagnosis, and thus can result in, for example, improved pharmacokinetic properties. (EP A
232,262). Alternatively, deleting the Fc part after the fusion protein has been expressed, detected, and purified, would be desired. For example, the Fc portion may hinder therapy and diagnosis if the fusion protein is used as an antigen for immunizations. In drug discovery, for example, human proteins, such as hIL-5, have been fused with Fc portions for the purpose of high-throughput screening assays to identify antagonists of hIL-5. (See, Bennett et al., J. Molecular Recognition

8:52-58 (1995); Johanson et al., J. Biol. Chem. 270:9459-9471 (1995).
Moreover, the antibodies or fragments thereof of the present invention can be fused to marker sequences, such as a peptide to facilitate purification. In preferred embodiments, the marker amino acid sequence is a hexa-histidine peptide, such as the tag provided in a pQE vector (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, CA, 91311), among others, many of which are commercially available. As described in Gentz et al., Proc. Natl. Acad. Sci. USA 86:821-824 (1989), for instance, hexa-histidine provides for convenient purification of the fusion protein. Other peptide tags useful for purification include, but are not limited to, the "HA" tag, which corresponds to an epitope derived from the influenza hemagglutinin protein (Wilson et al., Cell 37:767 (1984)) and the "flag" tag.

The present invention further encompasses antibodies or fragments thereof conjugated to a diagnostic or therapeutic agent. The antibodies can be used diagnostically to, for example, monitor the development or progression of a tumor as part of a clinical testing procedure to, e.g., determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, radioactive materials, positron emitting metals using various positron emission tomographies, and nonradioactive paramagnetic metal ions. The detectable substance may be coupled or conjugated either directly to the antibody (or fragment thereof) or indirectly, through an intermediate (such as, for example, a linker known in the art) using techniques known in the art. See, for example, U.S. Patent No.
4,741,900 for metal ions which can be conjugated to antibodies for use as diagnostics according to the present invention. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase;
examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin; and examples of suitable radioactive material include 125I, 131I, 111In or 99Tc.
Further, an antibody or fragment thereof may be conjugated to a therapeutic moiety such as a cytotoxin, e.g., a cytostatic or cytocidal agent, a therapeutic agent or a radioactive metal ion, e.g., alpha-emitters such as, for example, 213Bi. A
cytotoxin or cytotoxic agent includes any agent that is detrimental to cells. Examples include paclitaxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. Therapeutic agents include, but are not limited to, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g., vincristine and vinblastine).
The conjugates of the invention can be used for modifying a given biological response, the therapeutic agent or drug moiety is not to be construed as limited to classical chemical therapeutic agents. For example, the drug moiety may be a protein or polypeptide possessing a desired biological activity. Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a protein such as tumor necrosis factor, a-interferon,13-interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator, an apoptotic agent, e.g., TNF-alpha, TNF-beta, AIM I (See, International Publication No. WO
97/33899), A1M II (See, International Publication No. WO 97/34911), Fas Ligand (Takahashi et al., Int. Immunol., 6:1567-1574 (1994)), VEGI (See, International Publication No. WO 99/23105), a thrombotic agent or an anti- angiogenic agent, e.g., angiostatin or endostatin; or, biological response modifiers such as, for example, lymphokines, interleukin-1 ("IL-1"), interleukin-2 ("IL-2"), interleukin-6 ("IL-6"), granulocyte macrophage colony stimulating factor ("GM-CSF"), granulocyte colony stimulating factor ("G-CSF"), or other growth factors.
Antibodies may also be attached to solid supports, which are particularly useful for immunoassays or purification of the target antigen. Such solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride or polypropylene.
Techniques for conjugating such therapeutic moiety to antibodies are well known, see, e.g., Arnon et al., "Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy", in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al., "Antibodies For Drug Delivery", in Controlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp.
623-53 (Marcel Dekker, Inc. 1987); Thorpe, "Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review", in Monoclonal Antibodies '84: Biological And Clinical Applications, Pinchers et al. (eds.), pp. 475-506 (1985); "Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy", in Monoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al. (eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al., "The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates", Immunol.
Rev. 62:119-58 (1982).
Alternatively, an antibody can be conjugated to a second antibody to form an antibody heteroconjugate as described by Segal in U.S. Patent No. 4,676,980, which is incorporated herein by reference in its entirety.
An antibody, with or without a therapeutic moiety conjugated to it, administered alone or in combination with cytotoxic factors) and/or cytokine(s) can be used as a therapeutic.

Immunophenotyping The antibodies of the invention may be utilized for immunophenotyping of cell lines and biological samples. The translation product of the gene of the present invention may be useful as a cell specific marker, or more specifically as a cellular marker that is differentially expressed at various stages of differentiation and/or maturation of particular cell types. Monoclonal antibodies directed against a specific epitope, or combination of epitopes, will allow for the screening of cellular populations expressing the marker. Various techniques can be utilized using monoclonal antibodies to screen for cellular populations expressing the marker(s), and include magnetic separation using antibody-coated magnetic beads, "panning"
with antibody attached to a solid matrix (i.e., plate), and flow cytometry (See, e.g., U.S.
Patent 5,985,660; and Morrison et al., Cell, 96:737-49 (1999)).
These techniques allow for the screening of particular populations of cells, such as might be found with hematological malignancies (i.e. minimal residual disease (MRD) in acute leukemic patients) and "non-self" cells in transplantations to prevent Graft-versus-Host Disease (GVHD). Alternatively, these techniques allow for the screening of hematopoietic stem and progenitor cells capable of undergoing proliferation and/or differentiation, as might be found in human umbilical cord blood.
Assays For Antibody Binding The antibodies of the invention may be assayed for immunospecific binding by any method known in the art. The immunoassays which can be used include but are not limited to competitive and non-competitive assay systems using techniques such as western blots, radioimmunoassays, ELISA (enzyme linked immunosorbent assay), "sandwich" immunoassays, immunoprecipitation assays, precipitin reactions, gel diffusion precipitin reactions, immunodiffusion assays, agglutination assays, complement-fixation assays, immunoradiometric assays, fluorescent immunoassays, protein A immunoassays, to name but a few. Such assays are routine and well known in the art (see, e.g., Ausubel et al, eds, 1994, Current Protocols in Molecular Biology, Vol. l, John Wiley & Sons, Inc., New York, which is incorporated by reference herein in its entirety). Exemplary immunoassays are described briefly below (but are not intended by way of limitation).
Immunoprecipitation protocols generally comprise lysing a population of cells in a lysis buffer such as RIPA buffer (1% NP-40 or Triton X- 100, 1% sodium deoxycholate, 0.1% SDS, 0.15 M NaCI, 0.01 M sodium phosphate at pH 7.2, 1%
Trasylol) supplemented with protein phosphatase and/or protease inhibitors (e.g., EDTA, PMSF, aprotinin, sodium vanadate), adding the antibody of interest to the cell lysate, incubating for a period of time (e.g., 1-4 hours) at 4° C, adding protein A
and/or protein G sepharose beads to the cell lysate, incubating for about an hour or more at 4° C, washing the beads in lysis buffer and resuspending the beads in SDS/sample buffer. The ability of the antibody of interest to immunoprecipitate a particular antigen can be assessed by, e.g., western blot analysis. One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the binding of the antibody to an antigen and decrease the background (e.g., pre-clearing the cell lysate with sepharose beads). For further discussion regarding immunoprecipitation protocols see, e.g., Ausubel et al, eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York at 10.16.1.
Western blot analysis generally comprises preparing protein samples, electrophoresis of the protein samples in a polyacrylamide gel (e.g., 8%- 20%
SDS-PAGE depending on the molecular weight of the antigen), transferring the protein sample from the polyacrylamide gel to a membrane such as nitrocellulose, PVDF
or nylon, blocking the membrane in blocking solution (e.g., PBS with 3% BSA or non-fat milk), washing the membrane in washing buffer (e.g., PBS-Tween 20), blocking the membrane with primary antibody (the antibody of interest) diluted in blocking buffer, washing the membrane in washing buffer, blocking the membrane with a secondary antibody (which recognizes the primary antibody, e.g., an anti-human antibody) conjugated to an enzymatic substrate (e.g., horseradish peroxidase or alkaline phosphatase) or radioactive molecule (e.g., 32P or 125I) diluted in blocking buffer, washing the membrane in wash buffer, and detecting the presence of the antigen. One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the signal detected and to reduce the background noise. For further discussion regarding western blot protocols see, e.g., Ausubel et al, eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York at 1 0.8.1.
ELISAs comprise preparing antigen, coating the well of a 96 well microtiter plate with the antigen, adding the antibody of interest conjugated to a detectable compound such as an enzymatic substrate (e.g., horseradish peroxidase or alkaline phosphatase) to the well and incubating for a period of time, and detecting the presence of the antigen. In ELISAs the antibody of interest does not have to be conjugated to a detectable compound; instead, a second antibody (which recognizes the antibody of interest) conjugated to a detectable compound may be added to the well. Further, instead of coating the well with the antigen, the antibody may be coated to the well. In this case, a second antibody conjugated to a detectable compound may be added following the addition of the antigen of interest to the coated well. One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the signal detected as well as other variations of ELISAs known in the art. For further discussion regarding ELISAs see, e.g., Ausubel et al, eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York at 11.2.1.
The binding affinity of an antibody to an antigen and the off-rate of an antibody-antigen interaction can be determined by competitive binding assays.
One example of a competitive binding assay is a radioimmunoassay comprising the incubation of labeled antigen (e.g., 3H or 125I) with the antibody of interest in the presence of increasing amounts of unlabeled antigen, and the detection of the antibody bound to the labeled antigen. The affinity of the antibody of interest for a particular antigen and the binding off-rates can be determined from the data by scatchard plot analysis. Competition with a second antibody can also be determined using radioimmunoassays. In this case, the antigen is incubated with antibody of interest conjugated to a labeled compound (e.g., 3H or 125I) in the presence of increasing amounts of an unlabeled second antibody.
Therapeutic Uses The present invention is further directed to antibody-based therapies which involve administering antibodies of the invention to an animal, preferably a mammal, and most preferably a human, patient for treating one or more of the disclosed diseases, disorders, or conditions. Therapeutic compounds of the invention include, but are not limited to, antibodies of the invention (including fragments, analogs and derivatives thereof as described herein) and nucleic acids encoding antibodies of the invention (including fragments, analogs and derivatives thereof and anti-idiotypic antibodies as described herein). The antibodies of the invention can be used to treat, inhibit or prevent diseases, disorders or conditions associated with aberrant expression and/or activity of a polypeptide of the invention, including, but not limited to, any one or more of the diseases, disorders, or conditions described herein. The treatment and/or prevention of diseases, disorders, or conditions associated with aberrant expression and/or activity of a polypeptide of the invention includes, but is not limited to, alleviating symptoms associated with those diseases, disorders or conditions. Antibodies of the invention may be provided in pharmaceutically acceptable compositions as known in the art or as described herein.
A summary of the ways in which the antibodies of the present invention may be used therapeutically includes binding polynucleotides or polypeptides of the present invention locally or systemically in the body or by direct cytotoxicity of the antibody,.e.g. as mediated by complement (CDC) or by effector cells (ADCC).
Some of these approaches are described in more detail below. Armed with the teachings provided herein, one of ordinary skill in the art will know how to use the antibodies of the present invention for diagnostic, monitoring or therapeutic purposes without undue experimentation.
The antibodies of this invention may be advantageously utilized in combination with other monoclonal or chimeric antibodies, or with lymphokines or hematopoietic growth factors (such as, e.g., IL-2, IL-3 and IL-7), for example, which serve to increase the number or activity of effector cells which interact with the antibodies.
The antibodies of the invention may be administered alone or in combination with other types of treatments (e.g., radiation therapy, chemotherapy, hormonal therapy, immunotherapy and anti-tumor agents). Generally, administration of products of a species origin or species reactivity (in the case of antibodies) that is the same species as that of the patient is preferred. Thus, in a preferred embodiment, human antibodies, fragments derivatives, analogs, or nucleic acids, are administered to a human patient for therapy or prophylaxis.

