US2006281130A1PendingUtilityA1
Metod of modulation of interaction between receptor and ligand
Est. expiryDec 20, 2022(expired)· nominal 20-yr term from priority
A61P 9/00A61P 9/06A61P 41/00A61P 43/00A61P 9/14A61P 7/02A61P 9/10A61P 39/00A61P 25/14A61P 3/10A61P 25/18A61P 25/00A61P 35/00A61P 25/08A61P 31/00A61P 25/30A61P 25/16A61P 27/02A61P 25/02A61P 31/04A61P 25/28A61P 21/00A61P 17/00C07K 7/08A61P 11/00G01N 33/566A61P 19/00G01N 2333/50C07K 16/22A61P 17/02A61P 13/12C07K 7/06A61K 38/00G01N 33/74A61P 1/16A61P 15/04
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Claims
Abstract
The present invention relates to a method for modulating the interaction between at least two proteins, wherein at least one of the two proteins is a functional cell-surface receptor and the other protein is the receptor ligand. The invention features a binding site of said functional cell-surface receptor on the receptor ligand and discloses a series of amino acid sequences, which are part of the structure of said binding site and/or involved in the interaction between the receptor and the ligand. Moreover, the present invention features methods for molecular design and screening of a candidate compound capable of modulating the interaction between the functional cell-surface receptor and receptor ligand through the described binding site, and provides a screening assay for identification of such a compound. The invention further describes an antibody capable of binding to the above binding site and/or to an epitope comprising an amino acid sequence essential for executing the receptor ligand interaction through said binding site. The invention also concerns a variety of uses of the disclosed methods, peptide sequences and antibodies. The invention in preferred embodiments concerns the binding site of the fibroblast growth factor receptor (FGFR) on FGFR ligands, compounds capable of modulating the receptor ligand interaction through said binding site, and antibody capable of recognition of said binding site.
Claims
exact text as granted — not AI-modified1 . A method of modulating the interaction between a functional cell-surface fibroblast growth factor receptor, or a variant thereof, and a polypeptide having a binding site to said receptor, wherein said binding site comprises at least one of the sequences set forth in SEQ ID NOS: 2-146, said method comprising
i) providing a compound capable of interacting with the receptor at the binding site of the receptor for the polypeptide; ii) presenting the compound of step (i) to the the receptor and the polypeptide.
2 - 3 . (canceled)
4 . The method according to claim 1 , wherein the cell-surface receptor is selected from the family of fibroblast growth factor receptors (FGFRs) comprising FGFR1, FGFR2, FGFR3 and FGFR4
5 . The method according to claim 1 , wherein the receptor is FGFR1.
6 - 7 . (canceled)
8 . The method according to claim 1 , wherein the polypeptide is a cell adhesion molecule which is selected from the group consisting of
Neural Cell Adhesion Molecule (NCAM), Neural cell adhesion molecule L1, Neural Cell Adhesion Molecule-2 (NCAM-2) Neuron-glia Cell Adhesion Molecule (Ng-CAM), Neural cell adhesion molecule CALL, Neuroglian, Nr-CAM (HBRAVO, NRCAM, NR-CAM 12) Axonin-1/TAG-1, Myelin-Associated Glycoprotein (MAG), Neural cell adhesion molecule BIG-1, Neural cell adhesion molecule BIG-2, Fasciclin (FAS-2) Neural cell adhesion molecule HNB-3/NB-3 Neural cell adhesion molecule HNB-2/NB-2, Cadherin, Junctional Adhesion Molecule-1 (JAM-1), Neural cell adhesion F3/F11(Contactin), Neurofascin, B-lymphocyte cell adhesion molecule CD22, Neogenin (NEO1), Intercellular Cell Adhesion Molecule-5 (ICAM-5/telencephalin) Galactose binding lectin-12 (galectin-12), Galactose binding lectin-4 (galectin-4)
9 . The method according to claim 1 , wherein the polypeptide is a functional cell-surface receptor which is selected from the group consisting of
