WO2002095010A2 - Proteines secretees humaines - Google Patents

Proteines secretees humaines Download PDF

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Publication number
WO2002095010A2
WO2002095010A2 PCT/US2002/009785 US0209785W WO02095010A2 WO 2002095010 A2 WO2002095010 A2 WO 2002095010A2 US 0209785 W US0209785 W US 0209785W WO 02095010 A2 WO02095010 A2 WO 02095010A2
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Prior art keywords
seq
polypeptide
referenced
fragment
encoded
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PCT/US2002/009785
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English (en)
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WO2002095010A3 (fr
Inventor
Craig A. Rosen
Steven M. Ruben
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Human Genome Sciences, Inc.
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Priority to AU2002324424A priority Critical patent/AU2002324424A1/en
Priority to EP02759068A priority patent/EP1404702A4/fr
Priority to CA002441840A priority patent/CA2441840A1/fr
Publication of WO2002095010A2 publication Critical patent/WO2002095010A2/fr
Publication of WO2002095010A3 publication Critical patent/WO2002095010A3/fr
Priority to US11/366,486 priority patent/US20060246483A1/en

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    • 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 cardiovascular diseases, disorders, and/or conditions related thereto.
  • 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 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.
  • the cardiovascular system is a component of a complex physiological network involved in maintaining the oxygen and nutrient supply to tissues of the body.
  • the heart is the anatomical and functional centerpiece of the cardiovascular system. Weighing only 250-350 grams (less than a pound), the heart is one of our strongest and hardest working organs. It is composed of innervated muscle tissue with unique properties; e.g., it can pace itself in contraction. The main center of rhythm regulation is the sinoatrial (SA) node. Certain cardiac cells repeatedly fire impulses that trigger heart contractions. These autorhythmic cells have two important functions. One is to act as a pacemaker (set the pace for the entire heart), and the other is to form a conduction system, the route for conducting impulses throughout the heart muscle. This conduction system controls the pattern of blood flow through the heart.
  • SA sinoatrial
  • the heart pumps at least five quarts of blood through a full circuit of the body every minute.
  • the heart consists of two pumps, side by side.
  • the pump on the right side moves blood to the lungs, where waste gases, such as carbon dioxide, are removed and oxygen is added.
  • Freshly oxygenated blood returns to the pump on the left side, which moves it out into the rest of the body.
  • disorders of the cardiovascular system are many and varied, killing more Americans each year than any other category of disorders. For example, damage to the conduction system leads to arrhythmia, an irregular beating of the heart. If left untreated, the heart becomes unable to effectively pump blood, frequently leading to permanent heart damage and/or cardiac arrest.
  • Atherosclerosis is the buildup of fatty deposits in the intima of large and medium- sized arteries. The buildup of deposits narrowing of the arteries, reducing or potentially blocking the ability of blood to flow through the arteries. .Untreated, atherosclerosis typically results in cardiac arrest and, frequently, death.
  • Cardiovascular disorders include, but are not limited to, stroke, cardiovascular abnormalities, such as arterio-arterial fistula, arteriovenous fistula, cerebral arteriovenous malformations, congenital heart defects, pulmonary atresia, and Scimitar Syndrome.
  • cardiovascular abnormalities such as arterio-arterial fistula, arteriovenous fistula, cerebral arteriovenous malformations, congenital heart defects, pulmonary atresia, and Scimitar Syndrome.
  • Congenital heart defects include, but are not limited to, aortic coarctation, cor triatriatum, coronary vessel anomalies, crisscross heart, dextrocardia, patent ductus arteriosus, Ebstein's anomaly, Eisenmenger complex, hypoplastic left heart syndrome, levocardia, tetralogy of fallot, transposition of great vessels, double outlet right ventricle, tricuspid atresia, persistent truncus arteriosus, and heart septal defects, such as aortopulmonary septal defect, endocardial cushion defects, Lutembacher's Syndrome, trilogy of Fallot, ventricular heart septal defects.
