WO1998054209A2 - Mafa humaine - Google Patents

Mafa humaine Download PDF

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Publication number
WO1998054209A2
WO1998054209A2 PCT/GB1998/001572 GB9801572W WO9854209A2 WO 1998054209 A2 WO1998054209 A2 WO 1998054209A2 GB 9801572 W GB9801572 W GB 9801572W WO 9854209 A2 WO9854209 A2 WO 9854209A2
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Prior art keywords
pro
leu
ser
polypeptide
sequence
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PCT/GB1998/001572
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English (en)
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WO1998054209A3 (fr
Inventor
Ellen Louise Hewitt
Maria Bardina Antonia Cornelia Lamers
Alan Lamont
David Hugh Williams
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Peptide Therapeutics Limited
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Priority to AU76670/98A priority Critical patent/AU7667098A/en
Publication of WO1998054209A2 publication Critical patent/WO1998054209A2/fr
Publication of WO1998054209A3 publication Critical patent/WO1998054209A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2851—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the lectin superfamily, e.g. CD23, CD72
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4726—Lectins
    • 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
    • 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
    • C07K14/7056—Lectin superfamily, e.g. CD23, CD72
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to polypeptides, nucleotide sequences, antibodies or fragments thereof, ligands and compositions and their use in the medical fields of inflammation and allergy, disease examples of which include rheumatoid arthritis and asthma.
  • the invention relates to a method for production of the polypeptides. Methods of disease treatment are suggested relying on agents developed in combination with the cloning of the human MAFA molecule.
  • a use of the invention addresses the prevention of cell activation events in vivo which could lead to therapies for the prevention of tumour growth.
  • Nucleotides and amino acid residues are represented herein by their standard codes as identified by the IUPAC-IUB Biochemical Nomenclature Commission and they include all D or L amino acids or analogues and derivatives thereof.
  • the symbol X represents an unidentified amino acid or analogue thereof.
  • Mast cells comprise a heterogeneous family of cell types derived from the bone marrow, which are mainly found resident in the connective tissue of the skin, lung and gut. Their common feature is prominent cytoplasmic granules containing heparin, histamine and proteases, which can be released in a process known as degranulation, into the tissues when the cells are appropriately activated. Mast cells are gaining recognition as participants in many inflammatory responses in addition to their-documented role in anaphylaxis. However, the biochemical pathways underlying the ability of extracellular stimuli to activate intracellular events still require resolution.
  • FceRI high-affinity Fc receptors
  • IgE immunoglobulin E
  • signal transduction pathways are initiated including the tyrosine phosphorylation of cellular proteins, phosphoinositide hydrolysis, an increase in intracellular calcium, and protein kinase C activation.
  • the mast cell then releases a variety of mediators such as cytokines, lipid-derived mediators, amines, proteases and proteoglycans. These early activation events are believed to be involved in the release of the mediators.
  • the FceRI receptor is not only expressed on mast cells but also on basophils, langerhans cells, monocytes, and eosinophils, although it is now recognised that the receptor expressed on langerhan cells and monocytes is missing the ⁇ chain.
  • rat basophil leukaemic cell-line RBL-2H3 An abundant cell surface protein was identified on the surface of the rat basophil leukaemic cell-line RBL-2H3 as a result of monoclonal antibody screening.
  • the antibody used, G63 was later shown to also bind to the surface of mucosal and connnective-tissue mast cells (Ortega et al, 1991).
  • the cell surface protein was termed mast cell function-associated antigen (MAFA).
  • the cDNA sequence encoding rat MAFA (rMAFA) was isolated by expression cloning (Guthman et al, 1995).
  • Rat MAFA is a type II integral membrane glycoprotein that has extensive amino acid homology to calcium dependent (C-type) animal lectins.
  • C-type lectins have been associated with other immunological cell types, CD72 in B lymphocytes, FceRII (CD23), CD69 in T and B lymphocytes, and Ly-49 and NKR-P1 on natural killer
  • rat MAFA gene structure of rat MAFA has been published along with the sequences of two alternatively-spliced mRNA transcripts (Bocek et al, 1997).
  • the full length rat MAFA mRNA is made up from five exons and one of the alternative transcripts lacks the transmembrane exon, exon 2, but maintains the correct reading frame.