It is preferred to use high affinity and/or potent in vivo inhibiting and/or neutralizing antibodies against polypeptides or polynucleotides of the present invention, fragments or regions thereof, for both immunoassays directed to and therapy of disorders related to polynucleotides or polypeptides, including fragments thereof, of the present invention. Such antibodies, fragments, or regions, will preferably have an affinity for polynucleotides or polypeptides of the invention, including fragments thereof. Preferred binding affinities include those with a dissociation constant or Kd less than 5 X 10-z M, 10-z M, 5 X 10-3 M, 10-3 M, M, 10-4 M, 5 X 10-5 M, 105 M, 5 X 10-6 M, 10-6 M, 5 X 10-' M, 10-' M, 5 X 10-8 M, 10-8 M, 5 X 10-9 M, 10-9 M, 5 X 10-'° M, 10-'° M, 5 X 10-" M, 10-" M, 5 X 10-'z M, 10-lz M, 5 X 10-13 M, 10-'3 M, 5 X 10-'4 M, 10-'4 M, 5 X 10-'5 M, and 10-'5 M.
Gene Therany In a specific embodiment, nucleic acids comprising sequences encoding antibodies or functional derivatives thereof, are administered to treat, inhibit or prevent a disease or disorder associated with aberrant expression and/or activity of a polypeptide of the invention, by way of gene therapy. Gene therapy refers to therapy performed by the administration to a subject of an expressed or expressible nucleic acid. In this embodiment of the invention, the nucleic acids produce their encoded protein that mediates a therapeutic effect.
Any of the methods for gene therapy available in the art can be used according to the present invention. Exemplary methods are described below.
For general reviews of the methods of gene therapy, see Goldspiel et al., Clinical Pharmacy 12:488-505 (1993); Wu and Wu, Biotherapy 3:87-95 (1991);
Tolstoshev, Ann. Rev. Pharmacol. Toxicol. 32:573-596 (1993); Mulligan, Science 260:926-932 (1993); and Morgan and Anderson, Ann. Rev. Biochem. 62:191-217 (1993); May, TIBTECH 11(5):155-215 (1993). Methods commonly known in the art of recombinant DNA technology which can be used are described in Ausubel et al.
(eds.), Current Protocols in Molecular Biology, John Wiley & Sons, NY (1993);
and Kriegler, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY
( 1990).
In a preferred aspect, the compound comprises nucleic acid sequences encoding an antibody, said nucleic acid sequences being part of expression vectors that express the antibody or fragments or chimeric proteins or heavy or light chains thereof in a suitable host. In particular, such nucleic acid sequences have promoters operably linked to the antibody coding region, said promoter being inducible or constitutive, and, optionally, tissue- specific. In another particular embodiment, nucleic acid molecules are used in which the antibody coding sequences and any other desired sequences are flanked by regions that promote homologous recombination at a desired site in the genome, thus providing for intrachromosomal expression of the antibody encoding nucleic acids (Koller and Smithies, Proc. Natl. Acad. Sci.
USA
86:8932-8935 (1989); Zijlstra et al., Nature 342:435-438 (1989). In specific embodiments, the expressed antibody molecule is a single chain antibody;
alternatively, the nucleic acid sequences include sequences encoding both the heavy and light chains, or fragments thereof, of the antibody.
Delivery of the nucleic acids into a patient may be either direct, in which case the patient is directly exposed to the nucleic acid or nucleic acid- carrying vectors, or indirect, in which case, cells are first transformed with the nucleic acids in vitro, then transplanted into the patient. These two approaches are known, respectively, as in vivo or ex vivo gene therapy.
In a specific embodiment, the nucleic acid sequences are directly administered in vivo, where it is expressed to produce the encoded product. This can be accomplished by any of numerous methods known in the art, e.g., by constructing them as part of an appropriate nucleic acid expression vector and administering it so that they become intracellular, e.g., by infection using defective or attenuated retrovirals or other viral vectors (see U.S. Patent No. 4,980,286), or by direct injection of naked DNA, or by use of microparticle bombardment (e.g., a gene gun;
Biolistic, Dupont), or coating with lipids or cell-surface receptors or transfecting agents, encapsulation in liposomes, microparticles, or microcapsules, or by administering them in linkage to a peptide which is known to enter the nucleus, by administering it in linkage to a ligand subject to receptor-mediated endocytosis (see, e.g., Wu and Wu, J. Biol. Chem. 262:4429-4432 (1987)) (which can be used to target cell types specifically expressing the receptors), etc. In another embodiment, nucleic acid-ligand complexes can be formed in which the ligand comprises a fusogenic viral peptide to disrupt endosomes, allowing the nucleic acid to avoid lysosomal degradation. In yet another embodiment, the nucleic acid can be targeted in vivo for cell specific uptake and expression, by targeting a specific receptor (see, e.g., PCT
Publications WO 92/06180; WO 92/22635; W092/20316; W093/14188, WO
93/20221). Alternatively, the nucleic acid can be introduced intracellularly and incorporated within host cell DNA for expression, by homologous recombination (Koller and Smithies, Proc. Natl. Acad. Sci. USA 86:8932-8935 (1989); Zijlstra et al., Nature 342:435-438 (1989)).
In a specific embodiment, viral vectors that contains nucleic acid sequences encoding an antibody of the invention are used. For example, a retroviral vector can be used (see Miller et al., Meth. Enzymol. 217:581-599 (1993)). These retroviral vectors contain the components necessary for the correct packaging of the viral genome and integration into the host cell DNA. The nucleic acid sequences encoding the antibody to be used in gene therapy are cloned into one or more vectors, which facilitates delivery of the gene into a patient. More detail about retroviral vectors can be found in Boesen et al., Biotherapy 6:291-302 (1994), which describes the use of a retroviral vector to deliver the mdrl gene to hematopoietic stem cells in order to make the stem cells more resistant to chemotherapy. Other references illustrating the use of retroviral vectors in gene therapy are: Clowes et al., J. Clin. Invest.
93:644-651 (1994); Kiem et al., Blood 83:1467-1473 (1994); Salmons and Gunzberg, Human Gene Therapy 4:129-141 (1993); and Grossman and Wilson, Curr. Opin. in Genetics and Devel. 3:110-114 (1993).
Adenoviruses are other viral vectors that can be used in gene therapy.
Adenoviruses are especially attractive vehicles for delivering genes to respiratory epithelia. Adenoviruses naturally infect respiratory epithelia where they cause a mild disease. Other targets for adenovirus-based delivery systems are liver, the central nervous system, endothelial cells, and muscle. Adenoviruses have the advantage of being capable of infecting non-dividing cells. Kozarsky and Wilson, Current Opinion in Genetics and Development 3:499-503 (1993) present a review of adenovirus-based gene therapy. Bout et al., Human Gene Therapy 5:3-10 (1994) demonstrated the use of adenovirus vectors to transfer genes to the respiratory epithelia of rhesus monkeys. Other instances of the use of adenoviruses in gene therapy can be found in Rosenfeld et al., Science 252:431-434 (1991);
Rosenfeld et al., Cell 68:143- 155 (1992); Mastrangeli et al., J. Clin. Invest. 91:225-234 (1993);
PCT Publication W094/12649; and Wang, et al., Gene Therapy 2:775-783 (1995).
In a preferred embodiment, adenovirus vectors are used.
Adeno-associated virus (AAV) has also been proposed for use in gene therapy (Walsh et al., Proc. Soc. Exp. Biol. Med. 204:289-300 (1993); U.S. Patent No.
5,436,146).

Another approach to gene therapy involves transferring a gene to cells in tissue culture by such methods as electroporation, lipofection, calcium phosphate mediated transfection, or viral infection. Usually, the method of transfer includes the transfer of a selectable marker to the cells. The cells are then placed under selection to isolate those cells that have taken up and are expressing the transferred gene.
Those cells are then delivered to a patient.
In this embodiment, the nucleic acid is introduced into a cell prior to administration in vivo of the resulting recombinant cell. Such introduction can be carried out by any method known in the art, including but not limited to transfection, electroporation, microinjection, infection with a viral or bacteriophage vector containing the nucleic acid sequences, cell fusion, chromosome-mediated gene transfer, microcell-mediated gene transfer, spheroplast fusion, etc. Numerous techniques are known in the art for the introduction of foreign genes into cells (see, e.g., Loeffler and Behr, Meth. Enzymol. 217:599-618 (1993); Cohen et al., Meth.
Enzymol. 217:618-644 (1993); Cline, Pharmac. Ther. 29:69-92m (1985) and may be used in accordance with the present invention, provided that the necessary developmental and physiological functions of the recipient cells are not disrupted.
The technique should provide for the stable transfer of the nucleic acid to the cell, so that the nucleic acid is expressible by the cell and preferably heritable and expressible by its cell progeny.
The resulting recombinant cells can be delivered to a patient by various methods known in the art. Recombinant blood cells (e.g., hematopoietic stem or progenitor cells) are preferably administered intravenously. The amount of cells envisioned for use depends on the desired effect, patient state, etc., and can be determined by one skilled in the art.

