EP1218411A2 - Proteines secretees et leurs utilisations - Google Patents

Proteines secretees et leurs utilisations

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Publication number
EP1218411A2
EP1218411A2 EP00965288A EP00965288A EP1218411A2 EP 1218411 A2 EP1218411 A2 EP 1218411A2 EP 00965288 A EP00965288 A EP 00965288A EP 00965288 A EP00965288 A EP 00965288A EP 1218411 A2 EP1218411 A2 EP 1218411A2
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EP
European Patent Office
Prior art keywords
seq
accession number
nucleic acid
number pta
amino acid
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EP00965288A
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German (de)
English (en)
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EP1218411A4 (fr
Inventor
Susan J. Kirst
John D. Sharp
Christopher C. Fraser
Thomas Barnes
Gillian Kingsbury
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Millennium Pharmaceuticals Inc
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Millennium Pharmaceuticals Inc
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Publication of EP1218411A2 publication Critical patent/EP1218411A2/fr
Publication of EP1218411A4 publication Critical patent/EP1218411A4/fr
Withdrawn legal-status Critical Current

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the INTERCEPT 307, MANGO 511, TANGO 351, TANGO 361, TANGO 499, and TANGO 509 proteins, fragments, derivatives, and variants thereof of the present invention are collectively referred to herein as "polypeptides of the invention” or “proteins of the invention.”
  • Nucleic acid molecules encoding the polypeptides or proteins of the invention are collectively referred to as “nucleic acids of the invention.”
  • the invention features nucleic acid molecules which are at least 30%, 35%, 40%, 45%, 50%, 55%, 65%, 75%, 85%, 95%, or 98% identical to the nucleotide sequence of human SEQ ID NO:66, SEQ ID NO:67, the nucleotide sequence of the cDNA insert of an human EpT509 clone deposited August 5, 1999 with the ATCC® as Accession Number PTA-438, or a complement thereof
  • the invention features nucleic acid molecules of at least 550, 600, 650, 700, 750, 800, 850, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000 or 2020 contiguous nucleotides of the nucleotide sequence of SEQ ID NO:l, the nucleotide sequence of an INT307 cDNA of ATCC® Accession Number PTA-455, or a complement thereof.
  • the invention features nucleic acid molecules comprising at least 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600 or 645 contiguous nucleotides of nucleic acids 1 to 649 of SEQ ID NO:l, or a complement thereof.
  • the invention features nucleic acid molecules comprising at least 25, 50, 100, 150, 200, 250 or 300 contiguous nucleotides of nucleic acids 1120 to 1430 of SEQ ID NO:l, or a complement thereof.
  • the invention features nucleic acid molecules of at least 460, 500, 550, 600, 650, 700, 750, 800, 850, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300 or 3340 contiguous nucleotides of the nucleotide sequence of SEQ ID NO:34, the nucleotide sequence of an EpT351 cDNA of ATCC® Accession Number PTA-424, or a complement thereof.
  • the invention features nucleic acid molecules of at least 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, or 5000 contiguous nucleotides of the nucleotide sequence of SEQ ID NO:42, the nucleotide sequence of an EpT361 cDNA of ATCC® Accession Number PTA-438, or a complement thereof.
  • the invention also features nucleic acid molecules which include a nucleotide sequence encoding a protein having an amino acid sequence that is at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 85%, 95% or 98% identical to the amino acid sequence of SEQ ID NO:3, the amino acid sequence encoded by an INT307 cDNA of ATCC® Accession Number PTA-455, or a complement thereof.
  • nucleic acid molecules which encode a polypeptide having the amino acid sequence of SEQ ID NO:68 or a fragment thereof including at least 25, 30, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275 or 289 contiguous amino acids of SEQ ID NO:68 or the amino acid sequence encoded by a human EpT509 cDNA of ATCC® Accession Number PTA-438.
  • the invention also features isolated polypeptides or proteins which are encoded by a nucleic acid molecule having a nucleotide sequence that is at least about 25%, preferably 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 85%, 95% or 98% identical to a nucleic acid sequence encoding SEQ ID NO:3, 25, 36, 44, 56, 63, 68, or 78, isolated polypeptides or proteins which are encoded by a nucleic acid molecule having a nucleotide sequence which hybridizes under stringent hybridization conditions to a nucleic acid molecule having the nucleotide sequence of SEQ ID NO:l, 2, 23, 24, 34, 35, 42, 43, 54, 55, 61, 62, 66, 67, 76 or 77, or a complement thereof, or the non-coding strand of INTERCEPT 307, MANGO 511, TANGO 351, TANGO 361, TANGO 499, and TANGO 509
  • the nucleic acid molecules are at least 550, 600, 650, 700, 750, 800, 850, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000 or 2020 contiguous nucleotides in length and hybridize under stringent conditions to a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:l, an LNT307 cDNA of ATCC® Accession Number PTA-455, or a complement thereof.
  • the nucleic acid molecules are at least 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 900, 1000, 1100, 1200, 1300, 1400, 1450 or 1490 contiguous nucleotides in length and hybridize under stringent conditions to a nucleic acid molecule comprising nucleic acids 3564 to 5058 of SEQ ID NO:42, or a complement thereof.
  • the invention also features nucleic acid molecules that hybridize under stringent conditions to a nucleic acid molecule having the nucleotide sequence of SEQ ID NO:76 or 77, or a mouse EpT509 cDNA of ATCC® Accession Number PTA-438, or a complement thereof.
  • biological activities include, e.g., (1) the ability to modulate the development, differentiation, morphology, migration or chemotaxis, proliferation and/or activity of immune cells (e.g., B-lymphocytes and monocytes); (2) the ability to modulate, protein-protein interactions (e.g., homophilic and/or heterophilic), and protein-ligand interactions, e.g., in receptor-ligand recognition;
  • immune cells e.g., B-lymphocytes and monocytes
  • protein-protein interactions e.g., homophilic and/or heterophilic
  • protein-ligand interactions e.g., in receptor-ligand recognition
  • biological activities include, e.g., (1) the ability to modulate the development, differentiation, morphology, migration or chemotaxis, proliferation and/or activity of mammary cells, e.g., mammary epithelial cells; (2) the ability to modulate the development and progression of cell proliferative disorders such as cancer (e.g. breast or breast-associated cancer); (3) the ability to modulate, protein-protein interactions (e.g.
  • an INTERCEPT 307 protein includes at least one or more of the following domains: a signal sequence, an extracellular domain, a transmembrane domain, a gas vehicle protein GVPc domain, and an intracellular or cytoplasmic domain.
  • the invention provides methods for modulating activity of a polypeptide of the invention comprising contacting a cell with an agent that modulates (e.g., inhibits or stimulates) the activity or expression of a polypeptide of the invention such that activity or expression in the cell is modulated.
  • the agent is an antibody that specifically binds to a polypeptide of the invention.
  • the agent is a fragment of a polypeptide of the invention or a nucleic acid molecule encoding such a polypeptide fragment.
  • the invention also features methods for identifying a compound which modulates the expression of a polypeptide or nucleic acid of the invention by measuring the expression of the polypeptide or nucleic acid in the presence and absence of the compound.
  • an antibody or a fragment thereof i.e., human and non-human antibodies or fragments thereof and/or monoclonal antibodies or fragments thereof of the invention, specifically bind to an extracellular domain having the amino acid sequence of SEQ ID NO:6, 7, 8, 28, 39, 49, 75 or 84.
  • the dashed vertical line separates the signal sequence (amino acids 1 to 23 of SEQ ID NO:3, (SEQ ID NO:4)) on the left from the mature protein (amino acids 24 to 362 of SEQ ID NO:3, (SEQ ID NO:5)) on the right.
  • Figure 6 shows an alignment of the nucleotide sequence of INTERCEPT 307 coding region (SEQ ID NO:2) and the nucleotide sequence of human eosinophil granule major basic protein coding region (SEQ ID NO:87; Accession Number Z26248).
  • the nucleotide sequences of the coding regions are 38.1% identical.
  • the full-length INTERCEPT 307 nucleic acid sequence (SEQ ID NO:l) and human eosinophil granule major basic protein cDNA (SEQ ID NO:88; Accession Number Z26248) have an overall sequence identity of 57.3%>.
  • Figure 26 depicts a hydropathy plot of mouse TANGO 509. Relatively hydrophobic regions of the protein are above the dashed horizontal line, and relatively hydrophilic regions of the protein are below the dashed horizontal line.
  • the cysteine residues (cys) and N-glycosylation site (Ngly) are indicated by short vertical lines just below the hydropathy trace.
  • the dashed vertical line separates the signal sequence (amino acids 1 to 18 of SEQ ID NO:78 (SEQ ID NO:79)) on the left from the mature protein (amino acids 19 to 290 of SEQ ID NO:78) on the right.
  • Figure 27 shows an alignment of the mouse TANGO 509 amino acid sequence (SEQ ID NO:78) with the butyrophilin-like protein amino acid sequence (SEQ ID NO:85; Accession Number AF242780). The alignment shows that there is a 31.9% overall amino acid sequence identity between mouse TANGO 509 and the butyrophilin-like protein. This alignment was performed using the ALIGN alignment program with a PAM120 scoring matrix, a gap length penalty of 12, and a gap penalty of 4.
  • the INTERCEPT 307, MANGO 511, TANGO 351, TANGO 361, TANGO 499, and TANGO 509 proteins and nucleic acid molecules comprise families of molecules having certain conserved structural and functional features.
  • family or “families” are intended to mean two or more proteins or nucleic acid molecules having a common structural domain and having sufficient amino acid or nucleotide sequence identity as defined herein.
  • Family members can be from either the same or different species.
  • a family can comprise two or more proteins of human origin, or can comprise one or more proteins of human origin and one or more of non-human origin. Members of the same family may also have common structural domains.
  • a MANGO 511 family member includes one or more MANGO 511 Ig-like domains having an amino acid sequence that is at least 55%>, preferably at least about 65%, more preferably at least about 75%, yet more preferably at least about 85%, and most preferably at least about 95%> identical to amino acids 60 to 118 of SEQ ID NO:25 (SEQ ID NO:31), and has a conserved cysteine residue about 8 residues downstream from the N-terminus of the Ig-like domain, has a conserved cysteine within the consensus sequence that forms a disulfide with said first conserved cysteine, and has at least one MANGO 511 biological activity as described herein.
  • a TANGO 351 family member can include one or more of the following domains: (1) an extracellular domain; (2) a transmembrane domain; and (3) a cytoplasmic domain.
  • a TANGO 351 protein contains an extracellular domain at about amino acid residues 25 to 458 of SEQ ID NO:36 (SEQ ID NO:39), a transmembrane domain at about amino acid residues 459 to 476 of SEQ ID NO:36 (SEQ ID NO:40), and a cytoplasmic domain at about amino acid residues 477 to 482 of SEQ ID NO:36 (SEQ ID NO:41).
  • the mature TANGO 351 protein corresponds to amino acids 25 to 482 of SEQ ID NO:36 (SEQ ID NO:38).
  • a SEA domain typically has the following consensus sequence: h-t-h-Xaa-h-Xaa-Xaa-Xaa-Xaa-Xaa-h-Xaa-a-t-t-t-h-t-t-t-Xaa-o-Xaa-Xaa-a-Xaa-Xaa-Xaa-h-Xaa-t-t-H-Xaa-t- Xaa-h-Xaa-t-t-Xaa-Xaa-Xaa-Xaa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xa-Xaa
  • SEA domains are predominantly found in adhesive proteins present in heavily glycosylated environments.
  • SEA domains are found in a 63 kDa sea urchin sperm protein, agrin, enterokinase, perlecan, the breast cancer marker MUCl (episialin) and the cell surface antigen 114/A10 (Bork and Patthy, (1995) Prot. Sci. 4:1421-1425).
  • a TANGO 361 family member can include a serine protease domain.
  • Serine protease domains are typically found in serine proteases, and can be found in, among other proteins, e.g., blood coagulation factors VII, XI, and X, thrombin, plasminogen, tryptases, such as trypsin, airway trypsin-like proteases, mast cell proteases, and members of the complement system which are known for regulation of energy balance and suppression of infectious agents.
  • serine protease domain refers to a polypeptide sequence that includes about 100-400 amino acid residues, preferably about 150-350 amino acid residues, more preferably about 200-300 amino acid residues, and most preferably about 225-260 amino acid residues.