Neurotrophin Tyrosin Kinase Type-2 (NTRKT-2), Leukocyte Antigen Related Protein-Tyrosine Phosphatase (LAR-PTPRF) Nephrin, Protein-Tyrosine Phosphatase Receptor type S (PTPRS) Protein-Tyrosine Phosphatase Receptor type kappa (R-PTP-kappa), Protein-Tyrosine Phosphatase Receptor type D (PTPRD), Ephrin type-A receptor 8 (EPHA8/Tyrosine-Protein Kinase Receptor EEK) Ephrin type-A receptor 3 (EPHA8/Tyrosine-Protein Kinase Receptor ETK-1/CEK4), Ephrin type-A receptor 2 Insulin Receptor (IR) Insulin-like Growth Factor-1 Receptor (IGF-1) Insulin-related Receptor (IRR), Tyrosine-Protein Kinase Receptor Tie-1, Roundabout receptor-1 (robo-1), Neuronal nicotinic acetylcholine receptor alpha 3 subunit (CHRNA3) Neuronal acetylcholine receptor alpha 6 subunit Platelet-Derived Growth Factor Receptor Beta (PDGFRB) Interleukin-6 Receptor (IL-6R), Interleukin-23 Receptor (IL-23R), Beta-common cytokine receptor of IL-3, IL5 and GmCsf Cytokine Receptor-Like molecule 3 (CRLF1), Class I Cytokine Receptor (ZCYTOR5) Netrin-1 receptor DCC, Leukocyte Fc Receptor-like Protein (IFGP2), Macrophage Scavenger Receptor 2 (MSR2) and Granulocyte Colony Stimulating Factor Receptor (G-CSF-R).
10 . The method according to claim 1 , wherein the polypeptide is perlecan.
11 . The method according to, claim 1 , wherein the polypeptide is a metalloprotease is selected from the group consisting of
A disintegrin and metalloprotease-8 (ADAM-8) A disintegrin and metalloprotease-19 (ADAM-19) A disintegrin and metalloprotease-12 (ADAM-12) A disintegrin and metalloprotease-28 (ADAM-28) A disintegrin and metalloprotease-33 (ADAM-33) precursor, A disintegrin and metalloprotease-9 (ADAM-9), A disintegrin and metalloprotease-7 (ADAM-7), A disintegrin and metalloprotease-1A (ADAM-1A) Fertilin alpha, A disintegrin and metalloprotease-15 (ADAM-15) Metalloproteinase-desintegrin domain containing protein (TECAM), and Metalloproteinase 1.
12 . The method according to claim 1 , wherein the polypeptide is an extracellular matrix molecule which is selected from the group consisting of
Collagen type VII, Fibronectin and Tenascin-R.
13 . The method according to claim 1 , wherein the polypeptide is Cytokine-like factor-1 (CLF-1).
14 . The method according to claim 1 , wherein the interaction between the receptor and polypeptide is a low affinity interaction.
15 . The method according to claim 14 , wherein the affinity of interaction is within the range of Kd 10 −3 -10 −11 M, such as within the range Kd 10 −5 -10 −8 .
16 . (canceled)
17 . The method according to claim 1 , wherein the compound is a peptide.
18 . The method of claim 17 , wherein the peptide comprises 6 to 16 contiguous amino acid residues and consists of a sequence selected from any of the amino acid sequences set forth on SEQ ID NOS: 1-10, 100, or 125, or comprises a fragment of said sequence.
19 . (canceled)
20 . The method of claim 17 , wherein the peptide comprises 6 to 16 contiguous amino acid residues and consists of a sequence selected from any of the amino acid sequences set forth in SEQ ID NOS: 11-99, 101-124, or 126-146, or comprises a fragment of said sequence.
21 - 24 . (canceled)
25 . A screening method for a compound capable of modulating interaction between a functional cell-surface fibroblast growth factor receptor or a variant thereof, and a polypeptide having a binding site to said receptor, wherein said binding site comprises at least one of the sequences set forth in SEQ ID NOS: 2-146, said method comprising
i) providing the polypeptides of a fibroblast growth factor receptor (FGFR) and the neural cell adhesion molecule (NCAM); ii) providing a candidate compound which is designed by using structural data on the binding site of NCAM with FGFR; iii) presenting the candidate compound of (ii) to the polypeptides of (i); iv) determining the interaction between NCAM and FGFR before and after the presenting of the candidate compound to said polypeptides; v) determining whether the interaction between FGFR and NCAM is modulated by the candidate compound, vi) selecting a compound capable of modulating the interaction between FGFR and a polypeptide having a binding site to said receptor, wherein said binding site comprises at least one of the sequences set forth in SEQ ID NOS:2-146.