  • Cardiovascular disorders also include, but are not limited to, heart disease, such as arrhythmias, carcinoid heart disease, high cardiac output, low cardiac output, cardiac tamponade, endocarditis (including bacterial), heart aneurysm, cardiac arrest, congestive heart failure, congestive cardiomyopathy, paroxysmal dyspnea, cardiac edema, heart hypertrophy, congestive cardiomyopathy, left ventricular hypertrophy, right ventricular hypertrophy, post-infarction heart rupture, ventricular septal rupture, heart valve diseases, myocardial diseases, myocardial ischemia, pericardial effusion, pericarditis (including constrictive and tuberculous), pneumopericardium, postpericardiotomy syndrome, pulmonary heart disease, rheumatic heart disease, ventricular dysfunction, hyperemia, cardiovascular pregnancy complications, Scimitar Syndrome, cardiovascular syphilis, and cardiovascular tuberculosis.
  • heart disease such as arrhythmias, carcinoid heart disease
  • Arrhythmias include, but are not limited to, sinus arrhythmia, atrial fibrillation, atrial flutter, bradycardia, extrasystole, Adams-Stokes Syndrome, bundle-branch block, sinoatrial block, long QT syndrome, parasystole, Lown-Ganong-Levine Syndrome, Mahaim-type pre-excitation syndrome, Wolff-Parkinson-White syndrome, sick sinus syndrome, tachycardias, and ventricular fibrillation.
  • Tachycardias include paroxysmal tachycardia, supraventricular tachycardia, accelerated idioventricular rhythm, atrioventricular nodal reentry tachycardia, ectopic atrial tachycardia, ectopic junctional tachycardia, sinoatrial nodal reentry tachycardia, sinus tachycardia, Torsades de Pointes, and ventricular tachycardia.
  • Heart valve diseases include, but are not limited to, aortic valve insufficiency, aortic valve stenosis, hear murmurs, aortic valve prolapse, mitral valve prolapse, tricuspid valve prolapse, mitral valve insufficiency, mitral valve stenosis, pulmonary atresia, pulmonary valve insufficiency, pulmonary valve stenosis, tricuspid atresia, tricuspid valve insufficiency, and tricuspid valve stenosis.
  • Myocardial diseases include, but are not limited to, alcoholic cardiomyopathy, congestive cardiomyopathy, hypertrophic cardiomyopathy, aortic subvalvular stenosis, pulmonary subvalvular stenosis, restrictive cardiomyopathy, Chagas cardiomyopathy, endocardial fibroelastosis, endomyocardial fibrosis, Kearns Syndrome, myocardial reperfusion injury, and myocarditis.
  • Myocardial ischemias include, but are not limited to, coronary disease, such as angina pectoris, coronary aneurysm, coronary arteriosclerosis, coronary thrombosis, coronary vasospasm, myocardial infarction and myocardial stunning.
  • coronary disease such as angina pectoris, coronary aneurysm, coronary arteriosclerosis, coronary thrombosis, coronary vasospasm, myocardial infarction and myocardial stunning.
  • Cardiovascular diseases also include vascular diseases such as aneurysms, angiodysplasia, angiomatosis, bacillary angiomatosis, Hippel-Lindau Disease, Klippel-Trenaunay- Weber Syndrome, Sturge-Weber Syndrome, angioneurotic edema, aortic diseases, Takayasu's Arteritis, aortitis, Leriche's Syndrome, arterial occlusive diseases, arteritis, enarteritis, polyarteritis nodosa, cerebrovascular disorders, diabetic angiopathies, diabetic retinopathy, embolisms, thrombosis, erythromelalgia, hemorrhoids, hepatic veno-occlusive disease, hypertension, hypotension, ischemia, peripheral vascular diseases, phlebitis, pulmonary veno-occlusive disease, Raynaud's disease, CREST syndrome, retinal
  • Aneurysms include, but are not limited to, dissecting aneurysms, false aneurysms, infected aneurysms, ruptured aneurysms, aortic aneurysms, cerebral aneurysms, coronary aneurysms, heart aneurysms, and iliac aneurysms.