Cells into which a nucleic acid can be introduced for purposes of gene therapy encompass any desired, available cell type, and include but are not limited to epithelial cells, endothelial cells, keratinocytes, fibroblasts, muscle cells, hepatocytes;
blood cells such as Tlymphocytes, Blymphocytes, monocytes, macrophages, neutrophils, eosinophils, megakaryocytes, granulocytes; various stem or progenitor cells, in particular hematopoietic stem or progenitor cells, e.g., as obtained from bone marrow, umbilical cord blood, peripheral blood, fetal liver, etc.
In a preferred embodiment, the cell used for gene therapy is autologous to the patient.
In an embodiment in which recombinant cells are used in gene therapy, nucleic acid sequences encoding an antibody are introduced into the cells such that they are expressible by the cells or their progeny, and the recombinant cells are then administered in vivo for therapeutic effect. In a specific embodiment, stem or progenitor cells are used. Any stem and/or progenitor cells which can be isolated and maintained in vitro can potentially be used in accordance with this embodiment of the present invention (see e.g. PCT Publication WO 94/08598; Stemple and Anderson, Cell 71:973-985 (1992); Rheinwald, Meth. Cell Bio. 21A:229 (1980);
and Pittelkow and Scott, Mayo Clinic Proc. 61:771 (1986)).
In a specific embodiment, the nucleic acid to be introduced for purposes of gene therapy comprises an inducible promoter operably linked to the coding region, such that expression of the nucleic acid is controllable by controlling the presence or absence of the appropriate inducer of transcription. Demonstration of Therapeutic or Prophylactic Activity The compounds or pharmaceutical compositions of the invention are preferably tested in vitro, and then in vivo for the desired therapeutic or prophylactic activity, prior to use in humans. For example, in vitro assays to demonstrate the therapeutic or prophylactic utility of a compound or pharmaceutical composition include; the effect of a compound on a cell line or a patient tissue sample.
The effect of the compound or composition on the cell line and/or tissue sample can be determined utilizing techniques known to those of skill in the art including, but not limited to, rosette formation assays and cell lysis assays. In accordance with the invention, in vitro assays which can be used to determine whether administration of a specific compound is indicated, include in vitro cell culture assays in which a patient tissue sample is grown in culture, and exposed to or otherwise administered a compound, and the effect of such compound upon the tissue sample is observed.
Therapeutic/Prophylactic Administration and Composition The invention provides methods of treatment, inhibition and prophylaxis by administration to a subject of an effective amount of a compound or pharmaceutical composition of the invention, preferably an antibody of the invention. In a preferred aspect, the compound is substantially purified (e.g., substantially free from substances that limit its effect or produce undesired side-effects). The subject is preferably an animal, including but not limited to animals such as cows, pigs, horses, chickens, cats, dogs, etc., and is preferably a mammal, and most preferably human.
Formulations and methods of administration that can be employed when the compound comprises a nucleic acid or an immunoglobulin are described above;
additional appropriate formulations and routes of administration can be selected from among those described herein below.
Various delivery systems are known and can be used to administer a compound of the invention, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the compound, receptor-mediated endocytosis (see, e.g., Wu and Wu, J. Biol. Chem. 262:4429-4432 (1987)), construction of a nucleic acid as part of a retroviral or other vector, etc.
Methods of introduction include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compounds or compositions may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local. In addition, it may be desirable to introduce the pharmaceutical compounds or compositions of the invention into the central nervous system by any suitable route, including intraventricular and intrathecal injection; intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir. Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent.
In a specific embodiment, it may be desirable to administer the pharmaceutical compounds or compositions of the invention locally to the area in need of treatment;
this may be achieved by, for example, and not by way of limitation, local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers. Preferably, when administering a protein, including an antibody, of the invention, care must be taken to use materials to which the protein does not absorb.
In another embodiment, the compound or composition can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990);
Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353- 365 (1989); Lopez-Berestein, ibid., pp.
317-327; see generally ibid.) In yet another embodiment, the compound or composition can be delivered in a controlled release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment, polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Florida (1974);
Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J., Macromol. Sci.
Rev.
Macromol. Chem. 23:61 (1983); see also Levy et al., Science 228:190 (1985);
During et al., Ann. Neurol. 25:351 (1989); Howard et al., J.Neurosurg. 71:105 (1989)). In yet another embodiment, a controlled release system can be placed in proximity of the therapeutic target, i.e., the brain, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp.
115-138 (1984)).
Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990)).
In a specific embodiment where the compound of the invention is a nucleic acid encoding a protein, the nucleic acid can be administered in vivo to promote expression of its encoded protein, by constructing it as part of an appropriate nucleic acid expression vector and administering it so that it becomes intracellular, e.g., by use of a retroviral vector (see U.S. Patent No. 4,980,286), or by direct injection, or by use of microparticle bombardment (e.g., a gene gun; Biolistic, Dupont), or coating with lipids or cell-surface receptors or transfecting agents, or by administering it in linkage to a homeobox- like peptide which is known to enter the nucleus (see e.g., Joliot et al., Proc. Natl. Acad. Sci. USA 88:1864-1868 (1991)), etc.
Alternatively, a nucleic acid can be introduced intracellularly and incorporated within host cell DNA
for expression, by homologous recombination.
The present invention also provides pharmaceutical compositions. Such compositions comprise a therapeutically effective amount of a compound, and a pharmaceutically acceptable carrier. In a specific embodiment, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously.
Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH
buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences"
by E.W. Martin. Such compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.
In a preferred embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
The compounds of the invention can be formulated as neutral or salt forms.
Pharmaceutically acceptable salts include those formed with anions such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with cations such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.
The amount of the compound of the invention which will be effective in the treatment, inhibition and prevention of a disease or disorder associated with aberrant expression and/or activity of a polypeptide of the invention can be determined by standard clinical techniques. In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.
For antibodies, the dosage administered to a patient is typically 0.1 mg/kg to 100 mg/kg of the patient's body weight. Preferably, the dosage administered to a patient is between 0.1 mg/kg and 20 mg/kg of the patient's body weight, more preferably 1 mg/kg to 10 mg/kg of the patient's body weight. Generally, human antibodies have a longer half-life within the human body than antibodies from other species due to the immune response to the foreign polypeptides. Thus, lower dosages of human antibodies and less frequent administration is often possible.
Further, the dosage and frequency of administration of antibodies of the invention may be reduced by enhancing uptake and tissue penetration (e.g., into the brain) of the antibodies by modifications such as, for example, lipidation.
The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Optionally associated with such containers) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration. Diagnosis and lma ing Labeled antibodies, and derivatives and analogs thereof, which specifically bind to a polypeptide of interest can be used for diagnostic purposes to detect, diagnose, or monitor diseases, disorders, and/or conditions associated with the aberrant expression and/or activity of a polypeptide of the invention. The invention provides for the detection of aberrant expression of a polypeptide of interest, comprising (a) assaying the expression of the polypeptide of interest in cells or body fluid of an individual using one or more antibodies specific to the polypeptide interest and (b) comparing the level of gene expression with a standard gene expression level, whereby an increase or decrease in the assayed polypeptide gene expression level compared to the standard expression level is indicative of aberrant expression.
The invention provides a diagnostic assay for diagnosing a disorder, comprising (a) assaying the expression of the polypeptide of interest in cells or body fluid of an individual using one or more antibodies specific to the polypeptide interest and (b) comparing the level of gene expression with a standard gene expression level, whereby an increase or decrease in the assayed polypeptide gene expression level compared to the standard expression level is indicative of a particular disorder. With respect to cancer, the presence of a relatively high amount of transcript in biopsied tissue from an individual may indicate a predisposition for the development of the disease, or may provide a means for detecting the disease prior to the appearance of actual clinical symptoms. A more definitive diagnosis of this type may allow health professionals to employ preventative measures or aggressive treatment earlier thereby preventing the development or further progression of the cancer.
Antibodies of the invention can be used to assay protein levels in a biological sample using classical immunohistological methods known to those of skill in the art (e.g., see Jalkanen, et al., J. Cell. Biol. 101:976-985 (1985); Jalkanen, et al., J. Cell .
Biol. 105:3087-3096 (1987)). Other antibody-based methods useful for detecting protein gene expression include immunoassays, such as the enzyme linked immunosorbent assay (ELISA) and the radioimmunoassay (RIA). Suitable antibody assay labels are known in the art and include enzyme labels, such as, glucose oxidase;
radioisotopes, such as iodine (125I, 1211), carbon (14C), sulfur (35S), tritium (3H), indium (112In), and technetium (99Tc); luminescent labels, such as luminol;
and fluorescent labels, such as fluorescein and rhodamine, and biotin.
One aspect of the invention is the detection and diagnosis of a disease or disorder associated with aberrant expression of a polypeptide of interest in an animal, preferably a mammal and most preferably a human. In one embodiment, diagnosis comprises: a) administering (for example, parenterally, subcutaneously, or intraperitoneally) to a subject an effective amount of a labeled molecule which specifically binds to the polypeptide of interest; b) waiting for a time interval following the administering for permitting the labeled molecule to preferentially concentrate at sites in the subject where the polypeptide is expressed (and for unbound labeled molecule to be cleared to background level); c) determining background level; and d) detecting the labeled molecule in the subject, such that detection of labeled molecule above the background level indicates that the subject has a particular disease or disorder associated with aberrant expression of the polypeptide of interest. Background level can be determined by various methods including, comparing the amount of labeled molecule detected to a standard value previously determined for a particular system.
It will be understood in the art that the size of the subject and the imaging system used will determine the quantity of imaging moiety needed to produce diagnostic images. In the case of a radioisotope moiety, for a human subject, the quantity of radioactivity injected will normally range from about 5 to 20 millicuries of 99mTc. The labeled antibody or antibody fragment will then preferentially accumulate at the location of cells which contain the specific protein. In vivo tumor imaging is described in S.W. Burchiel et al., "Immunopharmacokinetics of Radiolabeled Antibodies and Their Fragments." (Chapter 13 in Tumor Imaging:
The Radiochemical Detection of Cancer, S.W. Burchiel and B. A. Rhodes, eds., Masson Publishing Inc. (1982).
Depending on several variables, including the type of label used and the mode of administration, the time interval following the administration for permitting the labeled molecule to preferentially concentrate at sites in the subject and for unbound labeled molecule to be cleared to background level is 6 to 48 hours or 6 to 24 hours or 6 to 12 hours. In another embodiment the time interval following administration is 5 to 20 days or 5 to 10 days.
In an embodiment, monitoring of the disease or disorder is carried out by repeating the method for diagnosing the disease or disease, for example, one month after initial diagnosis, six months after initial diagnosis, one year after initial diagnosis, etc.
Presence of the labeled molecule can be detected in the patient using methods known in the art for in vivo scanning. These methods depend upon the type of label used. Skilled artisans will be able to determine the appropriate method for detecting a particular label. Methods and devices that may be used in the diagnostic methods of the invention include, but are not limited to, computed tomography (CT), whole body scan such as position emission tomography (PET), magnetic resonance imaging (MRI), and sonography.
In a specific embodiment, the molecule is labeled with a radioisotope and is detected in the patient using a radiation responsive surgical instrument (Thurston et al., U.S. Patent No. 5,441,050). In another embodiment, the molecule is labeled with a fluorescent compound and is detected in the patient using a fluorescence responsive scanning instrument. In another embodiment, the molecule is labeled with a positron emitting metal and is detected in the patent using positron emission-tomography. In yet another embodiment, the molecule is labeled with a paramagnetic label and is detected in a patient using magnetic resonance imaging (MRI).
Kits The present invention provides kits that can be used in the above methods. In one embodiment, a'kit comprises an antibody of the invention, preferably a purified antibody, in one or more containers. In a specific embodiment, the kits of the present invention contain a substantially isolated polypeptide comprising an epitope which is specifically immunoreactive with an antibody included in the kit. Preferably, the kits of the present invention further comprise a control antibody which does not react with the polypeptide of interest. In another specific embodiment, the kits of the present invention contain a means for detecting the binding of an antibody to a polypeptide of interest (e.g., the antibody may be conjugated to a detectable substrate such as a fluorescent compound, an enzymatic substrate, a radioactive compound or a luminescent compound, or a second antibody which recognizes the first antibody may be conjugated to a detectable substrate).
In another specific embodiment of the present invention, the kit is a diagnostic kit for use in screening serum containing antibodies specific against proliferative and/or cancerous polynucleotides and polypeptides. Such a kit may include a control antibody that does not react with the polypeptide of interest. Such a kit may include a substantially isolated polypeptide antigen comprising an epitope which is specifically immunoreactive with at least one anti-polypeptide antigen antibody. Further, such a kit includes means for detecting the binding of said antibody to the antigen (e.g., the antibody may be conjugated to a fluorescent compound such as fluorescein or rhodamine which can be detected by flow cytometry). In specific embodiments, the kit may include a recombinantly produced or chemically synthesized polypeptide antigen. The polypeptide antigen of the kit may also be attached to a solid support.

