WO1999042470A1 - Proteines secretees et polynucleotides codant lesdites proteines - Google Patents

Proteines secretees et polynucleotides codant lesdites proteines Download PDF

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Publication number
WO1999042470A1
WO1999042470A1 PCT/US1999/003458 US9903458W WO9942470A1 WO 1999042470 A1 WO1999042470 A1 WO 1999042470A1 US 9903458 W US9903458 W US 9903458W WO 9942470 A1 WO9942470 A1 WO 9942470A1
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Prior art keywords
seq
polynucleotide
protein
nucleotide
amino acid
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PCT/US1999/003458
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English (en)
Inventor
Kenneth Jacobs
John M. Mccoy
Edward R. Lavallie
Lisa A. Collins-Racie
David Merberg
Maurice Treacy
Michael J. Agostino
Robert J. Ii Steininger
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Genetics Institute, Inc.
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Application filed by Genetics Institute, Inc. filed Critical Genetics Institute, Inc.
Priority to AU26855/99A priority Critical patent/AU2685599A/en
Priority to CA002320799A priority patent/CA2320799A1/fr
Priority to EP99907121A priority patent/EP1056764A4/fr
Priority to JP2000532422A priority patent/JP2002504488A/ja
Publication of WO1999042470A1 publication Critical patent/WO1999042470A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • polynucleotide that hybridizes under stringent conditions to any one of the polynucleotides specified in (a)-(i) and that has a length that is at least 25% of the length of SEQ ID NO:9.
  • polynucleotide comprises the nucleotide sequence of SEQ ID NO:
  • a polynucleotide comprising the nucleotide sequence of a mature protein coding sequence of clone nq34_12 deposited under accession number ATCC 98663;
  • the present invention provides a composition comprising a protein, wherein said protein comprises an amino acid sequence selected from the group consisting of:
  • the polynucleotide encodes the full-length or a mature protein encoded by the cDNA insert of clone pjl54_l deposited under accession number ATCC 98663.
  • the present invention provides a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO:14 having biological activity, the fragment preferably comprising eight (more preferably twenty, most preferably thirty) contiguous amino acids of SEQ ID NO:14, or a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO: 14 having biological activity, the fragment comprising the amino acid sequence from amino acid 28 to amino acid 37 of SEQ ID NO:14.
  • inventions provide the gene corresponding to the cDNA sequence of SEQ ID NO:15.
  • Further embodiments of the invention provide isolated polynucleotides produced according to a process selected from the group consisting of: (a) a process comprising the steps of:
  • 33 ID NO:20 having biological activity, the fragment comprising the amino acid sequence from amino acid 140 to amino acid 149 of SEQ ID NO:20.
  • SEQ ID NO:l includes a poly(A) tail.
  • Amino acids 87 to 99 of SEQ ID NO:2 are a predicted leader/signal sequence, with the predicted mature amino acid sequence beginning at amino acid 100. Due to the hydrophobic nature of the predicted leader/signal sequence, it is likely to act as a transmembrane domain should the predicted leader/signal sequence not be separated from the remainder of the co821_31 protein.
  • dk329_l demonstrated at least some similarity with sequences identified as AA147429 (zo39g07.rl Stratagene endothehal cell 937223 Homo sapiens cDNA clone 589308 5' similar to WP T14G10.6 CE06452 LEUCOCYTE SURFACE ANTIGEN CD53 LINE), AA190572 (zp42h08.rl Stratagene muscle 937209 Homo sapiens cDNA clone 612159 5' similar to WP T14G10.6 CE06452 LEUCOCYTE SURFACE ANTIGEN CD53 LINE), AA234042 (zr51a05.sl Soares NhHMPu SI Homo sapiens cDNA clone 666896 3'
  • the predicted amino acid sequence disclosed herein for fx317_ll was searched against the GenPept and GeneSeq amino acid sequence databases using the BLASTX search protocol.
  • the predicted fx317_ll protein demonstrated at least some similarity to sequences identified as W15413 (Human activated platelet protein-2 APP-2) and W15414 (Human activated platelet protein-2 APP-2 alternatively spliced variant).
  • APP-2 protein is expressed on activated human platelets. Based upon sequence similarity, fx317_ll proteins and each similar protein or peptide may share at least some activity.
  • the EcoRI/Notl restriction fragment obtainable from the deposit containing clone lp547_4 should be approximately 1800 bp.
  • the nucleotide sequence disclosed herein for lp547_4 was searched agamst the
  • nq34_12 protein was expressed in a COS cell expression system, and an expressed protein band of approximately 34 kDa was detected in membrane fractions using SDS polyacrylamide gel electrophoresis.
  • a polynucleotide of the present invention has been identified as clone "pjl54_l".