  • Arterial occlusive diseases include, but are not limited to, arteriosclerosis, intermittent claudication, carotid stenosis, fibromuscular dysplasias, mesenteric vascular occlusion, Moyamoya disease, renal artery obstruction, retinal artery occlusion, and thromboangiitis obliterans.
  • Cerebrovascular disorders include, but are not limited to, carotid artery diseases, cerebral amyloid angiopathy, cerebral aneurysm, cerebral anoxia, cerebral arteriosclerosis, cerebral arteriovenous malformation, cerebral artery diseases, cerebral embolism and thrombosis, carotid artery thrombosis, sinus thrombosis, Wallenberg's syndrome, cerebral hemorrhage, epidural hematoma, subdural hematoma, subaraxhnoid hemorrhage, cerebral infarction, cerebral ischemia (including transient), subclavian steal syndrome, periventricular leukomalacia, vascular headache, cluster headache, migraine, and vertebrobasilar insufficiency.
  • Embolisms include, but are not limited to, air embolisms, amniotic fluid embolisms, cholesterol embolisms, blue toe syndrome, fat embolisms, pulmonary embolisms, and thromoboembolisms.
  • Thrombosis include, but are not limited to, coronary thrombosis, hepatic vein thrombosis, retinal vein occlusion, carotid artery thrombosis, sinus thrombosis, Wallenberg's syndrome, and thrombophlebitis.
  • Ischemic disorders include, but are not limited to, cerebral ischemia, ischemic colitis, compartment syndromes, anterior compartment syndrome, myocardial ischemia, reperfusion injuries, and peripheral limb ischemia.
  • Vasculitis includes, but is not limited to, aortitis, arteritis, Behcet's Syndrome, Churg-Strauss Syndrome, mucocutaneous lymph node syndrome, thromboangiitis obliterans, hypersensitivity vasculitis, Schoenlein-Henoch purpura, allergic cutaneous vasculitis, and Wegener's granulomatosis.
  • 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 cardiovascular diseases and 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 info ⁇ nation 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
  • 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 1B.1 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 1B.1 and 1B.2 provide the gene numbers in the application for each clone identifier.
  • the second column of Tables 1B.1 and 1B.2 provide unique clone identifiers, "Clone ID:”, 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 ID NO:X", for each of the contig sequences disclosed in Table 1A and/or IB. Table IB.l
  • 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 ID 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 ID 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.
  • Table IB.l Column 9 labeled "OMDVI Disease Reference(s)".
  • a key to the OMIM 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 ID 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.
  • Table IC summarizes additional polynucleotides encompassed by the invention (including cDNA clones related to the sequences (Clone ID:), contig sequences (contig identifier (Contig ID:) contig nucleotide sequence identifiers (SEQ ID NO:X)), and genomic sequences (SEQ ID NO:B).
  • the first column provides a unique clone identifier, "Clone ID:”, for a cDNA clone related to each contig sequence.
  • the second column provides the sequence identifier, "SEQ ID NO:X”, for each contig sequence.
  • the third column provides a unique contig identifier, "Contig ID:” for each contig sequence.
  • the fourth column provides a BAC identifier "BAC ID NO:A” for the BAC clone referenced in the corresponding row of the table.
  • the fifth column provides the nucleotide sequence identifier, "SEQ ID 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 present invention encompasses a method of detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating cardiovascular diseases or 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. 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 thereof (including antibodies) 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 DD:”) provides the unique clone identifier for each clone as previously described and indicated in Tables 1A, IB, and IC.
  • the third column (“AA SEQ ID NO:Y”) indicates the Sequence Listing SEQ ID 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 (FMAT) 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.
  • 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)).
  • Table ID also describes the use of kinase assays for testing, demonstrating, or quantifying biological activity. In this regard, 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.
  • 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).
  • Table 2 summarizes homology and features of some of the polypeptides of the invention.
  • the first column provides a unique clone identifier, "Clone ID:”, corresponding to a cDNA clone disclosed in Table 1A or Table IB.