In a more specific embodiment the detecting means of the above-described kit includes a solid support to which said polypeptide antigen is attached. Such a kit may also.include a non-attached reporter-labeled anti-human antibody. In this embodiment, binding of the antibody to the polypeptide antigen can be detected by binding of the said reporter-labeled antibody.
In an additional embodiment, the invention includes a diagnostic kit for use in screening serum containing antigens of the polypeptide of the invention. The diagnostic kit includes a substantially isolated antibody specifically immunoreactive with polypeptide or polynucleotide antigens, and means for detecting the binding of the polynucleotide or polypeptide antigen to the antibody. In one embodiment, the antibody is attached to a solid support. In a specific embodiment, the antibody may be a monoclonal antibody. The detecting means of the kit may include a second, labeled monoclonal antibody. Alternatively, or in addition, the detecting means may include a labeled, competing antigen.
In one diagnostic configuration, test serum is reacted with a solid phase reagent having a surface-bound antigen obtained by the methods of the present invention. After binding with specific antigen antibody to the reagent and removing unbound serum components by washing, the reagent is reacted with reporter-labeled anti-human antibody to bind reporter to the reagent in proportion to the amount of bound anti-antigen antibody on the solid support. The reagent is again washed to remove unbound labeled antibody, and the amount of reporter associated with the reagent is determined. Typically, the reporter is an enzyme which is detected by incubating the solid phase in the presence of a suitable fluorometric, luminescent or colorimetric substrate (Sigma, St. Louis, MO).
The solid surface reagent in the above assay is prepared by known techniques for attaching protein material to solid support material, such as polymeric beads, dip sticks, 96-well plate or filter material. These attachment methods generally include non-specific adsorption of the protein to the support or covalent attachment of the protein, typically through a free amine group, to a chemically reactive group on the solid support, such as an activated carboxyl, hydroxyl, or aldehyde group.
Alternatively, streptavidin coated plates can be used in conjunction with biotinylated antigen(s).
Thus, the invention provides an assay system or kit for carrying out this diagnostic method. The kit generally includes a support with surface- bound recombinant antigens, and a reporter-labeled anti-human antibody for detecting surface-bound anti-antigen antibody.
Fusion Proteins Any polypeptide of the present invention can be used to generate fusion proteins. For example, the polypeptide of the present invention, when fused to a second protein, can be used as an antigenic tag. Antibodies raised against the polypeptide of the present invention can be used to indirectly detect the second protein by binding to the polypeptide. Moreover, because secreted proteins target cellular locations based on trafficking signals, the polypeptides of the present invention can be used as targeting molecules once fused to other proteins.
Examples of domains that can be fused to polypeptides of the present invention include not only heterologous signal sequences, but also other heterologous functional regions. The fusion does not necessarily need to be direct, but may occur through linker sequences.
Moreover, fusion proteins may also be engineered to improve characteristics of the polypeptide of the present invention. For instance, a region of additional amino acids, particularly charged amino acids, may be added to the N-terminus of the polypeptide to improve stability and persistence during purification from the host cell or subsequent handling and storage. Also, peptide moieties may be added to the polypeptide to facilitate purification. Such regions may be removed prior to final preparation of the polypeptide. The addition of peptide moieties to facilitate handling of polypeptides are familiar and routine techniques in the art.
Moreover, polypeptides of the present invention, including fragments, and specifically epitopes, can be combined with parts of the constant domain of immunoglobulins (IgA, IgE, IgG, IgM) or portions thereof (CH1, CH2, CH3, and any combination thereof, including both entire domains and portions thereof), resulting in chimeric polypeptides. These fusion proteins facilitate purification and show an increased half-life in vivo. One reported example describes chimeric proteins consisting of the first two domains of the human CD4-polypeptide and various domains of the constant regions of the heavy or light chains of mammalian immunoglobulins. (EP A 394,827; Traunecker et al., Nature 331:84-86 (1988).) Fusion proteins having disulfide-linked dimeric structures (due to the IgG) can also be more efficient in binding and neutralizing other molecules, than the monomeric secreted protein or protein fragment alone. (Fountoulakis et al., J. Biochem.
270:3958-3964 (1995).) Similarly, EP-A-O 464 533 (Canadian counterpart 2045869) discloses fusion proteins comprising various portions of constant region of immunoglobulin molecules together with another human protein or part thereof. In many cases, the Fc part in a fusion protein is beneficial in therapy and diagnosis, and thus can result in, for example, improved pharmacokinetic properties. (EP-A 0232 262.) Alternatively, deleting the Fc part after the fusion protein has been expressed, detected, and purified, would be desired. For example, the Fc portion may hinder therapy and diagnosis if the fusion protein is used as an antigen for immunizations. In drug discovery, for example, human proteins, such as hIL-5, have been fused with Fc portions for the purpose of high-throughput screening assays to identify antagonists of hIL-5.
(See, D. Bennett et al., J. Molecular Recognition 8:52-58 ( 1995); K. Johanson et al., J. Biol.
Chem. 270:9459-9471 (1995).) Moreover, the polypeptides of the present invention can be fused to marker sequences, such as a peptide which facilitates purification of the fused polypeptide.
In preferred embodiments, the marker amino acid sequence is a hexa-histidine peptide, such as the tag provided in a pQE vector (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, CA, 91311), among others, many of which are commercially available.
As described in Gentz et al., Proc. Natl. Acad. Sci. USA 86:821-824 (1989), for instance, hexa-histidine provides for convenient purification of the fusion protein.
Another peptide tag useful for purification, the "HA" tag, corresponds to an epitope derived from the influenza hemagglutinin protein. (Wilson et al., Cell 37:767 ( 1984). ) Thus, any of these above fusions can be engineered using the polynucleotides or the polypeptides of the present invention.
yectors, Host Cells, and Protein Production The present invention also relates to vectors containing the polynucleotide of the present invention, host cells, and the production of polypeptides by recombinant techniques. The vector may be, for example, a phage, plasmid, viral, or retroviral vector. Retroviral vectors may be replication competent or replication defective. In the latter case, viral propagation generally will occur only in complementing host cells.
The polynucleotides may be joined to a vector containing a selectable marker for propagation in a host. Generally, a plasmid vector is introduced in a precipitate, such as a calcium phosphate precipitate, or in a complex with a charged lipid.
If the vector is a virus, it may be packaged in vitro using an appropriate packaging cell line and then transduced into host cells.
The polynucleotide insert should be operatively linked to an appropriate promoter, such as the phage lambda PL promoter, the E. coli lac, trp, phoA and tac promoters, the SV40 early and late promoters and promoters of retroviral LTRs, to name a few. Other suitable promoters will be known to the skilled artisan. The expression constructs will further contain sites for transcription initiation, termination, and, in the transcribed region, a ribosome binding site for translation. The coding portion of the transcripts expressed by the constructs will preferably include a translation initiating codon at the beginning and a termination codon (UAA, UGA or UAG) appropriately positioned at the end of the polypeptide to be translated.
As indicated, the expression vectors will preferably include at least one selectable marker. Such markers include dihydrofolate reductase, 6418 or neomycin resistance for eukaryotic cell culture and tetracycline, kanamycin or ampicillin resistance genes for culturing in E. coli and other bacteria. Representative examples of appropriate hosts include, but are not limited to, bacterial cells, such as E. coli, Streptomyces and Salmonella typhimurium cells; fungal cells, such as yeast cells (e.g., Saccharomyces cerevisiae or Pichia pastoris (ATCC Accession No.
201178));
insect cells such as Drosophila S2 and Spodoptera Sf9 cells; animal cells such as CHO, COS, 293, and Bowes melanoma cells; and plant cells. Appropriate culture mediums and conditions for the above-described host cells are known in the art.
Among vectors preferred for use in bacteria include pQE70, pQE60 and pQE-