  • pjl54_l was isolated from a human fetal carcinoma (NTD2 cells treated with retinoic acid for 23 days) cDNA library using methods which are selective for cDNAs encoding secreted proteins (see U.S. Pat. No. 5,536,637), or was identified as encoding a secreted or transmembrane protein on the basis of computer analysis of the amino acid sequence of the encoded protein.
  • pjl54_l is a full-length clone, including the entire coding sequence of a secreted protein (also referred to herein as "pjl54_l protein").
  • the nucleotide sequence of qoll5_13 as presently determined is reported in SEQ ID NO:19, and includes a poly(A) tail. What applicants presently believe to be the proper reading frame and the predicted amino acid sequence of the qoll5_13 protein conesponding to the foregoing nucleotide sequence is reported in SEQ ID NO:20. Amino acids 29 to 41 of SEQ ID NO:20 are a predicted leader/signal sequence, with the predicted mature amino acid sequence beginning at amino acid 42. Due to the hydrophobic nature of the predicted leader/signal sequence, it is likely to act as a transmembrane domain should the predicted leader/signal sequence not be separated from the remainder of the qoll5_13 protein. The EcoRI/Notl restriction fragment obtainable from the deposit containing clone qoll5_13 should be approximately 1200 bp.
  • Each clone has been transfected into separate bacterial cells (E. coli) in this composite deposit. Each clone can be removed from the vector in which it was deposited by performing an EcoRI/Notl digestion (5' site, EcoRI; 3' site, Notl) to produce the appropriate fragment for such clone. Each clone was deposited in either the pED6 or pNOTs vector depicted in Figures IA and IB, respectively.
  • the pED6dpc2 vector (“pED6" was derived from pED ⁇ dpcl by insertion of a new polylinker to facilitate cDNA cloning (Kaufman et al., 1991, Nucleic Acids Res. 19: 4485-4490); the pNOTs vector was derived from pMT2 (Kaufman et al, 1989, Mol. Cell. Biol. 9: 946-958) by deletion of
  • the oligonucleotide should preferably be labeled with ⁇ - 32 P ATP (specific activity 6000 Ci/mmole) and T4 polynucleotide kinase using commonly employed techniques for labeling oligonucleotides. Other labeling techniques can also be used. Unincorporated label should preferably be removed by gel filtration chromatography or other established methods. The amount of radioactivity incorporated into the probe should be quantitated by measurement in a scintillation counter. Preferably, specific activity of the resulting probe should be approximately 4e+6 dpm/pmole.
  • the present invention also provides genes corresponding to the polynucleotide sequences disclosed herein.
  • "Corresponding genes” are the regions of the genome that are transcribed to produce the mRNAs from which cDNA polynucleotide sequences are derived and may include contiguous regions of the genome necessary for the regulated expression of such genes. Conesponding genes may therefore include but are not limited to coding sequences, 5' and 3' untranslated regions, alternatively spliced exons, introns, promoters, enhancers, and silencer or suppressor elements.
  • the conesponding genes can be isolated in accordance with known methods using the sequence information disclosed herein. Such methods include the preparation of probes or primers from the disclosed sequence information for identification and /or amplification of genes in appropriate genomic libraries or other sources of genomic materials.
  • An "isolated gene” is a gene that
  • the chromosomal location corresponding to the polynucleotide sequences disclosed herein may also be determined, for example by hybridizing appropriately labeled polynucleotides of the present invention to chromosomes in situ. It may also be possible to determine the corresponding chromosomal location for a disclosed polynucleotide by identifying significantly similar nucleotide sequences in public databases, such as expressed sequence tags (ESTs), that have already been mapped to particular chromosomal locations. For at least some of the polynucleotide sequences disclosed herein, public database sequences having at least some similarity to the polynucleotide of the present invention have been listed by database accession number.
  • ESTs expressed sequence tags
  • Organisms that have enhanced, reduced, or modified expression of the gene(s) corresponding to the polynucleotide sequences disclosed herein are provided.
  • the desired change in gene expression can be achieved through the use of antisense polynucleotides or ribozymes that bind and /or cleave the mRNA transcribed from the gene (Albert and Morris, 1994, Trends Pharmacol. Sci. 15(7): 250-254; Lavarosky et al., 1997, Biochem. Mol. Med. 62(1): 11-22; and Hampel, 1998, Prog. Nucleic Acid Res. Mol. Biol. 58: 1- 39; all of which are incorporated by reference herein).
  • WU-BLAST version 2.0 executable programs for several UNIX platforms can be downloaded from ftp://blast.wustl.edu/blast/executables.
  • the complete suite of search programs (BLASTP, BLASTN, BLASTX, TBLASTN, and TBLASTX) is provided at that site, in addition to several support programs.
