WO2000060099A1 - Map kinase phosphatase a double specificite dsp-4 - Google Patents

Map kinase phosphatase a double specificite dsp-4 Download PDF

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Publication number
WO2000060099A1
WO2000060099A1 PCT/US2000/009313 US0009313W WO0060099A1 WO 2000060099 A1 WO2000060099 A1 WO 2000060099A1 US 0009313 W US0009313 W US 0009313W WO 0060099 A1 WO0060099 A1 WO 0060099A1
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WIPO (PCT)
Prior art keywords
dsp
polypeptide
polynucleotide
cell
antibody
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PCT/US2000/009313
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English (en)
Inventor
Ralf M. Luche
Bo Wei
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Ceptyr, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ceptyr, Inc. filed Critical Ceptyr, Inc.
Priority to AU42131/00A priority Critical patent/AU4213100A/en
Priority to EP00921870A priority patent/EP1171614A1/fr
Priority to JP2000609589A priority patent/JP2002540795A/ja
Priority to CA002367109A priority patent/CA2367109A1/fr
Publication of WO2000060099A1 publication Critical patent/WO2000060099A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/03—Phosphoric monoester hydrolases (3.1.3)
    • C12Y301/03048—Protein-tyrosine-phosphatase (3.1.3.48)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/03—Phosphoric monoester hydrolases (3.1.3)
    • C12Y301/03016—Phosphoprotein phosphatase (3.1.3.16), i.e. calcineurin