  • the second column provides the unique contig identifier, "Contig ID:” corresponding to contigs in Table IB and allowing for correlation with the information in Table IB.
  • the third column provides the sequence identifier, "SEQ ID 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 ID 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 ID NO:X”, for contig sequences disclosed in Table 1A and/or Table IB.
  • the third column provides the unique contig identifier, "Contig ID:”, 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 ID 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 IB.2, column 5.
  • Column 1 provides the tissue/cell source identifier code disclosed in Table 1B.2,
  • tissue or cell source 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. a neoplasm), or may be disease-associated (e.g., a tissue sample from a normal portion of a diseased organ).
  • tissues and/or cells lacking the "disease" designation may still be derived from sources directly or indirectly involved in a disease state or disorder, and therefore may have a further utility in that disease state or disorder.
  • the tissue/cell source is a library
  • column 7 identifies the vector used to generate the library.
  • Table 5 provides a key to the OMIM reference identification numbers disclosed in Table IB.l.
  • OMIM reference identification numbers (Column 1) were derived from Online Mendelian Inheritance in Man (Online Mendelian Inheritance in Man, OMIM. 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, 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 ID 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 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 ID 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 ID NO:X is deposited at Human Genome Sciences, Inc. (HGS) in a catalogued and archived library.
  • HGS Human Genome Sciences, Inc.
  • Table IB each clone is identified by a cDNA Clone ED (identifier generally referred to herein as Clone ID:).
  • Clone ID identifier generally referred to herein as Clone ID:
  • Each Clone ID is unique to an individual clone and the Clone ID 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 DD) isolated from that library begins with the same four characters, for example "HTWEP07".
  • Table 1A and/or Table IB correlates the Clone ID names with SEQ ED NO:X. Thus, starting with an SEQ DD NO:X, one can use Tables 1A, IB, 6, 7, and 9 to determine the corresponding Clone DD, 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 DD: (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 the
  • “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.
  • polynucleotide embraces chemically, enzymatically, or metabolically modified forms.
  • the polynucleotides of the invention are at least 15, at least
  • 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).
  • 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 DD NO:Y is a translated open reading frame (ORF) encoded by polynucleotide SEQ ID 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 ED 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 DD NO:X refers to a polynucleotide sequence described, for example, in Tables
  • SEQ DD NO:Y refers to a polypeptide sequence described in column 11 of Table 1A and or Table IB.
  • SEQ ED NO:X is identified by an integer specified in Table IB.
  • the polypeptide sequence SEQ DD NO:Y is a translated open reading frame (ORF) encoded by polynucleotide SEQ DD NO:X.
  • Clone ED: refers to a cDNA clone described in column 2 of Table 1A and/or Table 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 cardiovascular diseases and 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 cardiovascular diseases and 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.
  • 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. In the case where dose dependency does exist, it need not be identical to that of the polypeptide, but rather substantially similar to the dose-dependence in a given activity as compared to the polypeptide of the present invention (i.e., the candidate polypeptide will exhibit greater activity or not more than about 25-fold less and, preferably, not more than about tenfold less activity, and most preferably, not more than about three-fold less activity relative to the polypeptide of the present invention).
  • 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 DD 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 DD 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 DD NO:X.
  • the nucleotide position of SEQ DD NO:X of the putative start codon (methionine) is identified as "5' NT of Start Codon.”
  • the nucleotide position of SEQ DD 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 ED 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 DD NO:X, and the predicted translated amino acid sequence identified as SEQ ED 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.
  • 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 __.. 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 ED 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 ED 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.
  • 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 DD:) and contig nucleotide sequence identifiers (SEQ DD 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 IB.
  • the third column of Tables IB.l and 1B.2 provide unique contig identifiers, "Contig DD:” 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 DD 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 ED 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 DD 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.
  • OMEVI identification number is disclosed in Table IB.l, column 9 labeled "OMEVI Disease Reference(s)".
  • a key to the OMIM reference identification numbers is provided in Table 5.
  • Table 5 is a key to the OMIM reference identification numbers (column 1), and provides a description of the associated disease in Column 2.