  • WU-BLAST 2.0 is copyrighted and may not be sold or redistributed in any form or manner without the express written consent of the author; but the posted executables may otherwise be freely used for commercial, nonprofit, or academic purposes.
  • the default amino acid comparison matrix is BLOSUM62, but other amino acid comparison matrices such as PAM can be utilized.
  • allelic variants of the disclosed polynucleotides or proteins that is, naturally-occurring alternative forms of the isolated polynucleotides which also encode proteins which are identical or have significantly similar sequences to those encoded by the disclosed polynucleotides.
  • allelic variants have at least 60% sequence identity (more preferably, at least 75% identity; most preferably at least 90% identity) with the given polynucleotide, where sequence identity is determined by comparing the nucleotide sequences of the polynucleotides when aligned so as to maximize overlap and identity while minimizing sequence gaps.
  • Allelic variants may be isolated and identified by making suitable probes or primers from the sequences provided herein and screening a suitable nucleic acid source from individuals of the appropriate species.
  • a protein of the present invention may also exhibit immune stimulating or immune suppressing activity, including without limitation the activities for which assays are described herein.
  • a protein may be useful in the treatment of various immune deficiencies and disorders (including severe combined immunodeficiency (SOD)), e.g., in regulating (up or down) growth and proliferation of T and /or B lymphocytes, as well as effecting the cytolytic activity of NK cells and other cell populations.
  • SOD severe combined immunodeficiency
  • These immune deficiencies may be genetic or be caused by viral (e.g., HIV) as well as bacterial or fungal infections, or may result from autoimmune disorders.
  • a molecule which inhibits or blocks interaction of a B7 lymphocyte antigen with its natural hgand(s) on immune cells such as a soluble, monomeric form of a peptide having B7-2 activity alone or in conjunction with a monomenc form of a peptide havmg an activity of another B lymphocyte antigen (e g., B7- 1, B7-3) or blocking antibody)
  • a B7 lymphocyte antigen e g., B7- 1, B7-3 or blocking antibody
  • Blocking B lymphocyte antigen function prevents cytokine synthesis by immune cells, such as T cells, and thus acts as an immunosuppressant
  • the lack of costimulation may also be sufficient to anergize the T cells, thereby inducing tolerance in a subject Induction of long-term
  • B lymphocyte antigen-blocking reagents may avoid the necessity of repeated administration of these blocking reagents. To achieve sufficient immunosuppression or tolerance in a subject, it may also be necessary to block the function of a combination of B lymphocyte antigens.
  • the efficacy of particular blocking reagents in preventing organ transplant rejection or GNHD can be assessed using animal models that are predictive of efficacy in humans.
  • a gene encoding an antisense construct which blocks expression of an MHC class II associated protein such as the mva ⁇ ant chain, can also be cotransfected with a DNA encoding a peptide having the activity of a B lymphocyte antigen to promote presentation of tumor associated antigens and induce tumor specific immunity
  • a T cell mediated immune response in a human subject may be sufficient to overcome tumor-specific tolerance in the subject.
  • MLR Mixed lymphocyte reaction
  • a protein of the present invention may be useful in regulation of hematopoiesis and, consequently, in the treatment of myeloid or lymphoid cell deficiencies. Even marginal biological activity in support of colony forming cells or of factor-dependent cell lines indicates involvement in regulating hematopoiesis, e.g. in supporting the growth and proliferation of erythroid progenitor cells alone or in combination with other cytokines, thereby indicating utility, for example, in treating various anemias or for use in conjunction with irradiation /chemotherapy to stimulate the production of erythroid precursors and/or erythroid cells; in supporting the growth and proliferation of myeloid
  • 66 cells such as granulocytes and monocytes /macrophages (i.e., traditional CSF activity) useful, for example, in conjunction with chemotherapy to prevent or treat consequent myelo-suppression; in supporting the growth and proliferation of megakaryocytes and consequently of platelets thereby allowing prevention or treatment of various platelet disorders such as thrombocytopenia, and generally for use in place of or complimentary to platelet transfusions; and /or in supporting the growth and proliferation of hematopoietic stem cells which are capable of maturing to any and all of the above- mentioned hematopoietic cells and therefore find therapeutic utility in various stem cell disorders (such as those usually treated with transplantation, including, without limitation, aplastic anemia and paroxysmal nocturnal hemoglobinuria), as well as in repopulating the stem cell compartment post inadiation/ chemotherapy, either in-vivo or ex-vivo (i.e., in conjunction with bone marrow transplantation or with peripheral progenitor cell transplantation (hom
  • Assays for embryonic stem cell differentiation include, without limitation, those described in: Johansson et al. Cellular Biology 15:141-151, 1995; Keller et al., Molecular and Cellular Biology 13:473-486, 1993; McClanahan et al, Blood 81:2903-2915, 1993.
