+

WO2001038357A2 - Nouveau membre de la famille des facteurs de croissance des fibroblastes, appele jaffa, et utilisations correspondantes - Google Patents

Nouveau membre de la famille des facteurs de croissance des fibroblastes, appele jaffa, et utilisations correspondantes Download PDF

Info

Publication number
WO2001038357A2
WO2001038357A2 PCT/US2000/032181 US0032181W WO0138357A2 WO 2001038357 A2 WO2001038357 A2 WO 2001038357A2 US 0032181 W US0032181 W US 0032181W WO 0138357 A2 WO0138357 A2 WO 0138357A2
Authority
WO
WIPO (PCT)
Prior art keywords
jaffa
nucleic acid
polypeptide
protein
seq
Prior art date
Application number
PCT/US2000/032181
Other languages
English (en)
Other versions
WO2001038357A3 (fr
Inventor
Mehran Mohamad Khodadoust
Original Assignee
Millennium Pharmaceuticals, 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 Millennium Pharmaceuticals, Inc. filed Critical Millennium Pharmaceuticals, Inc.
Priority to AU16281/01A priority Critical patent/AU1628101A/en
Publication of WO2001038357A2 publication Critical patent/WO2001038357A2/fr
Publication of WO2001038357A3 publication Critical patent/WO2001038357A3/fr

Links

Classifications

    • 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
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/50—Fibroblast growth factor [FGF]
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)

