WO2006021942A2 - Peptides bioactifs - Google Patents

Peptides bioactifs Download PDF

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Publication number
WO2006021942A2
WO2006021942A2 PCT/IE2005/000086 IE2005000086W WO2006021942A2 WO 2006021942 A2 WO2006021942 A2 WO 2006021942A2 IE 2005000086 W IE2005000086 W IE 2005000086W WO 2006021942 A2 WO2006021942 A2 WO 2006021942A2
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Prior art keywords
peptide
peptides
platelet
proteins
sequence
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PCT/IE2005/000086
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WO2006021942A3 (fr
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Niamh Moran
Dermot Kenny
Denis Shields
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Royal College Of Surgeons In Ireland
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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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70596—Molecules with a "CD"-designation not provided for elsewhere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily

Definitions

  • the invention relates to bioactive peptides and proteins.
  • the invention relates to peptides and proteins which modulate cellular, especially platelet, activity.
  • the invention also relates to bioactive peptides and proteins useful in treating or preventing diseases or conditions associated with thrombosis.
  • synthesising the peptides revealed by the screening step optionally, for each peptide, synthesising a peptide from an aligned region of a paralogous protein; and assaying the synthesised peptides for bioactivity.
  • orthologous protein means a protein which is equivalent to the protein containing the peptide of interest but separated by speciation (i.e. the equivalent protein in a different species).
  • paralogous protein means a non-equivalent, related, protein not separated by speciation, i.e. related proteins which have arisen by duplication within the genome (i.e. related human proteins).
  • a method of calculating a BAD score for any given residue is provided in the paper by Caffrey et al. [2].
  • the method of the invention is preferably a means of identifying proteins and peptides which are involved in modulating platelet activity or platelet signalling.
  • the library of proteins will be a library of platelet-specific, transmembrane, proteins.
  • the method of the invention can likewise be utilised in identifying bioactive peptides or proteins which are involved in modulating the activity of other types of cells, such as, for example, neutrophils, megakaryocytes, inflammatory cells, cancer cells, endothelial cells, stem cells, neuronal cells, cardiac cells, bone cells, bone marrow cells, epithelial cells and hepatic cells.
  • the library of proteins is screened for peptides having at least 5, preferably at least 6, more preferably at least 7, more preferably at least 8, and ideally at least 9, amino acids.
  • the library of proteins is screened for peptides having at most 15, preferably at most 14, more preferably at most 13, more preferably at most 12, and ideally at most 11, amino acids.
  • the library is screened for peptides having approximately 10 amino acids.
  • the invention also relates to oligopeptides comprising peptides produced by the method of the invention, and additionally the use of such oligopeptides to modulate cellular, especially platelet activity.
  • the invention also relates to the use of such oligopeptides in treating or preventing a condition or disease associated with thrombosis.
  • bioactive peptides revealed 18 short cytoplasmic regions of transmembrane platelet specific proteins which either activate or inhibit platelets.
  • sequences of these peptides is given in SEQUENCE ID NO 1 to 18.
  • the invention also relates to an isolated oligopeptide comprising: a peptide selected from the group comprising SEQUENCE ID NO 1 to 18; or a fragment or analogue of a peptide selected from the group comprising SEQUENCE ID NO 1 to 18.
  • oligopeptide means an isolated amino acid sequence comprising, or consisting essentially of, a peptide selected from the group comprising SEQUENCE JD NO 1 to 18, or fragments or analogues of such peptides. However, the term should be taken to exclude the native proteins from which the peptides of any of Sequence ID No's 1 to 18 have been isolated. Details of these native proteins are provided in Table 1.
  • the oligopeptide will contain from 5 to 100 amino acids, suitably from 5 to 50 amino acids, preferably from 10 to 30 amino acids, more preferably from 10 to 20 amino acids, and ideally from 10 to 12 amino acids.
  • the oligopeptide, or the fragment or analogue thereof is modified to make it cell permeable.
  • the oligopeptide, or fragment or analogue thereof is palmitylated by addition of a palmitylate group (H 3 C-(CH 2 )i 4 - CO-).