Definitions

  • MAP-kinase signaling In higher eukaryotes, the physiological role of MAP-kinase signaling has been correlated with cellular events such as proliferation, oncogenesis, development and differentiation. Accordingly, the ability to regulate signal transduction via these pathways could lead to the development of treatments and preventive therapies for human diseases associated with MAP-kinase signaling, such as cancer.
  • Figure 4 shows northern blot hybridization using a 2 P-labeled full length DSP-4 encoding nucleic acid sequence as probe.
  • Blot contained human polyA+ RNA from various tissue types as follows: (Fig. 4A) Lane 1, heart; lane 2, brain; lane 3, placenta; lane 4, lung; lane 5, liver; lane 6, skeletal muscle; lane 7, kidney; lane 8, pancreas; (Fig. 4B) Lane 1, spleen; lane 2, thymus; lane 3, prostate; lane 4, testis; lane 5, ovary; lane 6, small intestine; lane 7, colon; lane 8, peripheral blood leukocyte.
  • DSP-4 polypeptide variants within the scope of the present invention may contain one or more substitutions, deletions, additions and/or insertions.
  • the ability of the variant to dephosphorylate tyrosine and threonine residues within a DSP-4 substrate is not substantially diminished.
  • the ability of such a DSP-4 variant to dephosphorylate tyrosine and threonine residues within a DSP-4 substrate may be enhanced or unchanged, relative to a native DSP-4, or may be diminished by less than 50%, and preferably less than 20%, relative to native DSP-4.
  • Such variants may be identified using the representative assays provided herein.
  • negatively charged amino acids include aspartic acid and glutamic acid; positively charged amino acids include lysine and arginine; and amino acids with uncharged polar head groups having similar hydrophilicity values include leucine, isoleucine and valine; glycine and alanine; asparagine and glutamine; and serine, threonine, phenylalanine and tyrosine.
  • amino acids that may represent conservative changes include: (1) ala, pro, gly, glu, asp, gin, asn, ser, thr; (2) cys, ser, tyr, thr; (3) val, ile, leu, met, ala, phe; (4) lys, arg, his; and (5) phe, tyr, tip, his.
  • a variant may also, or alternatively, contain nonconservative changes.
  • a polynucleotide may be amplified from cDNA prepared from a suitable cell or tissue type, such as human thymus or skeletal muscle cells.
  • a suitable cell or tissue type such as human thymus or skeletal muscle cells.
  • Such polynucleotides may be amplified via polymerase chain reaction (PCR).
  • PCR polymerase chain reaction
  • sequence-specific primers may be designed based on the sequences provided herein, and may be purchased or synthesized.
  • An amplified portion may be used to isolate a full length gene from a suitable library (e.g., human thymus or skeletal muscle cDNA) using well known techniques.
  • a library cDNA or genomic
  • a library is screened using one or more polynucleotide probes or primers suitable for amplification.
  • a library is size-selected to include larger molecules. Random primed libraries may also be preferred for identifying 5' and upstream regions of genes. Genomic libraries are preferred for obtaining introns and extending 5' sequences.
  • Nucleotide sequences as described herein may be joined to a variety of other nucleotide sequences using established recombinant DNA techniques.
  • a polynucleotide may be cloned into any of a variety of cloning vectors, including plasmids, phagemids, lambda phage derivatives and cosmids.
  • Vectors of particular interest include expression vectors, replication vectors, probe generation vectors and sequencing vectors.
  • a suitable vector contains an origin of replication functional in at least one organism, convenient restriction endonuclease sites and one or more selectable markers. Other elements will depend upon the desired use, and will be apparent to those having ordinary skill in the art.
  • polynucleotides may be formulated so as to permit entry into a cell of a mammal, and expression therein. Such formulations are particularly useful for therapeutic purposes, as described below.
  • a polynucleotide may be incorporated into a viral vector using well known techniques.
  • a viral vector may additionally transfer or incorporate a gene for a selectable marker (to aid in the identification or selection of transduced cells) and/or a targeting moiety, such as a gene that encodes a ligand for a receptor on a specific target cell, to render the vector target specific.
  • Targeting may also be accomplished using an antibody, by methods known to those having ordinary skill in the art.
  • the present invention also contemplates the use of allelic variants of DSP-4, as well as DSP-4 sequences from other organisms. Such sequences may generally be identified based upon similarity to the sequences provided herein (e.g., using hybridization techniques) and based upon the presence of DSP-4 activity, using an assay provided herein.
  • substrates of DSP-4 may include full length tyrosine phosphorylated proteins and polypeptides as well as fragments (e.g., portions), derivatives or analogs thereof that can be phosphorylated at a tyrosine residue and that may, in certain preferred embodiments, also be able to undergo phosphorylation at a serine or a threonine residue.
  • fragments, derivatives and analogs include any naturally occurring or artificially engineered DSP-4 substrate polypeptide that retains at least the biological function of interacting with a DSP-4 as provided herein, for example by forming a complex with a DSP-4.
  • Preferred binding molecules include antibodies, which may be, for example, polyclonal, monoclonal, single chain, chimeric, anti-idiotypic, or CDR-grafted immunoglobulins, or fragments thereof, such as proteolytically generated or recombinantly produced immunoglobulin F(ab') 2 , Fab, Fv, and Fd fragments.
  • Certain preferred antibodies are those antibodies that inhibit or block DSP-4 activity within an in vitro assay, as described herein. Binding properties of an antibody to DSP-4 may generally be assessed using immunodetection methods including, for example, an enzyme-linked immunosorbent assay
  • Human monoclonal antibodies may be generated by any number of techniques with which those having ordinary skill in the art will be familiar. Such methods include but are not limited to, Epstein Barr Virus (EBV) transformation of human peripheral blood cells (e.g., containing B lymphocytes), in vitro immunization of human B cells, fusion of spleen cells from immunized transgenic mice carrying human immunoglobulin genes inserted by yeast artificial chromosomes (YAC), isolation from human immunoglobulin V region phage libraries, or other procedures as known in the art and based on the disclosure herein.
  • EBV Epstein Barr Virus
  • YAC yeast artificial chromosomes
  • isolation from human immunoglobulin V region phage libraries or other procedures as known in the art and based on the disclosure herein.
  • one method for generating human monoclonal antibodies includes immortalizing human peripheral blood cells by EBV transformation. See, e.g., U.S. Patent No. 4,464,456.
  • affinity polypeptides for construction of sFv fusion proteins may include streptavidin fusion proteins, as disclosed, for example, in WO 89/03422; U.S. 5,489,528; U.S. 5,672,691 ; WO 93/24631 ; U.S. 5,168,049; U.S. 5,272,254 and elsewhere, and avidin fusion proteins (see, e.g., EP 51 1,747).
  • sFv polypeptide sequences may be fused to fusion polypeptide sequences, including effector protein sequences, that may include full length fusion polypeptides and that may alternatively contain variants or fragments thereof.
  • An additional method for selecting antibodies that specifically bind to a DSP-4 polypeptide or variant or fragment thereof is by phage display. See, e.g., Winter et al., 1994 Annul. Rev. Immunol. 12:433-55; Burton et al., 1994 Adv. Immunol. 57:191-280.
  • Human or murine immunoglobulin variable region gene combinatorial libraries may be created in phage vectors that can be screened to select Ig fragments (Fab, Fv, sFv, or multimers thereof) that bind specifically to a DSP-4 polypeptide or variant or fragment thereof. See, e.g., U.S. Patent No.