  • Table 1B.2 Column 5 of Table IB.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 1B.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 ID:), contig sequences (contig identifier (Contig ID:) contig nucleotide sequence identifiers (SEQ ID NO:X)), and genomic sequences (SEQ ID NO:B).
  • the first column provides a unique clone identifier, "Clone ID:”, for a cDNA clone related to each contig sequence.
  • the second column provides the sequence identifier, "SEQ ID NO:X”, for each contig sequence.
  • the third column provides a unique contig identifier, "Contig ID:” for each contig sequence.
  • the fourth column provides a BAC identifier "BAC ID NO:A” for the BAC clone referenced in the corresponding row of the table.
  • the fifth column provides the nucleotide sequence identifier, "SEQ ID NO:B" for a fragment of the BAC clone identified in column four of the corresponding row of the table.
  • the sixth column 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).
  • HAUAI83 33 639009 AC010422 1039 1-315 2004-2289 2650-2741 3554-3830
  • 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 a cardiovascular disease or disorder 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 cardiovascular disease or disorder.
  • the present invention also encompasses methods of detecting, preventing, diagnosing, prognosticating, treating, and/or ameliorating a cardiovascular disease or disorder; 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 ID:”) 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 ID 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
  • 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).
  • Exemplary assays that may be used or routinely modified to measure calcium flux by polypeptides of the invention include assays disclosed in: Satin LS, et al., Endocrinology, 136(10):4589-601 (1995);Mogami H, al., Endocrinology, 136(7):2960-6 (1995); Richardson SB, et al., Biochem J, 288 ( Pt 3):847-51 (1992); and, Meats, JE, et al., Cell Calcium 1989 Nov-Dec;10(8):535-41 (1989), the contents of each of which is herein incorporated by reference in its entirety.
  • Pancreatic cells that may be used according to these assays are publicly available (e.g., through the ATCC) and/or may be routinely generated.
  • Exemplary pancreatic cells that may be used according to these assays include HITT15 Cells.
  • HTTT15 are an adherent epithelial cell line established from Syrian hamster islet cells transformed with SV40. These cells express glucagon, somatostatin, and glucocorticoid receptors. The cells secrete insulin, which is stimulated by glucose and glucagon and suppressed by somatostatin or glucocorticoids.
  • ATTC# CRL-1777 Refs Lord and Ashcroft. Biochem. J. 219: 547-551; Santerre et al. Proc. Natl. Acad. Sci. USA 78: 4339-4343, 1981.
  • HAPOM49 541 Regulation of Assays for the regulation of viability and proliferation of cells in vitro are well-known in the art an viability and may be used or routinely modified to assess the ability of polypeptides of the invention (including proliferation of antibodies and agonists or antagonists of the invention) to regulate viability and proliferation of pancreatic beta pancreatic beta cells.
  • the Cell Titer-Glo luminescent cell viability assay measures th cells. number of viable cells in culture based on quantitation of the ATP present which signals the presence of metabolically active cells.
  • Exemplary assays that may be used or routinely modified t test regulation of viability and proliferation of pancreatic beta cells by polypeptides of the inventio (including antibodies and agonists or antagonists of the invention) include assays disclosed in: Friedrichsen BN, et al., Mol Endocrinol, 15(1): 136-48 (2001); Huotari MA, et al., Endocrinology, 139(4): 1494-9 (1998); Hugl SR, et al., J Biol Chem 1998 Jul 10;273(28): 17771-9 (1998), the contents of each of which is herein incorporated by reference in its entirety.
  • Pancreatic cells that may be used according to these assays are publicly available (e.g., through the ATCC) and/or may be routinely generated.
  • Exemplary pancreatic cells that may be used according to these assays include rat INS-1 cells.
  • INS-1 cells are a semi-adherent cell line established from cells isolated from an X-ray induced rat transplantable insulinoma. These cells retain characteristics typical of native pancreatic beta cells including glucose inducible insulin secretion. References: Asfari et al. Endocrinology 1992 130: 167.