Definitions

  • FGF-10 is preferentially expressed in the adult lung (Yamasaki, M. et al. (1996) J. Biol Chem, 271:15918-15921).
  • FGFs 11-14 also referred to as FGF homologous factors (FHFs)
  • FHFs FGF homologous factors
  • FGF-15 displays a regionally restricted and dynamic pattern of expression in the developing nervous system (McWhirter, J.R. et al. (1997) Development, 124:3221-3232).
  • FGF-16 is predominantly expressed in rat embryonic brown adipose tissue and in the adult heart.
  • the JAFFA molecules of the present invention are members of a family of molecules having certain conserved structural and functional features.
  • family when referring to the protein and nucleic acid molecules of the invention is intended to mean two or more proteins or nucleic acid molecules having a common structural domain or motif and having sufficient amino acid or nucleotide sequence homology as defined herein.
  • family members can be naturally or non-naturally occurring and can be from either the same or different species.
  • a family can contain a first protein of human origin as well as other distinct proteins of human origin, or alternatively, can contain homologues of non-human origin, e.g., rat or mouse proteins.
  • Members of a family can also have common functional characteristics.
  • the hmmsf program which is available as part of the HMMER package of search programs, is a family specific default program for MILPAT0063 and a score of 15 is the default threshold score for determining a hit.
  • the threshold score for determining a hit can be lowered (e.g., to 8 bits).
  • a description of the Pfam database can be found in Sonhammer et al. (1997) Proteins 28(3):405-420 and a detailed description of HMMs can be found, for example, in Gribskov et ⁇ /.(1990) Meth. Enzymol.
  • cancer hyperproliferative and neoplastic are used interchangeably, and include those cells having the capacity for autonomous growth, i.e., an abnormal state or condition characterized by rapidly proliferating cell growth.
  • Hyperproliferative and neoplastic disease states may be categorized as pathologic, i.e., characterizing or constituting a disease state, or may be categorized as non-pathologic, i.e., a deviation from normal but not associated with a disease state.
  • the term is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness.
  • “Pathologic hyperproliferative” cells occur in disease states characterized by malignant tumor growth. Examples of non-pathologic hyperproliferative cells include proliferation of cells associated with wound repair.
  • the JAFFA proteins of the present invention can have one or more of the following activities: (1) induction of receptor dimerization, (2) tyrosine kinase activation, (3) phosphorylation of signaling molecules, e.g., phospholipase C-gamma and GTPase activating protein, (4) induction of gene expression, (5) modulation of cell proliferation, (6) modulation of cell differentiation, (7) modulation of cell survival, (8) modulation of chemotaxis, (9) modulation of migration, and/or (10) modulation of apoptosis, of a cell (e.g., a mesodermal, ectodermal, neural (e.g., neuroectodermal), endodermal or hematopoietic cell).
  • a cell e.g., a mesodermal, ectodermal, neural (e.g., neuroectodermal), endodermal or hematopoietic cell.
  • oligonucleotide can be modified with hybridization-triggered cleavage agents (See, e.g., Krol et al. (1988) Bio-Techniques 6:958-976) or intercalating agents. (See, e.g., Zon (1988) Pharm. Res. 5:539-549).
  • the oligonucleotide may be conjugated to another molecule, (e.g., a peptide, hybridization triggered cross- linking agent, transport agent, or hybridization-triggered cleavage agent).
  • sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes).
  • amino acid or nucleic acid “identity” is equivalent to amino acid or nucleic acid "homology”).
  • the percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.
  • the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions.
  • the recombinant expression vectors of the invention comprise a nucleic acid of the invention in a form suitable for expression of the nucleic acid in a host cell, which means that the recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression, which is operatively linked to the nucleic acid sequence to be expressed.
  • a "homologous recombinant animal” is a non-human animal, preferably a mammal, more preferably a mouse, in which an endogenous JAFFA gene has been altered by homologous recombination between the endogenous gene and an exogenous DNA molecule introduced into a cell of the animal, e.g., an embryonic cell of the animal, prior to development of the animal.
  • a transgenic animal of the invention can be created by introducing a JAFFA- encoding nucleic acid into the male pronuclei of a fertilized oocyte, e.g., by microinjection, retroviral infection, and allowing the oocyte to develop in a pseudopregnant female foster animal.
  • the JAFFA cDNA sequence of SEQ ID NO:l can be introduced as a transgene into the genome of a non-human animal.
  • a non-human homologue of a human JAFFA gene such as a rat or mouse JAFFA gene, can be used as a transgene.
  • a JAFFA gene homologue such as another JAFFA family member, can be isolated based on hybridization to the JAFFA cDNA sequences of SEQ ID NO:l or 3 (described further in subsection I above) and used as a transgene.
  • Intronic sequences and polyadenylation signals can also be included in the transgene to increase the efficiency of expression of the transgene.
  • the JAFFA gene can be a human gene (e.g., the cDNA of SEQ ID NO:3), but more preferably, is a non- human homolog of a human JAFFA gene (e.g., a cDNA isolated by stringent hybridization with the nucleotide sequence of SEQ ID NO:l),
  • a mouse JAFFA gene can be used to construct a homologous recombination nucleic acid molecule, e.g., a vector, suitable for altering an endogenous JAFFA gene in the mouse genome.
  • the altered portion of the JAFFA gene is flanked at its 5' and 3' ends by additional nucleic acid sequence of the JAFFA gene to allow for homologous recombination to occur between the exogenous JAFFA gene carried by the homologous recombination nucleic acid molecule and an endogenous JAFFA gene in a cell, e.g., an embryonic stem cell.