  • a library containing a plurality of polynucleotide sequences encoding Ig variable region fragments may be inserted into the genome of a filamentous bacteriophage, such as Ml 3 or a variant thereof, in frame with the sequence encoding a phage coat protein, for instance, gene III or gene VIII of Ml 3, to create an Ml 3 fusion protein.
  • a fusion protein may be a fusion of the coat protein with the light chain variable region domain and/or with the heavy chain variable region domain.
  • Phage display techniques may also be used to select polypeptides, peptides or single chain antibodies that bind to DSP-4.
  • candidate nucleic acid molecules e.g., DNA
  • suitable vectors having multicloning sites into which candidate nucleic acid molecules (e.g., DNA) encoding such peptides or antibodies may be inserted, see, e.g., McLafferty et al, Gene 725:29-36, 1993; Scott et al., 1990 Science 249:386-390; Smith et al, 1993 Methods Enzymol. 277:228-257; Fisch et al., 1996, Proc. Nat Acad. Sci. USA 93:7761-66.
  • Anti-idiotype antibodies or fragments thereof may also be generated by any of the recombinant genetic engineering methods described above, or by phage display selection.
  • An anti-idiotype antibody may react with the antigen binding site of the anti-DSP-4 antibody such that binding of the anti-DSP-4 antibody to a DSP-4 polypeptide is competitively inhibited.
  • an anti-idiotype antibody as provided herein may not competitively inhibit binding of an anti-DSP-4 antibody to a DSP-4 polypeptide.
  • Assays may generally be performed using any of a variety of samples obtained from a biological source, such as eukaryotic cells, bacteria, viruses, extracts prepared from such organisms and fluids found within living organisms.
  • Biological samples that may be obtained from a patient include blood samples, biopsy specimens, tissue explants, organ cultures and other tissue or cell preparations.
  • a patient or biological source may be a human or non-human animal, a primary cell culture or culture adapted cell line including but not limited to genetically engineered cell lines that may contain chromosomally integrated or episomal recombinant nucleic acid sequences, immortalized or immortalizable cell lines, somatic cell hybrid cell lines, differentiated or differentiatable cell lines, transformed cell lines and the like.
  • the reagent is typically an antibody, which may be prepared as described below.
  • an antibody which may be prepared as described below.
  • Assay formats known to those having ordinary skill in the art for using an antibody to detect a polypeptide in a sample. See, e.g., Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988.
  • the assay may be performed in a Western blot format, wherein a protein preparation from the biological sample is resolved by gel electrophoresis, transferred to a suitable membrane and allowed to react with the antibody. The presence of the antibody on the membrane may then be detected using a suitable detection reagent, as described below.
  • the assay involves the use of antibody immobilized on a solid support to bind to the target DSP-4 and remove it from the remainder of the sample.
  • the bound DSP-4 may then be detected using a second antibody or reagent that contains a reporter group.
  • a competitive assay may be utilized, in which a DSP-4 polypeptide is labeled with a reporter group and allowed to bind to the immobilized antibody after incubation of the antibody with the sample.
  • the extent to which components of the sample inhibit the binding of the labeled polypeptide to the antibody is indicative of the reactivity of the sample with the immobilized antibody, and as a result, indicative of the level of DSP-4 in the sample.
  • Agents that may be screened within such assays include, but are not limited to, antibodies and antigen-binding fragments thereof, competing substrates or peptides that represent, for example, a catalytic site or a dual phosphorylation motif, antisense polynucleotides and ribozymes that interfere with transcription and/or translation of DSP-4 and other natural and synthetic molecules, for example small molecule inhibitors, that bind to and inactivate DSP-4.
  • Candidate agents for use in a method of screening for a modulator of DSP-4 according to the present invention may be provided as "libraries” or collections of compounds, compositions or molecules. Such molecules typically include compounds known in the art as “small molecules” and having molecular weights less than 10 5 daltons, preferably less than 10 4 daltons and still more preferably less than 10 3 daltons.
  • members of a library of test compounds can be administered to a plurality of samples, each containing at least one DSP-4 polypeptide as provided herein, and then assayed for their ability to enhance or inhibit DSP-4-mediated dephosphorylation of, or binding to, a substrate.
  • DSP-4 function e.g., phosphotyrosine and/or phosphoserine/threonine dephosphorylation
  • DSP-4 activity e.g., phosphotyrosine and/or phosphoserine/threonine dephosphorylation
  • Such compounds are also valuable in research directed to molecular signaling mechanisms that involve DSP-4, and to refinements in the discovery and development of future DSP-4 compounds exhibiting greater specificity.
  • the resulting products comprise a library that can be screened followed by iterative selection and synthesis procedures, such as a synthetic combinatorial library of peptides (see e.g., PCT/US91/08694, PCT/US91/04666, which are hereby incorporated by reference in their entireties) or other compositions that may include small molecules as provided herein (see e.g., PCT/US94/08542, EP 0774464, U.S. 5,798,035, U.S. 5,789,172, U.S. 5,751,629, which are hereby incorporated by reference in their entireties).
  • Those having ordinary skill in the art will appreciate that a diverse assortment of such libraries may be prepared according to established procedures, and tested using DSP-4 according to the present disclosure.
  • modulating agents may be identified by combining a candidate agent with a DSP-4 polypeptide or a polynucleotide encoding such a polypeptide, in vitro or in vivo, and evaluating the effect of the candidate agent on the DSP-4 phosphatase activity using, for example, a representative assay described herein.
  • An increase or decrease in phosphatase activity can be measured by performing a representative assay provided herein in the presence and absence of a candidate agent.
  • a candidate agent may be included in a mixture of active DSP-4 polypeptide and substrate (e.g., a phosphorylated MAP-kinase), with or without pre-incubation with one or more components of the mixture.
  • an agent may effect apoptosis or necrosis of the cell, and/or may modulate the functioning of the cell cycle within the cell.
  • Ashkenazi et al. 1998 Science, 281 :1305; Thornberry et al., 1998 Science 281 :1312; Evan et al., 1998 Science 281 :1317; Adams et al., 1998 Science 257:1322; and references cited therein.
  • compositions may be formulated for any appropriate manner of administration, including, for example, topical, oral, nasal, intrathecal, rectal, vaginal, sublingual or parenteral administration, including subcutaneous, intravenous, intramuscular, intrasternal, intracavernous, intrameatal or intraurethral injection or infusion.
  • parenteral administration the carrier preferably comprises water, saline, alcohol, a fat, a wax or a buffer.
  • Dual specificity phosphatases belong to the larger family of protein tyrosine phosphatases (PTPs) that share a conserved catalytic domain containing a cysteine residue situated N-terminal to a stretch of five variable amino acids followed by an arginine residue (Fauman et al., Trends In Bioch. Sci. 21 :413-417, 1996). DSPs typically contain a PTP active site motif but lack sequence homology to PTPs in other regions (Jia, Biochem. and Cell Biol. 75:17-26, 1997).
  • PTPs protein tyrosine phosphatases
  • human thymus cDNA was screened in 5' and 3' RACE (rapid amplification of cDNA ends) reactions as described (Frohman et al., Proc. Nat. Acad. Sci. USA 85:8998, 1988; Ohara et al., Proc. Nat. Acad. Sci. USA 86:5673, 1989; Loh et al., Science 243:217, 1989) using 573' RACE kits (Boehringer Mannheim, Indianapolis, IN) according to the supplier's instructions. Sequence information immediately adjacent to the conserved sequence motif was used in the 5' and 3' RACE reactions with human skeletal muscle cDNA, using the following primers (SEQ ID NOs:5 to 11):