  • the other alternatively-spliced transcript lacks both exons 2 and 3 and does not maintain the full length rat MAFA reading frame. No function has yet been assigned to the alternately spliced rat MAFA variants.
  • T-cell receptor TCR
  • BCR B-cell receptor
  • FceRI FceRI
  • ITAM ITAM
  • Fc ⁇ RIIB has a single YXXL/I motif (similar to rat MAFA), responsible for the immunoreceptor inhibition, which is now known as an immunoreceptor tyrosine-based inhibition motif (ITIM).
  • ITIM immunoreceptor tyrosine-based inhibition motif
  • the ITIM mechanism of action in vivo is uncertain, however it is likely that the ITIM tyrosine residue is first phosphorylated by a src-like protein tyrosine kinase which allows the recruitment of an SH2-domain containing protein or lipid phosphatase which then acts on components of the immunoreceptor signalling cascade (Ono et al, 1996). Indeed, changes in the MAFA tyrosyl- and seryl-phosphorylation levels are observed in response to G63 binding, antigenic stimulation, and a combination of both treatments.
  • the rat MAFA molecule found on both mast cells and basophils has been cloned and shown to be a type II membrane glycoprotein with homology to calcium-dependent lectins. Alternatively spliced mRNA forms have been described, but the physiological relevance of these forms is unknown.
  • mRNA transcripts that are very different to the rat transcripts have been identified.
  • a major transcript not found in rat, but highly expressed in human lung and glanulocyte-enriched blood cells, encodes a putative protein with the MAFA intracellular and transmembrane domains followed by an 8 amino acid polyproline motif due to a reading frameshift.
  • This unique sequence has been used in the design of agents that can be used in the treatment of inflammation or allergy.
  • Interleukin 2 is an autocrine growth factor for T cells. Therefore inhibiting its production prevents T cell proliferation and hence suppresses the immune system.
  • the sequence of the human form of the MAFA molecule obtained from both the myelogenous leukaemic cell line KU812 and cDNA derived from human lung tissue is detailed in Fig. 1. Surprisingly, additional truncated forms of MAFA are provided which are expressed in the cells and tissues. One prominent form sequenced was found to encode a variant of the molecule in which the exon encoding the most N-terminal extracellular region (analogous to rat exon 3) was spliced out (huMAFA[E3-]).
  • truncated forms of the molecule or its production would be expected to downregulate mast cell activation, and might therefore be useful in the treatment of allergic diseases.
  • overproduction of truncated MAFA may be associated with the development of atopy, and diagnosis of this could be accomplished using antibodies directed against unique C-terminal sequences expressed on the truncated form.
  • Manipulation of the production and/or function of truncated MAFA are all encompassed within the scope of the invention.
  • the invention provides a polypeptide which comprises or consists of the sequence of amino acid residues: X-Pro-X-Pro-X-X-Pro. [SEQ ID No. 1]
  • It may comprise or consists of the sequence of amino acid residues corresponding to human MAFA or a truncated form thereof.
  • the truncated form is huMAFA[E3-] or huMAFA[E3/4-].
  • a polypeptide which comprises or consists of the sequence of animo acid sequences means either (i) a polypeptide which includes in its sequence the identified sequence "motif as part of the polypeptide, or; (ii) a polypeptide which is terminated and has the sequence of the identified sequence motif.
  • polypeptide of type (i) is cloned human MAFA or a truncated version thereof which includes the motif sequence -X-Pro-X-Pro-X-X-Pro- [SEQ ID No. 1]
  • polypeptide of type (ii) is a peptide of formula
  • polypeptides according to the invention may contain an amino acid motif included in a relatively long sequence (such as full length human MAFA) this invention also provides relatively short length amino acid sequences of general formula (aa) n wherein n is any integer between 7 and 20, preferably between 7 and 10, most preferably 7 or 8.
  • the invention provides a nucleotide sequence which codes for the polypeptide sequence.
  • the invention provides an antibody or fragment thereof specific for an epitope of the C terminal extracellular domain sequences expressed on spliced type II C-lectin- like membrane proteins or an epitope of the N terminal intracellular domain sequences of type II C-lectin-like membrane proteins.
  • the type II C-lectin-like membrane protein is human MAFA or a truncated form thereof.