  • a serine protease typically has two consensus sequences.
  • the Ig-like domain of human TANGO 509 is an Ig-like domain which has the following consensus sequence at the C-terminus of the domain: [FY]-Xaa-C-Xaa-[VAIF]-COO-, wherein [FY] is either a phenylalanine or a tyrosine residue (preferably tyrosine), where "Xaa” is any amino acid, C is a cysteine residue, [VA] is a valine, an alanine, an isoleucine or phenylalanine residue, and COO- is the C-terminus of the domain.
  • a mouse TANGO 509 family member includes one or more such Ig-like domains having an amino acid sequence that is at least about 55%, preferably at least about 65%, more preferably at least 75%, yet more preferably at least about 85%, and most preferably at least about 95% identical to amino acids 33 to 116 of SEQ ID NO:78 (SEQ ID NO:81).
  • a mouse TANGO 509 family member includes one or more mouse TANGO 509 Ig-like domains having an amino acid sequence that is at least 55%, preferably at least about 65%, more preferably at least about 75%, yet more preferably at least about 85%, and most preferably at least about 95% identical to amino acids 33 to 116 of SEQ ID NO:78 (SEQ ID NO:81), has a conserved cysteine residue about 8 residues downstream from the N-terminus of the Ig-like domain, and has a conserved cysteine within the consensus sequence that forms a disulfide with said first conserved cysteine.
  • a mouse TANGO 509 family member includes one or more Ig-like domains having an amino acid sequence that is at least about 55%, preferably at least about 65%, more preferably at least 75%, yet more preferably at least about 85%, and most preferably at least about 95% identical to amino acids 33 to 116 of SEQ ID NO:78 (SEQ ID NO:81).
  • a cDNA sequence of human INTERCEPT 307 has a nucleotide at position 54 which is cytosine (C)(SEQ ID NO:l).
  • the cDNA contains an open reading frame encoding a polypeptide having an amino acid at position 4 that is leucine (L)(SEQ ID NO:3).
  • a species variant cDNA sequence of human INTERCEPT 307 has a nucleotide at position 54 which is adenine (A)(SEQ ID NO:l 13).
  • the cDNA contains an open reading frame encoding a polypeptide having an amino acid at position 4 that is isoleucine (I)(SEQ ID NO:l 14), i.e., a conservative substitution.
  • the first has the sequence SLR (at amino acid residues 56 to 58 of SEQ ID NO:3)
  • the second has the sequence TTK (at amino acid residues 102 to 104 of SEQ ID NO:3)
  • the third has the sequence SAK (at amino acid residues 124 to 126 of SEQ ID NO:3)
  • the fourth has the sequence SRR (at amino acid residues 147 to 149 of SEQ ID NO:3)
  • the fifth has the sequence TWK (at amino acid residues 353 to 355 of SEQ ID NO:3).
  • INTERCEPT 307 has three casein kinase II phosphorylation sites.
  • Figure 3 shows an alignment of the human INTERCEPT 307 amino acid sequence (SEQ ID NO:3) with the prostate cancer gene PB39 amino acid sequence (SEQ ID NO:20; Accession Number NM_003627). The alignment shows that there is a 21.0% overall amino acid sequence identity between INTERCEPT 307 and PB39.
  • PB39 is expressed in tissues of the adult colon, small intestine, ovary, prostate, spleen, skeletal muscle and pancreas.
  • PB39 is also expressed in fetal kidney, liver and lung.
  • the expression of PB39 has been shown to be increased early in prostate cancer development and PB39 can play a role in the development of human prostate cancer.
  • INTERCEPT 307, nucleic acids and proteins may be useful, for example, as early markers for the development of prostate cancer (e.g., early markers for the development of prostatic intraepithelial neoplasia (PIN))-
  • PIN prostatic intraepithelial neoplasia
  • a cDNA encoding human MANGO 511 was identified by analyzing the sequences of clones present in a human dendritic cell library for sequences that encode wholly secreted or transmembrane proteins. This analysis led to the identification of a clone, jThxh005c 10, encoding full-length human MANGO 511.
  • the human MANGO 511 cDNA of this clone is 1477 nucleotides long ( Figure 7; SEQ ID NO:23).
  • the signal peptide prediction program SIGNALP (Nielsen et al., 1997, Protein Engineering 10:1-6) predicted that human MANGO 511 includes a 41 amino acid signal peptide (amino acid 1 to amino acid 41 of SEQ ID NO:25, (SEQ ID NO:26) preceding the mature MANGO 511 protein (corresponding to amino acid 42 to amino acid 299 of SEQ ID NO:25, (SEQ ID NO:27).
  • the molecular weight of MANGO 511 protein without post-translational modifications is 32.8 kDa prior to the cleavage of the signal peptide, and 28.6 kDa after cleavage of the signal peptide.
  • tyrosine phosphorylation of LIR-1 in monocytes has been shown to result in the binding of tyrosine phosphatase SHP- 1, and LIR-1 has been shown to be involved in the inhibition or down-modulation of monocyte activation signals (Fanger et al. (1998) Eur. J. Immunol. 28:3423-3434).
  • MANGO 511 nucleic acids, proteins and modulators thereof are useful in modulating MHC class I binding and monocyte activation.
  • Figure 10 shows an alignment of the coding regions of the nucleotide sequence of LIR-1 (SEQ ID NO:33; Accession Number AF009221) and the nucleotide sequence of human MANGO 511 (SEQ ID NO:23). The alignment shows a 34.0 % overall sequence identity between the two nucleotide sequences.
  • the coding region of the nucleotide sequence of LIR-1 (SEQ ID NO:33; Accession Number AF009221) and the full-length nucleotide sequence of human MANGO 511 cDNA (SEQ ID NO:24) have an overall sequence identity of 44.0%.
  • Such MANGO 511 compositions and modulators thereof can be utilized modulate or treat immune disorders that include, but are not limited to, immune proliferative disorders (e.g., carcinoma, lymphoma, e.g., follicular lymphoma), and disorders associated with fighting pathogenic infections, e.g., bacterial (e.g., chlamydia) infection, parasitic infection, and viral infection (e.g.
  • immune proliferative disorders e.g., carcinoma, lymphoma, e.g., follicular lymphoma
  • pathogenic infections e.g., bacterial (e.g., chlamydia) infection, parasitic infection, and viral infection (e.g.
  • MANGO 511 exhibits homology to LIR-1
  • MANGO 511 nucleic acids, proteins and/or modulators thereof can be used to modulate natural killer cell function, e.g., activation.
  • MANGO 511 nucleic acids, proteins and modulators thereof can be used to treat diseases associated with aberrant natural killer cell activation such as chronic natural killer cell lymphocytosis, aggressive non-T, non-B natural killer cell lymphoma/leukemia (ANKL/L), and Chediak-Higashi syndrome.
  • diseases associated with aberrant natural killer cell activation such as chronic natural killer cell lymphocytosis, aggressive non-T, non-B natural killer cell lymphoma/leukemia (ANKL/L), and Chediak-Higashi syndrome.
  • human TANGO 351 has extracellular domains at amino acid residues contains an extracellular domain at amino acid residues 1 to 458 of SEQ ID NO:36, a transmembrane domain at amino acid residues 459 to 476 of SEQ ID NO:36 (SEQ ID NO:40), and a cytoplasmic domain at amino acid residues 477 to 482 of SEQ ID NO:25 (SEQ ID NO:41).
  • a cDNA sequence of human TANGO 351 has a nucleotide at position 273 which is guanine (G)(SEQ ID NO:34).
  • the cDNA contains an open reading frame encoding a polypeptide having an amino acid at position
  • TANGO 351 has a prokaryotic membrane lipoprotein lipid attachment site with the sequence HLGGWWVSSGC (at amino acid residues 260 to 270 of SEQ ID NO:36).
  • TANGO 351 nucleic acids, proteins and modulators thereof can be used to modulate the proliferation, development, differentiation, and/or function of kidney cells and the kidney.
  • TANGO 351 nucleic acids, proteins and modulators thereof can be used to modulate or treat renal disorders, such as glomerular diseases (e.g., acute and chronic glomerulonephritis, rapidly progressive glomerulonephritis, nephrotic syndrome, focal proliferative glomerulonephritis, glomerular lesions associated with systemic disease, such as systemic lupus erythematosus, Goodpasture's syndrome, multiple myeloma, diabetes, neoplasia, sickle cell disease, and chronic inflammatory diseases), tubular diseases (e.g., acute tubular necrosis and acute renal failure, polycystic renal diseasemedullary sponge kidney, medullary cystic disease, nephrogenic diabetes, and renal tubular diseases (e.g., acute tubular necrosis and acute
  • Figure 14 depicts a hydropathy plot of human TANGO 361. Relatively hydrophobic regions of the protein are shown above the horizontal line, and relatively hydrophilic regions of the protein are below the horizontal line. The cysteine residues (cys) and N-glycosylation site are indicated by short vertical lines just below the hydropathy trace. The dashed vertical line separates the signal sequence on the left from the mature protein on the right.
  • Human TANGO 361 protein is a transmembrane protein that contains an extracellular domain at amino acid residues 235 to 423 of SEQ ID NO:49, (SEQ ID NO:49), a transmembrane domain at amino acid residues 217 to 234 of SEQ ID NO:44 (SEQ ID NO:47), and a cytoplasmic domain at amino acid residues 36 to 216 of SEQ ID NO:44 (SEQ ID NO:48).
  • a human TANGO 361 protein contains a cytoplasmic domain at amino acid residues 235 to 423 of SEQ ID NO:49, (SEQ ID NO:49), a transmembrane domain at amino acid residues 217 to 234 of SEQ ID NO:44 (SEQ ID NO:47), and an extracellular domain at amino acid residues 36 to 216 of SEQ ID NO:44 (SEQ ID NO:48).
  • a cDNA sequence of human TANGO 361 has a nucleotide at position 117 is thymine (T)(SEQ ID NO:42).
  • the cDNA contains an open reading frame encoding a polypeptide having an amino acid at position 15 that is phenylalanine (F)(SEQ ID NO:44).
  • a species variant cDNA sequence of human TANGO 361 has a nucleotide at position 117 which is adenine (a)(SEQ ID NO: 141).
  • the cDNA contains an open reading frame encoding a polypeptide having an amino acid at position 26 that is tyrosine (Y)(SEQ ID NO: 142), i.e., a conservative substitution.
  • a cDNA sequence of human TANGO 361 has a nucleotide at position 122 is thymidine (T)(SEQ ID NO:42).
  • the cDNA contains an open reading frame encoding a polypeptide having an amino acid at position 28 that is serine (S)(SEQ ID NO:44).
  • a species variant cDNA sequence of human TANGO 361 has a nucleotide at position 122 which is adenine (A)(SEQ ID NO: 143).
  • the cDNA contains an open reading frame encoding a polypeptide having an amino acid at position 28 that is threonine (T)(SEQ ID NO: 144), i.e., a conservative substitution.
  • TANGO 361 Four N-myristylation sites are present in TANGO 361.
  • the first has the sequence GTRRSK (at amino acid residues 179 to 184 of SEQ ID NO:44, the second has the sequence GSHRCG (at amino acid residues 213 to 218 of SEQ ID NO:44), the third has the sequence GALKND (at amino acid residues 317 to 322 of SEQ ID NO:44), and the fourth has the sequence GSLEGK (at amino acid residues 360 to 365 of SEQ ID NO:44).
  • TANGO 361 has a serine protease, serine active site, consensus sequence with the sequence GDSGG (at amino acid residues 371 to 375 of SEQ ID NO:44.
  • Clone EpT361 which encodes TANGO 361 was deposited with the American Type Culture Collection (10801 University Boulevard, Manassas, VA 20110-2209) on July 29, 1999 and assigned Accession Number PTA-438. This deposit will be maintained under the terms of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure. This deposit was made merely as a convenience for those of skill in the art and is not an admission that a deposit is required under 35 U.S.C. ⁇ 112.
  • variant 1 is a secreted protein having amino acids 1 to 254 depicted in SEQ ID NO:56.
  • Figure 17 shows an alignment of the human TANGO 499 form 1, variant 1 amino acid sequence SEQ ID NO:56 with the Artemin amino acid sequence SEQ ID NO:59. The alignment shows that there is a 23.5% overall amino acid sequence identity between TANGO 499 form 1, variant 1 and Artemin.