  • Assays for stem cell survival and differentiation include, without limitation, those described in: Methylcellulose colony forming assays, Freshney, M.G. In Culture of Hematopoietic Cells. R.I. Freshney, et al. eds. Vol pp. 265-268, Wiley-Liss, Inc., New York, NY. 1994; Hirayama et al., Proc. Natl. Acad. Sci. USA 89:5907-5911, 1992; Primitive hematopoietic colony forming cells with high proliferative potential, McNiece, I.K. and Briddell, R.A. In Culture of Hematopoietic Cells. R.I. Freshney, et al eds. Vol pp. 23-39,
  • a protein of the present invention also may have utility in compositions used for bone, cartilage, tendon, ligament and /or nerve tissue growth or regeneration, as well as for wound healing and tissue repair and replacement, and in the treatment of burns, incisions and ulcers.
  • a protein of the present invention which induces cartilage and /or bone growth in circumstances where bone is not normally formed, has application in the healing of bone fractures and cartilage damage or defects in humans and other animals.
  • Such a preparation employing a protein of the invention may have prophylactic use in closed as well as open fracture reduction and also in the improved fixation of artificial joints. De novo bone formation induced by an osteogenic agent contributes to the repair of congenital, trauma induced, or oncologic resection induced craniofacial defects, and also is useful in cosmetic plastic surgery.
  • a protein of this invention may also be used in the treatment of periodontal disease, and in other tooth repair processes. Such agents may provide an environment to attract bone-forming cells, stimulate growth of bone-forming cells or induce differentiation of progenitors of bone-forming cells.
  • a protein of the invention may also be useful in the treatment of osteoporosis or osteoarthritis, such as through stimulation of bone and /or cartilage repair or by blocking inflammation or processes of tissue destruction (coUagenase activity, osteoclast activity, etc.) mediated by inflammatory processes.
  • tissue regeneration activity that may be attributable to the protein of the present invention is tendon/ligament formation.
  • a protein of the present invention which induces tendon /ligament-like tissue or other tissue formation in circumstances where such tissue is not normally formed, has application in the healing of tendon or ligament tears, deformities and other tendon or ligament defects in humans and other animals.
  • Such a preparation employing a tendon/ligament-like tissue inducing protein may have prophylactic use in preventing damage to tendon or ligament tissue, as well as use in the improved fixation of tendon or ligament to bone or other tissues, and
  • compositions of the present invention may provide an environment to attract tendon- or ligament-forming cells, stimulate growth of tendon- or ligament-forming cells, induce differentiation of progenitors of tendon- or ligament-forming cells, or induce growth of tendon /ligament cells or progenitors ex vivo for return in vivo to effect tissue repair.
  • the compositions of the invention may also be useful in the treatment of tendinitis, carpal tunnel syndrome and other tendon or ligament defects.
  • the compositions may also include an appropriate matrix and /or sequestering agent as a carrier as is well known in the art.
  • the protein of the present invention may also be useful for proliferation of neural cells and for regeneration of nerve and brain tissue, i.e. for the treatment of central and peripheral nervous system diseases and neuropathies, as well as mechanical and traumatic disorders, which involve degeneration, death or trauma to neural cells or nerve tissue. More specifically, a protein may be used in the treatment of diseases of the peripheral nervous system, such as peripheral nerve injuries, peripheral neuropathy and localized neuropathies, and central nervous system diseases, such as Alzheimer's, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Shy-Drager syndrome. Further conditions which may be treated in accordance with the present invention include mechanical and traumatic disorders, such as spinal cord disorders, head trauma and cerebrovascular diseases such as stroke. Peripheral neuropathies resulting from chemotherapy or other medical therapies may also be treatable using a protein of the invention.
  • Proteins of the invention may also be useful to promote better or faster closure of non-healing wounds, including without limitation pressure ulcers, ulcers associated with vascular insufficiency, surgical and traumatic wounds, and the like.
  • a protein of the present invention may also exhibit activity for generation or regeneration of other tissues, such as organs (including, for example, pancreas, liver, intestine, kidney, skin, endothelium), muscle (smooth, skeletal or cardiac) and vascular (including vascular endothelium) tissue, or for promoting the growth of cells comprising such tissues.
  • organs including, for example, pancreas, liver, intestine, kidney, skin, endothelium
  • muscle smooth, skeletal or cardiac
  • vascular including vascular endothelium
  • a protein of the invention may also exhibit angiogenic activity.
  • a protem of the present mvention may also be useful for gut protection or regeneration and treatment of lung or liver fibrosis, reperfusion injury in various tissues, and conditions resulting from systemic cytokine damage.
