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EP1423134A2 - Proteines secretees par l'homme - Google Patents

Proteines secretees par l'homme

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Publication number
EP1423134A2
EP1423134A2 EP02780789A EP02780789A EP1423134A2 EP 1423134 A2 EP1423134 A2 EP 1423134A2 EP 02780789 A EP02780789 A EP 02780789A EP 02780789 A EP02780789 A EP 02780789A EP 1423134 A2 EP1423134 A2 EP 1423134A2
Authority
EP
European Patent Office
Prior art keywords
seq
polypeptide
referenced
fragment
encoded
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02780789A
Other languages
German (de)
English (en)
Inventor
Craig A. Rosen
Steven M. Ruben
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Human Genome Sciences Inc
Original Assignee
Human Genome Sciences Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Human Genome Sciences Inc filed Critical Human Genome Sciences Inc
Publication of EP1423134A2 publication Critical patent/EP1423134A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to human secreted proteins/polypeptides, and isolated nucleic acid molecules encoding said proteins/polypeptides, useful for detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating cancer and other hyperproliferative disorders.
  • Antibodies that bind these polypeptides are also encompassed by the present invention.
  • vectors, host cells, and recombinant and synthetic methods for producing said polynucleotides, polypeptides, and/or antibodies are also encompassed by the present invention.
  • the invention further encompasses screening methods for identifying agonists and antagonists of polynucleotides and polypeptides of the invention.
  • the present invention further encompasses methods and compositions for inhibiting or enhancing the production and function of the polypeptides of the present invention.
  • Cancer and other hyperproliferative disorders are a diverse group of disorders and diseases sharing one characteristic in common; all result from uncontrolled cell proliferation.
  • the human body is composed of many different cell types, e.g. liver cells, muscle cells, brain cells, etc. Normally, these cells grow and divide to produce more cells only as the body needs them (e.g. to regenerate blood cells or replace epithelial cells lining the stomach). Sometimes, however, cells begin to divide unchecked even though new cells are not needed. These extra cells accumulate and form a mass of tissue, called a tumor.
  • a tumor a mass of tissue
  • Tumors are either benign or malignant. Benign tumors are not cancerous; they can usually be removed, they do not spread to other parts of the body and, they rarely threaten life. Malignant tumors, however, are cancerous. Cells in malignant tumors can invade and damage nearby or distant tissues and organs. The spread of cancerous cells is called metastasis. Malignant (or metastatic) cells can invade adjacent organs by proliferating directly from the primary tumor. Additionally, malignant cells can also metastasize to distant organs by breaking away from the primary tumor, entering the bloodstream or lymphatic system, and settling down in a new organ or tissue to produce a secondary tumor. The origin of secondary tumors is established by comparing cells comprising these tumors to cells in the original (primary) tumor.
  • leukemia In contrast to solid organ cancers (such as cancer in the liver, lung, and brain) cancer can also develop in blood-forming cells. These cancers are referred to as leukemias or lymphomas.
  • Leukemia refers to cancer of blood forming cells such as red blood cells, platelets, and plasma cells.
  • Lymphomas are a subset of leukemias, primarily involving white blood cells, in which the cancerous cells originated in, or are associated with, the lymph system and lymph organs (e.g. T- lymphocytes in the lymph nodes, spleen, or thymus).
  • cancers are treated with one or a combination therapies consisting of surgery, radiation therapy, chemotherapy, hormone therapy, and/or biological therapy. These five therapeutic modes are either local or systemic treatment strategies. Local treatments affect cancer cells in the tumor and discretely adjacent areas (for example, surgical tumor removal is a local treatment as are most radiation treatments). In contrast, systemic treatments travel through the bloodstream, and reach cancer and other cells all over the body. Chemotherapy, hormone therapy, and biological therapy are examples of systemic treatments. Whether systemic or local, it is often difficult or impossible to protect healthy cells from the harmful effects of cancer treatment; healthy cells and tissues are inevitably damaged in the process of treating the cancerous cells. Damage and disruption of the normal functioning of healthy cells and tissues often produces the undesirable side effects experienced by patients undergoing cancer treatment.
  • cytokines e.g. interferons, interleukins, and colony stimulating factors
  • monoclonal antibodies targeted to particular cancer cells
  • the present invention encompasses human secreted proteins/polypeptides, and isolated nucleic acid molecules encoding said proteins/polypeptides, useful for detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating cancer and other hyperproliferative disorders.
  • Antibodies that bind these polypeptides are also encompassed by the present invention; as are vectors, host cells, and recombinant and synthetic methods for producing said polynucleotides, polypeptides, and/or antibodies.
  • the invention further encompasses screening methods for identifying agonists and antagonists of polynucleotides and polypeptides of the invention.
  • the present invention also encompasses methods and compositions for inhibiting or enhancing the production and function of the polypeptides of the present invention.
  • Table 1A summarizes information concerning certain polypnucleotides and polypeptides of the invention.
  • the first column provides the gene number in the application for each clone identifier.
  • the second column provides a unique clone identifier, "Clone ID:”, for a cDNA clone related to each contig sequence disclosed in Table 1A.
  • Third column the cDNA Clones identified in the second column were deposited as indicated in the third column (i.e. by ATCC Deposit No:Z and deposit date). Some of the deposits contain multiple different clones corresponding to the same gene.
  • "Vector” refers to the type of vector contained in the corresponding cDNA Clone identified in the second column.
  • nucleotide sequence identified as "NT SEQ ID NO:X” was assembled from partially homologous ("overlapping") sequences obtained from the corresponding cDNA clone identified in the second column and, in some cases, from additional related cDNA 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.
  • 'Total NT Seq.” refers to the total number of nucleotides in the contig sequence identified as SEQ ID NO:X.”
  • the deposited clone may contain all or most of these sequences, reflected by the nucleotide position indicated as "5' NT of Clone Seq.” (seventh column) and the "3' NT of Clone Seq.” (eighth column) of SEQ ID NO:X.
  • nucleotide position of SEQ ID NO:X of the putative start codon is identified as "5' NT of Start Codon.”
  • 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 routinely 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”.
  • the amino acid position of SEQ ID NO:Y of the last amino acid encoded by the open reading frame is identified in the fifteenth column 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.
  • 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.
  • 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 1A and/or elsewhere herein
  • 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.
  • 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).
  • 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 1A.
  • the nucleotide sequence of each deposited plasmid can readily be determined by sequencing the deposited plasmid in accordance with known methods The predicted amino acid sequence can then be verified from such deposits.
  • the amino acid sequence of the protein encoded by a particular plasmid 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.
  • Table 1A Also provided in Table 1A is the name of the vector which contains the cDNA plasmid. Each vector is routinely used in the art. The following additional information is provided for convenience.
  • pBS contains an ampicillin resistance gene and pBK contains a neomycin resistance gene.
  • Phagemid pBS may be excised from the Lambda Zap and Uni-Zap XR vectors, and phagemid pBK may be excised from the Zap Express vector. Both phagemids may be transformed into E. coli strain XL-1 Blue, also available from Stratagene
  • Vectors pSportl, pCMVSport 1.0, pCMVSport 2.0 and pCMVSport 3.0 were obtained from Life Technologies, Inc., P. O. Box 6009, Gaithersburg, MD 20897. All Sport vectors contain an ampicillin resistance gene and may be transformed into E. coli strain DH10B, also available from Life Technologies. See, for instance, Gruber, C. E., et al., Focus 15:59 (1993). Vector lafmid BA (Bento Soares, Columbia University, New York, NY) contains an ampicillin resistance gene and can be transformed into E. coli strain XL-1 Blue.
  • Vector pCR ® 2.1 which is available from Invitrogen, 1600 Faraday Avenue, Carlsbad, CA 92008, contains an ampicillin resistance gene and may be transformed into E. coli strain DH10B, available from Life Technologies. See, for instance, Clark, J. M., Nuc. Acids Res. 76:9677-9686 (1988) and Mead, D. et al, Bio/Technology 9: (1991).
  • the present invention also relates to the genes corresponding to SEQ ID NO:X, SEQ ID NO:Y, and/or a deposited cDNA (cDNA Clone ID).
  • the corresponding gene can be isolated in accordance with known methods using the sequence information disclosed herein. Such methods include, but are not limited to, preparing probes or primers from the disclosed sequence and identifying or amplifying the corresponding gene from appropriate sources of genomic material.
  • allelic variants, orthologs, and/or species homologs are also provided in the present invention. 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 and SEQ ID NO:Y using information from the sequences disclosed herein or the clones deposited with the ATCC.
  • 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 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 No.Z.
  • the present invention also provides a polypeptide comprising, or alternatively, consisting of, the polypeptide sequence of SEQ ID NO:Y, a polypeptide encoded by SEQ ID NO:X, and/or a polypeptide encoded by a cDNA contained in ATCC deposit No.Z.
  • Polynucleotides encoding a polypeptide comprising, or alternatively consisting of the polypeptide sequence of SEQ ID NO: Y, a polypeptide encoded by SEQ ID NO:X and/or a polypeptide encoded by the cDNA contained in ATCC Deposit No.Z, are also encompassed by the invention.
  • the present invention further encompasses a polynucleotide comprising, or alternatively consisting of the complement of the nucleic acid sequence of SEQ ID NO:X, and/or the complement of the coding strand of the cDNA contained in ATCC Deposit No.Z.
  • Table IB Comprised of Tables IB.l and 1B.2
  • Table IB.l and Table 1B.2 summarize some of the polynucleotides encompassed by the invention (including cDNA clones related to the sequences (Clone ID:), contig sequences (contig identifier (Contig ID:) and contig nucleotide sequence identifiers (SEQ ID NO:X)) and further summarizes certain characteristics of these polynucleotides and the polypeptides encoded thereby.
  • the first column of Tables IB.l and 1B.2 provide the gene numbers in the application for each clone identifier.
  • the second column of Tables IB.l and 1B.2 provide unique clone identifiers, "Clone ED:”, for cDNA clones related to each contig sequence disclosed in Table 1A and/or Table IB.
  • the third column of Tables IB.l and 1B.2 provide unique contig identifiers, "Contig ID:” for each of the contig sequences disclosed in these tables.
  • the fourth column of Tables IB.l and 1B.2 provide the sequence identifiers, "SEQ ED NO:X", for each of the contig sequences disclosed in Table 1A and/or IB.
  • the fifth column of Table IB.l provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence of SEQ ID NO:X that delineates the preferred open reading frame (ORF) that encodes the amino acid sequence shown in the sequence listing and referenced in Table IB.l as SEQ ED NO:Y (column 6).