  • the Artemin protein is widely expressed in the nervous system that has been shown to be involved in such processes as peripheral neuron survival and also dopaminergic midbrain neuron survival.
  • variant 3 has an N-glycosylation site with the sequence NISI (at amino acid residues 95 to 98 of SEQ ID NO:63).
  • N-myristylation sites are present in TANGO 499 form 2, variant 3.
  • the first has the sequence GVRQAQ (at amino acid residues 107 to 112 of SEQ ID NO:63)
  • the second has the sequence GCEPSC (at amino acid residues 144 to 149 of SEQ ID NO:63)
  • the third has the sequence GQTFAD (at amino acid residues 153 to 158 of SEQ ID NO:63)
  • the fourth has the sequence GTDLCR (at amino acid residues 159 to 164 of SEQ ID NO:63)
  • the fifth has the sequence GARHCF (at amino acid residues 177 to 182 of SEQ ID NO:63)
  • the sixth has the sequence GSGSGS (at amino acid residues 218 to 223 of SEQ ID NO:63).
  • Figure 21 depicts an alignment of TANGO 499 form 1, variant 1 amino acid sequence and TANGO 499 form 2, variant 3 amino acid sequence.
  • the amino acid sequences are 90.2% identical, the cDNAs are 85.6%> identical, and the ORFs are 90.2%) identical.
  • the alignment clearly demonstrates that the two forms are identical except for the result of a putative alternative exon splicing event in the illustrated region.
  • the invention contemplates additional splice variants of the presently claimed nucleic acids and proteins encoded by such splice variants.
  • the open reading frame of the form 2 TANGO 499 cDNA conserved region comprises nucleotides 1 to 708 of SEQ ID NO:92 (SEQ ID NO:93), and encodes a polypeptide comprising the sequence of SEQ ID NO: 94.
  • TANGO 499 was originally found in a human pituitary library, TANGO 499 nucleic acids, proteins, and modulators thereof can be used to modulate the proliferation, development, differentiation, and/or function of cells, tissues and/or organs, e.g. , the proliferation of tissues and cells of pituitary origin.
  • TANGO 499 was originally identified in a pituitary library, for example, TANGO 499 nucleic acids, proteins and modulators thereof can be used to regulate processes involved with sexual development and function, including, e.g., normal and abnormal reproductive hormonal function in the fetus, infant, adolescent and adult and also can modulate the effects of pituitary insufficiency and pituitary adenomas on sexual development, reproductive function and sexuality in men and women.
  • TANGO 499 nucleic acids, proteins and modulators thereof can be used to treat pituitary tumors causing Cushing's syndrome, and also hypopituitarism during pregnancy which may be the result of intrasellar adenomas, suprasellar lesions, lymphocytic hypophysitis or antepartum pituitary necrosis, and in the postpartum period may be because of postpartum hemorrhage and pituitary necrosis.
  • TANGO 499 nucleic acids, proteins and modulators thereof can be utilized to modulate the development and function of the eye, such as retinal development and function, ( e.g., photoreceptor disk morphogenesis).
  • TANGO 499 nucleic acids, proteins and modulators thereof can be utilized to treat eye diseases and/or disorders, e.g., autosomal dominant retinitis pigmentosa, autosomal dominant punctata albescens, butterfly-shaped pigment dystrophy, cataracts, macular degeneration, myopia, stigmatism and retinoblastoma.
  • TANGO 499 family members have homology to glial cell line-derived neurotrophic-related factors (e.g., GDNF, artemin, neurturin, and persephin).
  • glial cell line-derived neurotrophic-related factors e.g., GDNF, artemin, neurturin, and persephin.
  • TANGO 499 nucleic acids, proteins and modulators thereof can be utilized to modulate survival, activation, proliferation, motility, and differentiation of peripheral or central neurons.
  • TANGO 499 nucleic acids, proteins, and modulators thereof can be used to modulate the proliferation, development, differentiation, and/or function of neural organs, e.g., neural tissues and cells, e.g., cells of the central nervous system, e.g., cells of the peripheral nervous system.
  • TANGO 499 nucleic acids, proteins, and modulators thereof can also be used to modulate symptoms associated with abnormal neural signaling and function, e.g., epilepsy, stroke, traumatic injury.
  • TANGO 499 proteins could be useful to treat neural related disorders or neural damage, such as for regenerative neural repair after damage by trauma, degeneration, or inflammation e.g.
  • TANGO 499 nucleic acids, proteins and modulators thereof can be utilized to modulate the development and progression of cancerous and non-cancerous cell proliferative disorders, such as deregulated proliferation (such as hyperdysplasia, hyper- IgM syndrome, or lymphoproliferative disorders), cirrhosis of the liver (a condition in which scarring has overtaken normal liver regeneration processes), treatment of keloid (hypertrophic scar) formation (disfiguring of the skin in which the scarring process interferes with normal renewal), psoriasis (a common skin condition characterized by excessive proliferation of the skin and delay in proper cell fate determination), benign tumors, fibrocystic conditions, and tissue hypertrophy (e.g., prostatic hyperplasia), cancers such as neoplasms or tumors (such as carcinomas, sarcomas, adenomas or myeloid lymphoma tumors, e.g., f ⁇ brosarcoma, myxosarcoma,
  • TANGO 499 expression can be utilized as a marker (e.g., an in situ marker) for specific tissues (e.g., the pituitary) and/or cells (e.g., pituitary cells) in which TANGO 499 is expressed.
  • TANGO 499 nucleic acids can also be utilized for chromosomal mapping, or as chromosomal markers, e.g., in radiation hybrid mapping.
  • a cDNA encoding human TANGO 509 was identified by analyzing the sequences of clones present in a mammary epithelium library for sequences that encode wholly secreted or transmembrane proteins. This analysis led to the identification of a clone, jthvb017hl 1, encoding full-length human TANGO 509.
  • the human TANGO 509 cDNA of this clone is 3575 nucleotides long ( Figure 23; SEQ ID NO:66).
  • the signal peptide prediction program SIGNALP (Nielsen et al., 1997, Protein Engineering 10:1-6) predicted that human TANGO 509 includes a 18 amino acid signal peptide (amino acid 1 to amino acid 18 of SEQ ID NO:68; SEQ ID NO:69) preceding the mature TANGO 509 protein (corresponding to amino acid 19 to amino acid 290 of SEQ ID NO:68; SEQ ID NO:70).
  • the molecular weight of TANGO 509 protein without post-translational modifications is 33.3 kDa prior to the cleavage of the signal peptide, and 31.0 kDa after cleavage of the signal peptide.
  • a human TANGO 509 protein contains a cytoplasmic domain at amino acid residues 260 to 290 of SEQ ID NO:68, a transmembrane domain at amino acid residues 241 to 259 of SEQ ID NO:68 (SEQ ID NO:73), and an extracelluar domain at amino acid residues 19 to 240 of SEQ ID NO:68.
  • a cDNA sequence of human TANGO 509 has a nucleotide at position 69 which is thymidine (T)(SEQ ID NO:66).
  • the cDNA contains an open reading frame encoding a polypeptide having an amino acid at position 4 that is phenylalanine (F)(SEQ ID NO:68).
  • a species variant cDNA sequence of human TANGO 509 has a nucleotide at position 69 which is adenine (A)(SEQ ID NO: 153).
  • the cDNA contains an open reading frame encoding a polypeptide having an amino acid at position 4 that is tyrosine (Y)(SEQ ID NO: 154), i.e., a conservative substitution.
  • a cDNA sequence of human TANGO 509 has a nucleotide at position 72 which is cytosine (C)(SEQ ID NO:66).
  • the cDNA contains an open reading frame encoding a polypeptide having an amino acid at position 5 that is alanine (A)(SEQ ID NO:68).
  • a cDNA sequence of human TANGO 509 has a nucleotide at position 132 which is adenine (A)(SEQ ID NO:66).
  • the cDNA contains an open reading frame encoding a polypeptide having an amino acid at position 25 that is lysine (K)(SEQ ID NO:68).
  • a species variant cDNA sequence of human TANGO 509 has a nucleotide at position 132 which is guanine (G)(SEQ ID NO: 157).
  • the cDNA contains an open reading frame encoding a polypeptide having an amino acid at position 25 that is arginine (R)(SEQ ID NO: 158), i.e., a conservative substitution.
  • a cDNA sequence of human TANGO 509 has a nucleotide at position 191 which is guanine (G)(SEQ ID NO:66).
  • the cDNA contains an open reading frame encoding a polypeptide having an amino acid at position 45 that is glutamate (E)(SEQ ID NO:68).
  • a species variant cDNA sequence of human TANGO 509 has a nucleotide at position 191 which is cytosine (C)(SEQ ID NO: 159).
  • the cDNA contains an open reading frame encoding a polypeptide having an amino acid at position 45 that is glutamine (Q)(SEQ ID NO: 160), i.e., a conservative substitution.
  • Human TANGO 509 has four N-glycosylation sites with the first sequence NMTI (at amino acid residues 35 to 38 of SEQ ID NO:68), the second has the sequence NVTS (at amino acid residues 192 to 195 SEQ ID NO:68), the third has the sequence NTTT (at amino acid residues 200 to 203 SEQ ID NO:68), and the fourth has the sequence NHTA (at amino acid residues 219 to 222 SEQ ID NO:68).
  • Two cAMP and cGMP-dependent protein kinase phosphorylation sites are present in human TANGO 509.
  • the first has the sequence KRIT (at amino acid residues 124 to 127 SEQ ID NO:68), and the second has the sequence KKQS (at amino acid residues SEQ ID NO:68).
  • Human TANGO 509 has five casein kinase II phosphorylation sites. The first has the sequence SEHE (at amino acid residues 149 to 152 of SEQ ID NO:68), the second has the sequence TSSD (at amino acid residues 168 to 171 of SEQ ID NO:68), the third has the sequence SKRE (at amino acid residues 184 to 187 of SEQ ID NO:68), the fourth has the sequence TTNE (at amino acid residues 202 to 205 SEQ ID NO:68), and the fifth has the sequence THLE (at amino acid residues 285 to 288 SEQ ID NO:68).
  • SEHE amino acid residues 149 to 152 of SEQ ID NO:68
  • TSSD at amino acid residues 168 to 171 of SEQ ID NO:68
  • the third has the sequence SKRE (at amino acid residues 184 to 187 of SEQ ID NO:68)
  • the fourth has the sequence TTNE (at amino acid residues 202 to 205 SEQ ID NO:68)
  • Human TANGO 509 has a tyrosine kinase phosphorylation site with the sequence KLQDAGVY (at amino acid residues 105 to 112 of SEQ ID NO:68). Human TANGO 509 has four N-myristoylation sites. The first has the sequence GSNMTI (at amino acid residues 33 to 38 of SEQ ID NO:68), the second has the sequence GVYRCM (at amino acid residues 110 to 115 of SEQ ID NO:68), the third has the sequence GVALTF (at amino acid residues 252 to 257 SEQ ID NO:68), and fourth has the sequence GIQDTN (at amino acid residues 273 to 278 of SEQ ID NO:68).
  • Figure 24 shows an alignment of the human TANGO 509 amino acid sequence SEQ ID NO:68 with the butyrophilin-like amino acid sequence SEQ ID NO:85; Accession Number: AF 142780).
  • the alignment shows that there is a 31.9% overall amino acid sequence identity between TANGO 509 and Butyrophilin-like protein.
  • the Butyrophilin-like protein is expressed in dendritic cells which are involved in such processes as antigen presentation and immune stimulation.
  • nucleic acids and modulators thereof could be useful in immune modulation, for example in antigen presentation and immune stimulation.
  • a cDNA encoding mouse TANGO 509 was identified by analyzing the sequences of clones present in an alveolar macrophage cell line library. This analysis led to the identification of a clone, jtmca053b03, encoding mouse TANGO 509.
  • the mouse TANGO 509 cDNA of this clone is 3637 nucleotides long ( Figure 25; SEQ ID NO:76).
  • Figure 26 depicts a hydropathy plot of mouse TANGO 509. Relatively hydrophobic regions of the protein are shown above the horizontal line, and relatively hydrophilic regions of the protein are below the horizontal line. The cysteine residues (cys) and N-glycosylation site are indicated by short vertical lines just below the hydropathy trace. The dashed vertical line separates the signal sequence on the left from the mature protein on the right.