  • the additional flanking JAFFA nucleic acid sequence is of sufficient length for successful homologous recombination with the endogenous gene.
  • transgenic non-humans animals can be produced which contain selected systems which allow for regulated expression of the transgene.
  • a pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration.
  • the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • the invention provides methods (also referred to herein as "screening assays") for identifying modulators, i.e., candidate or test compounds or agents (e.g., peptides, peptidomimetics, peptoids, small molecules or other drugs) which bind to JAFFA proteins, have a stimulatory or inhibitory effect on, for example, JAFFA expression or JAFFA activity, or have a stimulatory or inhibitory effect on, for example, the expression or activity of a JAFFA substrate.
  • modulators i.e., candidate or test compounds or agents (e.g., peptides, peptidomimetics, peptoids, small molecules or other drugs) which bind to JAFFA proteins, have a stimulatory or inhibitory effect on, for example, JAFFA expression or JAFFA activity, or have a stimulatory or inhibitory effect on, for example, the expression or activity of a JAFFA substrate.
  • Compounds thus identified can be used to modulate the activity of target gene products in a therapeutic
  • an assay is a cell-based assay in which a cell which expresses a JAFFA protein or biologically active portion thereof is contacted with a test compound and the ability of the test compound to modulate JAFFA activity is determined. Determining the ability of the test compound to modulate JAFFA activity can be accomplished by monitoring, for example, intracellular calcium and inositol 1,4,5-trisphosphate (IP3) levels, cell growth, and cell chemotaxis.
  • IP3 intracellular calcium and inositol 1,4,5-trisphosphate
  • the cell for example, can be of mammalian origin, e.g., an endothehal cell.
  • the ability of the test compound to modulate JAFFA binding to a substrate or to bind to JAFFA can also be determined.
  • Binding of a test compound to a JAFFA protein, or interaction of a JAFFA protein with a target molecule in the presence and absence of a candidate compound can be accomplished in any vessel suitable for containing the reactants.
  • vessels include microtiter plates, test tubes, and micro- centrifuge tubes.
  • a fusion protein can be provided which adds a domain that allows one or both of the proteins to be bound to a matrix.
  • glutathione-S- transferase/JAFFA fusion proteins or glutathione-S-transferase/target fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St.
  • the assay for compounds that interfere with the interaction of the target gene products and binding partners can be conducted in a heterogeneous or homogeneous format.
  • Heterogeneous assays involve anchoring either the target gene product or the binding partner onto a solid phase and detecting complexes anchored on the solid phase at the end of the reaction.
  • homogeneous assays the entire reaction is carried out in a liquid phase. In either approach, the order of addition of reactants can be varied to obtain different information about the compounds being tested.
  • the partner of the immobilized species is exposed to the coated surface with or without the test compound. After the reaction is complete, unreacted components are removed (e.g., by washing) and any complexes formed will remain immobilized on the solid surface.
  • the detection of complexes anchored on the solid surface can be accomplished in a number of ways. Where the non-immobilized species is pre-labeled, the detection of label immobilized on the surface indicates that complexes were formed.
  • modulators of JAFFA expression are identified in a method wherein a cell is contacted with a candidate compound and the expression of JAFFA mRNA or protein in the cell is determined. The level of expression of JAFFA mRNA or protein in the presence of the candidate compound is compared to the level of expression of JAFFA mRNA or protein in the absence of the candidate compound. The candidate compound can then be identified as a modulator of JAFFA expression based on this comparison.
  • JAFFA nucleotide sequences (preferably 15-25 bp in length) from the JAFFA nucleotide sequences.
  • Computer analysis of the JAFFA sequences can be used to predict primers that do not span more than one exon in the genomic DNA, thus complicating the amplification process. These primers can then be used for PCR screening of somatic cell hybrids containing individual human chromosomes. Only those hybrids containing the human gene corresponding to the JAFFA sequences will yield an amplified fragment.
  • the samples used in the baseline determination will be from diseased, e.g., cancerous, or from non-diseased cells of endothehal or hematopoietic tissue.
  • the choice of the cell source is dependent on the use of the relative expression level. Using expression found in normal tissues as a mean expression score aids in validating whether the JAFFA gene assayed is hematopoietic cell-type specific (versus normal cells). Such a use is particularly important in identifying whether a JAFFA gene can serve as a target gene.
  • the mean expression value can be revised, providing improved relative expression values based on accumulated data.
  • An exemplary method for detecting the presence or absence of JAFFA protein or nucleic acid in a biological sample involves obtaining a biological sample from a test subject and contacting the biological sample with a compound or an agent capable of detecting JAFFA protein or nucleic acid (e.g., mRNA, genomic DNA) that encodes JAFFA protein such that the presence of JAFFA protein or nucleic acid is detected in the biological sample.
  • a compound or an agent capable of detecting JAFFA protein or nucleic acid e.g., mRNA, genomic DNA