  • a palmitylate group H 3 C-(CH 2 )i 4 - CO-.
  • a "fragment" of a peptide means a contiguous stretch of amino acid residues of at least 4 amino acids, typically at least 5 amino acids, preferably at least 6 amino acids, which retains the function of modulating platelet or other cell activity.
  • a fragment of this peptide could, for example, consist of any of the following non-exhaustive list of sequences (provided the fragment retained the function of modulating platelet or other cell activity): RRER; ERRD; DLFT; DLFTE; RRDLF; RDLFTE; and ERRDLFT.
  • an "analogue" of a peptide means a polypeptide modified by varying the amino acid sequence of one of the peptides of SEQUENCE ID NO's 1 to 18, or fragments thereof, e.g. by manipulation of the nucleic acid encoding the peptide or by altering the peptide itself.
  • Such peptide analogues may involve insertion, addition, deletion and/or substitution of one or more amino acids, while providing a peptide capable of modulating platelet or other cell activity. Insertion, addition and substitution with natural and modified amino acids is envisaged.
  • analogues involve the insertion, addition, deletion and/or substitution of 5 or fewer amino acids, more preferably of 4 or fewer, even more preferably of 3 or fewer, most preferably of 1 or 2 amino acids only.
  • Analogues also include derivatives of the above peptides, including the peptide linked to a coupling partner, e. g. an effector molecule, a label, a drug, a toxin and/or a carrier or transport molecule, or cyclised forms of the peptide.
  • a coupling partner e. g. an effector molecule, a label, a drug, a toxin and/or a carrier or transport molecule, or cyclised forms of the peptide.
  • Methods of cyclising peptides will be known to those skilled in the field of protein chemistry. Techniques for coupling the peptides of the invention to both peptidyl and non- peptidyl coupling partners are well known in the art.
  • Analogues of and for use in the present invention further include reverse-or retro- analogues of natural peptides or their synthetic derivatives. See, for example, EP 0497 366, U.S. 5,519,115, and Merrifield et al., 1995, PNAS, 92:3449-53, the disclosures of which are herein incorporated by reference.
  • reverse peptides are produced by reversing the amino acid sequence of a naturally occurring or synthetic peptide. Reverse peptides are purported not only to retain the biological activity of the non-reversed "normal" peptide but may possess enhanced properties, including increased biological activity. (See Iwahori et al., 1997, Biol. Pharm. Bull. 20: 267-70).
  • Peptides including reverse peptides, analogues and fragments thereof
  • the peptides of and for use in the present invention can be readily prepared according to well-established, standard liquid or, preferably, solid-phase peptide synthesis methods known in the art (see, for example, J. M. Stewart and J. D. Young, Solid Phase Peptide Synthesis, 2nd edition, Pierce Chemical Company, Rockford, Illinois (1984), in M. Bodanzsky and A. Bodanzsky, The Practice of Peptide Synthesis, Springer Verlag, New York (1984).
  • Cellular Activity Modulating Agents see, for example, J. M. Stewart and J. D. Young, Solid Phase Peptide Synthesis, 2nd edition, Pierce Chemical Company, Rockford, Illinois (1984), in M. Bodanzsky and A. Bodanzsky, The Practice of Peptide Synthesis, Springer Verlag, New York (1984).
  • the invention also relates to the use of an oligopeptide of the invention to modulate the activity of mammalian, especially human, cells, including megakaryocytes, inflammatory cells (inflammatory disease, i.e. RA), cancer cells (cancer), endothelial cells (vascular disease, hypertension), stem cells (direct development of pluripotent stem cells), neuronal cells (preventing cell death after stroke), cardiac cells (vascular diseases), bone cells (stimulating growth following trauma), bone marrow cells, epithelial cells (intestinal disease), hepatic cells (liver diseases), and vascular cells.