  • the truncated form is human MAFA[E3-] or human MAFA[E3/4-].
  • the invention provides a ligand specific for a fragment of human MAFA which is expressed on the surface of filamentous phage.
  • the invention provides a composition comprising a therapeutic amount of the polypeptide, antibody or fragment thereof or ligand, together with a pharmaceutically acceptable diluent or carrier.
  • the invention provides the polypeptide, nucleotide sequence, antibody, or fragment thereof, ligand or composition for use as a medicament. Preferably they are used in the treatment of inflammatory or allergic diseases or tumour growth.
  • the invention provides use of the polypeptide, nucleotide sequence, antibody or fragment thereof, ligand or composition in the manufacture of a medicament for the treatment of inflammatory or allergic diseases or tumour growth.
  • the invention provides a method of treatment for inflammatory or allergic diseases which comprises administering an effective dose of the polypeptide, antibody or fragment thereof, ligand or composition.
  • the invention provides a method of preparing the polypeptide which comprises the steps of: i) N ⁇ -Fmoc deprotection; ii) washing; iii) coupling of a single amino acid residue or amino acid mixtures; iv) washing; v) repeating until the desired polypeptide is constructed.
  • Figure 1 shows the nucleotide sequence [SEQ ID No. 8,9] encoding the full-length expressed form of human MAFA (nucleotides 1-570). The expected amino acid translation is shown beneath the nucleotide sequence. Putative N-linked glycosylation sites are underlined. (The two amino acids in italics refer to polymorphic mutations)
  • Figure 2 shows the nucleotide sequence and putative amino acid sequence [SEQ ID No. 10,11] of 400 bp alternative human transcript (huMAFA [E3-]). Amino acid translation resulting from reading frame-shift is shown in bold. (* represents a stop codon so no further transcription occurs. Italic amino acids from polymorphic mutations)
  • Figure 3 shows the nucleotide sequence and putative amino acid sequence [SEQ ID No. 12,13] of 301 bp alternative human MAFA transcript (huMAFA [E3/4-]).
  • the nucleotide sequence encoding the huMAFA C-terminal region is underlined (Analogous to rat Exon 5). (Italic amino acids from polymorphic mutations).
  • Figure 4 shows the nucleotide and amino acid sequence [SEQ ID No. 14,15] of rat MAFA. Putative N-linked glycosylation sites are underlined.
  • Blast program searches using the Internet NCBI software for human C-lectin-like sequences identified two expressed sequence tags (ESTs) AA 186699 and AA 188327 which showed some homology to the rat MAFA cDNA sequence. After careful analysis of the EST sequences, we designed PCR primers which we predicted represented the 5' and 3' end of the human MAFA coding cDNA.
  • ESTs expressed sequence tags
  • PCR using these primers on cDNA made from basophil- like leukaemic cells (KU812s), mast cell-enriched lung cells and basophil-enriched blood cells resulted in three different sized PCR DNA products of approximately 580, 400 and 300 bp. These DNA products were cloned into the sequencing vector pCR-script (Stratagene) and sequenced in both the forward and reverse directions using the T7 and T3 sequencing primers.
  • the largest PCR product was shown to represent the full coding sequence for human MAFA (fig.1 ), a 400 bp product huMAFA[E3-] (fig. 2.) and a 300 bp product huMAFA[E3/4-] (fig. 3).
  • the full length human MAFA is one amino acid longer than its rat homologue and possesses two additional N-linked glycosylation sites (fig. 1). Two presumed polymorphic mutations were detected between samples of nucleotide 95 A-G resulting in a codon change of Lys to Arg and nucleotide 124 A ⁇ G resulting in a codon change of threonine to analine. These changes are quite conservative and probably do not affect structure or function.
  • the human MAFA[E3-] variant has the same putative intracellular and transmembrane amino acid sequence as full length MAFA, but following this sequence is the unique sequence:
  • a library of peptides was constructed to represent the generic structure:
  • Inter leukin-2 Inhibitors are included in the following mixtures:
  • Degranulation Inhibitors are included in the following mixtures:
  • Ku 812 cells (Kishi, 1985) and Jurkat E17 T cells (Williams et al, 1995) were grown in RPMI 1640 (GIBCO) supplemented with 10 % (vol/vol) heat inactivated foetal calf serum, 50 IU/ml penicillin, 50 ⁇ g/ml streptomycin and 2 mM L-glutamine.