  • Column 7 of Table IB.l lists residues comprising predicted epitopes contained in the polypeptides encoded by each of the preferred ORFs (SEQ ID NO:Y).
  • polypeptides of the invention comprise, or alternatively consist of, one, two, three, four, five or more of the predicted epitopes described in Table IB.l. It will be appreciated that depending on the analytical criteria used to predict antigenic determinants, the exact address of the determinant may vary slightly.
  • Column 8 of Table IB.l (“Cytologic Band") provides the chromosomal location of polynucleotides corresponding to SEQ ED NO:X. Chromosomal location was determined by finding exact matches to EST and cDNA sequences contained in the NCBI (National Center for Biotechnology Information) UniGene database.
  • OMEM identification number is disclosed in Table IB.l, column 9 labeled "OMEM Disease Reference(s)". A key to the OMEM reference identification numbers is provided in Table 5.
  • Table 1B.2 Column 5 of Table 1B.2, "Tissue Distribution" shows the expression profile of tissue, cells, and/or cell line libraries which express the polynucleotides of the invention.
  • the first code number shown in Table IB.2 column 5 represents the tissue/cell source identifier code corresponding to the key provided in Table 4. Expression of these polynucleotides was not observed in the other tissues and/or cell libraries tested.
  • the second number in column 5 represents the number of times a sequence corresponding to the reference polynucleotide sequence (e.g., SEQ ED NO:X) was identified in the corresponding tissue/cell source.
  • tissue/cell source identifier codes in which the first two letters are "AR" designate information generated using DNA array technology.
  • cDNAs were amplified by PCR and then transferred, in duplicate, onto the array. Gene expression was assayed through hybridization of first strand cDNA probes to the DNA array. cDNA probes were generated from total RNA extracted from a variety of different tissues and cell lines. Probe synthesis was performed in the presence of 33 P dCTP, using oligo(dT) to prime reverse transcription. After hybridization, high stringency washing conditions were employed to remove non-specific hybrids from the array. The remaining signal, emanating from each gene target, was measured using a Phosphorimager.
  • Phosphor Stimulating Luminescence which reflects the level of phosphor signal generated from the probe hybridized to each of the gene targets represented on the array.
  • a local background signal subtraction was performed before the total signal generated from each array was used to normalize gene expression between the different hybridizations.
  • the value presented after "[array code]:” represents the mean of the duplicate values, following background subtraction and probe normalization.
  • One of skill in the art could routinely use this information to identify normal and/or diseased tissue(s) which show a predominant expression pattern of the corresponding polynucleotide of the invention or to identify polynucleotides which show predominant and/or specific tissue and/or cell expression.
  • Table IC summarizes additional polynucleotides encompassed by the invention (including cDNA clones related to the sequences (Clone ED:), contig sequences (contig identifier
  • the first column provides a unique clone identifier, "Clone ED:”, for a cDNA clone related to each contig sequence.
  • the second column provides the sequence identifier, "SEQ
  • the third column provides a unique contig identifier, "Contig ED:” for each contig sequence.
  • the fourth column provides a BAC identifier "BAC ED
  • nucleotide position numbers within the polynucleotide sequence of SEQ ED NO:B which delineate certain polynucleotides of the invention that are also exemplary members of polynucleotide sequences that encode polypeptides of the invention (e.g., polypeptides containing amino acid sequences encoded by the polynucleotide sequences delineated in column six, and fragments and variants thereof).
  • the present invention encompasses a method of detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating cancer and other hyperproliferative disorders; comprising administering to a patient in which such treatment, prevention, or amelioration is desired a protein, nucleic acid, or antibody of the invention (or fragment or variant thereof) represented by Table 1A, Table IB, and Table IC, in an amount effective to detect, prevent, diagnose, prognosticate, treat, and/or ameliorate the disease or disorder.
  • the polynucleotides, polypeptides, agonists, or antagonists of the present invention can be used in assays to test for one or more biological activities.
  • polypeptides and polypeptides do exhibit activity in a particular assay, it is likely that these molecules may be involved in the diseases associated with the biological activity.
  • the polynucleotides or polypeptides, or agonists or antagonists thereof could be used to treat the associated disease.
  • Table ID provides information related to biological activities for polynucleotides and polypeptides of the invention (including antibodies, agonists, and/or antagonists thereof). Table ID also provides information related to assays which may be used to test polynucleotides and polypeptides of the invention (including antibodies, agonists, and/or antagonists thereof) for the corresponding biological activities.
  • the first column (“Gene No.”) provides the gene number in the application for each clone identifier.
  • the second column (“cDNA Clone ED:”) provides the unique clone identifier for each clone as previously described and indicated in Tables 1A, IB, and IC.
  • the third column (“AA SEQ ED NO:Y”) indicates the Sequence Listing SEQ ED Number for polypeptide sequences encoded by the corresponding cDNA clones (also as indicated in Tables 1A, IB, and 2).
  • the fourth column (“Biological Activity”) indicates a biological activity corresponding to the indicated polypeptides (or polynucleotides encoding said polypeptides).
  • the fifth column (“Exemplary Activity Assay”) further describes the corresponding biological activity and provides information pertaining to the various types of assays which may be performed to test, demonstrate, or quantify the corresponding biological activity. Table ID describes the use of FMAT technology, inter alia, for testing or demonstrating various biological activities.
  • Fluorometric microvolume assay technology is a fluorescence-based system which provides a means to perform nonradioactive cell- and bead-based assays to detect activation of cell signal transduction pathways. This technology was designed specifically for ligand binding and immunological assays. Using this technology, fluorescent cells or beads at the bottom of the well are detected as localized areas of concentrated fluorescence using a data processing system. Unbound flurophore comprising the background signal is ignored, allowing for a wide variety of homogeneous assays. FMAT technology may be used for peptide ligand binding assays, immunofluorescence, apoptosis, cytotoxicity, and bead-based immunocapture assays.
  • FMAT technology may be used to test, confirm, and/or identify the ability of polypeptides (including polypeptide fragments and variants) to activate signal transduction pathways.
  • FMAT technology may be used to test, confirm, and/or identify the ability of polypeptides to upregulate production of immunomodulatory proteins (such as, for example, interleukins, GM-CSF, Rantes, and Tumor Necrosis factors, as well as other cellular regulators (e.g. insulin)).
  • immunomodulatory proteins such as, for example, interleukins, GM-CSF, Rantes, and Tumor Necrosis factors, as well as other cellular regulators (e.g. insulin)
  • Table ID also describes the use of kinase assays for testing, demonstrating, or quantifying biological activity.
  • the phosphorylation and de-phosphorylation of specific amino acid residues e.g. Tyrosine, Serine, Threonine
  • cell-signal transduction proteins provides a fast, reversible means for activation and de-activation of cellular signal transduction pathways.
  • cell signal transduction via phosphorylation de-phosphorylation is crucial to the regulation of a wide variety of cellular processes (e.g. proliferation, differentiation, migration, apoptosis, etc.).
  • kinase assays provide a powerful tool useful for testing, confirming, and/or identifying polypeptides (including polypeptide fragments and variants) that mediate cell signal transduction events via protein phosphorylation. See e.g., Forrer, P., Tamaskovic R., and Jaussi, R. "Enzyme-Linked Immunosorbent Assay for Measurement of JNK, ERK, and p38 Kinase Activities" Biol. Chem. 379(8-9): 1101-1110 (1998).
  • Polynucleotides encoding polypeptides of the present invention can be used in assays to test for one or more biological activities.
  • One such biological activity which may be tested includes the ability of polynucleotides and polypeptides of the invention to stimulate up-regulation or down-regulation of expression of particular genes and proteins.
  • polynucleotides and polypeptides of the present invention exhibit activity in altering particular gene and protein expression patterns, it is likely that these polynucleotides and polypeptides of the present invention may be involved in, or capable of effecting changes in, diseases associated with the altered gene and protein expression profiles.
  • polynucleotides, polypeptides, or antibodies of the present invention could be used to treat said associated diseases.
  • TaqMan® assays may be performed to assess the ability of polynucleotides (and polypeptides they encode) to alter the expression pattern of particular "target" genes.
  • TaqMan® reactions are performed to evaluate the ability of a test agent to induce or repress expression of specific genes in different cell types.
  • TaqMan® gene expression quantification assays ('TaqMan® assays") are well known to, and routinely performed by, those of ordinary skill in the art.
  • TaqMan® assays are performed in a two step reverse transcription / polymerase chain reaction (RT-PCR). In the first (RT) step, cDNA is reverse transcribed from total RNA samples using random hexamer primers. In the second (PCR) step, PCR products are synthesized from the cDNA using gene specific primers.
  • RT-PCR reverse transcription / polymerase chain reaction
  • the Taqman® PCR reaction exploits the 5' nuclease activity of AmpliTaq Gold ® DNA Polymerase to cleave a Taqman® probe (distinct from the primers) during PCR.
  • the Taqman® probe contains a reporter dye at the 5 '-end of the probe and a quencher dye at the 3' end of the probe. When the probe is intact, the proximity of the reporter dye to the quencher dye results in suppression of the reporter fluorescence.
  • the probe specifically anneals between the forward and reverse primer sites.
  • AmpliTaq Fold DNA Polymerase then cleaves the probe between the reporter and quencher when the probe hybridizes to the target, resulting in increased fluorescence of the reporter (see Figure 2). Accumulation of PCR products is detected directly by monitoring the increase in fluorescence of the reporter dye.
  • vector controls or constructs containing the coding sequence for the gene of interest are transfected into cells, such as for example 293T cells, and supematants collected after 48 hours.
  • cells such as for example 293T cells, and supematants collected after 48 hours.
  • multiple primary human cells or human cell lines are used; such cells may include but are not limited to, Normal Human Dermal Fibroblasts, Aortic Smooth Muscle, Human Umbilical Vein Endothelial Cells, HepG2, Daudi, Jurkat, U937, Caco, and THP-1 cell lines.
  • Cells are plated in growth media and growth is arrested by culturing without media change for 3 days, or by switching cells to low serum media and incubating overnight.
  • RNA is isolated; for example, by using Trizol extraction or by using the Ambion RNAqueous(TM)-4PCR RNA isolation system. Expression levels of multiple genes are analyzed using TAQMAN, and expression in the test sample is compared to control vector samples to identify genes induced or repressed.