  • inflammatory cells inflammatory disease, i.e. RA
  • cancer cells cancer cells
  • endothelial cells vascular disease, hypertension
  • stem cells direct development of pluripotent stem cells
  • neuronal cells preventing cell death after stroke
  • cardiac cells vascular diseases
  • bone cells stimulates growth following trauma
  • bone marrow cells epithelial cells (intestinal disease), hepatic cells (liver diseases), and vascular cells
  • the invention also relates to a platelet activity modulating agent comprising an oligopeptide of the invention, or a fragment or analogue thereof.
  • the invention also relates to the use of an oligopeptide of the invention, or a fragment or analogue thereof, to modulate the activity of platelets.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an oligopeptide according to the invention, or a fragment or analogue thereof.
  • the invention also relates to a method of modulating the activity of platelets in a mammalian subject comprising the step of administering to the mammal a suitable amount of an oligopeptide according to the invention, or a fragment or analogue thereof, or a pharmaceutical composition of the invention.
  • the invention also relates to a method of reducing or inhibiting platelet aggregation in a mammalian subject comprising the step of administering to the mammal a suitable amount of an oligopeptide according to the invention, or a fragment or analogue thereof, or a pharmaceutical composition of the invention.
  • the invention also relates to a method of treating or preventing a disease or condition associated with thrombosis comprising a step of administering to a subject a suitable amount of an oligopeptide according to the invention, or a fragment or analogue thereof.
  • Diseases or conditions associated with thrombosis include Stroke, Atherosclerosis and Coronory Artery Disease, Ischemic Cerebrovascular Disease and Peripheral Vascular Disease.
  • the oligopeptide, fragment, or analogue is modified to allow cell permeability, typically by incorporation of a palmitylate group.
  • the invention also relates to the use of the oligopeptides of the invention, or fragments or analogues thereof, as research tools.
  • oligopeptides according to the invention are used to screen a library of compounds (chemical or biological), or screen a cellular (i.e. platelet) lysate or cellular material preparation, to identify ligands which have the ability to modulate platelet activity.
  • a library of compounds chemical or biological
  • a cellular (i.e. platelet) lysate or cellular material preparation to identify ligands which have the ability to modulate platelet activity.
  • Means of designing such a screen will be well known to those skilled in the art.
  • the peptide of SEQUENCE ID NO 1 is modified to incorporate a HIS tag or a biotin moiety to facilitate immobilisation of the peptide to a support such as a 96 well plate.
  • Each well in the plate is then be reacted with a different candidate compound, and then washed with a labelled moiety having a high binding affinity for the peptide bound to the support.
  • the label may be, for example, FITC, carboxy-fluorescein or Cy-dye. Where the candidate compound binds to the peptide, reduced levels of fluorescence will be detected compared to a control.
  • the invention provides a method of identifying ligands to the oligopeptides of the invention, which method comprises the step of contacting a putative ligand with an oligopeptide of the invention, or a fragment or analogue thereof, and determining whether the putative ligand has a binding affinity for the oligopeptide, or fragment or analogue thereof.
  • the putative ligand must have at least a mMolar binding affinity.
  • the oligopeptides of the invention, or fragments or analogues thereof are also used to screen a library of proteins to identify any proteins which interact with the oligopeptides.
  • a biotinylated version of the peptide of SEQUENCE ID NO 1 is used to screen a human foetal brain expression array to identify any proteins having a binding affinity, typically a high binding affinity, for the biotinylated peptide.
  • Methods of performing such a screen are described in the paper by Larkin et al. [3]. Proteins identified by this screen form part of the present invention.
  • the invention also relates to oligopeptides of the invention, or fragments or analogues thereof, which incorporate a biotin moiety or a HIS tag.
  • the biotin moiety may be linked to the oligopeptide through a photoactivatable group, such as, for example, benzoyl phenylalanine.
  • the method of the invention revealed 18 short cytoplasmic regions of transmembrane platelet specific proteins which either activate or inhibit platelets.
  • the sequences of these peptides is given in SEQUENCE ID NO 1 to 18.
  • the sequence, and reference, of the native proteins containing the peptides of the invention are provided in Table 1 below.
  • the 10 amino acid peptide of SEQUENCE ID NO. 2 is part of the Nectin 3 protein, the full sequence of which is provided in SEQUENCE ID NO 19.