26 . The screening method according to claim 25 , wherein FGFR is selected from FGFR1, FGFR2, FGFR3 or FGFR4.
27 . The screening method according to claim 25 , wherein the polypeptide having a binding site for the cell-surface receptor, wherein said binding site comprises at least one of the sequences set forth in SEQ ID NOS:2-146, is selected from the group consisting of
Neural cell adhesion molecule L1, Neural Cell Adhesion Molecule-2 (NCAM-2), Neuron-glia Cell Adhesion Molecule (Ng-CAM), Neural cell adhesion molecule CALL, Neuroglian, Nr-CAM, Axonin-1/TAG-1, Axonal-associated Cell Adhesion Molecule, Myelin-Associated Glycoprotein (MAG), Neural cell adhesion molecule BIG-1, Neural cell adhesion molecule BIG-2, Fasciclin, Neural cell adhesion molecule HNB-3/NB-3, Neural cell adhesion molecule HNB-2/NB-2, Cadherin, Junctional Adhesion Molecule-1 (JAM-1) Neural cell adhesion F3/F11(Contactin), Neurofascin, B-lymphocyte cell adhesion molecule CD22, Neogenin (NEO1), Intercellular Cell Adhesion Molecule-5 (ICAM-5/telencephalin), Galactose binding lectin-12 (galectin-12), Galactose binding lectin-4 (galectin-4), Neurotrophin Tyrosin Kinase Type-2 (NTRKT-2), Leukocyte Antigen Related Protein-Tyrosine Phosphatase (LAR-PTPRF), Nephrin, Protein-Tyrosine Phosphatase Receptor type S (PTPRS), Protein-Tyrosine Phosphatase Receptor type kappa (R-PTP-kappa), Protein-Tyrosine Phosphatase Receptor type D (PTPRD), Ephrin type-A receptor 8, Ephrin type-A receptor 3, Ephrin type-A receptor 2, Insulin Receptor (IR), Insulin-like Growth Factor-1 Receptor (IGF-1), Insulin-related Receptor (IRR), Tyrosine-Protein Kinase Receptor Tie-1 Roundabout receptor-1 (robo-1), Neuronal nicotinic acetylcholine receptor alpha 3 subunit (CHRNA3), Neuronal acetylcholine receptor alpha 6 subunit, Platelet-Derived Growth Factor Receptor Beta (PDGFRB), Interleukin-6 Receptor (IL-6R), Interleukin-23 Receptor (IL-23R), Beta-common cytokine receptor of IL-3, IL5 and GmCsf, Cytokine Receptor-Like molecule 3 (CRLF1), Class I Cytokine Receptor (ZCYTOR5), Netrin-1 receptor DCC, Leukocyte Fc Receptor-like Protein (IFGP2), Macrophage Scavenger Receptor 2 (MSR2), Granulocyte Colony Stimulating Factor Receptor, Perlecan, A disintegrin and metalloprotease-8 (ADAM-8), A disintegrin and metalloprotease-19 (ADAM-19), A disintegrin and metalloprotease-12 (ADAM-12), A disintegrin and metalloprotease-28 (ADAM-28), A disintegrin and metalloprotease-33 (ADAM-33) precursor, A disintegrin and metalloprotease-9 (ADAM-9), A disintegrin and metalloprotease-7 (ADAM-7), A disintegrin and metalloprotease-1A (ADAM-1A Fertilin alpha), A disintegrin and metalloprotease-15 (ADAM-15), Metalloproteinase-desintegrin domain containing protein (TECAM), Metalloproteinase 1, Collagen type VII, Fibronectin, Tenascin-R, or Cytokine-like factor-1 (CLF-1).
28 . The screening method according to claim 25 , wherein the polypeptide, is NCAM.
29 . The screening method according to claim 25 , wherein the compound is for the manufacture of a medicament for the treatment of normal, degenerated or damaged NCAM presenting cells.