  • JNK and p38 kinase assays for signal transduction that regulate cell proliferation, Cell p38 or JNK activation, or apoptosis are well known in the art and may be used or routinely modified to assess Signaling the ability of polypeptides of the invention (including antibodies and agonists or antagonists of the
  • Cell receptor and CD3, CD4, or CD8 These cells mediate humoral or cell-mediated immunity an may be preactivated to enhance responsiveness to immunomodulatory factors.
  • TNFa FMAT 99 HFCCQ50 622 Production of TNFa FMAT.
  • Assays for immunomodulatory proteins produced by activated macrophages, T cell TNF alpha by fibroblasts, smooth muscle, and other cell types that exert a wide variety of inflammatory and dendritic cells cytotoxic effects on a variety of cells are well known in the art and may be used or routinely modified to assess the ability of polypeptides of the invention (including antibodies and agonists o antagonists of the invention) to mediate immunomodulation, modulate inflammation and cytotoxicity.
  • Exemplary assays that test for immunomodulatory proteins evaluate the production cytokines such as tumor necrosis factor alpha (TNFa), and the induction or inhibition of an inflammatory or cytotoxic response.
  • TNFa tumor necrosis factor alpha
  • Such assays that may be used or routinely modified to test immunomodulatory activity of polypeptides of the invention (including antibodies and agonists or antagonists of the invention) include assays disclosed in Miraglia et al., J Biomolecular Screening 4: 193-204(1999); Rowland et al., "Lymphocytes: a practical approach” Chapter 6:138-160 (2000); Verhasselt et al., Eur J Immunol 28(l l):3886-3890 (1198); Dahlen et al., J Immunol 160(7):3585- 3593 (1998); Verhasselt et al., J Immunol 158:2919-2925 (1997); and Nardelli et al., J Leukoc Bio 65:822-828 (1999), the contents of each of which are herein incorporated by reference in its entiret
  • Human dendritic cells that may be used according to these assays may be isolated using technique OJ disclosed herein or otherwise known in the art. Human dendritic cells are antigen presenting cells suspension culture, which, when activated by antigen and/or cytokines, initiate and upregulate T c proliferation and functional activities.
  • EL-4 FMAT 99 HFCCQ50 622 Production of EL-4 FMAT.
  • Assays for immunomodulatory proteins secreted by TH2 cells that stimulate B cells, IL-4 cells, macrophages and mast cells and promote polarization of CD4+ cells into TH2 cells are well known in the art and may be used or routinely modified to assess the ability of polypeptides of the invention (including antibodies and agonists or antagonists of the invention) to mediate immunomodulation, stimulate immune cells, modulate immune cell polarization, and/or mediate humoral or cell-mediated immunity.
  • Exemplary assays that test for immunomodulatory proteins evaluate the production of cytokines, such as IL-4, and the stimulation of immune cells, such as B cells, T cells, macrophages and mast cells.
  • Such assays that may be used or routinely modified to test immunomodulatory activity of polypeptides of the invention (including antibodies and agonist or antagonists of the invention) include the assays disclosed in Miraglia et al., J Biomolecular Screening 4: 193-204 (1999); Rowland et al., "Lymphocytes: a practical approach” Chapter 6: 138- 160 (2000); Gonzalez et al., J Clin Lab Anal 8(5):277-283 (1194); Yssel et al., Res Immunol 144(8):610-616 (1993); Bagley et al., Nat Immunol 1(3):257-261 (2000); and van der Graaff et al., Rheumatology (Oxford) 38(3):214-220 (1999), the contents of each of which are herein
  • insulin secretion modified to assess the ability of polypeptides of the invention (including antibodies and agonists o from pancreatic antagonists of the invention) to stimulate insulin secretion.
  • polypeptides of the invention including antibodies and agonists o from pancreatic antagonists of the invention
  • insulin secretion is beta cells. measured by FMAT using anti -rat insulin antibodies.
  • Insulin secretion from pancreatic beta cells i upregulated by glucose and also by certain proteins/peptides, and disregulation is a key componen in diabetes.