  • Table IE indicates particular disease classes and preferred indications for which polynucleotides, polypeptides, or antibodies of the present invention may be used in detecting, diagnosing, preventing, treating and/or ameliorating said diseases and disorders based on "target" gene expression patterns which may be up- or down-regulated by polynucleotides (and the encoded polypeptides) corresponding to each indicated cDNA Clone ED (shown in Table IE, Column 2).
  • the present invention encompasses a method of detecting, diagnosing, preventing, treating, and/or ameliorating a disease or disorder listed in the "Disease Class" and/or "Preferred Indication” columns of Table IE; comprising administering to a patient in which such detection, diagnosis, prevention, or treatment is desired a protein, nucleic acid, or antibody of the invention (or fragment or variant thereof) in an amount effective to detect, diagnose, prevent, treat, or ameliorate the disease or disorder.
  • the first and second columns of Table ID show the "Gene No.” and "cDNA Clone ED No.”, respectively, indicating certain nucleic acids and proteins (or antibodies against the same) of the invention (including polynucleotide, polypeptide, and antibody fragments or variants thereof) that may be used in detecting, diagnosing, preventing, treating, or ameliorating the disease(s) or disorder(s) indicated in the corresponding row in the "Disease Class” or "Preferred Indication” Columns of Table IE.
  • the present invention also encompasses methods of detecting, diagnosing, preventing, treating, or ameliorating a disease or disorder listed in the "Disease Class” or "Preferred Indication” Columns of Table IE; comprising administering to a patient combinations of the proteins, nucleic acids, or antibodies of the invention (or fragments or variants thereof), sharing similar indications as shown in the corresponding rows in the "Disease Class” or “Preferred Indication” Columns of Table IE.
  • the "Disease Class" Column of Table IE provides a categorized descriptive heading for diseases, disorders, and/or conditions (more fully described below) that may be detected, diagnosed, prevented, treated, or ameliorated by a protein, nucleic acid, or antibody of the invention (or fragment or variant thereof).
  • the "Preferred Indication" Column of Table IE describes diseases, disorders, and/or conditions that may be detected, diagnosed, prevented, treated, or ameliorated by a protein, nucleic acid, or antibody of the invention (or fragment or variant thereof).
  • Cell Line and “Exemplary Targets” Columns of Table IE indicate particular cell lines and target genes, respectively, which may show altered gene expression patterns (i.e., up- or down-regulation of the indicated target gene) in Taqman assays, performed as described above, utilizing polynucleotides of the cDNA Clone ED shown in the corresponding row. Alteration of expression patterns of the indicated “Exemplary Target” genes is correlated with a particular "Disease Class” and/or "Preferred Indication” as shown in the corresponding row under the respective column headings.
  • the "Exemplary Accessions” Column indicates GenBank Accessions (available online through the National Center for Biotechnology Information (NCBE) at http://www.ncbi.nlm.nih.gov/) which correspond to the "Exemplary Targets" shown in the adjacent row.
  • the recitation of "Cancer” in the “Disease Class” Column indicates that the corresponding nucleic acid and protein, or antibody against the same, of the invention (or fragment or variant thereof) may be used for example, to detect, diagnose, prevent, treat, and/or ameliorate neoplastic diseases and/or disorders (e.g., leukemias, cancers, etc., as described below under “Hyperproliferative Disorders").
  • the recitation of “Immune” in the "Disease Class” column indicates that the corresponding nucleic acid and protein, or antibody against the same, of the invention (or fragment or variant thereof), may be used for example, to detect, diagnose, prevent, treat, and/or ameliorate diseases and/or disorders relating to neoplastic diseases (e.g., as described below under "Hyperproliferative Disorders"), blood disorders (e.g., as described below under "Lmmune Activity” "Cardiovascular Disorders” and/or “Blood-Related Disorders”), and infections (e.g., as described below under "Infectious Disease”).
  • neoplastic diseases e.g., as described below under "Hyperproliferative Disorders”
  • blood disorders e.g., as described below under “Lmmune Activity” "Cardiovascular Disorders” and/or “Blood-Related Disorders”
  • infections e.g., as described below under "
  • Angiogenesis in the "Disease Class” column indicates that the corresponding nucleic acid and protein, or antibody against the same, of the invention (or fragment or variant thereof), may be used for example, to detect, diagnose, treat, prevent, and/or ameliorate diseases and/or disorders relating to neoplastic diseases (e.g., as described below under "Hyperproliferative Disorders"), diseases and/or disorders of the cardiovascular system (e.g., as described below under "Cardiovascular Disorders"), diseases and/or disorders involving cellular and genetic abnormalities (e.g., as described below under "Diseases at the Cellular Level"), diseases and/or disorders involving angiogenesis (e.g., as described below under "Anti- Angiogenesis Activity”), to promote or inhibit cell or tissue regeneration (e.g., as described below under “Regeneration”), or to promote wound healing (e.g., as described below under "Wound Healing and Epithelial Cell Proliferation”).
  • neoplastic diseases
  • Diabetes in the "Disease Class” column indicates that the corresponding nucleic acid and protein, or antibody against the same, of the invention (or fragment or variant thereof), may be used for example, to detect, diagnose, treat, prevent, and/or ameliorate diabetes (including diabetes mellitus types I and II), as well as diseases and/or disorders associated with, or consequential to, diabetes (e.g. as described below under “Endocrine Disorders,” “Renal Disorders,” and “Gastrointestinal Disorders”).
  • Table 2 summarizes homology and features of some of the polypeptides of the invention.
  • the first column provides a unique clone identifier, "Clone ED:”, corresponding to a cDNA clone disclosed in Table 1A or Table IB.
  • the second column provides the unique contig identifier, "Contig ED:” corresponding to contigs in Table IB and allowing for correlation with the information in Table IB.
  • the third column provides the sequence identifier, "SEQ ED NO:X”, for the contig polynucleotide sequence.
  • the fourth column provides the analysis method by which the homology/identity disclosed in the Table was determined.
  • NR non-redundant protein database
  • PFAM protein families
  • polypeptides of the invention comprise, or alternatively consist of, an amino acid sequence encoded by a polynucleotide in SEQ ED NO:X as delineated in columns 8 and 9, or fragments or variants thereof.
  • Table 3 provides polynucleotide sequences that may be disclaimed according to certain embodiments of the invention.
  • the first column provides a unique clone identifier, "Clone ED”, for a cDNA clone related to contig sequences disclosed in Table IB.
  • the second column provides the sequence identifier, "SEQ ED NO:X”, for contig sequences disclosed in Table 1A and/or Table IB.
  • the third column provides the unique contig identifier, "Contig ED:”, for contigs disclosed in Table IB.
  • the fourth column provides a unique integer 'a' where 'a' is any integer between 1 and the final nucleotide minus 15 of SEQ ED NO:X
  • the fifth column provides a unique integer 'b' where 'b' is any integer between 15 and the final nucleotide of SEQ ED NO:X, where both a and b correspond to the positions of nucleotide residues shown in SEQ ED NO:X, and where b is greater than or equal to a + 14.
  • the uniquely defined integers can be substituted into the general formula of a-b, and used to describe polynucleotides which may be preferably excluded from the invention.
  • preferably excluded from the invention are at least one, two, three, four, five, ten, or more of the polynucleotide sequence(s) having the accession number(s) disclosed in the sixth column of this Table (including for example, published sequence in connection with a particular BAC clone).
  • preferably excluded from the invention are the specific polynucleotide sequence(s) contained in the clones corresponding to at least one, two, three, four, five, ten, or more of the available material having the accession numbers identified in the sixth column of this Table (including for example, the actual sequence contained in an identified BAC clone).
  • Table 4 provides a key to the tissue/cell source identifier code disclosed in Table 1B.2, column 5.
  • Column 1 of Table 4 provides the tissue/cell source identifier code disclosed in Table 1B.2, Column 5.
  • Columns 2-5 provide a description of the tissue or cell source. Note that "Description” and “Tissue” sources (i.e. columns 2 and 3) having the prefix “a_” indicates organs, tissues, or cells derived from “adult” sources. Codes corresponding to diseased tissues are indicated in column 6 with the word “disease.” The use of the word “disease” in column 6 is non- limiting.
  • the tissue or cell source may be specific (e.g.
  • tissue/cell source is a library
  • column 7 identifies the vector used to generate the library.
  • Table 5 provides a key to the OMEM reference identification numbers disclosed in Table IB.l, column 9.
  • OMEM reference identification numbers (Column 1) were derived from Online Mendelian Inheritance in Man (Online Mendelian Inheritance in Man, OMEM. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine, (Bethesda, MD) 2000. World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/).
  • Column 2 provides diseases associated with the cytologic band disclosed in Table IB.l, column 8, as determined using the Morbid Map database.
  • Table 6 summarizes some of the ATCC Deposits, Deposit dates, and ATCC designation numbers of deposits made with the ATCC in connection with the present application. These deposits were made in addition to those described in the Table 1A.
  • Table 7 shows the cDNA libraries sequenced, and ATCC designation numbers and vector information relating to these cDNA libraries.
  • the first column shows the first four letters indicating the Library from which each library clone was derived.
  • the second column indicates the catalogued tissue description for the corresponding libraries.
  • the third column indicates the vector containing the corresponding clones.
  • the fourth column shows the ATCC deposit designation for each libray clone as indicated by the deposit information in Table 6.
  • 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.
  • 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.
  • 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.
  • 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.
  • a "polynucleotide” refers to a molecule having a nucleic acid sequence encoding SEQ ED NO:Y or a fragment or variant thereof (e.g., the polypeptide delinated in columns fourteen and fifteen of Table 1A); a nucleic acid sequence contained in SEQ ED NO:X (as described in column 5 of Table 1A and/or column 3 of Table IB) or the complement thereof; a cDNA sequence contained in Clone ED: (as described in column 2 of Table 1A and/or Table IB and contained within a library deposited with the ATCC); a nucleotide sequence encoding the polypeptide encoded by a nucleotide sequence in SEQ ED NO:B as defined in column 6 (EXON From-To) of Table IC or a fragment or variant thereof; or a nucleotide coding sequence in SEQ ID NO:B as defined in column 6 of Table IC or the complement thereof.
  • the polynucleotide can contain the nucleotide sequence of the full length cDNA sequence, including the 5' and 3' untranslated sequences, the coding region, as well as fragments, epitopes, domains, and variants of the nucleic acid sequence.
  • a "polypeptide” refers to a molecule having an amino acid sequence encoded by a polynucleotide of the invention as broadly defined (obviously excluding poly-Phenylalanine or poly-Lysine peptide sequences which result from translation of a polyA tail of a sequence corresponding to a cDNA).