  • RBL cells were grown in DMEM (GIBCO) supplemented with 10 % (vol/vol) heat inactivated foetal calf serum, 50 IU/ml penicillin, 50 ⁇ g/ml streptomycin. Growth of all cells was at 37 °C in humidified 5 % CO 2 /95 % air.
  • Peripheral blood cells obtained in "buffy" coats were fractionated using Ficoll ® and washed white cell pellet further fractionated using Percoll as described by Raghuprasad (1982) to provide basophil-enriched cell populations.
  • Red blood cells were lysed by suspending cell pellet twice in 8.29 g/1 NH 4 C1, 0.84 g/1 NaHCO 3, 37.3 ⁇ g/1 EDTA, pH 7.3.
  • Remaining cells were treated as basophil-enriched cells and shown to contain 10-20% basophils, after Wright's solution staining of cytospin prepared slide samples..
  • Human lung biopsy samples (100-170 g) were minced finely using scissors and placed in enzymatic digestion cocktail (35 mg/ml BSA, fraction V, 0.38 mg/ml Hyaluronidase, 0.25 mg/ml Pronase, 0.03 mg/ml Dnase I, 0.75 mg/ml bacterial collagenase in DMEM) at 5 ml cocktail/g tissue for 1 hour at 37 °C with agitation. The digest was then filtered through a 0.75 ⁇ m nylon mesh to remove undigested material and washed twice in PBS. Samples of these cells were stained using Wrights solution and found to contain 5-10% mast cells.
  • enzymatic digestion cocktail 35 mg/ml BSA, fraction V, 0.38 mg/ml Hyaluronidase, 0.25 mg/ml Pronase, 0.03 mg/ml Dnase I, 0.75 mg/ml bacterial collagenase in DMEM
  • RBL cells were harvested by scraping and resuspended to 1x10° cells/ml in DMEM supplemented with 10 % (vol/vol) heat inactivated foetal calf serum, 50 IU/ml penicillin, 50 ⁇ g/ml streptomycin. 50 ⁇ l cells were added to wells in a 96 well flat-bottomed plate and incubated overnight at 37 °C with 50 ⁇ l 200 ng/ml anti DNP-IgE. The medium was then replaced with degranulation buffer (phenol red free RPMI 1640 (Gibco), lg glucose , 0.5g BSA in 500 ml) containing 4 ⁇ M test peptide and 37 °C incubation performed for 1 hour. DNP-BSA was then added to 100 ng/ml and incubation performed for a further 45 minutes. Buffer was then removed from the cells and assayed for hexosaminidase activity.
  • degranulation buffer phenol red free RPMI
  • Jurkat E17 T cells were harvested from actively growing suspension culture and resuspended to 4xl0 6 cells/ml in fresh medium. Cells were plated out in 96 well plates with test peptide at 2 ⁇ M at a concentration of 2xl0 6 cells/ml. Precubation was then performed for 1 hour at 37 °C followed by the addition of 2 ⁇ g/ml PHA and 50 ng/ml PDBu and overnight 37 °C incubation. Medium was then removed and assayed to determine the amount of interleukin 2 by ELISA (Genzyme kit).
  • RNA messenger RNA was isolated cell pellets using a Pharmacia mRNA isolation kit, as described in manufacturers instructions, this was used to make cDNA utilising oligo dT primers. Single-stranded DNA 5' and 3' primers were designed to amplify the full human MAFA coding sequence flanked by Bam HI restriction enzyme sites.
  • PCR using these primers and 20 ng template cDNA was performed at 94°C, 2 minutes, then 35 cycles of 94°C for 15 seconds, 65°C for 30 seconds and 72°C for 45 seconds followed by 72°C for 5 minutes using Klentaq (Clontech, USA).
  • PCR amplicons were then cloned into pCR-script (Stratagene) as described in manufacturers instructions prior to DNA sequencing on an applied biosy stems DNA sequencer.
  • DNA sequencing was performed using the Perkin-Elmer Taq polymerase system in conjunction with an Applied Biosy stems 373 sequencer. Sequence analysis was performed using DNAstar and NCBI blast programs.