  • Exemplary assays that may be used or routinely modified to test for stimulation of insulin secretion (from pancreatic cells) by polypeptides of the invention (including antibodies and agonists or antagonists of the invention) include assays disclosed in: Ahren, B., et al., Am J Physi 277(4 Pt 2):R959-66 (1999); Li, M., et al., Endocrinology, 138(9):3735-40 (1997); Kim, K.H., et a FEBS Lett, 377(2):237-9 (1995); and, Miraglia S et.
  • pancreatic cells that may be used according to these assays are publicly available (e.g., through th ATCC) and/or may be routinely generated.
  • Exemplary pancreatic cells that may be used accordin to these assays include rat INS-1 cells.
  • BNS-l cells are a semi-adherent cell line established from cells isolated from an X-ray induced rat transplantable insulinoma. These cells retain characteristi typical of native pancreatic beta cells including glucose inducible insulin secretion. References: Asfari et al. Endocrinology 1992 130: 167.
  • Exemplary assays for caspase apoptosis that may b used or routinely modified to test capase apoptosis activity of polypeptides of the invention (including antibodies and agonists or antagonists of the invention) include the assays disclosed in Lee et al., FEBS Lett 485(2-3): 122-126 (2000); Nor et al., J Vase Res 37(3): 209-218 (2000); and Karsan and Harlan, J Atheroscler Thromb 3(2): 75-80 (1996); the contents of each of which are herein incorporated by reference in its entirety. Endothelial cells that may be used according to these assays are publicly available (e.g., through commercial sources).
  • Exemplary endothelial cell that may be used according to these assays include bovine aortic endothelial cells (bAEC), which are an example of endothelial cells which line blood vessels and are involved in functions that include, but are not limited to, angiogenesis, vascular permeability, vascular tone, and immune cel extravasation.
  • bAEC bovine aortic endothelial cells
  • SRE Serum Response Element
  • JNK and p38 kinase activity that may be used or routinely modified to test JNK and p38 kinase- induced activity of polypeptides of the invention (including antibodies and agonists or antagonists the invention) include the assays disclosed in Forrer et al., Biol Chem 379(8-9): 1101-1110 (1998); Gupta et al., Exp Cell Res 247(2): 495-504 (1999); Kyriakis JM, Biochem Soc Symp 64:29-48 (1999); Chang and Karin, Nature 410(6824):37-40 (2001); and Cobb MH, Prog Biophys Mol Biol 71(3-4):479-500 (1999); the contents of each of which are herein inco ⁇ orated by reference in its entirety.
  • Endothelial cells that may be used according to these assays are publicly available (e.g., through the ATCC).
  • Exemplary endothelial cells that may be used according to these assays include human umbilical vein endothelial cells (HUVEC), which are endothelial cells which line venous blood vessels, and are involved in functions that include, but are not limited to, angiogenesis, vascular permeability, vascular tone, and immune cell extravasation.
  • HUVEC human umbilical vein endothelial cells
  • Insulin Assays for measuring secretion of insulin are well-known in the art and may be used or routinely Secretion modified to assess the ability of polypeptides of the invention (including antibodies and agonists o antagonists of the invention) to stimulate insulin secretion.
  • polypeptides of the invention including antibodies and agonists o antagonists of the invention
  • insulin secretion is measured by FMAT using anti-rat insulin antibodies.
  • Insulin secretion from pancreatic beta cells i on upregulated by glucose and also by certain proteins/peptides, and disregulation is a key componen
  • Exemplary assays that may be used or routinely modified to test for stimulation of insulin secretion (from pancreatic cells) by polypeptides of the invention include assays disclosed in: Shimizu, H., et al., Endocr J, 47(3):261-9 (2000); Salapatek, A.M., et al., Mol Endocrinol, 13(8): 1305-17 (1999); Filipsson, K non al., Ann N Y Acad Sci, 865:441-4 (1998); Olson, L.K., et al., J Biol Chem, 271(28): 16544-52 (1996); and, Miraglia S et.