  • SEQ ED 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 SEQ ED NO:X is deposited at Human Genome Sciences, Inc. (HGS) in a catalogued and archived library.
  • HGS Human Genome Sciences, Inc.
  • each clone is identified by a cDNA Clone ID (identifier generally referred to herein as Clone ED:).
  • Clone ED identifier generally referred to herein as Clone ED:
  • Each Clone ED is unique to an individual clone and the Clone ED is all the information needed to retrieve a given clone from the HGS library.
  • Table 7 provides a list of the deposited cDNA libraries.
  • Table 7 lists the deposited cDNA libraries by name and links each library to an ATCC Deposit. Library names contain four characters, for example, "HTWE.” The name of a cDNA clone (Clone D) isolated from that library begins with the same four characters, for example "HTWEP07".
  • Table 1A and or Table IB correlates the Clone D names with SEQ ED NO:X. Thus, starting with an SEQ ED NO:X, one can use Tables 1A, IB, 6, 7, and 9 to determine the corresponding Clone ED, which library it came from and which ATCC deposit the library is contained in.
  • the ATCC is located at 10801 University Boulevard, Manassas, Virginia 20110-2209, USA.
  • the ATCC deposits were made pursuant to the terms of the Budapest Treaty on the international recognition of the deposit of microorganisms for the purposes of patent procedure.
  • 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, 7.5kb, 5 kb, 2.5 kb, 2.0 kb, or 1 kb, in length.
  • 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.
  • 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).
  • a "polynucleotide” of the present invention also includes those polynucleotides capable of hybridizing, under stringent hybridization conditions, to sequences contained in SEQ ED NO:X, or the complement thereof (e.g., the complement of any one, two, three, four, or more of the polynucleotide fragments described herein), the polynucleotide sequence delineated in columns 7 and 8 of Table 1A or the complement thereof, the polynucleotide sequence delineated in columns 8 and 9 of Table 2 or the complement thereof, and/or cDNA sequences contained in Clone ED: (e.g., the complement of any one, two, three, four, or more of the polynucleotide fragments, or the cDNA clone within the pool of cDNA clones deposited with the ATCC, described herein), and/or the polynucleotide sequence delineated in column 6 of Table IC or the complement thereof.
  • SEQ ED NO:X or
  • “Stringent hybridization conditions” refers to an overnight incubation at 42 degree C in a solution comprising 50% formamide, 5x SSC (750 mM NaCl, 75 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5x Denhardt's solution, 10% dextran sulfate, and 20 ⁇ 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.
  • washes performed following stringent hybridization can be done at higher salt concentrations (e.g. 5X SSC).
  • 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.
  • 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).
  • 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.
  • 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.
  • 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 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, 7.5kb, 5 kb, 2.5 kb, 2.0 kb, or 1 kb, in length.
  • 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.
  • 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).
  • SEQ ID NO:X refers to a polynucleotide sequence described in column 5 of Table 1A
  • SEQ ID NO:Y refers to a polypeptide sequence described in column 10 of Table 1A
  • SEQ ED NO:X is identified by an integer specified in column 6 of Table 1A.
  • the polypeptide sequence SEQ ED NO:Y is a translated open reading frame (ORF) encoded by polynucleotide SEQ ED NO:X.
  • the polynucleotide sequences are shown in the sequence listing immediately followed by all of the polypeptide sequences.
  • a polypeptide sequence corresponding to polynucleotide sequence SEQ ID NO:2 is the first polypeptide sequence shown in the sequence listing.
  • the second polypeptide sequence corresponds to the polynucleotide sequence shown as SEQ ED NO: 3, and so on.
  • 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.
  • 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.
  • SEQ ED NO:X refers to a polynucleotide sequence described, for example, in Tables 1A, Table IB, or Table 2, while “SEQ ID NO:Y” refers to a polypeptide sequence described in column 11 of Table 1A and or column 6 of Table IB.l. SEQ ED NO:X is identified by an integer specified in column 4 of Table IB. The polypeptide sequence SEQ ID NO:Y is a translated open reading frame (ORF) encoded by polynucleotide SEQ ED NO:X. "Clone ED:” refers to a cDNA clone described in column 2 of Table 1A and/or IB.
  • a polypeptide having functional activity refers to a polypeptide capable of displaying one or more known functional activities associated with a full-length (complete) protein.
  • Such functional activities include, but are not limited to, biological activity (e.g. activity useful in treating, preventing and/or ameliorating cancer and other hyperproliferative disorders), antigenicity (ability to bind [or compete with a polypeptide for binding] to an anti-polypeptide antibody), immunogenicity (ability to generate antibody which binds to a specific 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.
  • biological activity e.g. activity useful in treating, preventing and/or ameliorating cancer and other hyperproliferative disorders
  • antigenicity ability to bind [or compete with a polypeptide for binding] to an anti-polypeptide antibody
  • immunogenicity ability to generate antibody which binds to a specific polypeptide of the invention
  • polypeptides of the invention can be assayed for functional activity (e.g. biological activity) using or routinely modifying assays known in the art, as well as assays described herein. Specifically, one of skill in the art may routinely assay secreted polypeptides (including fragments and variants) of the invention for activity using assays as described in the examples section below.
  • a polypeptide having biological activity refers to a polypeptide exhibiting activity similar to, 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.
  • 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.
  • Table 1A summarizes information concerning certain polypnucleotides and polypeptides of the invention.
  • the first column provides the gene number in the application for each clone identifier.
  • the second column provides a unique clone identifier, "Clone ED:”, for a cDNA clone related to each contig sequence disclosed in Table 1A.
  • Third column the cDNA Clones identified in the second column were deposited as indicated in the third column (i.e. by ATCC Deposit No:Z and deposit date). Some of the deposits contain multiple different clones corresponding to the same gene.
  • “Vector” refers to the type of vector contained in the corresponding cDNA Clone identified in the second column.
  • nucleotide sequence identified as "NT SEQ ED NO:X” was assembled from partially homologous ("overlapping") sequences obtained from the corresponding cDNA clone identified in the second column and, in some cases, from additional related cDNA 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 ED NO:X.
  • 'Total NT Seq.” refers to the total number of nucleotides in the contig sequence identified as SEQ ED NO:X.”
  • the deposited clone may contain all or most of these sequences, reflected by the nucleotide position indicated as "5' NT of Clone Seq.” (seventh column) and the "3' NT of Clone Seq.” (eighth column) of SEQ ID NO:X.
  • the nucleotide position of SEQ ED NO:X of the putative start codon (methionine) is identified as "5' NT of Start Codon.”
  • the nucleotide position of SEQ ED 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 ED NO:Y,” although other reading frames can also be routinely 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 ED 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 ED NO:Y of the secreted portion is identified as "Predicted First AA of Secreted Portion”.
  • the amino acid position of SEQ ED NO:Y of the last amino acid encoded by the open reading frame is identified in the fifteenth column as "Last AA of ORF'.
  • SEQ ED NO:X (where X may be any of the polynucleotide sequences disclosed in the sequence listing) and the translated SEQ ED 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.
  • SEQ ED NO:X is useful for designing nucleic acid hybridization probes that will detect nucleic acid sequences contained in SEQ D 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.
  • polypeptides identified from SEQ ED 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 1A and/or elsewhere herein
  • 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.
  • 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).
  • the present invention provides not only the generated nucleotide sequence identified as SEQ ED 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 1A.
  • the nucleotide sequence of each deposited plasmid can readily be determined by sequencing the deposited plasmid in accordance with known methods
  • amino acid sequence of the protein encoded by a particular plasmid 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.
  • Table 1A Also provided in Table 1A is the name of the vector which contains the cDNA plasmid. Each vector is routinely used in the art. The following additional information is provided for convenience.
  • Vectors Lambda Zap U.S. Patent Nos. 5,128,256 and 5,286,636
  • Uni-Zap XR U.S.
  • Patent Nos. 5,128, 256 and 5,286,636 Zap Express (U.S. Patent Nos. 5,128,256 and 5,286,636), pBluescript (pBS) (Short, J. M. et al., Nucleic Acids Res. 76:7583-7600 (1988); Alting-Mees, M. A. and Short, J. M., Nucleic Acids Res. 77:9494 (1989)) and pBK (Alting-Mees, M. A. et al., Strategies 5:58-61 (1992)) are commercially available from Stratagene Cloning Systems, Inc., 11011 N. Torrey Pines Road, La Jolla, CA, 92037.
  • Phagemid pBS contains an ampicillin resistance gene and pBK contains a neomycin resistance gene.
  • Phagemid pBS may be excised from the Lambda Zap and Uni-Zap XR vectors, and phagemid pBK may be excised from the Zap Express vector. Both phagemids may be transformed into E. coli strain XL-1 Blue, also available from Stratagene
  • Vectors pSportl, pCMVSport 1.0, pCMVSport 2.0 and pCMVSport 3.0 were obtained from Life Technologies, Inc., P. O. Box 6009, Gaithersburg, MD 20897. All Sport vectors contain an ampicillin resistance gene and may be transformed into E. coli strain DH10B, also available from Life Technologies. See, for instance, Gruber, C. E., et al., Focus 75:59 (1993). Vector lafmid BA (Bento Soares, Columbia University, New York, NY) contains an ampicillin resistance gene and can be transformed into E. coli strain XL-1 Blue.
  • Vector pCR ® 2.1 which is available from Invitrogen, 1600 Faraday Avenue, Carlsbad, CA 92008, contains an ampicillin resistance gene and may be transformed into E. coli strain DH10B, available from Life Technologies. See, for instance, Clark, J. M., Nuc. Acids Res. 76:9677-9686 (1988) and Mead, D. et al, Bio/Technology 9: (1991).
  • the present invention also relates to the genes corresponding to SEQ ED NO:X, SEQ D NO:Y, and/or a deposited cDNA (cDNA Clone ED).
  • the corresponding gene can be isolated in accordance with known methods using the sequence information disclosed herein. Such methods include, but are not limited to, preparing probes or primers from the disclosed sequence and identifying or amplifying the corresponding gene from appropriate sources of genomic material.
  • allelic variants, orthologs, and/or species homologs are also provided in the present invention. 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 ED NO:X and SEQ ED NO:Y using information from the sequences disclosed herein or the clones deposited with the ATCC.
  • 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 present invention provides a polynucleotide comprising, or alternatively consisting of, the nucleic acid sequence of SEQ ED NO:X and/or a cDNA contained in ATCC Deposit No.Z.