  • Peptides were prepared by the multipin synthesis technique which is set out below:
  • the Fmoc-Rink-DA/MDA macrocrowns are assembled (simply clipped) onto stems and slotted into a 8 x 12 stem holder in the desired pattern for synthesis.
  • Peptides are then prepared as singles or defined equimolar mixtures by repetitive rounds of N ⁇ -Fmoc deprotection, washing, coupling of a single aminoacid or aminoacid mixtures, washing etc until the desired primary sequences have been constructed.
  • a 250 ml solvent resistant bath was charged with 200 ml of a 20% piperidine/DMF solution.
  • the multipin assembly was added and deprotection allowed to proceed for 30 minutes.
  • the assembly was then removed and excess solvent removed by brief shaking.
  • the assembly is then washed consecutively with (200 ml each), DMF (5 minutes) and MeOH (5 minutes, 2 minutes, 2 minutes) and left to air dry for 15 minutes.
  • a 1 cm path length UV cell was charged with 1.2 ml of a 20% piperidine/DMF solution and used to zero the absorbance of the UV spectrometer at a wavelength of 290nm.
  • Coupling reactions were performed by charging the appropriate wells of a polypropylene 96 well plate with the pattern of activated solutions required during a particular round of coupling. Macrocrown (approx 7 ⁇ mole) standard couplings were performed in DMF (500 ⁇ l). Coupling of an Amino-acid Residue To Appropriate Well
  • the appropriate N ⁇ -Fmoc amino acid pfp esters (10 equivalents calculated from the loading of each crown) and HOBt (10 equivalents) required for the particular round of coupling are accurately weighed into suitable containers.
  • the appropriate N ⁇ -Fmoc amino acids (10 equivalents calculated from the loading of each crown), desired coupling agent e.g. HBTU (9.9 equivalents calculated from the loading of each crown) and activation e.g. HOBt (9.9 equivalents calculated from the loading of each crown), NMM (19.9 equivalents calculated from the loading of each crown) are accurately weighed into suitable containers.
  • the protected and activated Fmoc amino acid derivatives are then dissolved in DMF (500 ⁇ l for each macrocrown e.g. for 20 macrocrowns, 20 x 10 eq. x 7 ⁇ moles of derivative would be dissolved in 10 000 ⁇ l DMF).
  • the appropriate derivatives were then dispensed to the appropriate wells ready for commencement of the 'coupling cycle' . As a standard, coupling reactions were allowed to proceed for 6 hours. The coupled assembly was then washed as detailed below.
  • Equimolar coupling reactions were performed by charging the appropriate wells of a polypropylene 96 well plate with the pattern of activated solutions required during a particular round of coupling.
  • the equimolar coupling cycle is a 3 stage cycle consisting of:-
  • the protected and activated Fmoc amino acid derivatives are then dissolved in DMF (500 ⁇ l for each macrocrown e.g. for 20 macrocrowns, 20 x 10 eq. x 7 ⁇ moles of derivative was dissolved in 10 000 ⁇ l DMF).
  • the appropriate derivatives were then dispensed to the appropriate wells ready for commencement of the 'coupling cycle'.
  • the standard equimolar coupling procedure is outlined above.
  • the coupled assembly was then washed as detailed below.
  • Acid mediated cleavage protocols were strictly performed in a fume hood.
  • a polystyrene 96 well plate (1 ml/well) was labelled, then the tare weight measured to the nearest mg.
  • Appropriate wells were then charged with a trifluoroacetic acid/triethylsilane (95:5, v/v, 600 ⁇ l) cleavage solution, in a pattern corresponding to that of the multipin assembly to be cleaved.
  • the multipin assembly was added, the entire construct covered in tin foil and left for 2 hours.
  • the multipin assembly was then added to another polystyrene 96 well plate (1 ml/well) containing trifluoroacetic acid/trirthylsilane (95:5, v/v, 600 ⁇ l) (as above) for 5 minutes.
  • the primary polystyrene cleavage plate (2 hour cleavage) and the secondary polystyrene plate (5 minute wash) were then placed in the SpeedVac and the solvents removed (minimum drying rate) for 90 minutes.