9, available from QIAGEN, Inc.; pBluescript vectors, Phagescript vectors, pNHBA, pNHl6a, pNHl8A, pNH46A, available from Stratagene Cloning Systems, Inc.; and ptrc99a, pKK223-3, pKK233-3, pDR540, pRITS available from Pharmacia Biotech, Inc. Among preferred eukaryotic vectors are pWLNEO, pSV2CAT, pOG44, pXTl and pSG available from Stratagene; and pSVK3, pBPV, pMSG and pSVL available from Pharmacia. Preferred expression vectors for use in yeast systems include, but are not limited to pYES2, pYDl, pTEFI/Zeo, pYES2/GS, pPICZ,pGAPZ, pGAPZaIph, pPIC9, pPIC3.5, pHIL-D2, pHIL-S 1, pPIC3.5K, pPIC9K, and PA0815 (all available from Invitrogen, Carlbad, CA). Other suitable vectors will be readily apparent to the skilled artisan.
Introduction of the construct into the host cell can be effected by calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, or other methods. Such methods are described in many standard laboratory manuals, such as Davis et al., Basie Methods In Molecular Biology (1986). It is specifically contemplated that the polypeptides of the present invention may in fact be expressed by a host cell lacking a recombinant vector.
A polypeptide of this invention can be recovered and purified from recombinant cell cultures by well-known methods including ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. Most preferably, high performance liquid chromatography ("HPLC") is employed for purification.
Polypeptides of the present invention, and preferably the secreted form, can also be recovered from: products purified from natural sources, including bodily fluids, tissues and cells, whether directly isolated or cultured; products of chemical synthetic procedures; and products produced by recombinant techniques from a prokaryotic or eukaryotic host, including, for example, bacterial, yeast, higher plant, insect, and mammalian cells. Depending upon the host employed in a recombinant production procedure, the polypeptides of the present invention may be glycosylated or may be non-glycosylated. In addition, polypeptides of the invention may also include an initial modified methionine residue, in some cases as a result of host-s mediated processes. Thus, it is well known in the art that the N-terminal methionine encoded by the translation initiation codon generally is removed with high efficiency from any protein after translation in all eukaryotic cells. While the N-terminal methionine on most proteins also is efficiently removed in most prokaryotes, for some proteins, this prokaryotic removal process is inefficient, depending on the nature of the amino acid to which the N-terminal methionine is covalently linked.
In one embodiment, the yeast Pichia pastoris is used to express the polypeptide of the present invention in a eukaryotic system. Pichia pastoris is a methylotrophic yeast which can metabolize methanol as its sole carbon source.
A
main step in the methanol metabolization pathway is the oxidation of methanol to formaldehyde using O2. This reaction is catalyzed by the enzyme alcohol oxidase. In order to metabolize methanol as its sole carbon source, Pichia pastoris must generate high levels of alcohol oxidase due, in part, to the relatively low affinity of alcohol oxidase for OZ. Consequently, in a growth medium depending on methanol as a main carbon source, the promoter region of one of the two alcohol oxidase genes (AOXl ) is highly active. In the presence of methanol, alcohol oxidase produced from the AOXI
gene comprises up to approximately 30% of the total soluble protein in Pichia pastoris. See, Ellis, S.B., et al., Mol. Cell. Biol. 5:1111-21 (1985); Koutz, P.J, et al., Yeast 5:167-77 (1989); Tschopp, J.F., et al., Nucl. Acids Res. 15:3859-76 (1987).
Thus, a heterologous coding sequence, such as, for example, a polynucleotide of the present invention, under the transcriptional regulation of all or part of the AOXI

regulatory sequence is expressed at exceptionally high levels in Pichia yeast grown in the presence of methanol.
In one example, the plasmid vector pPIC9K is used to express DNA encoding a polypeptide of the invention, as set forth herein, in a Pichea yeast system essentially as described in "Pichia Protocols: Methods in Molecular Biology," D.R. Higgins and J. Cregg, eds. The Humana Press, Totowa, NJ, 1998. This expression vector allows expression and secretion of a protein of the invention by virtue of the strong AOXI
promoter linked to the Pichia pastoris alkaline phosphatase (PHO) secretory signal peptide (i.e., leader) located upstream of a multiple cloning site.
Many other yeast vectors could be used in place of pPIC9K, such as, pYES2, pYDI, pTEFI/Zeo, pYES2/GS, pPICZ, pGAPZ, pGAPZalpha, pPIC9, pPIC3.5, pHIL-D2, pHIL-S1, pPIC3.5K, and PA0815, as one skilled in the art would readily appreciate, as long as the proposed expression construct provides appropriately located signals for transcription, translation, secretion (if desired), and the like, including an in-frame AUG as required.
In another embodiment, high-level expression of a heterologous coding sequence, such as, for example, a polynucleotide of the present invention, may be achieved by cloning the heterologous polynucleotide of the invention into an expression vector such as, for example, pGAPZ or pGAPZalpha, and growing the yeast culture in the absence of methanol.
In addition to encompassing host cells containing the vector constructs discussed herein, the invention also encompasses primary, secondary, and immortalized host cells of vertebrate origin, particularly mammalian origin, that have been engineered to delete or replace endogenous genetic material (e.g., coding sequence), and/or to include genetic material (e.g., heterologous polynucleotide sequences) that is operably associated with the polynucleotides of the invention, and which activates, alters, and/or amplifies endogenous polynucleotides. For example, techniques known in the art may be used to operably associate heterologous control regions (e.g., promoter and/or enhancer) and endogenous polynucleotide sequences via homologous recombination, resulting in the formation of a new transcription unit (see, e.g., U.S. Patent No. 5,641,670, issued June 24, 1997; U.S. Patent No.
5,733,761, issued March 31, 1998; International Publication No. WO 96/29411, published September 26, 1996; International Publication No. WO 94/12650, published August 4, 1994; Koller et al., Proc. Natl. Acad. Sci. USA 86:8932-(1989); and Zijlstra et al., Nature 342:435-438 (1989), the disclosures of each of which are incorporated by reference in their entireties).
In addition, polypeptides of the invention can be chemically synthesized using techniques known in the art (e.g., see Creighton, 1983, Proteins: Structures and Molecular Principles, W.H. Freeman & Co., N.Y., and Hunkapiller et al., Nature, 310:105-111 (1984)). For example, a polypeptide corresponding to a fragment of a polypeptide sequence of the invention can be synthesized by use of a peptide synthesizer. Furthermore, if desired, nonclassical amino acids or chemical amino acid analogs can be introduced as a substitution or addition into the polypeptide sequence.
Non-classical amino acids include, but are not limited to, to the D-isomers of the common amino acids, 2,4-diaminobutyric acid, a-amino isobutyric acid, 4-aminobutyric acid, Abu, 2-amino butyric acid, g-Abu, e-Ahx, 6-amino hexanoic acid, Aib, 2-amino isobutyric acid, 3-amino propionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, homocitrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, b-alanine, fluoro-amino acids, designer amino acids such as b-methyl amino acids, Ca-methyl amino acids, Na-methyl amino acids, and amino acid analogs in general. Furthermore, the amino acid can be D (dextrorotary) or L (levorotary).
The invention encompasses polypeptides which are differentially modified during or after translation, e.g., by glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to an antibody molecule or other cellular ligand, etc. Any of numerous chemical modifications may be carried out by known techniques, including but not limited, to specific chemical cleavage by cyanogen bromide, trypsin, chymotrypsin, papain, V8 protease, NaBH4; acetylation, formylation, oxidation, reduction;
metabolic synthesis in the presence of tunicamycin; etc.
Additional post-translational modifications encompassed by the invention include, for example, e.g., N-linked or O-linked carbohydrate chains, processing of N-terminal or C-terminal ends), attachment of chemical moieties to the amino acid backbone, chemical modifications of N-linked or O-linked carbohydrate chains, and addition or deletion of an N-terminal methionine residue as a result of procaryotic host cell expression. The polypeptides may also be modified with a detectable label, such as an enzymatic, fluorescent, isotopic or affinity label to allow for detection and isolation of the protein.
Also provided by the invention are chemically modified derivatives of the polypeptides of the invention which may provide additional advantages such as increased solubility, stability and circulating time of the polypeptide, or decreased immunogenicity (see U.S. Patent NO: 4,179,337). The chemical moieties for derivitization may be selected from water soluble polymers such as polyethylene glycol, ethylene glycol/propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol and the like. The polypeptides may be modified at random positions within the molecule, or at predetermined positions within the molecule and may include one, two, three or more attached chemical moieties.
The polymer may be of any molecular weight, and may be branched or unbranched. For polyethylene glycol, the preferred molecular weight is between about 1 kDa and about 100 kDa (the term "about" indicating that in preparations of polyethylene glycol, some molecules will weigh more, some less, than the stated molecular weight) for ease in handling and manufacturing. Other sizes may be used, depending on the desired therapeutic profile (e.g., the duration of sustained release desired, the effects, if any on biological activity, the ease in handling, the degree or lack of antigenicity and other known effects of the polyethylene glycol to a therapeutic protein or analog).
The polyethylene glycol molecules (or other chemical moieties) should be attached to the protein with consideration of effects on functional or antigenic domains of the protein. There are a number of attachment methods available to those.
skilled in the art, e.g., EP 0 401 384, herein incorporated by reference (coupling PEG
to G-CSF), see also Malik et al., Exp. Hematol. 20:1028-1035 (1992) (reporting pegylation of GM-CSF using tresyl chloride). For example, polyethylene glycol may be covalently bound through amino acid residues via a reactive group, such as, a free amino or carboxyl group. Reactive groups are those to which an activated polyethylene glycol molecule may be bound. The amino acid residues having a free amino group may include lysine residues and the N-terminal amino acid residues;
those having a free carboxyl group may include aspartic acid residues glutamic acid residues and the C-terminal amino acid residue. Sulfhydryl groups may also be used as a reactive group for attaching the polyethylene glycol molecules. Preferred for therapeutic purposes is attachment at an amino group, such as attachment at the N-terminus or lysine group.