  • the present invention also provides a polypeptide comprising, or alternatively, consisting of, the polypeptide sequence of SEQ ED NO:Y, a polypeptide encoded by SEQ ED NO:X, and/or a polypeptide encoded by a cDNA contained in ATCC deposit No.Z.
  • Polynucleotides encoding a polypeptide comprising, or alternatively consisting of the polypeptide sequence of SEQ ID NO: Y, a polypeptide encoded by SEQ ED NO:X and/or a polypeptide encoded by the cDNA contained in ATCC Deposit No.Z, are also encompassed by the invention.
  • the present invention further encompasses a polynucleotide comprising, or alternatively consisting of the complement of the nucleic acid sequence of SEQ ED NO:X, and/or the complement of the coding strand of the cDNA contained in ATCC Deposit No.Z.
  • the first column in Table IB.l and Table 1B.2 provides the gene number in the application corresponding to the clone identifier.
  • the second column in Table IB.l and Table 1B.2 provides a unique "Clone ID:" for the cDNA clone related to each contig sequence disclosed in Table IB.l and Table 1B.2.
  • This clone ID references the cDNA clone which contains at least the 5' most sequence of the assembled contig and at least a portion of SEQ ID NO:X as determined by directly sequencing the referenced clone.
  • the referenced clone may have more sequence than described in the sequence listing or the clone may have less.
  • a full-length cDNA can be obtained by methods described elsewhere herein.
  • the third column in Table IB.l and Table IB.2 provides a unique "Contig ED" identification for each contig sequence.
  • the fourth column in Table IB.l and Table 1B.2 provides the "SEQ ID NO:" identifier for each of the contig polynucleotide sequences disclosed in Table IB.
  • the fifth column in Table IB.l provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence "SEQ ED NO:X” that delineate the preferred open reading frame (ORF) shown in the sequence listing and referenced in Table IB.l, column 6, as SEQ ED NO:Y. Where the nucleotide position number 'To" is lower than the nucleotide position number "From”, the preferred ORF is the reverse complement of the referenced polynucleotide sequence.
  • the sixth column in Table IB.l provides the corresponding SEQ ED NO:Y for the polypeptide sequence encoded by the preferred ORF delineated in column 5.
  • the invention provides an amino acid sequence comprising, or alternatively consisting of, a polypeptide encoded by the portion of SEQ ED NO:X delineated by "ORF (From-To)". Also provided are polynucleotides encoding such amino acid sequences and the complementary strand thereto.
  • Column 7 in Table IB.l lists residues comprising epitopes contained in the polypeptides encoded by the preferred ORF (SEQ ID NO:Y), as predicted using the algorithm of Jameson and Wolf, (1988) Comp. Appl. Biosci. 4:181-186.
  • polypeptides of the invention comprise, or alternatively consist of, at least one, two, three, four, five or more of the predicted epitopes as described in Table IB. It will be appreciated that depending on the analytical criteria used to predict antigenic determinants, the exact address of the determinant may vary slightly.
  • Chromosomal location was determined by finding exact matches to EST and cDNA sequences contained in the NCBI (National Center for Biotechnology Information) UniGene database. Each sequence in the UniGene database is assigned to a "cluster"; all of the ESTs, cDNAs, and STSs in a cluster are believed to be derived from a single gene. Chromosomal mapping data is often available for one or more sequence(s) in a UniGene cluster; this data (if consistent) is then applied to the cluster as a whole. Thus, it is possible to infer the chromosomal location of a new polynucleotide sequence by determining its identity with a mapped UniGene cluster.
  • a modified version of the computer program BLASTN (Altshul, et al., J. Mol. Biol. 215:403-410 (1990), and Gish, and States, Nat. Genet. 3:266-272) (1993) was used to search the UniGene database for EST or cDNA sequences that contain exact or near-exact matches to a polynucleotide sequence of the invention (the 'Query').
  • a sequence from the UniGene database (the 'Subject') was said to be an exact match if it contained a segment of 50 nucleotides in length such that 48 of those nucleotides were in the same order as found in the Query sequence.
  • a presumptive chromosomal location was determined for a polynucleotide of the invention, an associated disease locus was identified by comparison with a database of diseases which have been experimentally associated with genetic loci.
  • the database used was the Morbid Map, derived from OMEMTM and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD) 2000;. If the putative chromosomal location of a polynucleotide of the invention (Query sequence) was associated with a disease in the Morbid Map database, an OMEM reference identification number was noted in column 9, Table IB.l, labelled "OMEM Disease Reference(s). Table 5 is a key to the OMEM reference identification numbers (column 1), and provides a description of the associated disease in Column 2.
  • Table 1B.2 Column 5, in Table 1B.2, provides an expression profile and library code ount for each of the contig sequences (SEQ ID NO:X) disclosed in Table IB, which can routinely be combined with the information provided in Table 4 and used to determine the tissues, cells, and/or cell line libraries which predominantly express the polynucleotides of the invention.
  • the second number in column 5 represents the number of times a sequence corresponding to the reference polynucleotide sequence was identified in the corresponding tissue/cell source.
  • tissue/cell source identifier codes in which the first two letters are "AR" designate information generated using DNA array technology.
  • cDNAs were amplified by PCR and then transferred, in duplicate, onto the array. Gene expression was assayed through hybridization of first strand cDNA probes to the DNA array.
  • cDNA probes were generated from total RNA extracted from a variety of different tissues and cell lines. Probe synthesis was performed in the presence of 33 P dCTP, using oligo (dT) to prime reverse transcription. After hybridization, high stringency washing conditions were employed to remove non-specific hybrids from the array. The remaining signal, emanating from each gene target, was measured using a Phosphorimager.
  • Phosphor Stimulating Luminescence which reflects the level of phosphor signal generated from the probe hybridized to each of the gene targets represented on the array.
  • a local background signal subtraction was performed before the total signal generated from each array was used to normalize gene expression between the different hybridizations.
  • the value presented after "[array code]:” represents the mean of the duplicate values, following background subtraction and probe normalization.
  • One of skill in the art could routinely use this information to identify normal and/or diseased tissue(s) which show a predominant expression pattern of the corresponding polynucleotide of the invention or to identify polynucleotides which show predominant and/or specific tissue and/or cell expression.
  • ARTCB92 603948 50 AR242 8, AR245 5, AR170 5.
  • AR182 2, AR277 2, AR293 2, AR231 2.
  • AR178 2, AR313 2, AR195: 2, AR230 2, AR266 2, AR316 2, AR060 2, AR240 2, AR176 2, AR272 2, AR172 2, AR289 2, AR267 1, AR283: 1, AR223 1.
  • AR247 1. AR181 1. AR257 1, AR261 1, AR238 1.
  • AR234 1. AR269 1, AR290 1. AR226 1.
  • AR217 1.
  • AR287 1.
  • AR294 1, AR268 1.
  • AR296 15, AR266: 6, AR176: 6, AR291: 6, AR289: 6, AR255: 5, AR257: 5, AR183: 5, AR182 5, AR269: 5, AR252: 4, AR253: 4, AR290: 4, AR294: 4, AR309: 4, AR297: 4, AR178: 3, AR060: 3, AR055: 3, AR221: 3, AR175: 3, AR288: 3, AR270: 3, AR181: 3, AR177: 3, AR256: 3, AR260: 3, AR267: 3, AR293: 3, AR286: 3, AR268: 3, AR223: 3, AR287: 3,
  • AR272 3, AR162: 3, AR224: 3, AR238: 3, AR262: 3, AR165: 3, AR173: 3, AR161 3, AR295: 3, AR179: 3, AR163: 3, AR277: 3, AR164: 3, AR217: 3, AR166: 2, AR299: 2, AR258: 2, AR205: 2, AR2362, AR243: 2, AR228: 2, AR226: 2, AR229: 2, AR168: 2, AR285: 2, AR191: 2, AR283: 2, AR231: 2, AR300: 2, AR1742, AR172: 2, AR204: 2, AR201: 2, AR104: 2, AR214: 2, AR239: 2, AR233: 2, AR089: 2, AR200: 2, AR246: 2, AR3162, AR190: 2, AR237: 2, AR240: 2, AR271: 2, AR312: 1, AR264: 1, AR189: 1, AR096: 1, AR213: 1, AR196: 1, AR215 1, AR199: 1, AR218: 1, AR170: 1, AR203: 1, AR313: 1,
  • AR17823, AR236 22, AR19922, AR26421.AR25721.AR181 20, AR212: 20, AR242: 20, AR180: 20, AR258 19, AR200 18, AR308 18,AR261 18.AR230 18,AR175 17,AR234: 17, AR191: 16, AR235: 16, AR247 16, AR240 16, AR297 16, AR229 15.AR188 15, AR260 15,AR179: 15.AR189: 15, AR207: 15, AR053 15,AR177 14.AR183 13, AR255 13,AR238 13, AR288 12, AR296: 12, AR300: 12, AR233: 12, AR214 11.AR263: 11.AR223 11, AR311 11.AR281 11.AR169 11.AR195: 11, AR213: 10, AR228: 10, AR222 10, AR280 10.AR211: 10, AR275: 10, AR269 10,AR185 10.AR193: 10, AR239: 10, AR089: 10, AR182 10,AR218 10, AR293 10.AR168 9,AR312:9,AR285:9, AR217: 9, AR171: 9, AR299:
  • AR171 4, AR3094.AR165 3, AR1623.AR161 3, AR164: 3, AR313: 3, AR166: 3, AR163: 3, AR183: 3, AR240: 3, AR2052, AR0392, AR0892, AR2382, ARI 042, AR053: 2, AR217: 2, AR312: 2, AR096: 2, AR282: 2, AR193: 2, AR2422, AR2362, AR213 2, AR2572, AR300: 2, AR176: 2, AR285: 2, AR272: 2, AR267: 2, AR283: 2, AR261: 2, AR293 2, AR2992.AR1682.AR271 2, AR2682, AR275: 2, AR212: 2, AR277: 1, AR214: 1, AR033: 1, AR274: 1, AR237 1, AR296 1.AR316 1.AR311 1.AR228 1, AR247: 1, AR264: 1, AR175: 1, AR234: 1, AR182: 1, AR185: 1, AR229 1.AR170
  • AR221 9, AR216: 9, AR179: 9, AR229: 9, AR214: 8, AR223: 8, AR225: 8, AR281: 8, AR207: 8, AR217: 8, AR224: 8, AR242: 8, AR259: 8, AR222: 8, AR060: 7, AR169: 7, AR230: 7, AR170: 7, AR244: 7, AR251: 6, AR194: 6, AR233: 6, AR202: 6, AR241: 6, AR171: 6, AR227: 6, AR168: 6, AR204: 5, AR172: 5, AR228: 5, AR206: 5 L0514: 16, L0500: 13, L0777: 11, L0499: 10, L0755: 10, L0769: 8, L0493: 8, L0747: 8, L0749: 7, L0766: 6, L0748: 6, S0360: 5, L0497: 5, L050 5, H0457: 4, L0507: 4, L0770: 4, L0805: 4, S0374: 4, H0659: 4, L0779: 4, L0596: 4, L0588: 4, S
  • AR223 4, AR225: 3, AR039: 3, AR213: 3, AR252: 2, AR282: 2, AR171: 2, AR308: 2, AR166: 2, AR195: 2, AR207: 1,
  • H0135 1.S0344: 1.L0763: 1,L0638: 1.L0761: 1.L0764: 1.L0363: 1,L0766: 1.L0651: 1.L0805: 1,L0655: 1.L0659: 1, L0666: 1.L2261: 1.H0701: 1.L0749: 1.L0756: 1.L0779: 1.L0752: 1.L0599: 1, H0542: 1.H0423: 1.H0422: 1 and H0506: 1.