  • the level of expression of the JAFFA gene can be measured in a number of ways, including, but not limited to: measuring the mRNA encoded by the JAFFA genes; measuring the amount of protein encoded by the JAFFA genes; or measuring the activity of the protein encoded by the JAFFA genes.
  • amplification primers are defined as being a pair of nucleic acid molecules that can anneal to 5' or 3' regions of a gene (plus and minus strands, respectively, or vice-versa) and contain a short region in between.
  • amplification primers are from about 10 to 30 nucleotides in length and flank a region from about 50 to 200 nucleotides in length. Under appropriate conditions and with appropriate reagents, such primers permit the amplification of a nucleic acid molecule comprising the nucleotide sequence flanked by the primers. Suitable primers for the amplification of the JAFFA gene are described herein.
  • mRNA does not need to be isolated from the hemaotopoietic or endothehal cells prior to detection.
  • a cell or tissue sample is prepared/processed using known histological methods. The sample is then immobilized on a support, typically a glass slide, and then contacted with a probe that can hybridize to mRNA that encodes the JAFFA gene being analyzed.
  • Proteins from hematopoietic or endothehal cells can be isolated using techniques that are well known to those of skill in the art.
  • the protein isolation methods employed can, for example, be such as those described in Harlow and Lane (Harlow and Lane, 1988, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York).
  • the kit can comprise, for example: (1) an oligonucleotide, e.g., a detectably labeled oligonucleotide, which hybridizes to a nucleic acid sequence encoding a polypeptide corresponding to a marker of the invention or (2) a pair of primers useful for amplifying a nucleic acid molecule corresponding to a marker of the invention.
  • the kit can also comprise, e.g., a buffering agent, a preservative, or a protein stabilizing agent.
  • the kit can also comprise components necessary for detecting the detectable agent (e.g., an enzyme or a substrate).
  • any of a variety of sequencing reactions known in the art can be used to directly sequence the JAFFA gene and detect mutations by comparing the sequence of the sample JAFFA with the corresponding wild-type (control) sequence.
  • Examples of sequencing reactions include those based on techniques developed by Maxam and Gilbert ((1977) Proc. Natl. Acad. Sci. USA 74:560) or Sanger ((1977) Proc. Natl Acad. Sci. USA 74:5463). It is also contemplated that any of a variety of automated sequencing procedures can be utilized when performing the diagnostic assays ((1995) Biotechniques 19:448), including sequencing by mass spectrometry (see, e.g., PCT International Publication No. WO 94/16101; Cohen et al. (1996) Adv. Chromatogr. 36: 127-162; and Griffin et al. (1993) Appl. Biochem. Biotechnol 38: 147-159).
  • genes, including JAFFA that are modulated in cells by treatment with an agent (e.g., compound, drug or small molecule) which modulates JAFFA activity (e.g., identified in a screening assay as described herein) can be identified.
  • an agent e.g., compound, drug or small molecule
  • JAFFA activity e.g., identified in a screening assay as described herein
  • cells can be isolated and RNA prepared and analyzed for the levels of expression of JAFFA and other genes implicated in the JAFFA- associated disorder, respectively.
  • the technique utilized can also efficiently reduce or inhibit the transcription (triple helix) and/or translation (antisense, ribozyme) of mRNA produced by normal target gene aileles such that the possibility can arise wherein the concentration of normal target gene product present can be lower than is necessary for a normal phenotype.
  • nucleic acid molecules that encode and express target gene polypeptides exhibiting normal target gene activity can be introduced into cells via gene therapy method.
  • the present invention provides methods of treating an individual afflicted with a disease or disorder characterized by aberrant or unwanted expression or activity of a JAFFA protein or nucleic acid molecule.
  • the method involves administering an agent (e.g., an agent identified by a screening assay described herein), or combination of agents that modulates (e.g., upregulates or downregulates) JAFFA expression or activity.
  • the method involves administering a JAFFA protein or nucleic acid molecule as therapy to compensate for reduced, aberrant, or unwanted JAFFA expression or activity.
  • Pharmacogenomics deals with clinically significant hereditary variations in the response to drugs due to altered drug disposition and abnormal action in affected persons. See, for example, Eichelbaum, M. et al. (1996) Clin. Exp. Pharmacol. Physiol 23(10-11) :983-985 and Linder, M.W. et al. (1997) Clin. Chem. 43(2):254-266.
  • two types of pharmacogenetic conditions can be differentiated. Genetic conditions transmitted as a single factor altering the way drugs act on the body (altered drug action) or genetic conditions transmitted as single factors altering the way the body acts on drugs (altered drug metabolism). These pharmacogenetic conditions can occur either as rare genetic defects or as naturally-occurring polymo ⁇ hisms.
  • the method can include contacting the JAFFA nucleic acid, polypeptide, or antibody with a first array having a plurality of capture probes and a second array having a different plurality of capture probes.
  • the results of each hybridization can be compared, e.g., to analyze differences in expression between a first and second sample.
  • the first plurality of capture probes can be from a control sample, e.g., a wild type, normal, or non-diseased, non- stimulated, sample, e.g., a biological fluid, tissue, or cell sample.
  • Binding e.g., in the case of a nucleic acid, hybridization with a capture probe at an address of the plurality, is detected, e.g., by signal generated from a label attached to the nucleic acid, polypeptide, or antibody.
  • the same array can be used for both samples or different arrays can be used. If different arrays are used the plurality of addresses with capture probes should be present on both arrays.
  • HMM Hidden Markov Model