  • a protem of the present mvention may also be useful for promoting or inhibiting differentiation of tissues descnbed above from precursor tissues or cells; or for inhibiting the growth of tissues described above
  • the activity of a protem of the invention may, among other means, be measured by the following methods:
  • Assays for tissue generation activity include, without limitation, those described in: International Patent Publication No WO95/ 16035 (bone, cartilage, tendon); International Patent Publication No. WO95/05846 (nerve, neuronal); International Patent Publication No. WO91/07491 (skin, endothelium ) Assays for wound healing activity mclude, without limitation, those described ⁇ v
  • a protem of the present invention may also exhibit activm- or lnhibm-related activities. Inhibms are characterized by their ability to inhibit the release of follicle stimulating hormone (FSH), while achvins and are characterized by their ability to stimulate the release of follicle stimulating hormone (FSH)
  • FSH follicle stimulating hormone
  • a protem of the present mvention alone or m heterodimers with a member of the rnhibin a family, may be useful as a contraceptive based on the ability of nhibins to decrease fertility m female mammals and decrease spermatogenesis in male mammals Administration of sufficient amounts of other rnhibins can induce infertility in these mammals
  • the protem of the mvention as a homodimer or as a heterodimer with other protem suburuts of the rnhibin- ⁇ group, may be useful as a fertility mducmg therapeutic, based upon the ability of activm molecules m stimulating F
  • Assays for activin/inhibin activity include, without limitation, those described in: Vale et al., Endocrinology 91:562-572, 1972; Ling et al., Nature 321:779-782, 1986; Vale et al, Nature 321:776-779, 1986; Mason et al., Nature 318:659-663, 1985; Forage et al., Proc. Natl. Acad. Sci. USA 83:3091-3095, 1986.
  • the activity of a protein of the invention may, among other means, be measured by the following methods:
  • such a protein is expected to be useful in treatment of various coagulation disorders (including hereditary disorders, such as hemophilias) or to enhance coagulation and other hemostatic events in treating wounds resulting from trauma, surgery or other causes.
  • a protein of the invention may also be useful for dissolving or inhibiting formation of thromboses and for treatment and prevention of conditions resulting therefrom (such as, for example, infarction of cardiac and central nervous system vessels (e.g., stroke).
  • the activity of a protein of the invention may, among other means, be measured by the following methods: Assay for hemostatic and thrombolytic activity include, without limitation, those described in: Linet et al., J. Clin. Pharmacol. 26:131-140, 1986; Burdick et al., Thrombosis Res.45:413-419, 1987; Humphrey et al., Fibrinolysis 5:71-79 (1991); Schaub, Prostaglandins 35:467-474, 1988.
  • a protein of the present invention may also demonstrate activity as receptors, receptor ligands or inhibitors or agonists of receptor/ligand interactions.
  • receptors and ligands include, without limitation, cytokine receptors and their ligands, receptor kinases and their ligands, receptor phosphatases and their ligands, receptors involved in cell-cell interactions and their ligands (including without limitation, cellular adhesion molecules (such as selectins, integrins and their ligands) and receptor/ligand pairs involved in antigen presentation, antigen recognition and development of cellular and humoral immune responses).
  • Receptors and ligands are also useful for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction.
  • a protein of the present invention may themselves be useful as inhibitors of receptor/ligand interactions.
  • Suitable assays for receptor-ligand activity include without limitation those described in:Current Protocols in Immunology, Ed by J.E. Coligan, A.M. Kruisbeek, D.H. Margulies, E.M. Shevach, W.Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 7.28, Measurement of Cellular Adhesion under static conditions 7.28.1-7.28.22), Takai et al., Proc. Natl. Acad. Sci. USA 84:6864-6868, 1987; Bierer et al., J. Exp. Med. 168:1145-1156, 1988; Rosenstein et al., J. Exp. Med. 169:149-160 1989; Stoltenborg et al., J. Immunol. Methods 175:59-68, 1994; Stitt et al., CeU 80:661-670, 1995.
  • Proteins of the present invention may also exhibit anti-inflammatory activity.
  • the anti-inflammatory activity may be achieved by providing a stimulus to cells involved in the inflammatory response, by inhibiting or promoting cell-cell interactions (such as, for example, cell adhesion), by inhibiting or promoting chemotaxis of cells involved in the inflammatory process, inhibiting or promoting cell extravasation, or by stimulating or suppressing production of other factors which more directly inhibit or promote an inflammatory response.