  • CD226 is a platelet T-cell activation protein previously described [4,5].
  • the CD226- paralogous protein is the adhesion molecule Nectin 3 [6], which also acts as a herpesvivus receptor [7].
  • ATP8A1 is a potential phospholipid transporting ATPase IA (EC 3.6.3.1) previously described [8].
  • ABCR has been previously identified as a retinal specific ATP-binding cassette, with gene defects associated with retinal disease. No platelet specific role has previously been identified.
  • the paralogous protein is encoded by the ABCl gene, which causes Tangiers disease, which is associated with platelet abnormalities [10].
  • VPPl is the 116 KlD subunit of the vacuolar proton pump, as determined by Swissprot database annotation (accession number Q93050; VPPl-HUMAN). While a related sequence has a role in the inhibition of endothelial cell proliferation [11], its specific role in cellular regulation is unknown. Mutations in the VPPl -paralogous protein, VPP4, are associated with tubular acidosis [12].
  • ADCY4 is an adenylate cyclase [14], identified as the paralogue of ADCY7, which may be the predominant adenylate cyclase expressed in platelets [15].
  • the peptide of SEQUENCE ID NO 10 is derived from the paralogue of a platelet- associated protein of unknown function.
  • the gene encoding the peptide has three protein sequences associated with it, with accession numbers Q8NDE1 (contains the peptide), Q8N219 (contains the peptide), and Q9NSG5 (fragment not containing the peptide).
  • EDG2-Human and its paralogue EDG7, are both members of the seven transmembrane receptor lysophospholipid receptor family. Both proteins are expressed in platelets [16,17].
  • KNC3 and KNCl are potassium voltage-gated channel protein subunits Kv3.3 KSHIIID (KNC3) and Kv3.1/Kv4/NGK2 (KNCl).
  • KNC3 and KNCl potassium voltage-gated channel protein subunits Kv3.3 KSHIIID (KNC3) and Kv3.1/Kv4/NGK2 (KNCl).
  • KNCl Kv3.3 KSHIIID
  • KNCl Kv3.1/Kv4/NGK2
  • PGRMCl has been identified as a putative progesterone receptor [19].
  • the paralogous protein, SPUF has had no functional assignments to date, and is identified by Swissprot database entry accession number Q9UMX5.
  • PTGER is the prostacyclin receptor [20].
  • the PTGIR peptide 17 is 3 and 5 residues upstream of naturally palmitoylated cysteines, which may act to bring the region close to the membrance in the native protein [21].
  • SCN8A is a sodium channel subunit [22]. Mouse mutants of SCN8A exhibit neurological disorders [23-25].
  • the invention also relates to a method of identifying a ligand for a protein selected from the group comprising SEQUENCE ID NO 19 TO 33, the method comprising the steps of: providing a candidate ligand; contacting a protein selected from the group comprising SEQUENCE ID NO 19 to 33 with the candidate ligand; and determining whether the candidate ligand binds to the protein.
  • a library of compounds may be screened to identify ligands for the proteins.
  • the proteins of SEQUENCE ID NO 19 TO 33 may also be used to screen a library of proteins to identify any interacting proteins.
  • a biotinylated version of the protein of SEQUENCE ID NO 19 may be used to screen a human foetal brain expression array to identify any proteins having a binding affinity, typically a high binding affinity, for the biotinylated protein. Methods of performing such a screen are described in the paper by Larkin et al [3]. Proteins identified by this screen form part of the present invention.
  • the invention relates to the use of known agonists or antagonists of a protein selected from the group comprising SEQUENCE ID NO 19 TO 33 to modulate platelet activity.
  • a protein selected from the group comprising SEQUENCE ID NO 19 TO 33 to modulate platelet activity.
  • agonists and antagonists of the proteins For example, the sodium channel , SCN8A is antagonised by the naturally occuring wasp peptide beta-pompilidotoxin [26] and its derivatives [27]. Further, extracellular fragments of nectin-3 act as agonists and antagonists [28].