  • Mouse TANGO 509 protein is a transmembrane protein that contains an extracellular domain at amino acid residues 261 to 290 of SEQ ID NO:78, (SEQ ID NO: 84), a transmembrane domain at amino acid residues 240 to 260 of SEQ ID NO:78, (SEQ ID NO:82), and a cytoplasmic domain at amino acid residues 19 to 239 of SEQ ID NO:78, (SEQ ID NO:83).
  • mouse TANGO 509 contains an extracellular domain at amino acid residues 261 to 290 of SEQ ID NO:78, (SEQ ID NO: 84), a transmembrane domain at amino acid residues 240 to 260 of SEQ ID NO:78, (SEQ ID NO:82), and a cytoplasmic domain at amino acid residues 1 to 239 of SEQ ID NO:78.
  • a cDNA sequence of mouse TANGO 509 has a nucleotide at position 132 which is cytosine (C)(SEQ ID NO:76).
  • the cDNA contains an open reading frame encoding a polypeptide having an amino acid at position
  • Mouse TANGO 509 has six N-glycosylation sites with the first sequence NVTM (at amino acid residues 35 to 38 of SEQ ID NO:78), the second has the sequence NVTS (at amino acid residues 191 to 194 SEQ ID NO: 78), the third has the sequence NAT A (at amino acid residues 199 to 202 SEQ ID NO:78), the fourth has the sequence NHTA (at amino acid residues 218 to 221 SEQ ID NO:78), the fifth has the sequence NRTH (at amino acid residues 236 to 239 SEQ ID NO:78), and the sixth has the sequence NDTQ (at amino acid residues 283 to 286 SEQ ID NO:78).
  • Mouse TANGO 509 has one cAMP and cGMP-dependent protein kinase phosphorylation site, having the sequence KRIT (at amino acid residues 124 to 127 SEQ ID NO:78).
  • Mouse TANGO 509 has five casein kinase II phosphorylation sites.
  • the first has the sequence SEHE (at amino acid residues 148 to 151 of SEQ ID NO:78), the second has the sequence TNSD (at amino acid residues 167 to 170 of SEQ ID NO:78), the third has the sequence SRTE (at amino acid residues 183 to 186 of SEQ ID NO:78), the fourth has the sequence TAND (at amino acid residues 201 to 204 SEQ ID NO:78), and the fifth has the sequence TQFE (at amino acid residues 285 to 288 SEQ ID NO:78).
  • TANGO 509 nucleic acids, proteins, and modulators thereof can be used to modulate the proliferation, activation, development, differentiation, and/or function of mammary cells, tissues and/or organs, e.g., tissues and cells of mammary epithelium origin.
  • TANGO 509 nucleic acids, proteins and modulators thereof can be used to treat mammary-related disorders, e.g. , breast cancer.
  • Antibodies may activate or inhibit the cell adhesion, proliferation and activation, and may help in treating infection, autoimmunity, inflammation, and cancer by affecting these cellular processes.
  • TANGO 509 nucleic acids, proteins and modulators thereof can also be utilized to modulate intercellular signaling in the immune system, e.g., modulate intercellular signal transduction in immune stimulation or suppression and modulate immune cell membrane adhesion to ECM components, during development, e.g., late stages of development.
  • TANGO 509 nucleic acids, proteins and modulators thereof can be used for immune cell receptor co-stimulation via CD28 to modulate IL-2 expression in addition to modulating the expression of other lymphokines.
  • TANGO 509 nucleic acids, proteins and modulators thereof can be used to modulate diseases of the immune system, in particular AIDS, asthma or chronic viral diseases such as hepatitis C virus or hepatitis B virus infections, or to modulate the immune system in cancer patients, or patients undergoing organ or tissue transplantation procedures, or inflammatory disorders, e.g. , bacterial or viral infection, psoriasis, septicemia, arthritis, allergic reactions.
  • a nucleic acid fragment encoding a biologically active portion of a polypeptide of the invention can be prepared by isolating a portion of any of SEQ ID 1, 2, 23, 24, 34, 35,
  • nucleic acid molecules encoding proteins of the invention from other species which have a nucleotide sequence which differs from that of the human or mouse protein described herein are intended to be within the scope of the invention.
  • Nucleic acid molecules corresponding to natural allelic variants and homologs of a cDNA of the invention can be isolated based on their identity to the human nucleic acid molecule disclosed herein using the human cDNAs, or a portion thereof, as a hybridization probe according to standard hybridization techniques under stringent hybridization conditions.
  • a cDNA encoding a soluble form of a membrane-bound protein of the invention isolated based on its hybridization to a nucleic acid molecule encoding all or part of the membrane-bound form.
  • a cDNA encoding a membrane-bound form can be isolated based on its hybridization to a nucleic acid molecule encoding all or part of the soluble form.
  • an isolated nucleic acid molecule of the invention is at least 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900 or 2000 contiguous nucleotides in length and hybridizes under stringent conditions to the nucleic acid molecule comprising the nucleotide sequence, preferably the coding sequence, of SEQ ID NO:l, 23, 34, 42, 54, 61, 66, or 76 or a complement thereof.
  • an isolated nucleic acid molecule of the invention that hybridizes under stringent conditions to the sequence of SEQ ID NO:l, 2, 23, 24, 34, 35, 42, 43, 54, 55, 61, 62, 66, 67, 76, or 77, or a complement thereof, corresponds to a naturally-occurring nucleic acid molecule.
  • a "naturally-occurring" nucleic acid molecule refers to an RNA or DNA molecule having a nucleotide sequence that occurs in nature (e.g., encodes a natural protein).
  • the isolated nucleic acid molecule includes a nucleotide sequence encoding a protein that includes an amino acid sequence that is at least about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 85%, 95%, or 98% identical to the amino acid sequence of SEQ ID NO:3, 25, 36, 44, 56, 63, 68, 78, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166 or 168.
  • the present invention encompasses antisense nucleic acid molecules, i.e., molecules which are complementary to a sense nucleic acid encoding a polypeptide of the invention, e.g., complementary to the coding strand of a double-stranded cDNA molecule or complementary to an mRNA sequence. Accordingly, an antisense nucleic acid can hydrogen bond to a sense nucleic acid.
  • the antisense nucleic acid can be complementary to an entire coding strand, or to only a portion thereof, e.g., all or part of the protein coding region (or open reading frame).
  • the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest, described further in the following subsection).
  • the antisense nucleic acid molecules of the invention are typically administered to a subject or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a selected polypeptide of the invention to thereby inhibit expression, e.g. , by inhibiting transcription and/or translation.
  • the hybridization can be by conventional nucleotide complementarity to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule which binds to DNA duplexes, through specific interactions in the major groove of the double helix.
  • An example of a route of administration of antisense nucleic acid molecules of the invention includes direct injection at a tissue site.
  • antisense nucleic acid molecules can be modified to target selected cells and then administered systemically.
  • antisense molecules can be modified such that they specifically bind to receptors or antigens expressed on a selected cell surface, e.g., by linking the antisense nucleic acid molecules to peptides or antibodies which bind to cell surface receptors or antigens.
  • the antisense nucleic acid molecules can also be delivered to cells using the vectors described herein. To achieve sufficient intracellular concentrations of the antisense molecules, vector constructs in which the antisense nucleic acid molecule is placed under the control of a strong pol II or pol III promoter are preferred.
  • DNA mimics in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained.
  • the neutral backbone of PNAs has been shown to allow for specific hybridization to DNA and RNA under conditions of low ionic strength.
  • the synthesis of PNA oligomers can be performed using standard solid phase peptide synthesis protocols as described in Hyrup et al. (1996), supra; Perry-O'Keefe et al. (1996) Proc. Natl. Acad. Sci. USA 93: 14670-675.
  • the protein or biologically active portion thereof is recombinantly produced, it is also preferably substantially free of culture medium, i.e., culture medium represents less than about 20%, 10%, or 5% of the volume of the protein preparation.
  • culture medium represents less than about 20%, 10%, or 5% of the volume of the protein preparation.
  • the protein is produced by chemical synthesis, it is preferably substantially free of chemical precursors or other chemicals, i.e., it is separated from chemical precursors or other chemicals which are involved in the synthesis of the protein. Accordingly such preparations of the protein have less than about 30%, 20%, 10%, 5% (by dry weight) of chemical precursors or compounds other than the polypeptide of interest.
  • One useful fusion protein is a GST fusion protein in which the polypeptide of the invention is fused to the C-terminus of GST sequences. Such fusion proteins can facilitate the purification of a recombinant polypeptide of the invention.
  • Chimeric and fusion proteins of the invention can be produced by standard recombinant DNA techniques.
  • the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers.
  • PCR amplification of gene fragments can be carried out using anchor primers which give rise to complementary overhangs between two consecutive gene fragments which can subsequently be annealed and reamplified to generate a chimeric gene sequence (see, e.g., Ausubel et al., supra).
  • many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST polypeptide).
  • a nucleic acid encoding a polypeptide of the invention can be cloned into such an expression vector such that the fusion moiety is linked in- frame to the polypeptide of the invention.
  • regulatory sequence is intended to include promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are described, for example, in Goeddel, Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, CA (1990). Regulatory sequences include those which direct constitutive expression of a nucleotide sequence in many types of host cell and those which direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc.
  • the expression vectors of the invention can be introduced into host cells to thereby produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein.
  • Fusion vectors add a number of amino acids to a protein encoded therein, usually to the amino terminus of the recombinant protein.
  • Such fusion vectors typically serve three purposes: 1) to increase expression of recombinant protein; 2) to increase the solubility of the recombinant protein; and 3) to aid in the purification of the recombinant protein by acting as a ligand in affinity purification.
  • host cell and "recombinant host cell” are used interchangeably herein. It is understood that such terms refer not only to the particular subject cell but to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein.
  • the expression characteristics of an endogenous within a cell, cell line or microorganism may be modified by inserting a DNA regulatory element heterologous to the endogenous gene of interest into the genome of a cell, stable cell line or cloned microorganism such that the inserted regulatory element is operatively linked with the endogenous gene (e.g., INTERCEPT 307, MANGO 511, TANGO 351, TANGO 361, TANGO 499 and TANGO 509) and controls, modulates or activates the endogenous gene.
  • a DNA regulatory element heterologous to the endogenous gene of interest into the genome of a cell, stable cell line or cloned microorganism such that the inserted regulatory element is operatively linked with the endogenous gene (e.g., INTERCEPT 307, MANGO 511, TANGO 351, TANGO 361, TANGO 499 and TANGO 509) and controls, modulates or activates the endogenous gene.
  • transgenic non-human animals can be produced which contain selected systems which allow for regulated expression of the transgene.
  • a system is the cre/loxP recombinase system of bacteriophage PL
  • Cre/loxP recombinase system of bacteriophage PL
  • Cre/loxP recombinase system of Saccharomyces cerevisiae
  • FLP recombinase system of Saccharomyces cerevisiae
  • mice containing transgenes encoding both the Cre recombinase and a selected protein are required.
  • Such animals can be provided through the construction of "double" transgenic animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected protein and the other containing a transgene encoding a recombinase.
  • compositions suitable for administration typically comprise the nucleic acid molecule, protein, or antibody and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF; Parsippany, NJ) or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • Sterile injectable solutions can be prepared by incorporating the active compound (e.g., a polypeptide or antibody) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the prefe ⁇ ed methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid earner is applied orally and swished and expectorated or swallowed.
  • the compounds are delivered in the form of an aerosol spray from a pressurized container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • the antibodies and cytotoxic factor(s), chemotherapeutic drug(s) and/or cytokine(s) can be administered by the same or separate routes, for example, by intravenous, intranasal or intramuscular administration.
  • Cytotoxic factors include, but are not limited to, TNF- ⁇ , TNF- ⁇ , IL-1, IFN- ⁇ and IL-2.
  • Chemotherapeutic drugs include, but are not limited to, 5-fluorouracil (5FU), vinblastine, actinomycin D, etoposide, cisplatin, methotrexate and doxorubicin.
  • doses of small molecule agents depends upon a number of factors within the ken of the ordinarily skilled physician, veterinarian, or researcher.