  • AR269 2, AR3132, AR2532, AR2342, AR2382, AR2472, AR2932, AR2892, AR300:2, AR171 2, AR239: 2, AR229: 2, AR2662, AR237 2, AR2952, AR2282, AR2992, AR2262, AR207 2, AR227: 2, AR233 2, AR268: 2, AR190: 2, AR291 2, AR2552.AR271 2, AR1932, AR277 1.AR203 1.AR174 1.AR168: 1.AR212 1.AR287: 1.AR236: 1, AR290 1.AR311 1.AR179 1, AR296 1.AR267 1, AR258 1, AR089 1.AR
  • AR226 11.AR268 11.AR250 11.AR231 11,AR199 11.AR104 11.AR055 11.AR313 11.AR178 11.AR179 AR175 11.AR039 10, AR228 10, AR227 10, AR267 10, AR234 10, AR219 10, AR232 10, AR233 10, AR299 AR254 10, AR237 10,AR191 10,AR185 10, AR060 9, AR290: 9, AR096: 9, AR188: 9, AR189: 9, AR211: 8, AR210:
  • AR170 3, AR163: 3, AR272: 3, AR261: 3, AR171: 2, AR161: 2, AR180: 2, AR162: 2, AR274: 2, AR224: 2, AR250: 2, AR214: 2, AR282: 2, AR240: 1. AR275: 1, AR257: 1.
  • AR201 1.
  • AR263 38 HHEPM33 877639 239 AR263 38, AR207 37. AR311 31, AR264 30, AR212 29, AR195 27, AR309: 27, AR308: 26, AR165 26, AR164: 25, AR053 24, AR166 24, AR213 24.
  • AR217 17, AR283 17, AR240 16, AR039: 16, AR216 16, AR275 15, AR215 15, AR235 15, AR172 15, AR104 15, AR201 15, AR168: 15, AR171 14, AR060: 14, AR096 14.
  • AR170 14, AR225 14.
  • AR254 11, AR288 11, AR291: 11, AR247 11, AR297 11. AR299 11, AR287 10, AR286 10, AR236 10, AR285 10, AR300: 9, AR177: 9, AR210: 9,
  • AR196 9, AR296: 8, AR176: 8, AR218: 8, AR211: 8, AR226: 7, AR293: 7, AR289: 7, AR266: 7, AR258: 7, AR181 : 7, AR199: 7, AR174: 7, AR262: 7, AR191: 7, AR061: 6, AR257: 6, AR238: 6, AR173: 6, AR178: 6, AR200: 6, AR175: 6, AR232: 6, AR270: 6, AR188: 6, AR294: 6, AR269: 6, AR255: 6, AR256: 6, AR182: 6, AR260: 5, AR183: 5, AR239: 5, AR229: 5, AR227: 5, AR189: 5, AR290: 5, AR231: 5, AR234: 5, AR179: 5, AR180: 5, AR237: 4, AR190: 4, AR203: 4, AR268: 4, AR233: 4, AR267: 4, AR230: 4, AR228: 3 L0777: 9, H0617: 5, S0418: 3, H0618: 3, H0556: 2, H0489: 2, H
  • H0441 1. H0559: 1, H0486: 1. H0599: 1, H0042: 1, H0575: 1, H0052: 1, H0597: 1. H0545: 1, H0373: 1, H0594: 1, H0266 1. T0023: 1, H0553: 1. H0063: 1, H0551: 1, HOlOO: 1, H0646: 1, H0529: 1, L0371: 1. L0662: 1, L0766: 1. L0804: 1, L077 1, L0378: 1. L0806: 1, L0805: 1. L0655: 1, L0659: 1, L0809: 1, L0663: 1, H0698: 1, H0547: 1, S3012: 1, S0028: 1. L0731 : 1, S0436: 1, S0192: 1. H0542: l and H0352: 1.
  • AR215 3, AR192: 3, AR178: 2, AR264: 2, AR245: 2, AR239: 2, AR282: 2, AR165: 2, AR271: 2, AR240: 2, AR166: 2, AR274: 2, AR222: 2, AR162: 2, AR164: 2, AR272: 2, AR089: 2, AR213: 1, AR312: 1, AR033: 1, AR161: 1, AR201: 1.
  • AR224 1, AR275: 1, AR246: 1, AR217: 1, AR195: 1, AR297: 1, AR163: 1, AR193: 1, AR060: 1, AR205: 1, AR287: 1, AR228: 1, AR257: 1, AR181: 1, AR196: 1, AR267: 1, AR291: 1, AR216: 1, AR290: 1, AR295: 1, AR211: 1. AR219: 1
  • AR089 2231 HHEPU04 838217 241 AR089: 22, AR316: 18, AR194: 17, AR283 16, AR282: 16, AR060: 16, AR219: 16, AR277: 15, AR231: 15, AR281: 14, AR218: 14, AR104: 14, AR232: 13, AR244 : 12, AR263: 12, AR096: 11, AR240: 11.
  • AR246 11, AR299: 11, AR055: 10, AR315: 10, AR265: 10, AR313: 10, AR185 10, AR280: 10, AR238: 9, AR310: 9, AR039: 9, AR205: 8, AR243: 8, AR202 8, AR314: 8, AR233: 7, AR275: 7, AR226: 7, AR177: 7, AR183: 7, AR198: 6, AR234: 6, AR300: 6, AR247: 6, AR271: 6, AR273: 6, AR309: 6, AR175: 6, AR241 : 6, AR249: 6, AR274: 5, AR061: 5, AR237: 5, AR206: 5, AR312: 5, AR227: 5, AR229: 5, AR192: 5, AR033: 5, AR268: 5, AR295: 5, AR292: 4, AR253: 4, AR053: 4, AR251: 4, AR269: 4, AR248: 3, AR204: 3, AR213: 3, AR052: 3, AR267: 3, AR266: 3, AR258: 2, ARI 86: 2,
  • AR314 1, AR299: 1, AR246: 1, AR238: 1, AR217 : 1, AR237: 1, AR033: 1, AR061: 1, AR259: 1, AR296: 1, AR262: 1, AR233: 1, AR189: 1, AR199: 1, AR247: 1, AR258 : 1 L0770: 7, L0769: 7, L0766: 7, L0748: 7, H0341: 6, H0318: 6, L077 6, H0083: 5, S0422: 5, L0764: 5, S0374: 5, L0750: 5, S0444: 4, H0486: 4, H0581: 4, L0761: 4, L0774: 4, L0655: 4, L0809: 4, L0740: 4, L0754: 4, L0749: 4, L0596: 4, H0657: 3, H0722: 3, H0494: 3, S0372: 3, L0804: 3, L0628: 3, S0126: 3, H0659: 3, H0648: 3, L0752: 3, H0445: 3, H0265: 2, H05
  • AR215 11, AR291: 11, AR225: 10, AR217: 9, AR216: 8, AR296: 8, AR214: 8, AR297: 8, AR266: 7, AR183: 7, AR257: 7 AR223: 7, AR170: 7, AR269: 7, AR287: 7, AR221: 6, AR270: 6, AR171: 6, AR182: 6, AR286: 6, AR169: 6, AR172: 6, AR294: 6, AR176: 6, AR235: 6, AR163: 5, AR295: 5, AR161: 5, AR168: 5, AR255: 5, AR162: 5, AR224: 5, AR285: 5, AR293: 5, AR268: 5, AR289: 5, AR288: 5, AR263: 5, AR264: 5, AR165: 4, AR173: 4, AR260: 4, AR262: 4, AR175: 4, AR164: 4, AR179: 4, AR055: 4, AR104: 4, AR222: 4, AR166: 4, AR060: 4, AR181: 4,
  • AR263 79, AR264: 68, AR252 65, AR246 63, AR254 61.AR311 60, AR308 54, AR053 52,AR309:51,AR312:46, AR212: 41, AR205: 40, AR25039.AR213 38, AR09637, AR272 37, AR245 36,AR218 36,AR219:36,AR243:35, AR039: 32, AR197: 29, AR24026.AR19825, AR201 24, AR27422, AR20022.AR313 22,AR271:21,AR195:20, AR242: 18, AR221: 18, AR224 18, AR174 18, AR275 18.AR165 18,AR316 17, AR164 17, AR185: 17, AR104: 17, AR189: 17, AR290: 17, AR222 17, AR210 16, AR223 16, AR269 16, AR033 16,AR188 16, AR268: 16, AR253: 16, AR211: 16.AR166: 15, AR192 15, AR295 15.AR193
  • AR266 4, AR269: 4, AR161: 4, AR217: 4, AR163: 4, AR162: 4, ft AR3094, AR181: 4, AR183: 3, AR272: 3, AR268: 3, AR214: 3, AR225: 3, AR196: 3, AR197: 3, AR191: 3, AR257: 3, AR261 3, AR188: 3, AR216: 3, AR285: 3, AR238: 3, AR182: 3, AR288: 3, AR274: 3, AR267: 3, AR313: 3, AR189: 3, AR2943, AR258: 3, AR282: 3, AR178: 3, AR236: 3, AR296: 2, AR172: 2, AR165: 2, AR255: 2, AR308: 2, AR289: 2, AR2702, AR287: 2, AR164: 2, AR297: 2, AR290: 2, AR262: 2, AR229: 2, AR166: 2, AR173: 2,
  • AR266 3, AR283: 3, AR055: 3, AR232: 3, AR061: 3, AR256: 3, AR233: 3, AR234: 3, AR227: 2, AR228: 1 H0581: 3, H0436: 3, 10752: 3, S0358: 2, 0598: 2, L0766: 2, 10664: 2, 0754: 2, 10745: 2, 0777: 2, SOI 14: 1, SOI 16: 1, H0663: 1, S0360: 1,H0645: 1,H0586: 1.H0587: 1.H0333: 1.H0331: 1.H0486: 1.S0280: 1.H0590: 1.S0318: 1.H0622: 1.H0553: H0598: 1,10770: 1,10767: 1,L0794: 1.L0803: 1,10636: 1,10666: 1,10663: 1,10665: 1,10438: 1.H0547: 1.S0328: 1 H0555: 1, 10439: 1, S0031: 1, S0194: 1 and H0543: 1.