  • Proteins exhibiting such activities can be used to treat inflammatory conditions including chronic or acute conditions), including without limitation inflammation associated with infection (such as septic shock, sepsis or systemic inflammatory response syndrome (SIRS)), ischemia-reperfusion injury, endotoxin lethality, arthritis, complement-mediated hyperacute rejection, nephritis, cytokine or chemokine-induced lung injury, inflammatory bowel disease, Crohn's disease or resulting from over production of cytokines such as TNF or IL-1. Proteins of the invention may also be useful to treat anaphylaxis and hypersensitivity to an antigenic substance or material.
  • infection such as septic shock, sepsis or systemic inflammatory response syndrome (SIRS)
  • ischemia-reperfusion injury such as endotoxin lethality, arthritis, complement-mediated hyperacute rejection, nephritis, cytokine or chemokine-induced lung injury, inflammatory bowel disease, Crohn's disease or resulting
  • Cadherins are calcium-dependent adhesion molecules that appear to play major roles during development, particularly in defining specific cell types. Loss or alteration of normal cadherin expression can lead to changes in cell adhesion properties linked to tumor growth and metastasis. Cadherin malfunction is also implicated in other human diseases, such as pemphigus vulgaris and pemphigus foliaceus (auto-immune blistering skin diseases), Crohn's disease, and some developmental abnormalities.
  • Fragments of proteins of the present invention with cadherin activity preferably a polypeptide comprising a decapeptide of the cadherin recognition site, and polynucleotides of the present invention encoding such protein fragments, can also be used to block cadherin function by binding to cadherins and preventing them from binding in ways that produce undesirable effects. Additionally, fragments of proteins of the present invention with cadherin activity, preferably truncated soluble cadherin fragments which have been found to be stable in the circulation of cancer patients, and polynucleotides encoding such protein fragments, can be used to disturb proper cell-cell adhesion.
  • effecting behavioral charactenstics including, without limitation, appetite, libido, stress, cognition (mcludmg cognitive disorders), depression (mcludmg depressive disorders) and violent behaviors; providing analgesic effects or other pain reducing effects; promoting differentiation and growth of embryonic stem cells in lineages other than hematopoietic lineages; hormonal or endocrine activity; in the case of enzymes, correcting deficiencies of the enzyme and treating deficiency-related diseases; treatment of hyperproliferative disorders (such as, for example, psoriasis); lmmunoglobulm-like activity (such as, for example, the ability to bind antigens or complement); and the ability to act as an antigen in a vaccine composition to raise an immune response against such protem or another material or entity which is cross-reactive with such protein.
  • hyperproliferative disorders such as, for example, psoriasis
  • lmmunoglobulm-like activity such as, for example, the ability to bind
  • a therapeutically effective amount of protein of the present invention is administered to a mammal having a condition to be treated.
  • Protein of the present invention may be administered in accordance with the method of the invention either alone or in combination with other therapies such as treatments employing cytokines, lymphokmes or other hematopoietic factors.
  • protein of the present invention may be administered either simultaneously with the cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors, or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administering protein of the present invention in combination with cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors.
  • Administration of protein of the present invention used in the pharmaceutical composition or to practice the method of the present invention can be carried out in a variety of conventional ways, such as oral ingestion, inhalation, topical application or cutaneous, subcutaneous, intraperitoneal, parenteral or intravenous injection. Intravenous administration to the patient is preferred.
  • protein of the present invention When a therapeutically effective amount of protein of the present invention is administered orally, protein of the present invention will be in the form of a tablet, capsule, powder, solution or elixir.
  • the pharmaceutical composition of the invention may additionally contain a solid carrier such as a gelatin or an adjuvant.
  • the tablet, capsule, and powder contain from about 5 to 95% protein of the present invention, and preferably from about 25 to 90% protein of the present invention.
  • a liquid carrier such as water, petroleum, oils of animal or plant origin such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils may be added.
  • protein of the present invention When a therapeutically effective amount of protein of the present invention is administered by intravenous, cutaneous or subcutaneous injection, protein of the present
  • Matrices may be comprised of combinations of any of the above mentioned types of material, such as polylactic acid and hydroxyapatite or collagen and tricalciumphosphate.
  • the bioceramics may be altered in composition, such as in calcium- aluminate-phosphate and processing to alter pore size, particle size, particle shape, and biodegradability.
  • a preferred family of sequestering agents is cellulosic materials such as alkylcelluloses (including hydroxyalkylcelluloses), including methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl- methylcellulose, and carboxymethylcellulose, the most preferred being cationic salts of carboxymethylcellulose (CMC).
  • CMC carboxymethylcellulose
  • Other preferred sequestering agents include hyaluronic acid, sodium alginate, poly(ethylene glycol), polyoxy ethylene oxide, carboxyvinyl polymer and poly(vinyl alcohol).
  • proteins of the invention may be combined with other agents beneficial to the treatment of the bone and /or cartilage defect, wound, or tissue in question.