  • the dose(s) of the small molecule will vary, for example, depending upon the identity, size, and condition of the subject or sample being treated, further depending upon the route by which the composition is to be administered, if applicable, and the effect which the practitioner desires the small molecule to have upon the nucleic acid or polypeptide of the invention.
  • a physician, veterinarian, or researcher may, for example, prescribe a relatively low dose at first, subsequently increasing the dose until an appropriate response is obtained.
  • the specific dose level for any particular animal subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, any drug combination, and the degree of expression or activity to be modulated.
  • compositions can be included in a container, pack, or dispenser together with instructions for administration.
  • nucleic acid molecules, proteins, protein homologs, and antibodies described herein can be used in one or more of the following methods: a) screening assays; b) detection assays (e.g., chromosomal mapping, tissue typing, forensic biology); c) predictive medicine (e.g., diagnostic assays, prognostic assays, monitoring clinical trials, and pharmacogenomics); and d) methods of treatment (e.g., therapeutic and prophylactic).
  • polypeptides of the invention can to used to (i) modulate cellular proliferation; (ii) modulate cellular differentiation; and/or (iii) modulate cellular adhesion.
  • the isolated nucleic acid molecules of the invention can be used to express proteins (e.g., via a recombinant expression vector in a host cell in gene therapy applications), to detect mRNA (e.g., in a biological sample) or a genetic lesion, and to modulate activity of a polypeptide of the invention.
  • the polypeptides of the invention can be used to screen drugs or compounds which modulate activity or expression of a polypeptide of the invention as well as to treat disorders characterized by insufficient or excessive production of a protein of the invention or production of a form of a protein of the invention which has decreased or abe ⁇ ant activity compared to the wild type protein.
  • the antibodies of the invention can be used to detect and isolate a protein of the and modulate activity of a protein of the invention.
  • the assay comprises contacting a cell which expresses a membrane-bound form of a polypeptide of the invention, or a biologically active portion thereof, on the cell surface with a known compound which binds the polypeptide to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with the polypeptide, wherein determining the ability of the test compound to interact with the polypeptide comprises determining the ability of the test compound to preferentially bind to the polypeptide or a biologically active portion thereof as compared to the known compound.
  • a target molecule can be a component of a signal transduction pathway which facilitates transduction of an extracellular signal (e.g., a signal generated by binding of a compound to a polypeptide of the invention) through the cell membrane and into the cell or a second intercellular protein which has catalytic activity or a protein which facilitates the association of downstream signaling molecules with a polypeptide of the invention. Determining the ability of a polypeptide of the invention to bind to or interact with a target molecule can be accomplished by determining the activity of the target molecule.
  • an extracellular signal e.g., a signal generated by binding of a compound to a polypeptide of the invention
  • an assay is a cell-free assay comprising contacting a polypeptide of the invention or biologically active portion thereof with a test compound and determining the ability of the test compound to modulate (e.g., stimulate or inhibit) the activity of the polypeptide or biologically active portion thereof. Determining the ability of the test compound to modulate the activity of the polypeptide can be accomplished, for example, by determining the ability of the polypeptide to bind to a target molecule by one of the methods described above for determining direct binding. In an alternative embodiment, determining the ability of the test compound to modulate the activity of the polypeptide can be accomplished by determining the ability of the polypeptide of the invention to further modulate the target molecule.
  • glutathione-S-transferase fusion proteins or glutathione-S-transferase fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical; St. Louis, MO) or glutathione derivatized microtitre plates, which are then combined with the test compound or the test compound and either the non-adsorbed target protein or A polypeptide of the invention, and the mixture incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads or microtitre plate wells are washed to remove any unbound components and complex formation is measured either directly or indirectly, for example, as described above.
  • glutathione sepharose beads Sigma Chemical; St. Louis, MO
  • glutathione derivatized microtitre plates which are then combined with the test compound or the test compound and either the non-adsorbed target protein or A polypeptide of the invention, and the mixture incubated under conditions conducive to complex formation (e
  • the complexes can be dissociated from the matrix, and the level of binding or activity of the polypeptide of the invention can be determined using standard techniques.
  • Other techniques for immobilizing proteins on matrices can also be used in the screening assays of the invention.
  • either the polypeptide of the invention or its target molecule can be immobilized utilizing conjugation of biotin and streptavidin.
  • Biotinylated polypeptide of the invention or target molecules can be prepared from biotin-NHS (N-hydroxy-succinimide) using techniques well known in the art (e.g. , biotinylation kit, Pierce Chemicals; Rockford, IL), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical).
  • the candidate compound when expression of the selected mRNA or protein is greater (statistically significantly greater) in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of the selected mRNA or protein expression.
  • the candidate compound when expression of the selected mRNA or protein is less (statistically significantly less) in the presence of the candidate compound than in its absence, the candidate compound is identified as an inhibitor of the selected mRNA or protein expression.
  • the level of the selected mRNA or protein expression in the cells can be determined by methods described herein.
  • nucleic acid sequences disclosed herein can be used to perform searches against "mapping databases", e.g., BLAST-type search, such that the chromosome position of the gene is identified by sequence homology or identity with known sequence fragments which have been mapped to chromosomes.
  • mapping databases e.g., BLAST-type search
  • a polypeptide and fragments and sequences thereof and antibodies specific thereto can be used to map the location of the gene encoding the polypeptide on a chromosome. This mapping can be carried out by specifically detecting the presence of the polypeptide in members of a panel of somatic cell hybrids between cells of a first species of animal from which the protein originates and cells from a second species of animal and then determining which somatic cell hybrid(s) expresses the polypeptide and noting the chromosome(s) from the first species of animal that it contains. For examples of this technique, see Pajunen et al. (1988) Cytogenet. Cell Genet. 47:31-41 and Van Keuren et al. (1986) Hum. Genet. 74:34-40.
  • the presence of the polypeptide in the somatic cell hybrids can be determined by assaying an activity or property of the polypeptide, for example, enzymatic activity, as described in Bordelon-Riser et al. (1979) Somatic Cell Genetics 5:597-613 and Owerbach et al. (1978) Proc. Natl. Acad. Sci. USA 75:5640-5644.
  • sequences of the present invention can be used to provide an alternative technique which determines the actual base-by-base DNA sequence of selected portions of an individual's genome.
  • the nucleic acid sequences described herein can be used to prepare two PCR primers from the 5' and 3' ends of the sequences. These primers can then be used to amplify an individual's DNA and subsequently sequence it.
  • a panel of reagents from the nucleic acid sequences described herein is used to generate a unique identification database for an individual, those same reagents can later be used to identify tissue from that individual.
  • positive identification of the individual, living or dead can be made from extremely small tissue samples.
  • Another aspect of the invention provides methods for expression of a nucleic acid or polypeptide of the invention or activity of a polypeptide of the invention in an individual to thereby select appropriate therapeutic or prophylactic agents for that individual (refe ⁇ ed to herein as "pharmacogenomics").
  • Pharmacogenomics allows for the selection of agents (e.g., drugs) for therapeutic or prophylactic treatment of an individual based on the genotype of the individual (e.g., the genotype of the individual examined to determine the ability of the individual to respond to a particular agent).
  • Yet another aspect of the invention pertains to monitoring the influence of agents (e.g., drugs or other compounds) on the expression or activity of a polypeptide of the invention in clinical trials.
  • agents e.g., drugs or other compounds
  • An exemplary method for detecting the presence or absence of a polypeptide or nucleic acid of the invention in a biological sample involves obtaining a biological sample from a test subject and contacting the biological sample with a compound or an agent capable of detecting a polypeptide or nucleic acid (e.g., mRNA, genomic DNA) of the invention such that the presence of a polypeptide or nucleic acid of the invention is detected in the biological sample.
  • a prefe ⁇ ed agent for detecting mRNA or genomic DNA encoding a polypeptide of the invention is a labeled nucleic acid probe capable of hybridizing to mRNA or genomic DNA encoding a polypeptide of the invention.
  • the nucleic acid probe can be, for example, a full-length cDNA, such as the nucleic acid of SEQ ID NO:l, 23, 34, 42, 54, 61, 66, or 76, or a portion thereof, such as an oligonucleotide of at least 15, 30, 50, 100, 250 or 500 contiguous nucleotides in length and sufficient to specifically hybridize under stringent conditions to a mRNA or genomic DNA encoding a polypeptide of the invention.
  • a full-length cDNA such as the nucleic acid of SEQ ID NO:l, 23, 34, 42, 54, 61, 66, or 76, or a portion thereof, such as an oligonucleotide of at least 15, 30, 50, 100, 250 or 500 contiguous nucleotides in length and sufficient to specifically hybridize under stringent conditions to a mRNA or genomic DNA encoding a polypeptide of the invention.
  • Other suitable probes for use in the diagnostic assays of the invention are described
  • a prefe ⁇ ed agent for detecting a polypeptide of the invention is an antibody capable of binding to a polypeptide of the invention, preferably an antibody with a detectable label.
  • Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g., Fab or F(ab')2) can be used.
  • the term "labeled", with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled.
  • Examples of indirect labeling include detection of a primary antibody using a fluorescently labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently labeled streptavidin.
  • biological sample is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. That is, the detection method of the invention can be used to detect mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo.
  • in vitro techniques for detection of mRNA include Northern hybridizations and in situ hybridizations.
  • the methods further involve obtaining a control biological sample from a control subject, contacting the control sample with a compound or agent capable of detecting a polypeptide of the invention or mRNA or genomic DNA encoding a polypeptide of the invention, such that the presence of the polypeptide or mRNA or genomic DNA encoding the polypeptide is detected in the biological sample, and comparing the presence of the polypeptide or mRNA or genomic DNA encoding the polypeptide in the control sample with the presence of the polypeptide or mRNA or genomic DNA encoding the polypeptide in the test sample.
  • kits for detecting the presence of a polypeptide or nucleic acid of the invention in a biological sample can be used to determine if a subject is suffering from or is at increased risk of developing a disorder associated with abe ⁇ ant expression of a polypeptide of the invention as discussed, for example, in sections above relating to uses of the sequences of the invention.
  • kits can be used to determine if a subject is suffering from or is at risk for brain-related disorders such as peripheral nerve survival, cerebral edema, hydrocephalus, brain herniations, iatrogenic disease (due to, e.g., infection, toxins, or drugs), inflammations (e.g., bacterial and viral meningitis, encephalitis, and cerebral toxoplasmosis), cerebrovascular diseases (e.g., hypoxia, ischemia, and infarction, intracranial hemo ⁇ hage and vascular malformations, and hypertensive encephalopathy), and tumors (e.g., neuroglial tumors, neuronal tumors, tumors of pineal cells, meningeal tumors, primary and secondary lymphomas, intracranial tumors, and medulloblastoma), and to treat injury or trauma to the brain, which are associated with abe ⁇ ant TANGO 499 activity and/or expression.
  • iatrogenic disease due to, e.g., infection
  • the kit can comprise a labeled compound or agent capable of detecting the polypeptide or mRNA encoding the polypeptide in a biological sample and means for determining the amount of the polypeptide or mRNA in the sample (e.g., an antibody which binds the polypeptide or an oligonucleotide probe which binds to DNA or mRNA encoding the polypeptide).
  • Kits can also include instructions for observing that the tested subject is suffering from or is at risk of developing a disorder associated with abe ⁇ ant expression of the polypeptide if the amount of the polypeptide or mRNA encoding the polypeptide is above or below a normal level.
  • the kit can comprise, for example: (1) an oligonucleotide, e.g., a detectably labeled oligonucleotide, which hybridizes to a nucleic acid sequence encoding a polypeptide of the invention or (2) a pair of primers useful for amplifying a nucleic acid molecule encoding a polypeptide of the invention.
  • the kit can also comprise, e.g., a buffering agent, a preservative, or a protein stabilizing agent.
  • the kit can also comprise components necessary for detecting the detectable agent (e.g., an enzyme or a substrate).
  • the methods described herein can furthermore be utilized as diagnostic or prognostic assays to identify subjects having or at risk of developing a disease or disorder associated with abe ⁇ ant expression or activity of a polypeptide of the invention.
  • the assays described herein such as the preceding diagnostic assays or the following assays, can be utilized to identify a subject having or at risk of developing a disorder associated with abe ⁇ ant expression or activity of a polypeptide of the invention, e.g., an immunologic disorder, or embryonic disorders.