One may specifically desire proteins chemically modified at the N-terminus.
Using polyethylene glycol as an illustration of the present composition, one may select from a variety of polyethylene glycol molecules (by molecular weight, branching, etc.), the proportion of polyethylene glycol molecules to protein (polypeptide) molecules in the reaction mix, the type of pegylation reaction to be performed, and the method of obtaining the selected N-terminally pegylated protein.
The method of obtaining the N-terminally pegylated preparation (i.e., separating this moiety from other monopegylated moieties if necessary) may be by purification of the N-terminally pegylated material from a population of pegylated protein molecules.
Selective proteins chemically modified at the N-terminus modification may be accomplished by reductive alkylation which exploits differential reactivity of different types of primary amino groups (lysine versus the N-terminal) available for derivatization in a particular protein. Under the appropriate reaction conditions, substantially selective derivatization of the protein at the N-terminus with a carbonyl group containing polymer is achieved.
The polypeptides of the invention may be in monomers or multimers (i.e., dimers, trimers, tetramers and higher multimers). Accordingly, the present invention relates to monomers and multimers of the polypeptides of the invention, their preparation, and compositions (preferably, Therapeutics) containing them. In specific embodiments, the polypeptides of the invention are monomers, dimers, trimers or tetramers. In additional embodiments, the multimers of the invention are at least dimers, at least trimers, or at least tetramers.
Multimers encompassed by the invention may be homomers or heteromers.
As used herein, the term homomer, refers to a multimer containing only polypeptides corresponding to the amino acid sequence of SEQ ID NO:Y or encoded by the cDNA
contained in a deposited clone (including fragments, variants, splice variants, and fusion proteins, corresponding to these polypeptides as described herein).
These homomers may contain polypeptides having identical or different amino acid sequences. In a specific embodiment, a homomer of the invention is a multimer containing only polypeptides having an identical amino acid sequence. In another specific embodiment, a homomer of the invention is a multimer containing polypeptides having different amino acid sequences. In specific embodiments, the multimer of the invention is a homodimer (e.g., containing polypeptides having identical or different amino acid sequences) or a homotrimer (e.g., containing polypeptides having identical and/or different amino acid sequences). In additional embodiments, the homomeric multimer of the invention is at least a homodimer, at least a homotrimer, or at least a homotetramer.
As used herein, the term heteromer refers to a multimer containing one or more heterologous polypeptides (i.e., polypeptides of different proteins) in addition to the polypeptides of the invention. In a specific embodiment, the multimer of the invention is a heterodimer, a heterotrimer, or a heterotetramer. In additional embodiments, the heteromeric multimer of the invention is at least a heterodimer, at least a heterotrimer, or at least a heterotetramer.
Multimers of the invention may be the result of hydrophobic, hydrophilic, ionic and/or covalent associations and/or may be indirectly linked, by for example, liposome formation. Thus, in one embodiment, multimers of the invention, such as, for example, homodimers or homotrimers, are formed when polypeptides of the invention contact one another in solution. In another embodiment, heteromultimers of the invention, such as, for example, heterotrimers or heterotetramers, are formed when polypeptides of the invention contact antibodies to the polypeptides of the invention (including antibodies to the heterologous polypeptide sequence in a fusion protein of the invention) in solution. In other embodiments, multimers of the invention are formed by covalent associations with and/or between the polypeptides of the invention. Such covalent associations may involve one or more amino acid residues contained in the polypeptide sequence ( e.g., that recited in the sequence listing, or contained in the polypeptide encoded by a deposited clone). In one instance, the covalent associations are cross-linking between cysteine residues located within the polypeptide sequences which interact in the native (i.e., naturally occurring) polypeptide. In another instance, the covalent associations are the consequence of chemical or recombinant manipulation. Alternatively, such covalent associations may involve one or more amino acid residues contained in the heterologous polypeptide sequence in a fusion protein of the invention.
In one example, covalent associations are between the heterologous sequence contained in a fusion protein of the invention (see, e.g., US Patent Number 5,478,925). In a specific example, the covalent associations are between the heterologous sequence contained in an Fc fusion protein of the invention (as described herein). In another specific example, covalent associations of fusion proteins of the invention are between heterologous polypeptide sequence from another protein that is capable of forming covalently associated multimers, such as for example, oseteoprotegerin (see, e.g., International Publication NO: WO
98/49305, the contents of which are herein incorporated by reference in its entirety). In another embodiment, two or more polypeptides of the invention are joined through peptide linkers. Examples include those peptide linkers described in U.S. Pat. No.
5,073,627 (hereby incorporated by reference). Proteins comprising multiple polypeptides of the invention separated by peptide linkers may be produced using conventional recombinant DNA technology.
Another method for preparing multimer polypeptides of the invention involves use of polypeptides of the invention fused to a leucine zipper or isoleucine zipper polypeptide sequence. Leucine zipper and isoleucine zipper domains are polypeptides that promote multimerization of the proteins in which they are found. Leucine zippers were originally identified in several DNA-binding proteins (Landschulz et al., Science 240:1759, (1988)), and have since been found in a variety of different proteins. Among the known leucine zippers are naturally occurring peptides and derivatives thereof that dimerize or trimerize. Examples of leucine zipper domains suitable for producing soluble multimeric proteins of the invention are those described in PCT application WO 94/10308, hereby incorporated by reference. Recombinant fusion proteins comprising a polypeptide of the invention fused to a polypeptide sequence that dimerizes or trimerizes in solution are expressed in suitable host cells, and the resulting soluble multimeric fusion protein is recovered from the culture supernatant using techniques known in the art.
Trimeric polypeptides of the invention may offer the advantage of enhanced biological activity. Preferred leucine zipper moieties and isoleucine moieties are those that preferentially form trimers. One example is a leucine zipper derived from lung surfactant protein D (SPD), as described in Hoppe et al. (FEBS Letters 344:191, (1994)) and in U.S. patent application Ser. No. 08/446,922, hereby incorporated by reference. Other peptides derived from naturally occurring trimeric proteins may be employed in preparing trimeric polypeptides of the invention.
In another example, proteins of the invention are associated by interactions between Flag~ polypeptide sequence contained in fusion proteins of the invention containing Flag~ polypeptide seuqence. In a further embodiment, associations proteins of the invention are associated by interactions between heterologous polypeptide sequence contained in Flag~ fusion proteins of the invention and anti-Flag~ antibody.

The multimers of the invention may be generated using chemical techniques known in the art. For example, polypeptides desired to be contained in the multimers of the invention may be chemically cross-linked using linker molecules and linker molecule length optimization techniques known in the art (see, e.g., US Patent Number 5,478,925, which is herein incorporated by reference in its entirety).
Additionally, multimers of the invention may be generated using techniques known in the art to form one or more inter-molecule cross-links between the cysteine residues located within the sequence of the polypeptides desired to be contained in the multimer (see, e.g., US Patent Number 5,478,925, which is herein incorporated by reference in its entirety). Further, polypeptides of the invention may be routinely modified by the addition of cysteine or biotin to the C terminus or N-terminus of the polypeptide and techniques known in the art may be applied to generate multimers containing one or more of these modified polypeptides (see, e.g., US Patent Number 5,478,925, which is herein incorporated by reference in its entirety).
Additionally, techniques known in the art may be applied to generate liposomes containing the polypeptide components desired to be contained in the multimer of the invention (see, e.g., US Patent Number 5,478,925, which is herein incorporated by reference in its entirety).
Alternatively, multimers of the invention may be generated using genetic engineering techniques known in the art. In one embodiment, polypeptides contained in multimers of the invention are produced recombinantly using fusion protein technology described herein or otherwise known in the art (see, e.g., US
Patent Number 5,478,925, which is herein incorporated by reference in its entirety).
In a specific embodiment, polynucleotides coding for a homodimer of the invention are generated by ligating a polynucleotide sequence encoding a polypeptide of the invention to a sequence encoding a linker polypeptide and then further to a synthetic polynucleotide encoding the translated product of the polypeptide in the reverse orientation from the original C-terminus to the N-terminus (lacking the leader sequence) (see, e.g., US Patent Number 5,478,925, which is herein incorporated by reference in its entirety). In another embodiment, recombinant techniques described herein or otherwise known in the art are applied to generate recombinant polypeptides of the invention which contain a transmembrane domain (or hyrophobic or signal peptide) and which can be incorporated by membrane reconstitution techniques into liposomes (see, e.g., US Patent Number 5,478,925, which is herein incorporated by reference in 'its entirety).
Uses of the Polvnucleotides Each of the polynucleotides identified herein can be used in numerous ways as reagents. The following description should be considered exemplary and utilizes known techniques.
The polynucleotides of the present invention are useful for chromosome identification. There exists an ongoing need to identify new chromosome markers, since few chromosome marking reagents, based on actual sequence data (repeat polymorphisms), are presently available. Each polynucleotide of.the present invention can be used as a chromosome marker.
Briefly, sequences can be mapped to chromosomes by preparing PCR primers (preferably 15-25 bp) from the sequences shown in SEQ ID NO:X. Primers can be selected using computer analysis so that primers do not span more than one predicted exon in the genomic DNA. These primers are then used for PCR screening of somatic cell hybrids containing individual human chromosomes. Only those hybrids containing the human gene corresponding to the SEQ ID NO:X will yield an amplified fragment.