30 . The screening method according to claim 25 , wherein the compound is for the manufacture of a medicament treatment of diseases and conditions of the central and peripheral nervous system, or of the muscles or of various organs.
31 . The screening method according to claim 25 , wherein the compound is for the manufacture of a medicament for the treatment of diseases or conditions of the central and peripheral nervous system, such as postoperative nerve damage, traumatic nerve damage, impaired myelination of nerve fibers, postischaemic damage, e.g. resulting from a stroke, Parkinson's disease, Alzheimer's disease, Huntington's disease, dementias such as multiinfarct dementia, sclerosis, nerve degeneration associated with diabetes mellitus, disorders affecting the circadian clock or neuro-muscular transmission, and schizophrenia, mood disorders, such as manic depression; for treatment of diseases or conditions of the muscles including conditions with impaired function of neuro-muscular connections, such as after organ transplantation, or such as genetic or traumatic atrophic muscle disorders; or for treatment of diseases or conditions of various organs, such as degenerative conditions of the gonads, of the pancreas such as diabetes mellitus type I and II, of the kidney such as nephrosis and of the heart, liver and bowel.
32 . The screening method according to claim 25 , wherein the compound is for the manufacture of a medicament for the treatment of postoperative nerve damage, traumatic nerve damage, impaired myelination of nerve fibers, postischaemic, e.g. resulting from a stroke, Parkinson's disease, Alzheimer's disease, Huntington's disease, dementias such as multiinfarct dementia, sclerosis, nerve degeneration associated with diabetes mellitus, disorders affecting the circadian clock or neuro-muscular transmission, and schizophrenia, mood disorders, such as manic depression.
33 . The screening method according to claim 25 , wherein the compound is for the manufacture of a medicament for the promotion of wound-healing.
34 . The screening method according to claim 25 , wherein the compound is for the manufacture of a medicament for the treatment of cancer.
35 . The screening method according to claim 31 , wherein the cancer is any type of solid tumors requiring neoangiogenesis.
36 . The screening method according to claim 25 , wherein the first compound is for the manufacture of a medicament for the prevention of cell death of heart muscle cells, such as after acute myocardial infarction, or after angiogenesis.
37 . The screening method according to claim 25 , wherein the compound is for the manufacture of a medicament for revascularsation.
38 . The screening method according to claim 25 , wherein the compound is for the manufacture of a medicament for the stimulation of the ability to learn and/or the short and/or long-term memory.
39 . An assay for sequential screening of a candidate compound for the capability of modulating the interaction between a functional cell-surface fibroblast growth factor receptor (FGFR) or a variant thereof, and a polypeptide having a binding site to said receptor, wherein said binding site comprises at least one of the sequences set forth in SEQ ID NOS: 2-146, said method comprising
i) providing at least one functional FGFR molecule, and a molecule of at least one polypeptide having a binding site to said receptor, wherein said binding site comprises at least one of the sequences set forth in SEQ ID NOS: 2-146, ii) presenting the at least one receptor molecule of step (i) to the at least one polypeptide of step (i), or presenting the at least one polypeptide of step (i) to the at least one receptor molecule of step (i) and permitting the interaction between the said receptor and said polypeptide, iii) recording the interaction between the molecules of step (ii), iv) presenting a candidate compound to the molecules of step (ii); v) recording the interaction between the molecules of step (iv), vi) assessing at least one effect of the candidate compound on the interaction between the molecules of step (iv), vii) selecting a compound capable of modulating interaction between receptor and polypeptide of step (i).
40 . The assay according to claim 39 , wherein step (vii) is followed by the steps of
viii) presenting the selected on step (vii) candidate compound to at least one cell presenting at least one FGFR molecule or a variant thereof, and the at least one polypeptide having a binding site to said receptor, wherein said binding site comprises at least one of the sequences set forth in SEQ ID NOS: 2-146, and ix) assessing at least one effect of the compound on the cell of step (viii).