  • agents include various growth factors such as epidermal growth factor

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Abstract

On décrit de nouveaux polynucléotides et les protéines codées par lesdits polynucléotides.
PCT/US1999/003458 1998-02-18 1999-02-18 Proteines secretees et polynucleotides codant lesdites proteines WO1999042470A1 (fr)

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AU26855/99A AU2685599A (en) 1998-02-18 1999-02-18 Secreted proteins and polynucleotides encoding them
CA002320799A CA2320799A1 (fr) 1998-02-18 1999-02-18 Proteines secretees et polynucleotides codant lesdites proteines
EP99907121A EP1056764A4 (fr) 1998-02-18 1999-02-18 Proteines secretees et polynucleotides codant lesdites proteines
JP2000532422A JP2002504488A (ja) 1998-02-18 1999-02-18 分泌蛋白およびそれらをコードするポリヌクレオチド

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US7503898P 1998-02-18 1998-02-18
US60/075,038 1998-02-18
US25160099A 1999-02-17 1999-02-17
US09/251,600 1999-02-17

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EP0883625A1 (fr) * 1995-10-06 1998-12-16 President And Fellows Of Harvard College Nouvelle proteine activatrice des thrombocytes
EP1218411A2 (fr) * 1999-09-20 2002-07-03 Millennium Pharmaceuticals, Inc. Proteines secretees et leurs utilisations
EP1230360A2 (fr) * 1999-11-09 2002-08-14 Human Genome Sciences 15 proteines secretees humaines
EP1282644A1 (fr) * 2000-04-10 2003-02-12 Human Genome Sciences, Inc. Anticorps, polypeptides et polynucleotides du recepteur tm4sf
EP1292827A1 (fr) * 2000-04-07 2003-03-19 Senomyx Inc. Recepteurs gustatifs t2r et genes codant pour eux
US6558910B2 (en) * 1999-09-10 2003-05-06 The Regents Of The University Of California SF, a novel family of taste receptors
US7041474B2 (en) 1998-12-30 2006-05-09 Millennium Pharmaceuticals, Inc. Nucleic acid encoding human tango 509
US7465550B2 (en) 1999-09-10 2008-12-16 The Regents Of The University Of California Method for screening taste-modulating compounds
US7517972B2 (en) 2002-07-29 2009-04-14 Senomyx, Inc. Nucleic acid sequences encoding a bitter taste receptor, T2R76
US8163503B2 (en) 1998-12-30 2012-04-24 Millennium Pharmaceuticals, Inc. Methods of identifying compounds that bind TANGO509

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See also references of EP1056764A4 *

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US6750323B1 (en) 1995-10-06 2004-06-15 President And Fellows Of Harvard College Platelet activation protein
EP0883625A4 (fr) * 1995-10-06 2001-04-25 Harvard College Nouvelle proteine activatrice des thrombocytes
EP0883625A1 (fr) * 1995-10-06 1998-12-16 President And Fellows Of Harvard College Nouvelle proteine activatrice des thrombocytes
US8163503B2 (en) 1998-12-30 2012-04-24 Millennium Pharmaceuticals, Inc. Methods of identifying compounds that bind TANGO509
US7385036B2 (en) 1998-12-30 2008-06-10 Millennium Pharmaceuticals, Inc. Human tango 509 polypeptides
US7041474B2 (en) 1998-12-30 2006-05-09 Millennium Pharmaceuticals, Inc. Nucleic acid encoding human tango 509
US9063124B2 (en) 1999-09-10 2015-06-23 The Regents Of The University Of California Method for identifying compounds that modulate a T2R taste receptor
US7888045B2 (en) 1999-09-10 2011-02-15 The Regents Of The University Of California Methods for identifying modulators of SF taste receptor signaling
US7868150B2 (en) 1999-09-10 2011-01-11 The Regents Of The University Of California Nucleic acids encoding T2R taste receptors
US8624012B2 (en) 1999-09-10 2014-01-07 The Regents Of The University Of California Nucleic acids encoding T2R bitter taste receptors
US7595166B2 (en) 1999-09-10 2009-09-29 The Regents Of The University Of California Methods of screening modulators of T2R taste receptors
US7745601B2 (en) 1999-09-10 2010-06-29 The Regents Of The University Of California Nucleic acids encoding T2R, a novel family of taste receptors
US8580527B2 (en) 1999-09-10 2013-11-12 The Regents Of The University Of California Methods for identifying compounds which modulate T2R bitter taste receptors