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Toxicology (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

Cette invention se rapporte à des molécules d'acide nucléique isolées, appelées molécules d'acide nucléique JAFFA, qui codent de nouveaux membres de la famille des facteurs de croissance des fibroblastes. Cette invention concerne également des molécules d'acide nucléique antisens, des vecteurs d'expression recombinés contenant ces molécules d'acide nucléique JAFFA, des cellules hôtes dans lesquelles ont été introduits ces vecteurs d'expression, et des animaux transgéniques non humains dans lesquels un gène JAFFA a été introduit ou dissocié. Cette invention concerne également des protéines JAFFA isolées, des protéines de fusion, des peptides antigéniques et des anticorps anti-JAFFA. Des procédés diagnostiques utilisant ces compositions sont également présentés.
PCT/US2000/032181 1999-11-22 2000-11-22 Nouveau membre de la famille des facteurs de croissance des fibroblastes, appele jaffa, et utilisations correspondantes WO2001038357A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU16281/01A AU1628101A (en) 1999-11-22 2000-11-22 Jaffa, a novel fibroblast growth factor family member and uses therefor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US44416599A 1999-11-22 1999-11-22
US09/444,165 1999-11-22

Publications (2)

Publication Number Publication Date
WO2001038357A2 true WO2001038357A2 (fr) 2001-05-31
WO2001038357A3 WO2001038357A3 (fr) 2001-10-18

Family

ID=23763768

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/032181 WO2001038357A2 (fr) 1999-11-22 2000-11-22 Nouveau membre de la famille des facteurs de croissance des fibroblastes, appele jaffa, et utilisations correspondantes

Country Status (2)

Country Link
AU (1) AU1628101A (fr)
WO (1) WO2001038357A2 (fr)

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001018172A3 (fr) * 1999-09-07 2002-05-02 Amgen Inc Polypeptides de type facteur de croissance des fibroblastes
EP1443818A4 (fr) * 2001-09-28 2006-03-08 Lilly Co Eli Proteines secretees et utilisations associees
WO2006028714A1 (fr) * 2004-09-02 2006-03-16 Eli Lilly And Company Muteines du facteur de croissance 21 du fibroblaste
US7408047B1 (en) 1999-09-07 2008-08-05 Amgen Inc. Fibroblast growth factor-like polypeptides
WO2008153705A3 (fr) * 2007-05-22 2009-03-05 Novartis Ag Procédés de traitement, de diagnostic et de détection de troubles liés à fgf21
US7563769B2 (en) 2002-05-09 2009-07-21 ProChon Biotech, Ltd. FGF variants and methods for use thereof
US7582607B2 (en) 2004-09-02 2009-09-01 Eli Lilly And Company Muteins of fibroblast growth factor 21
US7815926B2 (en) 2005-07-11 2010-10-19 Musculoskeletal Transplant Foundation Implant for articular cartilage repair
US7901457B2 (en) 2003-05-16 2011-03-08 Musculoskeletal Transplant Foundation Cartilage allograft plug
USRE42208E1 (en) 2003-04-29 2011-03-08 Musculoskeletal Transplant Foundation Glue for cartilage repair
US8034770B2 (en) 2008-06-04 2011-10-11 Amgen Inc. FGF21 polypeptides comprising two or more mutations
US8188040B2 (en) 2009-05-05 2012-05-29 Amgen Inc. FGF21 mutants and uses thereof
US8292968B2 (en) 2004-10-12 2012-10-23 Musculoskeletal Transplant Foundation Cancellous constructs, cartilage particles and combinations of cancellous constructs and cartilage particles
US8435551B2 (en) 2007-03-06 2013-05-07 Musculoskeletal Transplant Foundation Cancellous construct with support ring for repair of osteochondral defects
US8906110B2 (en) 2007-01-24 2014-12-09 Musculoskeletal Transplant Foundation Two piece cancellous construct for cartilage repair
US9279013B2 (en) 2008-10-10 2016-03-08 Amgen Inc. FGF-21 mutants comprising polyethylene glycol and uses thereof
US9493530B2 (en) 2009-05-05 2016-11-15 Amgen Inc. FGF21 mutants comprising a mutation at position 98, 171 and/or 180
US9517264B2 (en) 2010-04-15 2016-12-13 Amgen Inc. Human FGF receptor and β-Klotho binding proteins
US9687590B2 (en) 2007-07-03 2017-06-27 Histogenics Corporation Double-structured tissue implant and a method for preparation and use thereof
US9701940B2 (en) 2005-09-19 2017-07-11 Histogenics Corporation Cell-support matrix having narrowly defined uniformly vertically and non-randomly organized porosity and pore density and a method for preparation thereof
US9993326B2 (en) 2007-07-03 2018-06-12 Histogenics Corporation Method for use of a double-structured tissue implant for treatment of tissue defects
US10077420B2 (en) 2014-12-02 2018-09-18 Histogenics Corporation Cell and tissue culture container
WO2018204847A2 (fr) 2017-05-05 2018-11-08 Trefoil Therapeutics, Inc. Facteurs de croissance fibroblastique modifiés recombinés et leurs utilisations thérapeutiques
US10570205B2 (en) 2009-12-07 2020-02-25 Amgen, Inc. Human antigen binding proteins that bind β-Klotho, FGF receptors and complexes thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010006939A1 (en) * 1997-10-03 2001-07-05 Ralph W. Niven Secretory leukocyte protease inhibitor dry powder pharmaceutical compositions