Similarly, somatic hybrids provide a rapid method of PCR mapping the polynucleotides to particular chromosomes. Three or more clones can be assigned per day using a single thermal cycler. Moreover, sublocalization of the polynucleotides can be achieved with panels of specific chromosome fragments. Other gene mapping strategies that can be used include in situ hybridization, prescreening with labeled flow-sorted chromosomes, and preselection by hybridization to construct chromosome specific-cDNA libraries.
Precise chromosomal location of the polynucleotides can also be achieved using fluorescence in situ hybridization (FISH) of a metaphase chromosomal spread.
This technique uses polynucleotides as short as 500 or 600 bases; however, polynucleotides 2,000-4,000 by are preferred. For a review of this technique, see Verma et al., "Human Chromosomes: a Manual of Basic Techniques," Pergamon Press, New York (1988).
For chromosome mapping, the polynucleotides can be used individually (to mark a single chromosome or a single site on that chromosome) or in panels (for marking multiple sites and/or multiple chromosomes). Preferred polynucleotides correspond to the noncoding regions of the cDNAs because the coding sequences are more likely conserved within gene families, thus increasing the chance of cross hybridization during chromosomal mapping.
Once a polynucleotide has been mapped to a precise chromosomal location, the physical position of the polynucleotide can be used in linkage analysis.
Linkage analysis establishes coinheritance between a chromosomal location and presentation of a particular disease. (Disease mapping data are found, for example, in V.
McKusick, Mendelian Inheritance in Man (available on line through Johns Hopkins University Welch Medical Library) .) Assuming 1 megabase mapping resolution and one gene per 20 kb, a cDNA precisely localized to a chromosomal region associated with the disease could be one of 50-500 potential causative genes.
Thus, once coinheritance is established, differences in the polynucleotide and the corresponding gene between affected and unaffected individuals can be examined.
First, visible structural alterations in the chromosomes, such as deletions or translocations, are examined in chromosome spreads or by PCR. If no structural alterations exist, the presence of point mutations are ascertained. Mutations observed in some or all affected individuals, but not in normal individuals, indicates that the mutation may cause the disease. However, complete sequencing of the polypeptide and the corresponding gene from several normal individuals is required to distinguish the mutation from a polymorphism. If a new polymorphism is identified, this polymorphic polypeptide can be used for further linkage analysis.
Furthermore, increased or decreased expression of the gene in affected individuals as compared to unaffected individuals can be assessed using polynucleotides of the present invention. Any of these alterations (altered expression, chromosomal rearrangement, or mutation) can be used as a diagnostic or prognostic marker.
Thus, the invention also provides a diagnostic method useful during diagnosis of a disorder, involving measuring the expression level of polynucleotides of the present invention in cells or body fluid from an individual and comparing the measured gene expression level with a standard level of polynucleotide expression level, whereby an increase or decrease in the gene expression level compared to the standard is indicative of a disorder.
In still another embodiment, the invention includes a kit for analyzing samples for the presence of proliferative and/or cancerous polynucleotides derived from a test subject. In a general embodiment, the kit includes at least one polynucleotide probe containing a nucleotide sequence that will specifically hybridize with a polynucleotide of the present invention and a suitable container. In a specific embodiment, the kit includes two polynucleotide probes defining an internal region of the polynucleotide of the present invention, where each probe has one strand containing a 31'mer-end internal to the region. In a further embodiment, the probes may be useful as primers for polymerise chain reaction amplification.
Where a diagnosis of a disorder, has already been made according to conventional methods, the present invention is useful as a prognostic indicator, whereby patients exhibiting enhanced or depressed polynucleotide of the present invention expression will experience a worse clinical outcome relative to patients expressing the gene at a level nearer the standard level.
By. "measuring the expression level of polynucleotide of the present invention" is intended qualitatively or quantitatively measuring or estimating the level of the polypeptide of the present invention or the level of the mRNA encoding the polypeptide in a first biological sample either directly (e.g., by determining or estimating absolute protein level or mRNA level) or relatively (e.g., by comparing to the polypeptide level or mRNA level in a second biological sample).
Preferably, the polypeptide level or mRNA level in the first biological sample is measured or estimated and compared to a standard polypeptide level or mRNA level, the standard being taken from a second biological sample obtained from an individual not having the disorder or being determined by averaging levels from a population of individuals not having a disorder. As will be appreciated in the art, once a standard polypeptide level or mRNA level is known, it can be used repeatedly as a standard for comparison.
By "biological sample" is intended any biological sample obtained from an individual, body fluid, cell line, tissue culture, or other source which contains the polypeptide of the present invention or mRNA. As indicated, biological samples include body fluids (such as semen, lymph, sera, plasma, urine, synovial fluid and spinal fluid) which contain the polypeptide of the present invention, and other tissue sources found to express the polypeptide of the present invention. Methods for S obtaining tissue biopsies and body fluids from mammals are well known in the art.
Where the biological sample is to include mRNA, a tissue biopsy is the preferred source.
The methods) provided above may preferrably be applied in a diagnostic method and/or kits in which polynucleotides and/or polypeptides are attached to a solid support. In one exemplary method, the support may be a "gene chip" or a "biological chip" as described in US Patents 5,837,832, 5,874,219, and 5,856,174.
Further, such a gene chip with polynucleotides of the present invention attached may be used to identify polymorphisms between the polynucleotide sequences, with polynucleotides isolated from a test subject. The knowledge of such polymorphisms (i.e. their location, as well as, their existence) would be beneficial in identifying disease loci for many disorders, including cancerous diseases and conditions.
Such a method is described in US Patents 5,858,659 and 5,856,104. The US Patents referenced supra are hereby incorporated by reference in their entirety herein.
The present invention encompasses polynucleotides of the present invention that are chemically synthesized, or reproduced as peptide nucleic acids (PNA), or according to other methods known in the art. The use of PNAs would serve as the preferred form if the polynucleotides are incorporated onto a solid support, or gene chip. For the purposes of the present invention, a peptide nucleic acid (PNA) is a polyamide type of DNA analog and the monomeric units for adenine, guanine, thymine and cytosine are available commercially (Perceptive Biosystems).
Certain components of DNA, such as phosphorus, phosphorus oxides, or deoxyribose derivatives, are not present in PNAs. As disclosed by P. E. Nielsen, M.
Egholm, R. H.
Berg and O. Buchardt, Science 254, 1497 (1991); and M. Egholm, O. Buchardt, L.Christensen, C. Behrens, S. M. Freier, D. A. Driver, R. H. Berg, S. K. Kim, B.
Norden, and P. E. Nielsen, Nature 365, 666 (1993), PNAs bind specifically and tightly to complementary DNA strands and are not degraded by nucleases. In fact, PNA binds more strongly to DNA than DNA itself does. This is probably because there is no electrostatic repulsion between the two strands, and also the polyamide backbone is more flexible. Because of this, PNA/DNA duplexes bind under a wider range of stringency conditions than DNA/DNA duplexes, making it easier to perform multiplex hybridization. Smaller probes can be used than with DNA due to the strong binding. In addition, it is more likely that single base mismatches can be determined with PNA/DNA hybridization because a single mismatch in a PNA/DNA 15-mer lowers the melting point (T_m) by 8°-20° C, vs. 4°-16° C for the DNA/DNA 15-mer duplex. Also, the absence of charge groups in PNA means that hybridization can be done at low ionic strengths and reduce possible interference by salt during the analysis.
The present invention is useful for detecting cancer in mammals. In particular the invention is useful during diagnosis of pathological cell proliferative neoplasias which include, but are not limited to: acute myelogenous leukemias including acute monocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute erythroleukemia, acute megakaryocytic leukemia, and acute undifferentiated leukemia, etc.; and chronic myelogenous leukemias including chronic myelomonocytic leukemia, chronic granulocytic leukemia, etc. Preferred mammals include monkeys, apes, cats, dogs, cows, pigs, horses, rabbits and humans. Particularly preferred are humans.

Pathological cell proliferative diseases, disorders, and/or conditions are often associated with inappropriate activation of proto-oncogenes. (Gelmann, E. P.
et al., "The Etiology of Acute Leukemia: Molecular Genetics and Viral Oncology," in Neoplastic Diseases of the Blood, Vol 1., Wiernik, P. H. et al. eds., 161-182 (1985)).
Neoplasias are now believed to result from the qualitative alteration of a normal cellular gene product, or from the quantitative modification of gene expression by insertion into the chromosome of a viral sequence, by chromosomal translocation of a gene to a more actively transcribed region, or by some other mechanism.
(Gelmann et al., supra) It is likely that mutated or altered expression of specific genes is involved in the pathogenesis of some leukemias, among other tissues and cell types.
(Gelmann et al., supra) Indeed, the human counterparts of the oncogenes involved in some animal neoplasias have been amplified or translocated in some cases of human leukemia and carcinoma. (Gelmann et al., supra) For example, c-myc expression is highly amplified in the non-lymphocytic leukemia cell line HL-60. When HL-60 cells are chemically induced to stop proliferation, the level of c-myc is found to be downregulated. (International Publication Number WO
91/15580) However, it has been shown that exposure of HL-60 cells to a DNA
construct that is complementary to the 5' end of c-myc or c-myb blocks translation of the corresponding mRNAs which downregulates expression of the c-myc or c-myb proteins and causes arrest of cell proliferation and differentiation of the treated cells.
(International Publication Number WO 91/15580; Wickstrom et al., Proc. Natl.
Acad.
Sci. 85:1028 (1988); Anfossi et al., Proc. Natl. Acad. Sci. 86:3379 (1989)).
However, the skilled artisan would appreciate the present invention's usefulness would not be limited to treatment of proliferative diseases, disorders, and/or conditions of hematopoietic cells and tissues, in light of the numerous cells and cell types of varying origins which are known to exhibit proliferative phenotypes.