  • the invention also provides a method of assaying for modulation of platelet activity, comprising the steps of: contacting a platelet preparation with a putative platelet agonist/antagonist in a reaction vessel; assaying the mixture for platelet activation; adding a known platelet aggregating agent to the mixture; and monitoring the level of platelet aggregation.
  • the mixture is assayed for platelet activation by monitoring platelet aggregation.
  • the known platelet aggregating agent is thrombin.
  • the assay is carried out on a multi-well plate.
  • X platelet ligand
  • Y universal ligand
  • Z non-platelet ligand
  • dark grey segments are 10-mer peptide sequences of interest that are aligned between the platelet and paralogue proteins, overlapping at least one residue that exhibits apparent specificity
  • ticks represent peptide interaction mimicking that seen naturally for parental protein
  • crosses indicate peptide effect of paralogous peptide where region in parental protein would not normally interact with protein X.
  • paralogous peptides were similarly synthesised from the aligned region of a paralogue.
  • Hydrophobic peptides and those likely to cause problems of synthesis were excluded. These 52 decameric oligopeptides from 22 platelet proteins and their 22 paralogues were then used in aggregation and ADP- release assays of resting and thrombin-stimulated platelets. Agonists of platelet activation were defined as those that caused resting platelets to either secrete ADP or to aggregate, while antagonists were defined as those peptides that inhibited the thrombin-induced aggregation of platelet activation and ADP release. Statistical modelling compared the effects of each peptide compared to all other peptides, as well as to controls containing the medium in which each peptide was re-suspended.
  • 129 likely transmembrane proteins were defined as being of interest in platelet biology, based on published literature, RNA array and proteomic survey studies. Of these, 91 had sufficient evolutionary information (related orthologues in other species and at least one paralogue within the human genome). From 22 of these proteins a total of 26 peptides were chosen, selecting peptides from aligned regions that included residues with apparent specificity in comparison with the paralogous protein. Peptides were synthesised chemically and a pamitylate group added to the N-terminus, permitting the targeting of the peptide to the transmembrane region[4, 8]. Peptides were then added to 96 well plate assays containing fresh platelets replicated across six donors at lO ⁇ m and 50 ⁇ m concentrations.
  • Agg-R level of aggregation of resting platelets
  • ADP-R ADP release from resting platelets
  • Agg-TA level of the aggregation of thrombin-activated platelets
  • ADP-TA level of ADP release from thrombin-activated platelets
  • the Fmoc-protected amino acids, coupling reagents and the Rink Amide MBHA resin were purchased from Novabiochem. AU other reagents and solvents were purchased from Aldrich and used without further purification.
  • the peptides were prepared by standard Solid Phase Peptide Synthesis [35,36] according to the Fmoc-tBu strategy [37,38] with HBTU/HOBt/DEEA coupling chemistry, in DMF solvent. Double coupling cycles, using a total 10-fold excess of Fmoc amino acid derivatives to resin-bound peptide, were employed.
  • the side chain protecting groups were Acm for Cys; Boc for Lys and Trp; tBu, for Ser, Thr, and Tyr; O-tBu for Asp and GIu; Pbf, for Arg; Trt, for Asn, GIn and His.
  • the peptides were characterised by Matrix Assisted Laser Desorption Ionisation — Time Of Flight - Mass Spectrometry on a Bruker Reflex III ( ⁇ -cyano-4-hydroxy- cinnamic acid matrix).
  • Agg-R level of aggregation of resting platelets
  • ADP-R ADP release from resting platelets
  • Agg- TA level of the aggregation of thrombin-activated platelets
  • ADP-TA level of ADP release from thrombin-activated platelets
  • Washed platelets were prepared as described previously [31] and diluted in Buffer A (13OmM NaCl, 1OmM trisodum citrate, 9mM NaHCO 3 , 6mM Dextrose, 0.9mM MgCl 2 , 0.8ImM KH 2 PO 4 , 1.8mM CaCl 2 Tris HCl pH 7.4) to a concentration of 6X10 s /ml.