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Abstract

L'invention concerne des compositions et des méthodes pour le traitement de maladies associées à la prolifération cellulaire, la différenciation cellulaire et/ou la survie cellulaire. L'invention concerne notamment la phosphatase à double spécificité DSP-4 ainsi que ses variantes polypeptidiques qui stimulent la déphosphorylation des substrats de DSP-4. Les polypeptides peuvent servir, par exemple, à identifier des anticorps et d'autres agents qui inhibent l'activité de DSP-4. Ces polypeptides et ces agents peuvent servir à moduler la prolifération cellulaire, la différenciation cellulaire et la survie cellulaire.
PCT/US2000/009313 1999-04-07 2000-04-07 Map kinase phosphatase a double specificite dsp-4 WO2000060099A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU42131/00A AU4213100A (en) 1999-04-07 2000-04-07 Dsp-4 dual-specificity map kinase phosphatase
EP00921870A EP1171614A1 (fr) 1999-04-07 2000-04-07 Map kinase phosphatase a double specificite dsp-4
JP2000609589A JP2002540795A (ja) 1999-04-07 2000-04-07 Ｄｓｐ−４二重特異性ｍａｐキナーゼホスファターゼ
CA002367109A CA2367109A1 (fr) 1999-04-07 2000-04-07 Map kinase phosphatase a double specificite dsp-4