In addition to the foregoing, a polynucleotide can be used to control gene expression through triple helix formation or antisense DNA or RNA. Antisense techniques.are discussed, for example, in Okano, J. Neurochem. 56: 560 (1991);
"Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression,CRCPress, Boca Raton, FL (1988). Triple helix formation is discussed in, for instance Lee et al., Nucleic Acids Research 6: 3073 (1979); Cooney et al., Science 241: 456 (1988);
and Dervan et al., Science 251: 1360 (1991). Both methods rely on binding of the polynucleotide to a complementary DNA or RNA. For these techniques, preferred polynucleotides are usually oligonucleotides 20 to 40 bases in length and complementary to either the region of the gene involved in transcription (triple helix -see Lee et al., Nucl. Acids Res. 6:3073 (1979); Cooney et al., Science 241:456 (1988); and Dervan et al., Science 251:1360 (1991) ) or to the mRNA itself (antisense - Okano, J. Neurochem. 56:560 (1991); Oligodeoxy-nucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, FL (1988).) Triple helix formation optimally results in a shut-off of RNA transcription from DNA, while antisense RNA hybridization blocks translation of an mRNA molecule into polypeptide. Both techniques are effective in model systems, and the information disclosed herein can be used to design antisense or triple helix polynucleotides in an effort to treat or prevent disease.
Polynucleotides of the present invention are also useful in gene therapy. One goal of gene therapy is to insert a normal gene into an organism having a defective gene, in an effort to correct the genetic defect. The polynucleotides disclosed in the present invention offer a means of targeting such genetic defects in a highly accurate manner. Another goal is to insert a new gene that was not present in the host genome, thereby producing a new trait in the host cell.

The polynucleotides are also useful for identifying individuals from minute biological samples. The United States military, for example, is considering the use of restriction fragment length polymorphism (RFLP) for identification of its personnel.
In this technique, an individual's genomic DNA is digested with one or more restriction enzymes, and probed on a Southern blot to yield unique bands for identifying personnel. This method does not suffer from the current limitations of "Dog Tags" which can be lost, switched, or stolen, making positive identification difficult. The polynucleotides of the present invention can be used as additional DNA
markers for RFLP.
The polynucleotides of the present invention can also be used as an alternative to RFLP, by determining the actual base-by-base DNA sequence of selected portions of an individual's genome. These sequences can be used to prepare PCR primers for amplifying and isolating such selected DNA, which can then be sequenced. Using this technique, individuals can be identified because each individual will have a unique set of DNA sequences. Once an unique ID database is established for an individual, positive identification of that individual, living or dead, can be made from extremely small tissue samples.
Forensic biology also benefits from using DNA-based identification techniques as disclosed herein. DNA sequences taken from very small biological samples such as tissues, e.g., hair or skin, or body fluids, e.g., blood, saliva, semen, synovial fluid, amniotic fluid, breast milk, lymph, pulmonary sputum or surfactant,urine,fecal matter, etc., can be amplified using PCR. In one prior art technique, gene sequences amplified from polymorphic loci, such as DQa class II
HLA gene, are used in forensic biology to identify individuals. (Erlich, H., PCR
Technology, Freeman and Co. (1992).) Once these specific polymorphic loci are amplified, they are digested with one or more restriction enzymes, yielding an identifying set of bands on a Southern blot probed with DNA corresponding to the DQa class II HLA gene. Similarly, polynucleotides of the present invention can be used as polymorphic markers for forensic purposes.
There is also a need for reagents capable of identifying the source of a particular tissue. Such need arises, for example, in forensics when presented with tissue of unknown origin. Appropriate reagents can comprise, for example, DNA
probes or primers specific to particular tissue prepared from the sequences of the present invention. Panels of such reagents can identify tissue by species and/or by organ type. In a similar fashion, these reagents can be used to screen tissue cultures for contamination.
In the very least, the polynucleotides of the present invention can be used as molecular weight markers on Southern gels, as diagnostic probes for the presence of a specific mRNA in a particular cell type, as a probe to "subtract-out" known sequences in the process of discovering novel polynucleotides, for selecting and making oligomers for attachment to a "gene chip" or other support, to raise anti-DNA
antibodies using DNA immunization techniques, and as an antigen to elicit an immune response.
Uses of the PolyPePtides Each of the polypeptides identified herein can be used in numerous ways. The following description should be considered exemplary and utilizes known techniques.
A polypeptide of the present invention can be used to assay protein levels in a biological sample using antibody-based techniques. For example, protein expression in tissues can be studied with classical immunohistological methods.
(Jalkanen, M., et al., J. Cell. Biol. 101:976-985 (1985); Jalkanen, M., et al., J. Cell .
Biol. 105:3087-3096 (1987).) Other antibody-based methods useful for detecting protein gene DEMANDES OU BREVETS VOLUMINEUX
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Claims

What Is Claimed Is:

I. An isolated nucleic acid molecule comprising a polynucleotide having a nucleotide sequence at least 95% identical to a sequence selected from the group consisting of:
(a) a polynucleotide fragment of SEQ ID NO:X or a polynucleotide fragment of the cDNA sequence included in ATCC Deposit No:Z, which is hybridizable to SEQ ID NO:X;
(b) a polynucleotide encoding a polypeptide fragment of SEQ ID NO:Y or a polypeptide fragment encoded by the cDNA sequence included in ATCC Deposit No:Z, which is hybridizable to SEQ ID NO:X;
(c) a polynucleotide encoding a polypeptide domain of SEQ ID NO:Y or a polypeptide domain encoded by the cDNA sequence included in ATCC Deposit No:Z, which is hybridizable to SEQ ID NO:X;
(d) a polynucleotide encoding a polypeptide epitope of SEQ ID NO:Y or a polypeptide epitope encoded by the cDNA sequence included in ATCC Deposit No:Z, which is hybridizable to SEQ ID NO:X;
(e) a polynucleotide encoding a polypeptide of SEQ ID NO:Y or the cDNA
sequence included in ATCC Deposit No:Z, which is hybridizable to SEQ ID NO:X, having biological activity;
(f) a polynucleotide which is a variant of SEQ ID NO:X;
(g) a polynucleotide which is an allelic variant of SEQ ID NO:X;
(h) a polynucleotide which encodes a species homologue of the SEQ ID
NO:Y;

(i) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a)-(h), wherein said polynucleotide does not hybridize under stringent conditions to a nucleic acid molecule having a nucleotide sequence of only A residues or of only T residues.
2. The isolated nucleic acid molecule of claim 1, wherein the polynucleotide fragment comprises a nucleotide sequence encoding a secreted protein.
3. The isolated nucleic acid molecule of claim 1, wherein the polynucleotide fragment comprises a nucleotide sequence encoding the sequence identified as SEQ ID NO:Y or the polypeptide encoded by the cDNA sequence included in ATCC Deposit No:Z, which is hybridizable to SEQ ID NO:X.
4. The isolated nucleic acid molecule of claim 1, wherein the polynucleotide fragment comprises the entire nucleotide sequence of SEQ ID
NO:X
or the cDNA sequence included in ATCC Deposit No:Z, which is hybridizable to SEQ ID NO:X.
5. The isolated nucleic acid molecule of claim 2, wherein the nucleotide sequence comprises sequential nucleotide deletions from either the C-terminus or the N-terminus.
6. The isolated nucleic acid molecule of claim 3, wherein the nucleotide sequence comprises sequential nucleotide deletions from either the C-terminus or the N-terminus.
7. A recombinant vector comprising the isolated nucleic acid molecule of claim 1.
8. A method of making a recombinant host cell comprising the isolated nucleic acid molecule of claim 1.
9. A recombinant host cell produced by the method of claim 8.
10. The recombinant host cell of claim 9 comprising vector sequences.
11. An isolated polypeptide comprising an amino acid sequence at least 95% identical to a sequence selected from the group consisting of:
(a) a polypeptide fragment of SEQ ID NO:Y or the encoded sequence included in ATCC Deposit No:Z;
(b) a polypeptide fragment of SEQ ID NO:Y or the encoded sequence included in ATCC Deposit No:Z, having biological activity;
(c) a polypeptide domain of SEQ ID NO:Y or the encoded sequence included in ATCC Deposit No:Z;
(d) a polypeptide epitope of SEQ ID NO:Y or the encoded sequence included in ATCC Deposit No:Z;
(e) a secreted form of SEQ ID NO:Y or the encoded sequence included in ATCC Deposit No:Z;
(f) a full length protein of SEQ ID NO:Y or the encoded sequence included in ATCC Deposit No:Z;
(g) a variant of SEQ ID NO:Y;

(h) an allelic variant of SEQ ID NO:Y; or (i) a species homologue of the SEQ ID NO:Y.
12. The isolated polypeptide of claim 11, wherein the secreted form or the full length protein comprises sequential amino acid deletions from either the C-terminus or the N-terminus.
13. An isolated antibody that binds specifically to the isolated polypeptide of claim 11.
14. A recombinant host cell that expresses the isolated polypeptide of claim 11.
15. A method of making an isolated polypeptide comprising:
(a) culturing the recombinant host cell of claim 14 under conditions such that said polypeptide is expressed; and (b) recovering said polypeptide.
16. The polypeptide produced by claim 15.
17. A method for preventing, treating, or ameliorating a medical condition, comprising administering to a mammalian subject a therapeutically effective amount of the polypeptide of claim 11 or the polynucleotide of claim 1.
18. A method of diagnosing a pathological condition or a susceptibility to a pathological condition in a subject comprising:

(a) determining the presence or absence of a mutation in the polynucleotide of claim 1; and (b) diagnosing a pathological condition or a susceptibility to a pathological condition based on the presence or absence of said mutation.
19. A method of diagnosing a pathological condition or a susceptibility to a pathological condition in a subject comprising:
(a) determining the presence or amount of expression of the polypeptide of claim 11 in a biological sample; and (b) diagnosing a pathological condition or a susceptibility to a pathological condition based on the presence or amount of expression of the polypeptide.
20. A method for identifying a binding partner to the polypeptide of claim 11 comprising:
(a) contacting the polypeptide of claim 11 with a binding partner; and (b) determining whether the binding partner effects an activity of the polypeptide.
21. The gene corresponding to the cDNA sequence of SEQ ID NO:Y.
22. A method of identifying an activity in a biological assay, wherein the method comprises:
(a) expressing SEQ ID NO:X in a cell;
(b) isolating the supernatant;
(c) detecting an activity in a biological assay; and (d) identifying the protein in the supernatant having the activity.
23. The product produced by the method of claim 20.