  • AR222 28, AR223: 27, AR205 27, AR28026.AR16925.AR235: 25, AR26324.AR19824, AR19223, AR21223,
  • AR22423.AR171 21.AR314 21.AR241 21.AR172: 21.AR168: 20,AR311 19, AR197 19,AR216 19,AR217 19,
  • AR213 19.AR271: 19, AR165 19, AR245 19, AR225: 18,AR310 18, AR273 18, AR242 18, AR243 18, AR164 18,
  • AR221 17, AR264: 17, AR265 17, AR033 17.
  • AR170 16.AR166 16, AR053 16.AR215 16, AR204 16, AR295 16,
  • AR201 14 AR096: 13.AR285 13, AR308 13, AR247 13.AR193 13, AR052 13,AR283 13,AR039 13,AR196 13,
  • AR312 13, AR232: 13, AR261 13,AR177 13,AR210 12, AR240 12, AR181 12, AR288 12, AR277 12, AR089 12,
  • AR300 12,AR183: 12, AR211 12, AR298 11.AR299 11.AR272 11.AR313 11.AR236 11.AR251 11.AR238: 11,
  • AR226 9, AR060: 9, AR239 8, AR234: 8, AR258: 8, AR250: 8, AR227: 8, AR254 8, AR259 8,AR173:8,AR182:8,
  • H06862 S0358: 2, S0360: 2, H0632: 2, S0049: 2, H0545: 2, H0620: 2, H0594: 2, S0022: 2, H0553: 2, H0090: 2, HOlOO:
  • H0696 1 H0134: 1, H0436: 1, S0027: 1, 13330: 1, 10742: 1, 10757: 1, H0444: 1, S0026: 1, S0196: 1, S0412: 1 and H050
  • AR202 2, AR253: 2, AR312: 2, AR162: 2, AR266: 2, AR182: 2, AR165: 2, AR216: 2, AR171: 2, AR190: 1, AR213: 1,
  • AR272 1, AR280: 1, AR240: 1, AR252: 1, AR316: 1, AR277: 1, AR284: 1, AR263: 1, AR172: 1, AR096: 1, AR271: 1
  • AR053 61 AR173 55, AR234: 55, AR244: 54, AR189: 43, AR240: 38, AR188: 38, AR193 32, AR289 , AR231 30, AR194 29, AR207 28, AR205: 27, AR206: 26, AR228: 25, AR266: 25, AR164: 24, AR165 24, AR175 , AR166 22, AR273 21, AR192 20, AR316: 20, AR163: 20, AR161: 19, AR162: 19, AR212: 19, AR263 19, AR256 , AR214 18, AR299 18, AR269 17, AR238: 16, AR195: 16, AR247: 15, AR055: 15, AR052: 15, AR191 15, AR223 , AR222 14, AR281 14, AR264 14, AR265: 14, AR235: 14, AR169: 14, AR168: 14, AR282: 13, AR224 13, AR170 , AR172 13, AR311 12, AR272 12, AR217: 12, AR310: 12, AR284: 12.
  • AR171 12, AR039: 12, AR216 12, AR274 , AR061 11, AR197 11. AR174: 11. AR185: 11, AR180: 11. AR204: 11. AR271: 11. AR251: 11, AR196 10, AR186 , AR249 10, AR089 10, AR239 10, AR177: 10, AR308: 10, AR309: 10, AR225: 10, AR215: 10, AR232 10, AR312 AR295: 9, AR221 9, AR181: 9, AR315: 9 AR237: 8, AR292: 8, AR033: 8, AR254: 8, AR261: 8, AR288: 8 , AR190: 8 , AR176: 7, AR230 7, AR291: 7, AR275: 7 , AR248: 7, AR229: 7, AR296: 7, AR280: 7, AR277: 7, AR236: 7 , AR199: 7 , AR210: 7, AR286 6, AR297: 6, AR182: 6 , AR298: 6, AR283: 6, AR287: 6, AR184: 6, AR226: 6,
  • S0354 1, S0045: 1, S6026: 1, 12767: 1, H0586: 1, 13816: 1, 13499: 1, 10015: 1, H0013: 1.
  • H0560 1, H0281 1, S0210: 1, 10506: 1, 10637: 1, 10800: 1, 10662: 1, 10767: 1, 10794: 1, 10804: 1, 10775: 1, 10375: 1, 10378: 1, 10806:
  • AR298 3, AR171: 3, AR300: 3, AR272: 2, AR264: 2, AR207: 2, AR291: 2, AR275: 2, AR254: 2, AR293: 2, AR033: 2, AR175: 2, AR277: 2, AR284: 2, AR260: 2, AR223: 2, AR227: 2, AR211: 2, AR233: 2, AR268: 2, AR230: 2, AR203: 2, AR219: 2, AR312: 2, AR243: 2, AR237: 2, AR267: 2, AR238: 2, AR239: 2, AR197: 2, AR177: 2, AR283: 2, AR286: 2, AR234: 2, AR168: 2, AR192: 2, AR232: 2, AR294: 2, AR206: 2, AR246: 2, AR226: 1, AR210: 1, AR199: 1, AR186: 1, AR263: 1, AR252: 1 L0740: 9, 10748: 6, 10777: 3, 10783: 2, 10809: 2, 10741: 2, 10746: 2, 10759: 2, H0392: 1,
  • AR274 47, AR309 35, AR312: 34, AR245: 33, AR271: 32, AR308: 30, AR272: 27, AR247: 26, AR215: 26, AR053: 26, AR246: 25, AR311 25, AR212: 24, AR216: 23, AR263: 23, AR162: 23, AR161 : 22, AR188: 22, AR225: 22, AR164: 22, AR163: 22, AR165 21, AR214: 21, AR213: 21, AR217: 21, AR192: 20, AR243: 20, AR264: 20, AR166: 19, AR196: 19, AR198: 18. AR254 16, AR197: 16.
  • AR216 52, AR214 45, AR205 44, AR215 39,AR199 38, AR274 34, AR222 33.AR217 33,AR225:33,AR172:31, AR171 30, ARI 68 30, AR22329, AR245 28.AR16928, AR22427.AR17027,AR210: 25,AR221:24,AR272:24, AR175 23, AR24722, AR24622, AR19521.AR21321.AR21820,AR21220, ARI 89 19,AR211: 19, AR053: 19, AR188 : 18,AR089 18, AR096 18.AR173 18,AR185 18.AR191 17,AR312 17,AR164 16, AR299: 16, AR104: 16, AR174 16, AR219 16, AR192 16.AR177 16.AR313 16.AR161 16, AR163 16,AR162 16, AR275: 16, AR039: 15, AR166 : 15,AR165 15.AR197 15, AR236 15,AR291 15.AR190 15, AR254 14,
  • AR253 151, AR250: 141, AR254: 138, AR296: 108, AR260: 100, AR252: 98, AR294: 96, AR180: 90, AR197: 87, AR20 87, AR256: 86, AR266: 85, AR293: 82, AR297: 81, AR204: 81, AR198: 80, AR176: 78, AR286: 78, AR181: 77, AR242: 76, AR245: 75, AR243: 74, AR235: 73, AR210: 73, AR289: 72, AR257: 72, AR192: 71, AR033: 70, AR200: 70, AR203: 68, AR285: 68, AR246: 68, AR287: 66, AR211: 66, AR178: 66, AR258: 65, AR237: 63, AR201: 62, AR053: 62
  • H0645 1, H0619: 1, H0600: 1, H0592: 1, H0486: 1, H0013: 1, H0042: 1, H0706: 1, S0010: 1, H0581: 1, H0196: 1, H0052: 1, H0263: 1, H0544: 1, H0150: 1, H0009: 1, H0123: 1, H0023: 1, H0200: 1, H0039: 1, H0644: 1, 10143: 1. H0606: 1, L0055: 1, H0673: 1. H0674: 1. S0364: 1.
  • AR267 559 HTJMA95 706618 569 AR182: 7, AR184: 5 , AR194 5, AR310 4, AR206: 4, AR170: 4, AR284: 4, AR263: 3, AR223: 3, AR282: 3, AR265: 3, AR243: 3, AR183: 3 , AR298 3, AR202 3, AR169: 3, AR186: 3, AR309: 2, AR195: 2, AR292: 2, AR166: 2, AR268: 2, AR199: 2, AR270: 2 , AR267 2.
  • AR162 2, AR221: 2, AR201: 2, AR052: 2, AR266: 2, AR289: 2, AR178: 2, AR269: 2, AR277: 2, AR248: 2 , AR281 2, AR286 2, AR296: 2, AR291: 2, AR229: 2, AR308: 2, AR232: 2, AR283: 2, AR033: 2, AR316: 2, AR224: 2 , AR290 2, AR231 2, AR060: 2, AR238: 2, AR295: 2, AR053: 2, AR173: 2, AR253: 2, AR313: 2, AR272: 2, AR089: 2.
  • AR244 2, AR213 1, AR300: 1, AR299: 1, AR312: 1, AR161: 1, AR204: 1, AR212: 1, AR172: 1, AR198: 1, AR285: 1 , AR061 1, AR288 1, AR293: 1, AR176: 1, AR275: 1, AR241: 1, AR163: 1, AR247: 1, AR174: 1, AR227: 1, AR216: 1 , AR254 1, AR240 1, AR096: 1, AR294: 1, AR314: 1, AR191: 1, AR175: 1, AR235: 1, AR226: 1, AR237: 1, AR225: 1 , AR258 1, AR259 1 H0264: 4, H0488: 4, S0328: 3, S0306: 2, S0476: 1, H0272: 1, H0487: 1, H049 1. H0633: 1. L5623: 1, 12264 : 1, 13665 l and S0330: 1.