  • Buffer A 13OmM NaCl, 1OmM trisodum citrate, 9mM NaHCO 3 , 6mM Dextrose, 0.9mM MgCl 2 , 0.8ImM KH 2 PO 4 , 1.8mM CaCl 2 Tris HCl pH 7.4
  • Peptides stock solutions were prepared in an appropriate vehicle depending on individual solubility (H 2 O, DMSO; 1% w/v or methanol; 5%w/v final concentration; See Table ??) and stored at -8O 0 C.
  • Dual agonist-antagonist assessment was performed as follows: Platelets (80 ⁇ l) and peptide pairs (lO ⁇ M and 50 ⁇ M) or the relevant vehicle were added to a 96 well plate to a final volume of lOO ⁇ l and shaken at 37 0 C. Absorbance readings (405nm; 0.1 sec; Wallac Victor 2 1420 spectrophotometer) were taken before addition of peptide (TO) and at subsequent 3 minute intervals. Thrombin (0.2U/ml) was added after 6 mins (T6) and an addidional 2 absorbance readings were taken at T9 and T12. A total of 6 donors (3 male and 3 female) were selected for each peptide.
  • platelets were prepared as above but diluted to 3XlO 8 AnI and aliquoted into black and white 96 well isoplates. Peptide pairs (lO ⁇ M and 50 ⁇ M) or the relevant vehicle were added and the plates shaken at 37oC. T 0 Luminescence reading at 405nm was obtained using the Wallac Victor 2 1420 multi label counter from Perkin Elmer at 37 0 C. Chronolume (lO ⁇ l) was added after 3 mins and luminescence recorded to measure the peptide-induced ADP release. Parallel plates were prepared with platelets activated by 0.2U/ml thrombin. Changes in absorbance reflected antagonistic properties of peptides to inhibit thrombin-induced ADP release.
  • VPPl ADP-R 6 0.0100 24.1% 9.62% Activator
  • VPP4 ADP-R 7 0.0053 35.7% 9.38% Activator
  • Nectin3 ADP-R 2 0.0020 35.8% 7.82% Activator
  • Activation indicates the mean % activation of the peptide across donors.
  • SE Standard error of mean % activation.
  • p-value p-value from 2-tailed Mann-Whitney Test.
  • ADP-R ADP release from resting platelets induced by peptide.
  • ADP-TA inhibition by peptide of ADP release from thrombin-activated platelets.
  • Agg-R aggregation of resting platelets induced by peptide.
  • Agg-TA inhibition by peptide of aggregation of thrombin-activated platelets.
  • Agg-CA inhibition by peptide of aggregation of calcium ionophore (A23187) activated platelets.

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Abstract

L'invention se rapporte aux peptides représentés par les identificateurs de séquence SEQ ID NO 1 à 18. Ces peptides se sont avérés utiles pour moduler l'activité plaquettaire, et pour moduler d'autres types d'activité cellulaire. La présente invention concerne en outre des fragments ou analogues de ces peptides qui peuvent également moduler l'activité plaquettaire.
PCT/IE2005/000086 2004-08-26 2005-08-25 Peptides bioactifs WO2006021942A2 (fr)

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Citations (4)

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WO2000029579A1 (fr) * 1998-11-13 2000-05-25 Zymogenetics, Inc. Proteine de type chondromoduline de mammmifere
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WO2004048550A2 (fr) * 2002-11-26 2004-06-10 Incyte Corporation Proteines associees a une reponse immune

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998016548A1 (fr) * 1996-10-11 1998-04-23 University Of Massachusetts Peptides recepteurs de thrombine et utilisations correspondantes
WO2000029579A1 (fr) * 1998-11-13 2000-05-25 Zymogenetics, Inc. Proteine de type chondromoduline de mammmifere
WO2004016653A2 (fr) * 2002-08-15 2004-02-26 Leukotech A/S Peptides bactericides, anti-apoptose, pro-inflammatoires et anti-inflammatoires de la proteine de liaison heparine (hbp)
WO2004048550A2 (fr) * 2002-11-26 2004-06-10 Incyte Corporation Proteines associees a une reponse immune

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