WO2008013082A1 - Conjugué galectine 9/polymère - Google Patents
Conjugué galectine 9/polymère Download PDFInfo
- Publication number
- WO2008013082A1 WO2008013082A1 PCT/JP2007/064144 JP2007064144W WO2008013082A1 WO 2008013082 A1 WO2008013082 A1 WO 2008013082A1 JP 2007064144 W JP2007064144 W JP 2007064144W WO 2008013082 A1 WO2008013082 A1 WO 2008013082A1
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- Prior art keywords
- galectin
- chemically modified
- polymer
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- variant
- Prior art date
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Definitions
- the present invention relates to a galectin9_polymer conjugate.
- the present invention relates to a chemically modified galectin 9 and a variant thereof (stabilized galectin 9).
- Galectins are a lectin family that has an affinity for ⁇ -galatatoside and a conserved region on the primary sequence. To date, more than 10 types of mammalian galectins have been discovered, and various biological activities such as cell-cell adhesion or cell-extracellular matrix adhesion, cell activation, cell proliferation, and apoptosis have been reported.
- Gal9-containing drugs are promising as antitumor agents (anticancer agents), antiallergic agents, immunosuppressive agents, autoimmune disease agents, anti-inflammatory agents and corticosteroid substitutes 857 (2004.08.05) [Patent Document 1].
- Gal9 has also been reported to induce apoptosis in activated T cells.
- stabilized Gal9 (Gal9 variant) and its use are disclosed in WO 2005/093064 (2005.10.06) [Patent Document 2].
- Biologically active proteins are ligated with polymers to suppress the occurrence of immune reactions, extend the circulation life of the protein in vivo, and are soluble in water and / or antigenic. Techniques to improve the properties have been applied to insulin, hemoglobin, interferon, interleukin-2, etc., and research and development of various proteins are currently being attempted. A typical example is when a peptide or polypeptide is replaced with polyethylene glycol (PEG) or a similar water-soluble polymer. Coupling is performed [Patent Document 3].
- Patent Document 1 WO 2004/064857 (2004.08.05)
- Patent Document 2 WO 2005/093064 (2005.10.06)
- Patent Document 3 Japanese Patent Publication No. 56-23587
- Non-Patent Document l Tureci 0. et al "J Biol Chem” 1997, 272 (10): 6416-22
- Non-Patent Document 2 Matsumoto R. et al., J Biol Chem., 1998, 273: 16976-84
- Non-Patent Document 3 Matsushita N. et al., J Biol Chem., 2000, 275: 8355-60
- Galectin 9 is an immune function modulating factor belonging to a new class different from known cytodynamic ins, and is expected to be used as a therapeutic agent for various immune-related diseases including autoimmune diseases. Is done.
- galectin 9 has problems to be solved in therapeutic drug development, such as high sensitivity to protease and low solubility.
- a linker peptide of galectin 9 is modified to produce a modified galectin 9, that is, stabilized galectin 9.
- Stabilized galectin 9 has the following characteristics compared to the natural type.
- [11] It should be selected from the group consisting of antitumor agents (anticancer agents), antiallergic agents, immunosuppressive agents, autoimmune disease agents, anti-inflammatory agents and corticosteroid substitutes.
- antitumor agents anticancer agents
- antiallergic agents antiallergic agents
- immunosuppressive agents anti-inflammatory agents
- autoimmune disease agents anti-inflammatory agents
- corticosteroid substitutes corticosteroid substitutes.
- a product selected from the group consisting of galectin 9 and a variant of galectin 9 and a PEGylation reagent are reacted under conditions in which a covalent bond is formed and the protein is PEGylated to produce a PEGylated galectin 9 conjugate.
- the chemically modified galectin 9 obtained by the present invention or a variant thereof, i.e., galectin 9_polymer conjugate gives more useful solubility and extended elimination half-life, and is effective against tumor cells, particularly malignant tumor cells. Therefore, it shows a more enhanced cytotoxic (disorder) activity, and can achieve a reduction in side effect of disappearing red blood cell agglutinating action, and it is considered possible to achieve excellent biodistribution. Therefore, the galectin 9 polymer conjugate is useful and excellent as a medicine and a physiologically active substance.