  • AR294 3, AR273: 3, AR260: 3, AR033: 3, AR229: 3, AR202: 3, AR226: 3, AR216: 3, AR171: 3, AR299: 3, AR263: 3, AR316: 3, AR239: 3, AR217: 3, AR298: 2, AR055: 2, AR227: 2, AR237: 2, AR232: 2, AR214: 2, AR310: 2, AR096: 2, AR286: 2, AR039: 2, AR211 : 2, AR284: 2, AR265: 2, AR061: 2, AR210: 2, AR219: 2, AR267: 2, AR251 : 2, AR266: 2, AR218: 2, AR194: 1, AR169: 1, AR292: 1, AR104: 1, AR283: 1, AR256: 1 SOI 14: 1 and H0264: 1.
  • AR231 10, AR287: 10, AR176 10, AR188 10, AR261 9, AR308: 9, AR205: 9, AR286: 9, AR295: 9, AR254: 9, AR277: 9, AR264: 9, AR255: 9, AR237 9, AR282: 8 , AR033: 8, AR239: 8, AR271: 8, AR253: 8, AR290: 7, AR266: 7, AR250: 7, AR288: 7, AR263: 7, AR228 7, AR267: 7 , AR275: 7, AR245: 7, AR207: 7, AR283: 6, AR190: 6, AR246: 5, AR291: 5, AR227: 5, AR211: 5, AR256 5, AR309: 5 , AR104: 5, AR311: 4, AR210: 4, AR289: 4, AR274: 4, AR232: 4, AR223: 4, AR235: 4, AR214: 3, AR170 3, AR055: 3 , AR222: 3, AR216: 3, AR168: 3, AR061: 2, AR171: 2, AR217: 2, AR172: 2,
  • AR236 12, AR192 12, AR181 12, AR242: 12, AR296 12, AR293 12, AR207 12, AR219 11 AR179 11, AR260 11.
  • AR212 11, AR312 10, AR316 10, AR261 10, AR199 10, AR297: 10, AR270 10, AR053 10, AR233 10, AR269 10, AR200 10, AR226 10.
  • AR104 1, AR096: 1, AR204: 1, AR294: 1, AR258: 1, AR246: 1, AR300: 1, AR250: 1, AR199: 1, AR033: 1 10439: 4, L0748: 2, H0351: 1, S0364: 1, 10768: 1, 10650: 1, 10375: 1, 10747: 1 and H0352: 1.
  • AR181 13, AR311 13, AR178: 13, AR299: 13, AR180: 13, AR033: 13, AR192: 13, AR177: 13, AR219: 13, AR282 13.
  • AR316 12, AR263 12, AR233: 12, AR193: 12, AR238: 12, AR053: 12, AR226: 12, AR296: 12, AR104: 12, AR285 11, AR182 11, AR242 11, AR261: 11.
  • Table IC summarizes additional polynucleotides encompassed by the invention (including cDNA clones related to the sequences (Clone ED:), contig sequences (contig identifier (Contig ED:) contig nucleotide sequence identifiers (SEQ ED NO:X)), and genomic sequences (SEQ ED NO:B).
  • the first column provides a unique clone identifier, "Clone ED:”, for a cDNA clone related to each contig sequence.
  • the second column provides the sequence identifier, "SEQ ED NO:X", for each contig sequence.
  • the third column provides a unique contig identifier, "Contig ED:” for each contig sequence.
  • the fourth column provides a BAC identifier "BAC ED NO:A” for the BAC clone referenced in the corresponding row of the table.
  • the fifth column provides the nucleotide sequence identifier, "SEQ ED NO:B" for a fragment of the BAC clone identified in column four of the corresponding row of the table.
  • the sixth column "Exon From- To" provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence of SEQ ID NO:B which delineate certain polynucleotides of the invention that are also exemplary members of polynucleotide sequences that encode polypeptides of the invention (e.g., polypeptides containing amino acid sequences encoded by the polynucleotide sequences delineated in column six, and fragments and variants thereof).
  • the polynucleotides or polypeptides, or agonists or antagonists of the present invention can be used in assays to test for one or more biological activities. If these polynucleotides and polypeptides do exhibit activity in a particular assay, it is likely that these molecules may be involved in the diseases associated with the biological activity. Thus, the polynucleotides or polypeptides, or agonists or antagonists could be used to treat the associated disease.
  • the present invention encompasses methods of detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating a disease or disorder.
  • the present invention encompasses a method of treating cancer and other hyperproliferative disorders comprising administering to a patient in which such detection, treatment, prevention, and/or amelioration is desired a protein, nucleic acid, or antibody of the invention (or fragment or variant thereof) in an amount effective to detect, prevent, diagnose, prognosticate, treat, and/or ameliorate the cancer and other hyperproliferative disorders.
  • the present invention also encompasses methods of detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating cancer and other hyperproliferative disorders; comprising administering to a patient combinations of the proteins, nucleic acids, or antibodies of the invention (or fragments or variants thereof), sharing similar indications as shown in the corresponding rows in Column 3 of Table ID.
  • Table ID provides information related to biological activities for polynucleotides and polypeptides of the invention (including antibodies, agonists, and/or antagonists thereof). Table ID also provides information related to assays which may be used to test polynucleotides and polypeptides of the invention (including antibodies, agonists, and/or antagonists thereof) for the corresponding biological activities.
  • the first column (“Gene No.") provides the gene number in the application for each clone identifier.
  • the second column (“cDNA Clone ED:”) provides the unique clone identifier for each clone as previously described and indicated in Table 1A through Table ID.
  • the third column (“AA SEQ ID NO:Y”) indicates the Sequence Listing SEQ ED Number for polypeptide sequences encoded by the corresponding cDNA clones (also as indicated in Tables 1A, Table IB, and Table 2).
  • the fourth column (“Biological Activity”) indicates a biological activity corresponding to the indicated polypeptides (or polynucleotides encoding said polypeptides).
  • the fifth column (“Exemplary Activity Assay”) further describes the corresponding biological activity and also provides information pertaining to the various types of assays which may be performed to test, demonstrate, or quantify the corresponding biological activity.
  • Fluorometric microvolume assay technology is a fluorescence-based system which provides a means to perform nonradioactive cell- and bead- based assays to detect activation of cell signal transduction pathways. This technology was designed specifically for ligand binding and immunological assays. Using this technology, fluorescent cells or beads at the bottom of the well are detected as localized areas of concentrated fluorescence using a data processing system. Unbound flurophore comprising the background signal is ignored, allowing for a wide variety of homogeneous assays.
  • FMAT technology may be used for peptide ligand binding assays, immunofluorescence, apoptosis, cytotoxicity, and bead- based immunocapture assays. See, Miraglia S et. al., "Homogeneous cell and bead based assays for highthroughput screening using flourometric microvolume assay technology," Journal of Biomolecular Screening; 4:193-204 (1999).
  • FMAT technology may be used to test, confirm, and/or identify the ability of polypeptides (including polypeptide fragments and variants) to activate signal transduction pathways.
  • FMAT technology may be used to test, confirm, and/or identify the ability of polypeptides to upregulate production of immunomodulatory proteins (such as, for example, interleukins, GM-CSF, Rantes, and Tumor Necrosis factors, as well as other cellular regulators (e.g. insulin)).
  • immunomodulatory proteins such as, for example, interleukins, GM-CSF, Rantes, and Tumor Necrosis factors, as well as other cellular regulators (e.g. insulin)
  • Table ID also describes the use of kinase assays for testing, demonstrating, or quantifying biological activity.
  • the phosphorylation and de-phosphorylation of specific amino acid residues (e.g. Tyrosine, Serine, Threonine) on cell-signal transduction proteins provides a fast, reversible means for activation and de-activation of cellular signal transduction pathways.
  • kinase assays provide a powerful tool useful for testing, confirming, and/or identifying polypeptides (including polypeptide fragments and variants) that mediate cell signal transduction events via protein phosphorylation. See e.g., Forrer, P., Tamaskovic R., and Jaussi, R. "Enzyme-Linked Immunosorbent Assay for Measurement of JNK, ERK, and p38 Kinase Activities" Biol. Chem. 379(8-9): 1101-1110 (1998).

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Abstract

L'invention concerne des polypeptides sécrétés par l'homme et des molécules d'acides nucléiques isolées codant lesdits polypeptides, servant au diagnostic et au traitement du cancer et d'autres maladies et troubles hyperproliférants. L'invention concerne également des anticorps liant ces polypeptides, des vecteurs, des cellules hôtes, et des procédés de recombinaison et de synthèse destinés à la fabrication desdits polynucléotides, polypeptides et/ou anticorps. L'invention concerne également des procédés de criblage destinés à identifier des agonistes et des antagonistes des polynucléotides et polypeptides selon l'invention. L'invention concerne également des procédés et des compostions destinés à inhiber ou promouvoir la production et la fonction des polypeptides selon l'invention.
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AU2002354719A1 (en) 2003-01-21
WO2003038063A2 (fr) 2003-05-08
WO2002102994A2 (fr) 2002-12-27
WO2003004622A2 (fr) 2003-01-16
AU2002324424A1 (en) 2002-12-03
CA2441417A1 (fr) 2002-11-14
WO2002102993A2 (fr) 2002-12-27
EP1414845A2 (fr) 2004-05-06
EP1390390A4 (fr) 2009-07-08
AU2002332391A1 (en) 2003-01-02
EP1390390A2 (fr) 2004-02-25
CA2441397A1 (fr) 2002-10-03
EP1381622A2 (fr) 2004-01-21
WO2002095010A2 (fr) 2002-11-28
WO2002102993A3 (fr) 2004-03-25
AU2002326293A1 (en) 2003-01-02
WO2003004622A3 (fr) 2004-02-19
WO2002076488A1 (fr) 2002-10-03
CA2441840A1 (fr) 2002-11-28
AU2002363296A1 (en) 2003-05-12
EP1379132A2 (fr) 2004-01-14
EP1379264A1 (fr) 2004-01-14
WO2002102994A3 (fr) 2003-07-24
CA2441755A1 (fr) 2003-05-08
EP1379132A4 (fr) 2009-07-01
CA2441832A1 (fr) 2002-12-27
WO2003038063A3 (fr) 2003-12-11
EP1414845A4 (fr) 2009-07-08
WO2002090526A2 (fr) 2002-11-14
CA2441702A1 (fr) 2002-12-27
EP1379264A4 (fr) 2009-07-08

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