  • the contents of the secondary polystyrene plate were transferred to their corresponding wells on the primary plate using an acetonitrile/ water/acetic acid (50:45:5, v/v/v) solution (3 x 150 ⁇ l) and the spent secondary plate discarded.
  • the plate was covered with tin foil, held to the plate with an elastic band. A pin prick was placed in the foil directly above each well and the plate placed at -80°C for 30 minutes. The plate was then lyophilised on the 'Heto freeze drier' overnight.
  • MOLECULE TYPE peptide
  • SEQUENCE DESCRIPTION SEQ ID NO : 5:
  • MOLECULE TYPE DNA (genomic)
  • ATA ACG GAC AAT CAG GAA ATG AGC CTG CTC CAA GTT TTC CTC AGT GAG 384 lie Thr Asp Asn Gin Glu Met Ser Leu Leu Gin Val Phe Leu Ser Glu 115 120 125
  • MOLECULE TYPE DNA (genomic)
  • GCT CCA AGT TTT CCT CAG TGAGGCCTTT TGCTGGATTG GTCTGAGGAA 240
  • Val Leu Leu Ser Val Leu Leu Tyr Gin Trp lie Leu Cys Gin Glu Pro 50 55 60 Ala Pro Ser Phe Pro Gin 65 70
  • MOLECULE TYPE DNA (genomic)
  • TCT TCT AAT AGC TTT GTG CAG ACA TGC GGT GCC ATC ACC AAA AAT GGT 240 Ser Ser Asn Ser Phe Val Gin Thr Cys Gly Ala lie Thr Lys Asn Gly 135 140 145 150
  • MOLECULE TYPE DNA (genomic)
  • Xaa at postion 6 is selected from the group which comprises A,E,F,G,I,L,K,B,N,P,Q,S,T,V,Y.”
  • Xaa at postion 6 is selected from the group which comprises A,E,F,G,I,L,K,H,N,P,Q,S,T,V,Y.”
  • a secretion inhibitory signal transduction molecule on mast cells is another C-type lectin. Proc. Natl Acad. Sci. USA. 92, 9397- 9401.
  • Protein kinase C is not a downstream effector of p21 ras in activated T cells. Eur. I. Immunol, 25, 42-47.

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Abstract

L'invention concerne des polypeptides, des séquences de nucléotides, des anticorps ou leurs fragments, des ligands et des compositions, ainsi que leur utilisation dans les domaines médicaux de l'inflammation et de l'allergie, dont des exemples concernent des maladies, telles que la polyarthrite rhumatoïde et l'asthme. Elle concerne, de plus, un procédé servant à produire ces polypeptides. Elle propose des méthodes de traitement de ces maladies basées sur des agents conçus en combinaison avec le clonage de la molécule humaine MAFA. Une mise en application de l'invention consiste à empêcher des événements d'activation cellulaire in vivo, ce qui pourrait conduire à des thérapies servant à empêcher la croissance tumorale.
PCT/GB1998/001572 1997-05-31 1998-05-29 Mafa humaine WO1998054209A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU76670/98A AU7667098A (en) 1997-05-31 1998-05-29 Human mafa

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9711148.8A GB9711148D0 (en) 1997-05-31 1997-05-31 Human MAFA
GB9711148.8 1997-05-31

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WO1998054209A2 true WO1998054209A2 (fr) 1998-12-03
WO1998054209A3 WO1998054209A3 (fr) 1999-03-11

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001070805A2 (fr) * 2000-03-17 2001-09-27 Gemini Science, Inc. Antigene associe aux fonctions de mastocyte (mafa) soluble, compositions pharmaceutiques et leurs procedes de fabrication et d'utilisation
EP1467752A1 (fr) * 2002-01-03 2004-10-20 Tanox, Inc. Proteines membranaires de mastocytes exprimees
EP1572987A2 (fr) * 2000-02-03 2005-09-14 Nuvelo, Inc. Acides nucleiques et polypeptides
JP2021531246A (ja) * 2018-07-11 2021-11-18 イミュニティ ファルマ リミテッドImmunity Pharma Ltd. ペプチド化合物およびその治療的用途
CN114621320A (zh) * 2020-12-14 2022-06-14 清华大学 一种可用于减缓glp-1酶解的短肽及其组合物

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