- the galectin 9 moiety in the galectin 9 polymer conjugate is derived from “galectin 9” (galectin 9: Gal9), and the galectin 9 includes, for example, L-type galectin-9 (Gal9L ), M-type galectin-9 (Gal9M), S-type galectin-9 (Gal9S), and further modified galectin-9 modified by the amino acid sequence of these galectin-9, for example, stabilized galectin-9 (e.g., G9NC (dish 11 >> Galectin 9 can be prepared, isolated or purified from various sources, for example, human leukocytes having the ability to produce Gal9 or cell line production of cell lines.
- Natural galectin 9 (natural gal9 or naturally-occurring gal9) and a gene encoding the above-mentioned leukocyte or Gal9 derived from a specific cell line of microorganisms using microorganisms such as animal cells and E. coli It means recombinant galectin 9 (recombinant galectin 9: rGal9) obtained by integration, and any of them can be used advantageously.It can be obtained from a transgenic animal, etc. Such transgenic animals may include mice, rats, rabbits, rabbits, butterflies, goats, hidges, etc. As the Gal9, a mixture of two or more types of galectin 9 may be used. From the viewpoint of antigenicity, Gal9 (hGal9) can be used advantageously.
- Galectin 9 typically includes natural Gal9.
- long type (L type) galectin 9 galectin 9 long isoform or long type galectin 9: Gal9L
- medium type (M type) galectin 9 galectin 9 medium isoform or medium type galectin 9: Gal9M
- short type (S type) Galek Chin 9 Gal9L has an N-terminal domain (N-terminal saccharide) due to the putative linked peptide region of SEQ ID NO: 4 disclosed in WO 02/37114 A1.
- Gal9M is WO 02 / NC114 and CCRD were linked by the putative linked peptide region of SEQ ID NO: 5 of 37114 Al, and GalRD was linked by the putative linked peptide region of SEQ ID NO: 6 of WO 02/37 114
- A1 Gal9M differs from Gal9L in that the amino acid residue of the sequence of SEQ ID NO: 7 of W002 / 37114 Al is deleted from the linked peptide region of Gal9L.
- the WO 02/37 is obtained from the linked peptide region of Gal9M.
- Gal9M is different from Gal9M in that the amino acid residue of SEQ ID NO: 8 is deleted, that is, Gal9S lacks the amino acid residue of SEQ ID NO: 9 of WO 02/37114 Al from the putative Gal9L linked peptide region. It differs from L-type galectin 9 in that it is lost.
- the amino acid sequence IJ of Gal9L is SEQ ID NO: 1 disclosed in WO 02/37114 A1
- the amino acid sequence of Gal9M is SEQ ID NO: 2 disclosed in WO 02/37114 A1
- the amino acid sequence of Gal9S is WO SEQ ID NO: 3 disclosed in 02/37114 A1 shows the typical sequence respectively.
- galectin 9 includes Gal9L, Gal9M and Gal9S, other naturally occurring mutants of the galectin 9 family, and artificial mutations (ie, one or more amino acid residues such as one or several). In the group, it may mean a group that has been subjected to deletion, addition, modification, insertion, etc.) or that includes a partial domain or partial peptide fragment thereof.
- WO 2004/064857 2004.08.05
- J. Biol. Chem "275 (12): pp. 8355-8360 (2000) should all be included.
- Galectin 9 contains natural substances.
- Galectin 9 variants as well as ⁇ galectin 9 variant '', ⁇ galectin 9 variant polypeptide '', and ⁇ galectin 9 variant therapeutic agent '' disclosed in PCT / JP 2005/006580 (filing date 2005.03.2 9) All may be included. Particularly preferred is G9NC (null) (PCT / JP 2005/006580 (filing date 2005.03.29) manufactured and obtained in Example 1 of PCT / JP 2 005/006580 (filing date 2005.03.29). A polypeptide encoded by the base sequence represented by SEQ ID NO: 1 and having the amino acid sequence represented by SEQ ID NO: 2].
- Gare It has been recognized that some of the “cutin 9 variants” or “galectin 9 variant polypeptides” exhibit more stable properties than native galectin 9. Is also referred to herein as "stabilized galectin 9". Representative examples of the stabilized galactin 9 include the above-mentioned G9NC (null), and those that show similar properties that are not limited thereto may be included therein.
- the therapeutic and Z or prophylactic agent of the present invention and the therapeutic and / or prophylactic method thereof are the same as those disclosed in WO 2004/064857 (2004.08.05) and PCT / JP 2005/006580 (filing date 2005.03.29).