41 . The assay according to claim 39 , wherein the recording of interaction between the molecules on step (iii) or step (v), and the assessment of the at least one effect of the candidate compound on step (vi) is achieved by using a method selected from surface plasmon resonance analysis, nucleic magnetic resonance spectroscopy, sedimentation, immunoprecipitation, two-hybrid system, or resonance energy transfer analysis.
42 . The assay according to claim 40 , wherein the at least one effect of step (ix) is selected from stimulation/inhibition of receptor phosphorylation, intracellular signal transduction, gene expression, cellular adhesion, cell motility, neuritogenesis, apoptosis, cell proliferation or synaptic plasticity.
43 . A method for molecular design for a compound capable of modulating the interaction between fibroblast growth factor receptor and a polypeptide having a binding site for said receptor, wherein said binding site comprises at least one of the sequences set forth in SEQ ID NOS: 2-146, comprising using structural data on the binding site of NCAM with FGFR.
44 . (canceled)
45 . A peptide fragment consisting of an amino acid sequence selected from the group consisting of the following amino acid sequences:
NIEVWVEAENALGKKV,
(SEQ ID NO: 2)
ATNRQGKVKAFAHL,
(SEQ ID NO: 3)
RYVELYVVADSQEFQK,
(SEQ ID NO: 4)
VAENSRGKNVAKG,
(SEQ ID NO: 5)
GEYWCVAENQYGQR,
(SEQ ID NO: 6)
RLAALNGKGLGEIS,
(SEQ ID NO: 7)
KYIAENMKAQNVAKEI,
(SEQ ID NO: 8)
TIMGLKPETRYAVR,
(SEQ ID NO: 9)
KGLGEISAATEFKT,
(SEQ ID NO: 10)
NMGIWVQAENALG,
(SEQ ID NO: 11)
IWVQAENMLG,
(SEQ ID NO: 12)
EIWVEATNRLG,
(SEQ ID NO: 13)
VWVQAANALG,
(SEQ ID NO: 14)
EVWIEKDPAKGRI,
(SEQ ID NO: 15)
ATNKGGEVKKNGHL,
(SEQ ID NO: 16)
KYVELYLVADYLEFQK,
(SEQ ID NO: 17)
RYVELYVVVDNAEFQ,
(SEQ ID NO: 18)
KYVELVIVADNREFQR,
(SEQ ID NO: 19)
KYIEYYLVLDNGEFKR,
(SEQ ID NO: 20)
RYLELYIVADHTLF,
(SEQ ID NO: 21)
KYVEMFVVVNHQRFQ,
(SEQ ID NO: 22)
RYVELFIVVDKERY,
(SEQ ID NO: 23)
KYVELFIVADDTVYRR,
(SEQ ID NO: 24)
KFIELFVVADEYVYRR,
(SEQ ID NO: 25)
KIVEKVIVADNSEVRK,
(SEQ ID NO: 26)
VELVIVADHSEAQK,
(SEQ ID NO: 27)
VAENSRGKNIAKG,
(SEQ ID NO: 28)
IAENSRGKNVARG,
(SEQ ID NO: 29)
AENSRGKNSFRG,
(SEQ ID NO: 30)
IASNLRGRNLAKG,
(SEQ ID NO: 31)
IPENSLGKTYAKG,
(SEQ ID NO: 32)
IAENMKAQNEAK,
(SEQ ID NO: 33)
QFIAENMKSHNETKEV,
(SEQ ID NO: 34)
GEYWCVAKNRVGQ,
(SEQ ID NO: 35)
GSYTCVAENMVGK,
(SEQ ID NO: 36)
GKYVCVGTNMVGER,
(SEQ ID NO: 37)
GNYTCVVENEYG,