Cited By (63)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7879323B2 (en) 1999-09-07 2011-02-01 Amgen Inc. Antibodies to fibroblast growth factor-like polypeptides
US7887799B2 (en) 1999-09-07 2011-02-15 Amgen Inc. Antibodies to fibroblast growth factor-like polypeptides
EP2258722A3 (fr) * 1999-09-07 2011-10-12 Amgen, Inc Anticorps anti-polypeptides de type facteur de croissance des fibroblastes
US7408047B1 (en) 1999-09-07 2008-08-05 Amgen Inc. Fibroblast growth factor-like polypeptides
US7459540B1 (en) 1999-09-07 2008-12-02 Amgen Inc. Fibroblast growth factor-like polypeptides
EP2284189A3 (fr) * 1999-09-07 2011-10-12 Amgen, Inc Polypeptides de type facteur de croissance des fibroblastes
US8053408B2 (en) 1999-09-07 2011-11-08 Amgen Inc. Methods for treating obesity using fibroblast growth factor-like polypeptides
US7700558B2 (en) 1999-09-07 2010-04-20 Amgen Inc. Methods for treating diabetes using fibroblast growth factor-like polypeptides
WO2001018172A3 (fr) * 1999-09-07 2002-05-02 Amgen Inc Polypeptides de type facteur de croissance des fibroblastes
US7667008B2 (en) 1999-09-07 2010-02-23 Amgen, Inc. Fibroblast growth factor-like polypeptides and variants thereof
US7671180B2 (en) 1999-09-07 2010-03-02 Amgen, Inc. Fibroblast growth factor-like polypeptides and variants thereof
US7695938B2 (en) 1999-09-07 2010-04-13 Amgen Inc. Vectors and recombinant host cells comprising nucleic acid molecules encoding Fibroblast Growth Factor-like polypeptides
US7696172B2 (en) 1999-09-07 2010-04-13 Amgen Inc. Fibroblast growth factor-like polypeptides
US8030275B2 (en) 1999-09-07 2011-10-04 Amgen Inc. Methods for treating obesity using fibroblast growth factor-like polypeptides
US8044024B2 (en) 1999-09-07 2011-10-25 Amgen Inc. Identifying modulators of fibroblast growth factor-like polypeptides
US7727742B2 (en) 1999-09-07 2010-06-01 Amgen Inc. Nucleic acid molecules encoding fibroblast growth factor-like polypeptides
US7704952B2 (en) 1999-09-07 2010-04-27 Amgen Inc. Methods for treating diabetes using fibroblast growth factor-like polypeptides
EP2189475A3 (fr) * 1999-09-07 2010-11-17 Amgen Inc. Polypeptides de type facteur de croissance des fibroblastes
EP1443818A4 (fr) * 2001-09-28 2006-03-08 Lilly Co Eli Proteines secretees et utilisations associees
US8119783B2 (en) 2002-05-09 2012-02-21 Prochon Biotech Ltd. FGF variants and methods for use thereof
US8609823B2 (en) 2002-05-09 2013-12-17 ProChon Biotech, Ltd. FGF-9 variants and methods for use thereof
US7563769B2 (en) 2002-05-09 2009-07-21 ProChon Biotech, Ltd. FGF variants and methods for use thereof
US8916522B2 (en) 2002-05-09 2014-12-23 Prochon Biotech Ltd. FGF-9 variants and methods of use thereof
US9487568B2 (en) 2002-05-09 2016-11-08 Prochon Biotech Ltd. FGF-2 variants and methods of use thereof
USRE43258E1 (en) 2003-04-29 2012-03-20 Musculoskeletal Transplant Foundation Glue for cartilage repair
USRE42208E1 (en) 2003-04-29 2011-03-08 Musculoskeletal Transplant Foundation Glue for cartilage repair
US8221500B2 (en) 2003-05-16 2012-07-17 Musculoskeletal Transplant Foundation Cartilage allograft plug
US7901457B2 (en) 2003-05-16 2011-03-08 Musculoskeletal Transplant Foundation Cartilage allograft plug
WO2006028714A1 (fr) * 2004-09-02 2006-03-16 Eli Lilly And Company Muteines du facteur de croissance 21 du fibroblaste
US7622445B2 (en) 2004-09-02 2009-11-24 Eli Lilly And Company Muteins of fibroblast growth factor 21
US7582607B2 (en) 2004-09-02 2009-09-01 Eli Lilly And Company Muteins of fibroblast growth factor 21
US8292968B2 (en) 2004-10-12 2012-10-23 Musculoskeletal Transplant Foundation Cancellous constructs, cartilage particles and combinations of cancellous constructs and cartilage particles