Applications Claiming Priority (2)

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US12820499P 1999-04-07 1999-04-07
US60/128,204 1999-04-07

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JP (1) JP2002540795A (fr)
AU (1) AU4213100A (fr)
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WO (1) WO2000060099A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001012819A2 (fr) * 1999-08-13 2001-02-22 Sugen, Inc. Nouvelles phosphatases de proteines et diagnostic et traitement des troubles lies a la phosphatase
WO2001073060A2 (fr) * 2000-03-24 2001-10-04 Millennium Pharmaceuticals, Inc. 18221, nouveau phosphatase a specificite double et ses utilisations
WO2003106646A2 (fr) * 2002-06-17 2003-12-24 Isis Pharmaceuticals, Inc. Modulation antisens de l'expression de la phosphatase 4 a double specificite

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
DATABASE EMBL 19 June 1998 (1998-06-19), NCI-CGAP: "ow27b10.s1 Soares_parathyroid_tumor_NbHPA Homo sapiens cDNA clone IMAGE:1648027 3' similar to SW:DUS5_HUMAN Q16690 DUAL SPECIFICITY PROTEIN PHOSPHATASE 5 ;, mRNA sequence", XP002144714 *
DATABASE EMBL 24 June 1998 (1998-06-24), NCI-CGAP: "ow48e06.x1 Soares_parathyroid_tumor_NbHPA Homo sapiens cDNA clone IMAGE:1650082 3' similar to SW:PTP3_CHLEU Q39491 PUTATIVE PROTEIN TYROSINE PHOSPHATASE ;, mRNA sequence.", XP002144713 *
DATABASE SWISSPROT 15 July 1998 (1998-07-15), HARING M A ET AL: "DUAL SPECIFICITY PROTEIN PHOSPHATASE (EC 3.1.3.48) (EC 3.1.3.16).", XP002144715 *
FLINT A J ET AL: "DEVELOPMENT OF SUBSTRATE-TRAPPING MUTANTS TO IDENTIFY PHYSIOLOGICAL SUBSTRATES OF PROTEIN TYROSINE PHOSPHATASES", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA,US,NATIONAL ACADEMY OF SCIENCE. WASHINGTON, vol. 94, 1 March 1997 (1997-03-01), pages 1680 - 1685, XP002051429, ISSN: 0027-8424 *
KEYSE S M: "AN EMERGING FAMILY OF DUAL SPECIFICITY MAP KINASE PHOSPHATASES", BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH,NL,ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, vol. 1265, 1995, pages 152 - 160, XP000196716, ISSN: 0167-4889 *
MUDA MARCO ET AL: "Molecular cloning and functional characterization of a novel mitogen-activated protein kinase phosphatase, MKP-4.", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 272, no. 8, 1997, pages 5141 - 5151, XP002144712, ISSN: 0021-9258 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001012819A2 (fr) * 1999-08-13 2001-02-22 Sugen, Inc. Nouvelles phosphatases de proteines et diagnostic et traitement des troubles lies a la phosphatase
WO2001012819A3 (fr) * 1999-08-13 2002-01-24 Sugen Inc Nouvelles phosphatases de proteines et diagnostic et traitement des troubles lies a la phosphatase
WO2001073060A2 (fr) * 2000-03-24 2001-10-04 Millennium Pharmaceuticals, Inc. 18221, nouveau phosphatase a specificite double et ses utilisations
WO2001073060A3 (fr) * 2000-03-24 2002-04-04 Millennium Pharm Inc 18221, nouveau phosphatase a specificite double et ses utilisations
WO2003106646A2 (fr) * 2002-06-17 2003-12-24 Isis Pharmaceuticals, Inc. Modulation antisens de l'expression de la phosphatase 4 a double specificite
WO2003106646A3 (fr) * 2002-06-17 2004-07-01 Isis Pharmaceuticals Inc Modulation antisens de l'expression de la phosphatase 4 a double specificite

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JP2002540795A (ja) 2002-12-03
AU4213100A (en) 2000-10-23
EP1171614A1 (fr) 2002-01-16

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