  • the prognostic assays can be utilized to identify a subject having or at risk for developing such a disease or disorder.
  • bacterial infection e.g., bacterial infection, psoriasis, septicemia, cerebral malaria, inflammatory bowel disease, arthritis (e.g., rheumatoid arthritis, osteoarthritis), and allergic inflammatory disorders (e.g. , asthma, psoriasis), which are associated with abe ⁇ ant INTERCEPT 307, MANGO 511 and TANGO 361 activity and/or expression.
  • prognostic assays described herein can be used to identify a subject having or at risk of developing renal disorders e.g., glomerular diseases, tubular diseases and tubulo-interstitial diseases, embryonic disorders and fetal disorders, and which are associated with abe ⁇ ant INTERCEPT 307 activity and/or expression.
  • renal disorders e.g., glomerular diseases, tubular diseases and tubulo-interstitial diseases, embryonic disorders and fetal disorders, and which are associated with abe ⁇ ant INTERCEPT 307 activity and/or expression.
  • prognostic assays described herein can be used to identify a subject having or at risk of developing brain-related disorders such as cerebral edema, hydrocephalus, brain hemiations, iatrogenic disease (due to, e.g., infection, toxins, or drugs), inflammations (e.g., bacterial and viral meningitis, encephalitis, and cerebral toxoplasmosis), cerebrovascular diseases (e.g., hypoxia, ischemia, and infarction, intracranial hemo ⁇ hage and vascular malformations, and hypertensive encephalopathy), and tumors (e.g., neuroglial tumors, neuronal tumors, tumors of pineal cells, meningeal tumors, primary and secondary lymphomas, intracranial tumors, and medulloblastoma), and to treat injury or trauma to the brain, which are associated with abe ⁇ ant TANGO 509 and/or expression.
  • iatrogenic disease due to, e.g., infection
  • prognostic assays described herein can be used to identify a subject having or at risk of developing prostate-related disorders (e.g, prostate cancer, prostatis, benign prostatic hypertrophy, benign prostatic hype ⁇ lasmia and atypical prostatic stromal lesions) which are associated with abe ⁇ ant INTERCEPT 307, and TANGO 361 activity and/or expression.
  • prostate-related disorders e.g, prostate cancer, prostatis, benign prostatic hypertrophy, benign prostatic hype ⁇ lasmia and atypical prostatic stromal lesions
  • prognostic assays described herein can be used to identify a subject having or at risk of developing pituitary-related disorders (e.g., Cushing's disease, hype ⁇ rolactinemia, acromegaly-gigantism, and precocious and delayed puberty disorders), or Parkinson's disease or peripheral neuropathy-related disorders (e.g., amylothrophic lateral sclerosis) which are associated with abe ⁇ ant TANGO 499 activity and/or expression.
  • pituitary-related disorders e.g., Cushing's disease, hype ⁇ rolactinemia, acromegaly-gigantism, and precocious and delayed puberty disorders
  • Parkinson's disease or peripheral neuropathy-related disorders e.g., amylothrophic lateral sclerosis
  • the prognostic assays described herein can be used to determine whether a subject can be administered an agent (e.g., an agonist, antagonist, peptidomimetic, protein, peptide, nucleic acid, small molecule, or other drug candidate) to treat a disease or disorder associated with abe ⁇ ant expression or activity of a polypeptide of the invention.
  • an agent e.g., an agonist, antagonist, peptidomimetic, protein, peptide, nucleic acid, small molecule, or other drug candidate
  • agents e.g., an agonist, antagonist, peptidomimetic, protein, peptide, nucleic acid, small molecule, or other drug candidate
  • agents e.g., an agonist, antagonist, peptidomimetic, protein, peptide, nucleic acid, small molecule, or other drug candidate
  • such methods can be used to determine whether a subject can be effectively treated with a specific agent or class of agents (e.g., agents of a type which decrease activity
  • the present invention provides methods for determining whether a subject can be effectively treated with an agent for a disorder associated with abe ⁇ ant expression or activity of a polypeptide of the invention in which a test sample is obtained and the polypeptide or nucleic acid encoding the polypeptide is detected (e.g., wherein the presence of the polypeptide or nucleic acid is diagnostic for a subject that can be administered the agent to treat a disorder associated with abe ⁇ ant expression or activity of the polypeptide).
  • such genetic lesions or mutations can be detected by ascertaining the existence of at least one of: 1) a deletion of one or more nucleotides from the gene; 2) an addition of one or more nucleotides to the gene; 3) a substitution of one or more nucleotides of the gene; 4) a chromosomal rea ⁇ angement of the gene; 5) an alteration in the level of a messenger RNA transcript of the gene; 6) an abe ⁇ ant modification of the gene, such as of the methylation pattern of the genomic DNA; 7) the presence of a non-wild type splicing pattern of a messenger RNA transcript of the gene; 8) a non-wild type level of a the protein encoded by the gene; 9) an allelic loss of the gene; and 10) an inappropriate post-translational modification of the protein encoded by the gene.
  • assay techniques known in the art which can be used for detecting lesions in a gene.
  • detection of the lesion involves the use of a probe/primer in a polymerase chain reaction (PCR) (see, e.g., U.S. Patent Nos. 4,683,195 and 4,683,202), such as anchor PCR or RACE PCR, or, alternatively, in a ligation chain reaction (LCR) (see, e.g., Landegran et al. (1988) Science 241 :1077-1080; and Nakazawa et al. (1994) Proc. Natl. Acad. Sci. USA 91 :360-364), the latter of which can be particularly useful for detecting point mutations in a gene (see, e.g., Abravaya et al.
  • PCR polymerase chain reaction
  • LCR ligation chain reaction
  • This method can include the steps of collecting a sample of cells from a patient, isolating nucleic acid (e.g., genomic, mRNA or both) from the cells of the sample, contacting the nucleic acid sample with one or more primers which specifically hybridize to the selected gene under conditions such that hybridization and amplification of the gene (if present) occurs, and detecting the presence or absence of an amplification product, or detecting the size of the amplification product and comparing the length to a control sample. It is anticipated that PCR and or LCR may be desirable to use as a preliminary amplification step in conjunction with any of the techniques used for detecting mutations described herein.
  • nucleic acid e.g., genomic, mRNA or both
  • mutations in a selected gene from a sample cell can be identified by alterations in restriction enzyme cleavage patterns.
  • sample and control DNA is isolated, amplified (optionally), digested with one or more restriction endonucleases, and fragment length sizes are determined by gel electrophoresis and compared. Differences in fragment length sizes between sample and control DNA indicates mutations in the sample DNA.
  • sequence specific ribozymes see, e.g., U.S. Patent No. 5,498,531 can be used to score for the presence of specific mutations by development or loss of a ribozyme cleavage site.
  • genetic mutations can be identified by hybridizing a sample and control nucleic acids, e.g., DNA or RNA, to high density arrays containing hundreds or thousands of oligonucleotides probes (Cronin et al. (1996) Human Mutation 7:244-255; Kozal et al. (1996) Nature Medicine 2:753-759).
  • genetic mutations can be identified in two-dimensional a ⁇ ays containing light-generated DNA probes as described in Cronin et al., supra.
  • a first hybridization a ⁇ ay of probes can be used to scan through long stretches of DNA in a sample and control to identify base changes between the sequences by making linear a ⁇ ays of sequential overlapping probes. This step allows the identification of point mutations. This step is followed by a second hybridization a ⁇ ay that allows the characterization of specific mutations by using smaller, specialized probe a ⁇ ays complementary to all variants or mutations detected.
  • Each mutation a ⁇ ay is composed of parallel probe sets, one complementary to the wild-type gene and the other complementary to the mutant gene.
  • any of a variety of sequencing reactions known in the art can be used to directly sequence the selected gene and detect mutations by comparing the sequence of the sample nucleic acids with the co ⁇ esponding wild-type (control) sequence.
  • Examples of sequencing reactions include those based on techniques developed by Maxim and Gilbert ((1977) Proc. Natl. Acad. Sci. USA 74:560) or Sanger ((1977) Proc. Natl. Acad. Sci. USA 74:5463). It is also contemplated that any of a variety of automated sequencing procedures can be utilized when performing the diagnostic assays ((1995) Bio/Techniques 19:448), including sequencing by mass spectrometry ( see, e.g., PCT Publication No. WO 94/16101; Cohen et al. (1996) Adv. Chromatogr. 36:127-162; and Griffin et al. (1993) Appl. Biochem. Biotechnol. 38:147-159).
  • either DNA/DNA or RNA/DNA duplexes can be treated with hydroxylamine or osmium tetroxide and with piperidine in order to digest mismatched regions. After digestion of the mismatched regions, the resulting material is then separated by size on denaturing polyacrylamide gels to determine the site of mutation. See, e.g., Cotton et al. (1988) Proc. Natl. Acad. Sci. USA 85:4397; Saleeba et al. (1992) Methods Enzymol. 217:286-295. In a prefe ⁇ ed embodiment, the control DNA or RNA can be labeled for detection.
  • the mismatch cleavage reaction employs one or more proteins that recognize mismatched base pairs in double-stranded DNA (so called "DNA mismatch repair" enzymes) in defined systems for detecting and mapping point mutations in cDNAs obtained from samples of cells.
  • DNA mismatch repair enzymes
  • the mutY enzyme of E. coli cleaves A at G/A mismatches and the thymidine DNA glycosylase from HeLa cells cleaves T at G/T mismatches (Hsu et al. (1994) Carcinogenesis 15:1657-1662).
  • a probe based on a selected sequence is hybridized to a cDNA or other DNA product from a test cell(s).
  • the duplex is treated with a DNA mismatch repair enzyme, and the cleavage products, if any, can be detected from electrophoresis protocols or the like. See, e.g., U.S. Patent No. 5,459,039.
  • alterations in electrophoretic mobility will be used to identify mutations in genes.
  • single strand conformation polymo ⁇ hism may be used to detect differences in electrophoretic mobility between mutant and wild type nucleic acids (Orita et al. (1989) Proc. Natl.
  • RNA rather than DNA
  • the subject method utilizes heteroduplex analysis to separate double stranded heteroduplex molecules on the basis of changes in electrophoretic mobility (Keen et al. (1991) Trends Genet. 7:5).
  • the movement of mutant or wild-type fragments in polyacrylamide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (DGGE) (Myers et al. (1985) Nature 313:495).
  • DGGE denaturing gradient gel electrophoresis
  • DNA will be modified to insure that it does not completely denature, for example by adding a "GC clamp of approximately 40 bp of high-melting GC-rich DNA by PCR.
  • a temperature gradient is used in place of a denaturing gradient to identify differences in the mobility of control and sample DNA (Rosenbaum and Reissner (1987) Biophys. Chem. 265:12753).
  • oligonucleotide primers may be prepared in which the known mutation is placed centrally and then hybridized to target DNA under conditions which permit hybridization only if a perfect match is found (Saiki et al. (1986) Nature 324:163); Saiki et al. (1989) Proc. Natl. Acad. Sci. USA 86:6230).
  • Such allele specific oligonucleotides are hybridized to PCR amplified target DNA or a number of different mutations when the oligonucleotides are attached to the hybridizing membrane and hybridized with labeled target DNA.
  • Oligonucleotides used as primers for specific amplification may carry the mutation of interest in the center of the molecule (so that amplification depends on differential hybridization) (Gibbs et al. (1989) Nucleic Acids Res. 17:2437-2448) or at the extreme 3' end of one primer where, under appropriate conditions, mismatch can prevent or reduce polymerase extension (Prossner (1993) Tibtech 11 :238).
  • amplification may also be performed using Taq ligase for amplification (Barany (1991) Proc. Natl. Acad. Sci. USA 88:189). In such cases, ligation will occur only if there is a perfect match at the 3' end of the 5' sequence making it possible to detect the presence of a known mutation at a specific site by looking for the presence or absence of amplification.
  • Pharmacogenomics deals with clinically significant hereditary variations in the response to drugs due to altered drug disposition and abnormal action in affected persons. See, e.g., Linder (1997) Clin. Chem. 43(2):254-266.
  • two types of pharmacogenetic conditions can be differentiated. Genetic conditions transmitted as a single factor altering the way drugs act on the body are refe ⁇ ed to as "altered drug action.” Genetic conditions transmitted as single factors altering the way the body acts on drugs are refe ⁇ ed to as "altered drug metabolism”. These pharmacogenetic conditions can occur either as rare defects or as polymo ⁇ hisms.