US7815926B2 (en) 2005-07-11 2010-10-19 Musculoskeletal Transplant Foundation Implant for articular cartilage repair
US9701940B2 (en) 2005-09-19 2017-07-11 Histogenics Corporation Cell-support matrix having narrowly defined uniformly vertically and non-randomly organized porosity and pore density and a method for preparation thereof
US8906110B2 (en) 2007-01-24 2014-12-09 Musculoskeletal Transplant Foundation Two piece cancellous construct for cartilage repair
US8435551B2 (en) 2007-03-06 2013-05-07 Musculoskeletal Transplant Foundation Cancellous construct with support ring for repair of osteochondral defects
WO2008153705A3 (fr) * 2007-05-22 2009-03-05 Novartis Ag Procédés de traitement, de diagnostic et de détection de troubles liés à fgf21
US10842610B2 (en) 2007-07-03 2020-11-24 Histogenics Corporation Method for use of a double-structured tissue implant for treatment of tissue defects
US9687590B2 (en) 2007-07-03 2017-06-27 Histogenics Corporation Double-structured tissue implant and a method for preparation and use thereof
US9993326B2 (en) 2007-07-03 2018-06-12 Histogenics Corporation Method for use of a double-structured tissue implant for treatment of tissue defects
US8410051B2 (en) 2008-06-04 2013-04-02 Amgen Inc. FGF21 mutants and uses thereof
US11072640B2 (en) 2008-06-04 2021-07-27 Amgen Inc. Methods of treating non-alcoholic steatohepatitis using FGF21 mutants
US8642546B2 (en) 2008-06-04 2014-02-04 Amgen Inc. FGF21 mutant fusion polypeptides and uses thereof
US9273106B2 (en) 2008-06-04 2016-03-01 Amgen Inc. FGF mutants with reduced proteolysis and aggregation
US8034770B2 (en) 2008-06-04 2011-10-11 Amgen Inc. FGF21 polypeptides comprising two or more mutations
EA034847B1 (ru) * 2008-06-04 2020-03-27 Амген Инк. Мутанты fgf21 и их применение
US10011642B2 (en) 2008-06-04 2018-07-03 Amgen Inc. Methods of treating of diabetes and obesity using FGF21 mutants
US8361963B2 (en) 2008-06-04 2013-01-29 Amgen Inc. Uses of FGF21 polypeptides comprising two or more mutations
US11840558B2 (en) 2008-06-04 2023-12-12 Amgen Inc. Methods of treating non-alcoholic steatohepatitis using FGF21 mutants
US9279013B2 (en) 2008-10-10 2016-03-08 Amgen Inc. FGF-21 mutants comprising polyethylene glycol and uses thereof
US8618053B2 (en) 2009-05-05 2013-12-31 Amgen Inc. FGF21 mutants multimers and uses thereof
US9493530B2 (en) 2009-05-05 2016-11-15 Amgen Inc. FGF21 mutants comprising a mutation at position 98, 171 and/or 180
US8835385B2 (en) 2009-05-05 2014-09-16 Amgen Inc. FGF21 polypeptides comprising two or more mutations and uses thereof
US8795985B2 (en) 2009-05-05 2014-08-05 Amgen Inc. FGF 21 polypeptides comprising two or more mutations and uses thereof
US8188040B2 (en) 2009-05-05 2012-05-29 Amgen Inc. FGF21 mutants and uses thereof
US10570205B2 (en) 2009-12-07 2020-02-25 Amgen, Inc. Human antigen binding proteins that bind β-Klotho, FGF receptors and complexes thereof
US12116413B2 (en) 2009-12-07 2024-10-15 Amgen Inc. Human antigen binding proteins that bind β-klotho, FGF receptors and complexes thereof
US9517264B2 (en) 2010-04-15 2016-12-13 Amgen Inc. Human FGF receptor and β-Klotho binding proteins
US10077420B2 (en) 2014-12-02 2018-09-18 Histogenics Corporation Cell and tissue culture container
US11555172B2 (en) 2014-12-02 2023-01-17 Ocugen, Inc. Cell and tissue culture container
WO2018204847A2 (fr) 2017-05-05 2018-11-08 Trefoil Therapeutics, Inc. Facteurs de croissance fibroblastique modifiés recombinés et leurs utilisations thérapeutiques
EP3619324A4 (fr) * 2017-05-05 2020-12-30 Trefoil Therapeutics, Inc. Facteurs de croissance fibroblastique modifiés recombinés et leurs utilisations thérapeutiques
US11479591B2 (en) 2017-05-05 2022-10-25 Trefoil Therapeutics, Inc. Recombinant modified fibroblast growth factors and therapeutic uses thereof