  • pancreatic cells that may be used according to these assays are publicly available (e.g., through the ATCC) and/or may be routinely generated.
  • Exemplary pancreatic cells that may be used according to these assays include HITT15 Cells.
  • HFTT15 are an adherent epithelial cell line established from Syrian hamster islet cells transformed with SV40. These cells express glucagon, somatostatin, and glucocorticoid receptors. The cells secrete insulin, which is stimulated by glucose and glucagon and suppressed by somatostatin or glucocorticoids.
  • Activation of Assays for the activation of transcription through the NFKB response element are well-known in t transcription art and may be used or routinely modified to assess the ability of polypeptides of the invention through NFKB (including antibodies and agonists or antagonists of the invention) to regulate NFKB transcription

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Abstract

Cette invention se rapporte à des polypeptides sécrétés humains, et à des molécules d'acide nucléique isolées codant ces polypeptides, qui sont utiles pour le diagnostic et le traitement des maladies cardio-vasculaires et des troubles et/ou états associés à ces maladies. Font également l'objet de cette invention des anticorps qui se fixent à ces polypeptides, ainsi que des vecteurs, des cellules hôtes et des procédés de recombinaison et de synthèse permettant de produire ces polynucléotides, ces polypeptides et/ou ces anticorps. Cette invention concerne en outre des procédés de criblage pour identifier des agonistes et des antagonistes de ces polynucléotides et polypeptides, ainsi que des procédés et des compositions pour inhiber ou améliorer la production et les fonctions de ces polypeptides.
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US9593167B2 (en) 2006-10-27 2017-03-14 Genentech, Inc. Antibodies and immunoconjugates and uses therefor
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US8962579B2 (en) 2007-10-26 2015-02-24 Dynavax Technologies Corporation Methods and compositions for inhibition of immune responses and autoimmunity
US9476053B2 (en) 2007-10-26 2016-10-25 Dynavax Technologies Corporation Methods and compositions for inhibition of immune responses and autoimmunity
EP3536336A1 (fr) * 2007-11-30 2019-09-11 Siemens Healthcare Diagnostics Inc. Fragments de récepteur de l'adiponectine et procédés d'utilisation
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CA2441417A1 (fr) 2002-11-14
WO2002090526A3 (fr) 2003-10-30
CA2441416A1 (fr) 2003-01-16
AU2002363296A1 (en) 2003-05-12
WO2002095010A3 (fr) 2004-02-12
CA2441840A1 (fr) 2002-11-28
WO2002076488A1 (fr) 2002-10-03
EP1390390A4 (fr) 2009-07-08
WO2003038063A3 (fr) 2003-12-11
AU2002326293A1 (en) 2003-01-02
EP1423134A2 (fr) 2004-06-02
EP1404702A4 (fr) 2009-07-08
EP1414845A2 (fr) 2004-05-06
WO2003038063A2 (fr) 2003-05-08
WO2002102993A3 (fr) 2004-03-25
CA2441397A1 (fr) 2002-10-03
EP1381622A2 (fr) 2004-01-21
EP1379132A4 (fr) 2009-07-01
CA2441832A1 (fr) 2002-12-27
WO2003004622A2 (fr) 2003-01-16
CA2441702A1 (fr) 2002-12-27
WO2003004622A3 (fr) 2004-02-19
EP1390390A2 (fr) 2004-02-25
EP1404702A2 (fr) 2004-04-07
AU2002332391A1 (en) 2003-01-02
WO2002102994A2 (fr) 2002-12-27
EP1379264A1 (fr) 2004-01-14
WO2002102994A3 (fr) 2003-07-24
WO2002090526A2 (fr) 2002-11-14
EP1414845A4 (fr) 2009-07-08
AU2002354719A1 (en) 2003-01-21
EP1379264A4 (fr) 2009-07-08
WO2002102993A2 (fr) 2002-12-27
EP1379132A2 (fr) 2004-01-14
AU2002320013A1 (en) 2002-11-18
AU2002324424A1 (en) 2002-12-03
CA2441755A1 (fr) 2003-05-08

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