  • G6PD glucose-6-phosphate dehydrogenase deficiency
  • oxidant drugs anti-malarials, sulfonamides, analgesics, nitro furans
  • the activity of drug metabolizing enzymes is a major determinant of both the intensity and duration of drug action.
  • drug metabolizing enzymes e.g., N-acetyltransferase 2 (NAT 2) and cytochrome P450 enzymes CYP2D6 and CYP2C19
  • NAT 2 N-acetyltransferase 2
  • CYP2D6 and CYP2C19 cytochrome P450 enzymes
  • the gene coding for CYP2D6 is highly polymo ⁇ hic and several mutations have been identified in PM, which all lead to the absence of functional CYP2D6. Poor metabolizers of CYP2D6 and CYP2C19 quite frequently experience exaggerated drug response and side effects when they receive standard doses. If a metabolite is the active therapeutic moiety, a PM will show no therapeutic response, as demonstrated for the analgesic effect of codeine mediated by its CYP2D6-formed metabolite mo ⁇ hine. The other extreme are the so called ultra-rapid metabolizers who do not respond to standard doses. Recently, the molecular basis of ultra-rapid metabolism has been identified to be due to CYP2D6 gene amplification.
  • the activity of a polypeptide of the invention, expression of a nucleic acid encoding the polypeptide, or mutation content of a gene encoding the polypeptide in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment of the individual.
  • pharmacogenetic studies can be used to apply geno typing of polymo ⁇ hic alleles encoding drug-metabolizing enzymes to the identification of an individual's drug responsiveness phenotype.
  • genes including those of the invention, that are modulated in cells by treatment with an agent (e.g., compound, drug or small molecule) which modulates activity or expression of a polypeptide of the invention (e.g., as identified in a screening assay described herein) can be identified.
  • an agent e.g., compound, drug or small molecule
  • a polypeptide of the invention e.g., as identified in a screening assay described herein
  • cells can be isolated and RNA prepared and analyzed for the levels of expression of a gene of the invention and other genes implicated in the disorder.
  • the levels of gene expression can be quantified by Northern blot analysis or RT-PCR, as described herein, or alternatively by measuring the amount of protein produced, by one of the methods as described herein, or by measuring the levels of activity of a gene of the invention or other genes.
  • the gene expression pattern can serve as a marker, indicative of the physiological response of the cells to the agent. Accordingly, this response state may be determined before, and at various points during, treatment of the individual with the agent.
  • increased administration of the agent may be desirable to increase the expression or activity of the polypeptide to higher levels than detected, i.e., to increase the effectiveness of the agent.
  • decreased administration of the agent may be desirable to decrease expression or activity of the polypeptide to lower levels than detected, i.e., to decrease the effectiveness of the agent.
  • the present invention provides for both prophylactic and therapeutic methods of treating a subject at risk of (or susceptible to) a disorder or having a disorder associated with abe ⁇ ant expression or activity of a polypeptide of the invention.
  • disorders characterized by abe ⁇ ant expression or activity of the polypeptides of the invention include proliferative disorders such as cancer.
  • an agonist or antagonist agent can be used for treating the subject.
  • an antagonist of an INTERCEPT 307, MANGO 511 or TANGO 509 protein may be used to treat an immunological disorder.
  • the appropriate agent can be determined based on screening assays described herein.
  • the modulatory method of the invention involves contacting a cell with an agent that modulates one or more of the activities of the polypeptide.
  • An agent that modulates activity can be an agent as described herein, such as a nucleic acid or a protein, a naturally-occurring cognate ligand of the polypeptide, a peptide, a peptidomimetic, or other small molecule.
  • the agent stimulates one or more of the biological activities of the polypeptide.
  • stimulatory agents include the active polypeptide of the invention and a nucleic acid molecule encoding the polypeptide of the invention that has been introduced into the cell.
  • the agent inhibits one or more of the biological activities of the polypeptide of the invention.
  • inhibitory agents include antisense nucleic acid molecules and antibodies.
  • the method involves administering an agent (e.g., an agent identified by a screening assay described herein), or combination of agents that modulates (e.g., upregulates or downregulates) expression or activity.
  • an agent e.g., an agent identified by a screening assay described herein
  • the method involves administering a polypeptide of the invention or a nucleic acid molecule of the invention as therapy to compensate for reduced or abe ⁇ ant expression or activity of the polypeptide.
  • Clones containing cDNA molecules encoding MANGO 511 were deposited with the American Type Culture Collection (Manassas, VA) on July 23, 1999 as Accession Number PTA-425, as part of a composite deposit representing a mixture of three strains, each carrying one recombinant plasmid harboring a particular cDNA clone.
  • an aliquot of the mixture can be streaked out to single colonies on nutrient medium (e.g., LB plates) supplemented with lOO ⁇ g/ml ampicillin, single colonies grown, and then plasmid DNA extracted using a standard minipreparation procedure.
  • a sample of the DNA minipreparation can be digested with a combination of the restriction enzymes Sal I and Not I and the resultant products resolved on a 0.8%> agarose gel using standard DNA electrophoresis conditions.
  • the digest liberates 1.5 kb fragments that co ⁇ espond to MANGO 511 (511).
  • the identity of the strain containing MANGO 511 can be infe ⁇ ed from the liberation of a fragment of the above identified size.
  • 15 aliquot of the mixture can be streaked out to single colonies on nutrient medium (e.g., LB plates) supplemented with lOO ⁇ g/ml ampicillin, single colonies grown, and then plasmid DNA extracted using a standard minipreparation procedure.
  • a sample of the DNA minipreparation can be digested with a combination of the restriction enzymes Sal I and 2 Not I and the resultant products resolved on a 0.8% agarose gel using standard DNA electrophoresis conditions. The digest liberates fragments as follows:
  • INTERCEPT 307 (307): 2.0 kb TANGO 361 (361): 5.1 kb 25 TANGO 509 (509): 3.6 kb
  • strains can be infe ⁇ ed from the fragments liberated.
  • Clones containing cDNA molecules encoding TANGO 499 form 1, variant 1 (clone EpT499 form 1, variant 1), were deposited with the American Type Culture r . Collection (Manassas, VA) on August 5, 1999 as Accession Number PTA-455, as part of a composite deposit representing a mixture of three strains, each carrying one recombinant plasmid harboring a particular cDNA clone.
  • an aliquot of the mixture can be streaked out to single colonies on nutrient medium (e.g., LB 35 plates) supplemented with lOO ⁇ g/ml ampicillin, single colonies grown, and then plasmid DNA extracted using a standard minipreparation procedure.
  • a sample of the DNA minipreparation can be digested with a combination of the restriction enzymes Sal I and Not I and the resultant products resolved on a 0.8% agarose gel using standard DNA electrophoresis conditions.
  • the digest liberates 1.1 kb fragments that co ⁇ espond to TANGO 499 form 1, variant 1 (EpT499 form 1, variant 1).
  • the identity of the strain containing TANGO 499 form 1, variant 1 can be infe ⁇ ed from the liberation of a fragment of the above identified size.
  • an aliquot of the mixture can be streaked out to single colonies on nutrient medium (e.g., LB plates) supplemented with lOO ⁇ g/ml ampicillin, single colonies grown, and then plasmid DNA extracted using a standard minipreparation procedure.
  • a sample of the DNA minipreparation can be digested with a combination of the restriction enzymes Sal I and Not I and the resultant products resolved on a 0.8% agarose gel using standard DNA electrophoresis conditions.
  • the digest liberates 1.1 kb fragments that co ⁇ espond to TANGO 499 form 2, variant 3 (EpT499 form 2, variant 3).
  • the identity of the strain containing TANGO 499 form 2, variant 3 can be infe ⁇ ed from the liberation of a fragment of the above identified size.

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Abstract

Cette invention concerne des molécules d'acides nucléiques isolées appelées INTERCEPT 307, MANGO 511, TANGO 351, TANGO 361, TANGO 499 et TANGO 509, et des molécules polypeptidiques. La molécule INTERCEPT 307 code pour un polypeptide transmembranaire associé au produit génique PB36 à régulation positive en rapport avec le cancer de la prostate. La molécule MANGO 511 code pour des polypeptides transmembranaires associés aux récepteurs de leucocyte type Ig (LIR). La molécule TANGO 351 code pour un polypeptide transmembranaire qui intervient dans la signalisation. Des variants de TANGO 499 codent pour des polypeptides sécrétés en rapport avec des polypeptides de type facteur de croissance neurotrophique issu de cellules gliales (GDNF). La protéine humaine et de souris TANGO 509 code pour des polypeptides transmembranaires renfermant des domaines de l'immunoglobuline. L'invention concerne aussi des molécules d'acides nucléiques antisens, des vecteurs d'expression contenant les molécules d'acides nucléiques de l'invention, des cellules hôtes dans lesquelles on a introduit les vecteurs d'expression, et des animaux transgéniques non humains dans lesquels une molécule d'acides nucléiques de l'invention a été introduite ou rompue. Elle concerne encore des polypeptides isolés, des polypeptides de fusion, des peptides antigéniques et des anticorps, ainsi que des méthodes de diagnostic, de traitement et de criblage qui font intervenir des compositions de l'invention.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2389722A1 (fr) * 1999-11-09 2001-05-17 Human Genome Sciences, Inc. 15 proteines secretees humaines
WO2001039722A2 (fr) 1999-11-30 2001-06-07 Mayo Foundation For Medical Education And Research Nouvelle molecule immunoregulatrice b7-h1,
US20030031675A1 (en) 2000-06-06 2003-02-13 Mikesell Glen E. B7-related nucleic acids and polypeptides useful for immunomodulation
US6965018B2 (en) 2000-06-06 2005-11-15 Bristol-Myers Squibb Company Antibodies directed to B7-related polypeptide, BSL-2
DK2116259T3 (da) * 2001-05-24 2012-05-21 Zymogenetics Inc TACI-immunoglobulinfusionsproteiner
MX349137B (es) 2005-06-08 2017-07-13 Dana-Farber Cancer Inst Metodos y composiciones para el tratamiento de infecciones persistentes y cancer por inhibicion de la ruta de muerte celular programada (pd-1).
CN101437933B (zh) 2005-12-28 2013-11-06 斯克里普斯研究所 作为药物靶标的天然反义和非编码的rna转录物
BRPI0921321A2 (pt) 2008-11-28 2018-10-16 Emory University métodos para o tratamento de indwcções e tumores
US8927511B2 (en) 2008-12-04 2015-01-06 Curna, Inc. Treatment of vascular endothelial growth factor (VEGF) related diseases by inhibition of natural antisense transcript to VEGF
MX2011005918A (es) 2008-12-04 2011-06-17 Opko Curna Llc Tratamiento de enfermedades relacionadas con un gen supresor de tumor mediante inhibicion del transcrito antisentido natural para el gen.