Also Published As

Publication number Publication date
WO2001038357A3 (fr) 2001-10-18
AU1628101A (en) 2001-06-04

Similar Documents

Publication Publication Date Title
WO2001038357A2 (fr) Nouveau membre de la famille des facteurs de croissance des fibroblastes, appele jaffa, et utilisations correspondantes
EP1290190A2 (fr) 33167, nouvelle hydrolase humaine, et utilisations associees
WO2002018556A9 (fr) 8797, nouvelle galactosyltransferase humaine et ses applications
EP1137665A1 (fr) Molecules d'acide nucleique et proteines cark, et leurs utilisations
WO2002020765A2 (fr) 38646, nouveau facteur d'echange de guanine nucleotide et ses utilisations
WO2001090321A2 (fr) 55158, une nouvelle anhydrase carbonique humaine et son utilisation
US20050176671A1 (en) 22437, a novel human sulfatase and uses therefor
EP1238984A1 (fr) 54498, un transporteur d'acide aminé et ses utilisations
EP1236797A1 (fr) 63744, membre de la famille des transporteurs de sucre humain et applications de celui-ci
US20020042098A1 (en) 32253 transferase family members and uses therefor
US20020025554A1 (en) Novel leucine rich repeat-containing molecules and uses therefor
US20020090705A1 (en) 62088, a novel human nucleoside phosphatase family member and uses thereof
US20020123094A1 (en) 57250, a novel human sugar transporter family member and uses thereof
US20020107192A1 (en) 23686, a novel human aminotransferase and uses therefor
WO2002008395A2 (fr) 42755, une nouveau membre de la famille de la methyl-transferase humaine et ses applications
US20050203049A1 (en) 47169 and 33935, novel human glycosyl transferases and uses therefor
US20020077462A1 (en) 33556, a novel human transporter and uses thereof
US20020077312A1 (en) 3700, a novel human protein kinase and uses therefor
WO2002059314A2 (fr) 52020, nouvel antigene associe a un melanome humain et ses utilisations
WO2001064902A2 (fr) Membres de la famille des transferases 46867 et leurs utilisations
US20030049727A1 (en) 25658, a novel human calcium channel subunit and uses thereof
EP1343878A2 (fr) 17903, nouvelle aminopeptidase humaine et utilisations correspondantes
WO2002024925A2 (fr) Nouvelle tyrosine phosphatase humaine appelee 69109 et utilisations de cette derniere
EP1313861A2 (fr) 50566 : un nouveau facteur apparente a la glyoxalase ii humaine et utilisations de ce facteur
WO2002048330A2 (fr) 21908 et 21911, membres de la famille de la guanylate kinase, et leurs utilisations

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
AK Designated states

Kind code of ref document: A3

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载