US8329885B2 (en) 1999-09-10 2012-12-11 The Regents Of The University Of California Nucleic acid encoding a T2R taste receptor
US9817000B2 (en) 1999-09-10 2017-11-14 The Regents Of The University Of California Method for identifying compounds that modulate a T2R taste receptor
US6558910B2 (en) * 1999-09-10 2003-05-06 The Regents Of The University Of California SF, a novel family of taste receptors
US7452694B2 (en) 1999-09-10 2008-11-18 The Regents Of The University Of California Nucleic acids encoding T2R of taste receptors
US7465550B2 (en) 1999-09-10 2008-12-16 The Regents Of The University Of California Method for screening taste-modulating compounds
US7479373B2 (en) 1999-09-10 2009-01-20 The Regents Of The University Of California Method for identifying compounds modulating taste transduction
EP1218411A4 (fr) * 1999-09-20 2004-09-01 Millennium Pharm Inc Proteines secretees et leurs utilisations
EP1218411A2 (fr) * 1999-09-20 2002-07-03 Millennium Pharmaceuticals, Inc. Proteines secretees et leurs utilisations
EP1230360A2 (fr) * 1999-11-09 2002-08-14 Human Genome Sciences 15 proteines secretees humaines
EP1230360A4 (fr) * 1999-11-09 2003-04-02 Human Genome Sciences Inc 15 proteines secretees humaines
US7704698B2 (en) 2000-04-07 2010-04-27 Senomyx, Inc. Human T2R51 taste receptor and related assays for identifying bitter taste modulators
US8153386B2 (en) 2000-04-07 2012-04-10 Senomyx, Inc. Human T2R64 taste receptor and related assays for identifying human bitter taste modulators
US7736862B2 (en) 2000-04-07 2010-06-15 Senomyx, Inc. Human T2R63 receptor and related assays for identifying human bitter taste modulators
US7718383B2 (en) 2000-04-07 2010-05-18 Senomyx, Inc. Human T2R65 taste receptor and related assays for identifying human bitter taste modulators
US7785802B2 (en) 2000-04-07 2010-08-31 Senomyx, Inc. Human T2R71 receptor and related assays for identifying human bitter taste modulators
US7816093B2 (en) 2000-04-07 2010-10-19 Senomyx, Inc. Assays for identifying human bitter taste modulators
US7638289B2 (en) 2000-04-07 2009-12-29 Senomyx, Inc. Human T2R55 taste receptor and related assays for identifying human bitter taste modulators
US10324098B2 (en) 2000-04-07 2019-06-18 Senomyx, Inc. T2R taste receptors and genes encoding same
US8017751B2 (en) 2000-04-07 2011-09-13 Senomyx, Inc. hT2R54 receptor polypeptides and nucleic acid sequences
US8030468B2 (en) 2000-04-07 2011-10-04 Senomyx, Inc. Human T2R51 taste receptor nucleic acid sequences and polypeptides
US8030009B2 (en) 2000-04-07 2011-10-04 Senomyx, Inc. Human T2R67 taste receptor and related assays for identifying human bitter taste modulators
US7723051B2 (en) 2000-04-07 2010-05-25 Senomyx, Inc. HT2R75 taste receptor and related assays for identifying human bitter taste modulators
US7393654B2 (en) 2000-04-07 2008-07-01 Senomyx, Inc. Human T2R54 taste receptor and use for identifying bitter taste modulators
US7105650B2 (en) * 2000-04-07 2006-09-12 Senomyx, Inc. T2R taste receptors and genes encoding same
US8334367B2 (en) 2000-04-07 2012-12-18 Senomyx, Inc. T2R taste receptors and genes encoding same
EP1292827A4 (fr) * 2000-04-07 2006-07-12 Senomyx Inc Recepteurs gustatifs t2r et genes codant pour eux
US9778270B2 (en) 2000-04-07 2017-10-03 Senomyx, Inc. T2R taste receptors and genes encoding same
EP1292827A1 (fr) * 2000-04-07 2003-03-19 Senomyx Inc. Recepteurs gustatifs t2r et genes codant pour eux
US9163074B2 (en) 2000-04-07 2015-10-20 Senomyx, Inc. Human T2R nucleic acid sequences
EP1282644A4 (fr) * 2000-04-10 2004-08-18 Human Genome Sciences Inc Anticorps, polypeptides et polynucleotides du recepteur tm4sf
EP1282644A1 (fr) * 2000-04-10 2003-02-12 Human Genome Sciences, Inc. Anticorps, polypeptides et polynucleotides du recepteur tm4sf
US7517972B2 (en) 2002-07-29 2009-04-14 Senomyx, Inc. Nucleic acid sequences encoding a bitter taste receptor, T2R76

Also Published As

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JP2002504488A (ja) 2002-02-12
AU2685599A (en) 1999-09-06
EP1056764A4 (fr) 2001-08-29
CA2320799A1 (fr) 1999-08-26
EP1056764A1 (fr) 2000-12-06

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