ES2629630T3 (es) 2008-12-04 2017-08-11 Curna, Inc. Tratamiento de enfermedades relacionadas con eritropoyetina (EPO) mediante inhibición del transcrito antisentido natural a EPO
CN108997498A (zh) 2008-12-09 2018-12-14 霍夫曼-拉罗奇有限公司 抗-pd-l1抗体及它们用于增强t细胞功能的用途
CA2752237C (fr) 2009-02-12 2020-03-24 Opko Curna, Llc Traitement des maladies associees au facteur neurotrophique derive du cerveau (bdnf) par inhibition du produit antisens naturel de la transcription en bdnf
JP6066035B2 (ja) * 2009-02-12 2017-01-25 クルナ・インコーポレーテッド グリア細胞由来神経栄養因子（ｇｄｎｆ）関連疾病の、ｇｄｎｆに対する天然アンチセンス転写物の抑制による治療
CA2755409C (fr) 2009-03-16 2019-04-30 Joseph Collard Traitement de maladies associees au facteur nucleaire 2 similaire au derive d'erythroide 2 (nrf2) par inhibition de produit de transcription antisens naturel pour nrf2
CA2755404C (fr) 2009-03-17 2020-03-24 Joseph Collard Traitement des maladies associees a l'homologue du delta-like 1 (dlk1) par inhibition du transcrit antisens naturel de dlk1
CA2761142C (fr) 2009-05-06 2021-06-08 Opko Curna, Llc Traitement de maladies liees a la tristetraproline (ttp) par l'inhibition d'un transcrit antisens naturel de ttp
CN103223177B (zh) 2009-05-06 2016-08-10 库尔纳公司 通过针对脂质转运和代谢基因的天然反义转录物的抑制治疗脂质转运和代谢基因相关疾病
US9012139B2 (en) 2009-05-08 2015-04-21 Curna, Inc. Treatment of dystrophin family related diseases by inhibition of natural antisense transcript to DMD family
CN102575251B (zh) 2009-05-18 2018-12-04 库尔纳公司 通过抑制针对重编程因子的天然反义转录物来治疗重编程因子相关的疾病
US8895527B2 (en) 2009-05-22 2014-11-25 Curna, Inc. Treatment of transcription factor E3 (TFE3) and insulin receptor substrate 2(IRS2) related diseases by inhibition of natural antisense transcript to TFE3
CA2764683A1 (fr) 2009-05-28 2010-12-02 Joseph Collard Traitement de maladies associees a un gene antiviral grace a l'inhibition d'un produit de transcription antisens naturel d'un gene antiviral
JP6128846B2 (ja) 2009-06-16 2017-05-17 クルナ・インコーポレーテッド パラオキソナーゼ（ｐｏｎ１）に対する天然アンチセンス転写物の抑制によるｐｏｎ１遺伝子関連疾患の治療
ES2620960T3 (es) 2009-06-16 2017-06-30 Curna, Inc. Tratamiento de enfermedades relacionadas con un gen de colágeno mediante la inhibición de un transcrito antisentido natural a un gen de colágeno
JP6073133B2 (ja) 2009-06-24 2017-02-01 クルナ・インコーポレーテッド 腫瘍壊死因子受容体２（ｔｎｆｒ２）に対する天然アンチセンス転写物の抑制によるｔｎｆｒ２関連疾患の治療
WO2010151674A2 (fr) 2009-06-26 2010-12-29 Curna, Inc. Traitement de maladies associées aux gènes liés au syndrome de down par inhibition des gènes liés au syndrome de down médiée par le produit de transcription antisens naturel
KR101801407B1 (ko) 2009-07-24 2017-11-24 큐알엔에이, 인크. 시르투인 (ｓｉｒｔ)에 대한 천연 안티센스 전사체의 억제에 의한 시르투인 관련된 질환의 치료
KR101802536B1 (ko) 2009-08-05 2017-11-28 큐알엔에이, 인크. 인슐린 유전자 (ｉｎｓ)에 대한 자연 안티센스 전사체의 저해에 의한 인슐린 유전자 (ｉｎｓ) 관련된 질환의 치료
WO2011019815A2 (fr) 2009-08-11 2011-02-17 Curna, Inc. Traitement de maladies associées à l’adiponectine (adipoq) par inhibition du produit de transcription anti-sens naturel d’une adiponectine (adipoq)
JP5943836B2 (ja) 2009-08-21 2016-07-05 カッパーアールエヌエー，インコーポレイテッド ‘ｈｓｐ７０相互作用タンパク質ｃ末端’（ｃｈｉｐ）に対する天然アンチセンス転写産物の阻害によるｃｈｉｐ関連疾患の治療
JP5964232B2 (ja) 2009-08-25 2016-08-03 カッパーアールエヌエー，インコーポレイテッド ‘ｉｑモチーフ含有ｇｔｐアーゼ活性化タンパク質’（ｉｑｇａｐ）に対する天然アンチセンス転写産物の阻害によるｉｑｇａｐ関連疾患の治療
JP6175236B2 (ja) 2009-09-25 2017-08-09 カッパーアールエヌエー，インコーポレイテッド フィラグリン（ｆｌｇ）の発現および活性の調整によるｆｌｇ関連疾患の処置
DK2513310T3 (en) 2009-12-16 2018-02-05 Curna Inc TREATMENT OF DISEASES CONNECTED WITH MEMBRANE-BONDED TRANSCRIPTION FACTOR Peptidase, site 1 (MBTPS1), BY INHIBITION OF NATURAL ANTISENCE TRANSCRIPTION TO MBTPS1
DK2516648T3 (en) 2009-12-23 2018-02-12 Curna Inc TREATMENT OF HEPATOCYTE GROWTH FACTOR (HGF) RELATED DISEASES BY INHIBITION OF NATURAL ANTISENSE TRANSCRIPT AGAINST HGF
EP2515947B1 (fr) 2009-12-23 2021-10-06 CuRNA, Inc. Traitement de maladies associées à la protéine ucp2 (uncoupling protein) par inhibition du produit de transcription antisens naturel en ucp2
EP2519634B1 (fr) 2009-12-29 2016-06-01 CuRNA, Inc. Traitement de maladies liées à la protéine tumorale 63 (p63) par l'inhibition du produit de transcription antisens naturel de p63
JP5993744B2 (ja) 2009-12-29 2016-09-14 カッパーアールエヌエー，インコーポレイテッド 核呼吸因子１（ｎｒｆ１）に対する天然アンチセンス転写物の阻害による核呼吸因子１関連疾患の治療
US20120289583A1 (en) 2009-12-31 2012-11-15 Curna, Inc. Treatment of insulin receptor substrate 2 (irs2) related diseases by inhibition of natural antisense transcript to irs2 and transcription factor e3 (tfe3)
EP2521784B1 (fr) 2010-01-04 2017-12-06 CuRNA, Inc. Traitement de maladies liées au facteur de régulation de l'interféron 8 (irf8) par l'inhibition du produit de transcription antisens naturel de l'irf8
EP2521785B1 (fr) 2010-01-06 2022-03-09 CuRNA, Inc. Inhibition de la transcription antisens naturelle du gène de développement du pancrea pour l'utilisation dans le traitement des maladies du développement du pancréa
ES2664866T3 (es) 2010-01-11 2018-04-23 Curna, Inc. Tratamiento de enfermedades relacionadas con la globulina fijadora de hormonas sexuales (shbg) mediante inhibición del transcrito antisentido natural a shbg
DK2529015T3 (en) 2010-01-25 2018-02-26 Curna Inc TREATMENT OF RNASE H1-RELATED DISEASES BY INHIBITION OF NATURAL ANTISENSE TRANSCRIPT TO RNASE H1
CA2790506A1 (fr) 2010-02-22 2011-08-25 Curna, Inc. Traitement de maladies liees a la pyrroline-5-carboxylate reductase 1 (pycr1) par inhibition du produit de transcription antisens naturel de pycr1
CA2795145C (fr) 2010-04-02 2019-01-22 Curna, Inc. Traitement de maladies liees au facteur de stimulation des colonies 3 (csf3) par inhibition du produit de la transcription antisens naturel en csf3
TWI644675B (zh) 2010-04-09 2018-12-21 可娜公司 藉由抑制纖維母細胞生長因子２１（ｆｇｆ２１）之天然反義轉錄物以治療ｆｇｆ２１相關疾病
KR20130101442A (ko) 2010-05-03 2013-09-13 큐알엔에이, 인크. 시르투인 (sirt)에 대한 자연 안티센스 전사체의 저해에 의한 시르투인 (sirt) 관련된 질환의 치료
TWI531370B (zh) 2010-05-14 2016-05-01 可娜公司 藉由抑制ｐａｒ４天然反股轉錄本治療ｐａｒ４相關疾病
JP5973996B2 (ja) 2010-05-26 2016-08-23 カッパーアールエヌエー，インコーポレイテッド Ａｔｏｈ１に対する天然アンチセンス転写物の阻害による無調ホモログ１（ａｔｏｈ１）関連疾患の治療
RU2620978C2 (ru) 2010-05-26 2017-05-30 Курна, Инк. Лечение заболеваний, связанных с метионинсульфоксидредуктазой а (msra), путем ингибирования природного антисмыслового транскрипта гена msra
RU2016118528A (ru) 2010-06-23 2018-10-31 Курна, Инк. Лечение заболеваний, связанных с альфа-субъединицей потенциалзависимого натриевого канала (scna), путем ингибирования природного антисмыслового транскрипта гена scna
RU2611190C2 (ru) 2010-07-14 2017-02-21 Курна, Инк. Лечение заболеваний, связанных с геном dlg, путем ингибирования природного антисмыслового транскрипта гена dlg
US8993533B2 (en) 2010-10-06 2015-03-31 Curna, Inc. Treatment of sialidase 4 (NEU4) related diseases by inhibition of natural antisense transcript to NEU4
US9222088B2 (en) 2010-10-22 2015-12-29 Curna, Inc. Treatment of alpha-L-iduronidase (IDUA) related diseases by inhibition of natural antisense transcript to IDUA
US10000752B2 (en) 2010-11-18 2018-06-19 Curna, Inc. Antagonat compositions and methods of use
KR102010598B1 (ko) 2010-11-23 2019-08-13 큐알엔에이, 인크. Nanog에 대한 자연 안티센스 전사체의 저해에 의한 nanog 관련된 질환의 치료
CN103620036B (zh) 2011-06-09 2016-12-21 库尔纳公司 通过抑制共济蛋白(fxn)的天然反义转录物而治疗fxn 相关疾病
EA029151B1 (ru) 2011-09-06 2018-02-28 Курна, Инк. ЛЕЧЕНИЕ ЗАБОЛЕВАНИЙ, СВЯЗАННЫХ С АЛЬФА-СУБЪЕДИНИЦАМИ ПОТЕНЦИАЛЗАВИСИМЫХ НАТРИЕВЫХ КАНАЛОВ (SCNxA), С ПОМОЩЬЮ МАЛЫХ МОЛЕКУЛ
HUE040179T2 (hu) 2012-03-15 2019-02-28 Curna Inc Agyi eredetû neutrotróf faktorral (Brain-derived neurotrophic factor, BDNF) összefüggõ betegségek kezelése a BDNF-fel kapcsolatos természetes antiszensz transzkriptumok gátlása révén
CN104470949A (zh) 2012-05-15 2015-03-25 百时美施贵宝公司 通过破坏pd-1/pd-l1信号传输的免疫治疗

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999041284A1 (fr) * 1998-02-11 1999-08-19 Genetics Institute, Inc. Proteines secretees et polynucleotides les codant
WO1999042470A1 (fr) * 1998-02-18 1999-08-26 Genetics Institute, Inc. Proteines secretees et polynucleotides codant lesdites proteines
EP1130094A2 (fr) * 1999-07-08 2001-09-05 Helix Research Institute Amorces pour la synthèse de cADN de pleine longueur et leur utilisation
WO2001075067A2 (fr) * 2000-03-31 2001-10-11 Hyseq, Inc. Nouveaux acides nucleiques et polypeptides

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2287085A1 (fr) * 1997-04-16 1998-10-22 Millennium Biotherapeutics, Inc. Proteines tango-63d et tango-63e apparentees au recepteur du facteur de necrose des tumeurs

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999041284A1 (fr) * 1998-02-11 1999-08-19 Genetics Institute, Inc. Proteines secretees et polynucleotides les codant
WO1999042470A1 (fr) * 1998-02-18 1999-08-26 Genetics Institute, Inc. Proteines secretees et polynucleotides codant lesdites proteines
EP1130094A2 (fr) * 1999-07-08 2001-09-05 Helix Research Institute Amorces pour la synthèse de cADN de pleine longueur et leur utilisation
WO2001075067A2 (fr) * 2000-03-31 2001-10-11 Hyseq, Inc. Nouveaux acides nucleiques et polypeptides

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CELIS J E ET AL: "SECRETED PROTEINS FROM NORMAL AND SV40 TRANSFORMED HUMAN MRC-5 FIBROBLASTS: TOWARD ESTABLISHING A DATABASE OF HUMAN SECRETED PROTEINS" LEUKEMIA, MACMILLAN PRESS LTD, US, vol. 1, no. 10, October 1987 (1987-10), pages 707-717, XP001118789 ISSN: 0887-6924 *
HALVORSEN Y-D C ET AL: "Adipose as an endocrine organ: The characterization of secreted proteins from human cultured adipocytes" FASEB JOURNAL, FED. OF AMERICAN SOC. FOR EXPERIMENTAL BIOLOGY, BETHESDA, MD, US, vol. 13, no. 4 part 11, 12 March 1999 (1999-03-12), page A369, XP002146933 ISSN: 0892-6638 *
See also references of WO0121631A2 *

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