(SEQ ID NO: 38)
GEYTCLAGNSIG,
(SEQ ID NO: 39)
QYYCVAENGYG,
(SEQ ID NO: 40)
GEYYQEAEQNGYG,
(SEQ ID NO: 41)
GNYTCLVENEYG,
(SEQ ID NO: 42)
GMYQCLAENAYG,
(SEQ ID NO: 43)
GMYQCAENTHG,
(SEQ ID NO: 44)
GIYYCLASNNYG,
(SEQ ID NO: 45)
GGYYCTADNSYG,
(SEQ ID NO: 46)
GEYQCFARNDYG,
(SEQ ID NO: 47)
GEYFCLASNKMG,
(SEQ ID NO: 48)
GEYQCFARNKFG,
(SEQ ID NO: 49)
GEYFCLASNKMG,
(SEQ ID NO: 50)
GGYYCTADNNYG,
(SEQ ID NO: 51)
GNYSCEAENAWGTK,
(SEQ ID NO: 52)
GEYTCLAENSLG,
(SEQ ID NO: 53)
GEYECVAENGRLG,
(SEQ ID NO: 54)
GNYTCVVENKFGR,
(SEQ ID NO: 55)
GEYTCLAGNSIG,
(SEQ ID NO: 56)
GEYFCVASNPIG,
(SEQ ID NO: 57)
EYTCIANNQAGE,
(SEQ ID NO: 58)
GMYQCVAENKHLG,
(SEQ ID NO: 59)
GEYMCTASNTIGQ,
(SEQ ID NO: 60)
EYVCIAENKAGEQ,
(SEQ ID NO: 61)
GDYTLIAKNEYGK,
(SEQ ID NO: 62)
GFYQCVAENEAG,
(SEQ ID NO: 63)
GKYECVATNSAGTR,
(SEQ ID NO: 64)
GEYFCVYNNSLG,
(SEQ ID NO: 65)
GEYECAATNAHGR,
(SEQ ID NO: 66)
GAYWCQGTNSVGK,
(SEQ ID NO: 67)
GTYSCVAENILG,
(SEQ ID NO: 68)
RVAAVNGKGQGDYS,
(SEQ ID NO: 69)
RVAAINGCGIGPFS,
(SEQ ID NO: 70)
AVLNGKGLG,
(SEQ ID NO: 71)
ALNGQGLGATS,
(SEQ ID NO: 72)
RLAAKNRAGLGE,
(SEQ ID NO: 73)
RLGVVTGKDLGEI,
(SEQ ID NO: 74)
TVTGLKPETSYMVK,
(SEQ ID NO: 75)
TLTGLKPSTRYRI,
(SEQ ID NO: 76)
TLTGLQPSTRYRV,
(SEQ ID NO: 77)
TLLGLKPDTTYDIK,
(SEQ ID NO: 78)
TLQGLRPETAYELR,
(SEQ ID NO: 79)
TLRGLRPETAYELR,
(SEQ ID NO: 80)
TLMNLRPKTGYSVR,
(SEQ ID NO: 81)
TVSGLKPGTRY,
(SEQ ID NO: 82)
TISGLKPDTTY,
(SEQ ID NO: 83)
TLQGLKPDTAY,
(SEQ ID NO: 84)
LRGLKPWTQYAV,
(SEQ ID NO: 85)
IDGLEPDTEYIVR,
(SEQ ID NO: 86)
LQGLKPWTQYAI,
(SEQ ID NO: 87)
TITGLEPGTEYTIQ,
(SEQ ID NO: 88)
GLKPWTQYAV,
(SEQ ID NO: 89)
TLASLKPWTQYAV,
(SEQ ID NO: 90)
LMGLQPATEYIV,
(SEQ ID NO: 91)
KGMGPMSEAVQFRT,
(SEQ ID NO: 92)
TLTGLKPDTTYDVK,
(SEQ ID NO: 93)
ISGLQPETSYSL,
(SEQ ID NO: 94)
TLLGLKPDTTYDIK,
(SEQ ID NO: 95)
TISGLTPETTYSI,
(SEQ ID NO: 96)
GNYSCLAENRLGR,
(SEQ ID NO: 97)
GNYTCVVENRVG,
(SEQ ID NO: 98)
GTYHCVATNAHG,
(SEQ ID NO: 99)
LSHNGVLTGYLLSY,
(SEQ ID NO: 100)
NGVLTGYVLRY,
(SEQ ID NO: 101)
NGVLTGYNLRY,
(SEQ ID NO: 102)
NGNLTGYLLQY,
(SEQ ID NO: 103)
VDENGVLTGYKIYY,
(SEQ ID NO: 104)
THNGALVGYSVRY,
(SEQ ID NO: 105)
NGILTEYILKY,
(SEQ ID NO: 106)
NGILIGYTLRY,
(SEQ ID NO: 107)
THSGQITGYKIRY,
(SEQ ID NO: 108)
NGKITGYIIYY,
(SEQ ID NO: 109)
LSHNGIFTLY,
(SEQ ID NO: 110)
NGILTEYTLKY,
(SEQ ID NO: 111)
LDPNGIITQYEISY,
(SEQ ID NO: 112)
NGKITGYIIYY,
(SEQ ID NO: 113)
HLEVQAFNGRGSGPA,
(SEQ ID NO: 114)
HLTVRAYNGAGYGP,
(SEQ ID NO: 115)
HLSVKAYNSAGTGPS,
(SEQ ID NO: 116)
HLAVKAYNSAGTGPS,
(SEQ ID NO: 117)
NLEVRAFNSAGDGP,
(SEQ ID NO: 118)
HLTVLAYNSKGAGP,
(SEQ ID NO: 119)
LRVLVFNGRGDGP,
(SEQ ID NO: 120)
HIDVSAFNSAGYGP,
(SEQ ID NO: 121)
HLAVELFNGR,
(SEQ ID NO: 122)
LELQSINFLGGQPA,
(SEQ ID NO: 123)
HFTVRAYNGAGYGP,
(SEQ ID NO: 124)
HLEVQAFNGRGSQPA,
(SEQ ID NO: 125)
VIADQPTFVKYLIK,
(SEQ ID NO: 126)
TIKGLRPGVVYEGQ,
(SEQ ID NO: 127)
TLTELSPSTQYTVK,
(SEQ ID NO: 128)
TLDDLAPDTTYLVQ,
(SEQ ID NO: 129)
TVSDVTPHAIYTVR,
(SEQ ID NO: 130)
IIRGLNASTRYLFR,
(SEQ ID NO: 131)
TLMNLRPKTGYSVR,
(SEQ ID NO: 132)
TLTGLKPGTEYEVR,
(SEQ ID NO: 133)
GPEHLMPSSTYVAR,
(SEQ ID NO: 134)
RVTGLTPKKTYEFR,
(SEQ ID NO: 135)
LTGLKPGTEYEFR,
(SEQ ID NO: 136)
EVRVQAVNGGGNGPP,
(SEQ ID NO: 137)
LIKVVAINDRGE,
(SEQ ID NO: 138)
VVSIIAVNGREE,
(SEQ ID NO: 139)
VVSVYAQNQNGE,
(SEQ ID NO: 140)
TISLVAEKGRHK,
(SEQ ID NO: 141)
HLEVQAFNGRGSGPA,
(SEQ ID NO: 142)
HVEVQAFNGRGLGPA,
(SEQ ID NO: 143)
HVEVQAFNGRGLGPA,
(SEQ ID NO: 144)
EFRVPAVNGAGEG,
(SEQ ID NO: 145)
or
VARVRTRLAPGSRLS,
(SEQ ID NO: 146)
or a fragment, or variant of said sequence,
herein said amino acid sequence is isolated by a method according to claim 25 or a method of claim 43 .
46 . A compound comprising at least one peptide fragment consisting of at least one of the sequences set forth in SEQ ID NO: 2-146 or a fragment, or variant, or homologue of said sequences.
47 . (canceled)
48 . An antibody capable of binding to an epitope comprising a binding site to a cell surface receptor, wherein said binding site comprises at least one of the sequences set forth in SEQ ID NOS: 1-146, or a fragment or a variant of said antibody.
49 . An antibody capable of binding to an epitope comprising at least one of the sequences set forth in SEQ ID NOS: 1-146, or a fragment, or a variant of said antibody.
50 - 54 . (canceled)
55 . A method for treating an individual in need, wherein said treatment comprising using a peptide fragment as defined in claim 45 .
56 . A method for treatment an individual in need, wherein said treatment comprising using an antibody capable of binding to an epitope comprising at least one of the sequences set forth in SEQ ID NOS: 1-146, or a fragment, or a variant of said antibody.
57 . A method for determining in a sample the presence of a substance comprising an epitope comprising at least one of the sequences set forth in SEQ ID NOS: 1-146.Cited by (0)
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