- the descriptions contained therein can be included in the disclosure of this specification by reference thereto.
- FIG. 2 shows the results of examining the growth inhibitory activity of a modified PEGylated galectin 9 (PEGylated stabilized galectin 9) against human prostate cancer-derived cell line PC-3.
- G9Null G9NC (null)
- G9Null -PEG-5K-SE2 SE2 fraction of stabilized galectin 9 (G9 NC (null)) PEGylated with mPEG_SPA molecular weight 5,000
- G9NuU-PEG-10K-SE2 mPEG2- SE2 fraction of stabilized galectin 9 (G9NC (null)) that has been converted to EG using NHS molecular weight 10,000
- FIG. 3 shows the results of examining the growth inhibitory activity of a modified PEGylated galectin 9 (PEGylated stabilized galectin 9) against human prostate cancer-derived cell line PC-3.
- G9Null G9NC (null)
- G9Null -PEG-20K-SE2 Stabilized galectin 9 PEGylated with mPEG2_NHS molecular weight 20,000 (SE2 fraction of G9NC (null)
- G9Nul ⁇ PEG-40K-SE2 mPEG2_NHS SE2 fraction of stabilized galectin 9 (G9NC (null)) PEGylated
- FIG. 4 shows the results of examining the growth inhibitory activity of a modified PEGylated galectin 9 variant (PEGylated stabilized galectin 9) on human prostate cancer cell line PC-3.
- G9Null-PEG-5K-SE2 Stabilized galectin 9 PEGylated with mPE G-SPA molecular weight 5,000 (SE2 fraction of G9NC (dish 11), G9Nul ⁇ PEG-5K-SE1: SE1 fraction of stabilized galactin 9 (G9NC (null)) PEGylated with mPEG-SPA molecular weight 5,000, G9NuU-PEG_10K_SE2: PEGylated with mPEG2-NHS molecular weight 10,000 Stabilized galectin 9 (SE1 fraction of G9NC (dish 11), G9NuU-PEG-10K_SE 1: mPEG2-NHS with molecular weight 10,000? SE1 of stabilized galectin 9 ( ⁇ 9 ⁇ (111111))
- FIG. 5 shows the results of examining the growth inhibitory activity of a modified PEGylated galectin 9 (PEGylated stabilized galectin 9) against human prostate cancer-derived cell line PC-3.
- G9Null-PEG-20K-SE2 SE2 fraction of stabilized galectin 9 (G9NC (null)) PEGylated using mP EG2-NHS molecular weight 20,000
- G9Nul ⁇ PEG-20K-SE1 mPEG2-NHS molecular weight 20,000
- G9Nul ⁇ PEG-40K- SE2 mPEG2- NHS molecular weight 40,000
- PEGylated stabilized galectin 9 (G9NC (null) >> SE2 fraction
- G9NuU_PEG-400K-SE2 SE1 fraction of stabilized galectin 9 (G9NC (null)) PEGylated using m
- FIG. 6 shows the results of measuring the hemagglutination activity of PEGylated and stabilized galectin 9 against rabbit erythrocytes and human erythrocytes.
- FIG. 7 shows the results of examining the therapeutic activity of PEGylated and stabilized galectin 9 on rat CIA model.
- gene recombination technology is used to construct or obtain a predetermined nucleic acid (polynucleotide) or a predetermined peptide (polypeptide), or to isolate / sequence, Can be made.
- gene recombination techniques including recombinant DNA technology
- Examples of gene recombination techniques that can be used in the present specification include those known in the art, such as J. Sambrook et al, Molecular Cloning: A Laboratory Manual (2nd edition ( 1989) & 3rd edition (20 01), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York; DM Glover et al. Ed., "DNA Cloning", 2nd ed., Vol.
- galectin-9 polypeptides of the invention may be used to produce the galectin-9 polypeptides of the invention, or galectin-9 variant polypeptides.
- host cells include, but are not limited to, bacteria, yeast, insects, mammals, plants and the like.
- Escherichia coli for example, those derived from Escherichia coli K1 2 strain or B strain can be mentioned, for example, NM533, XLl-Blue, C600, DH1, DH5, DH11S, DH12S, DH5, DH10B, HB101, MC1061,
- Examples derived from JM109, ST BL2, B834 strain include BL21 (DE3) pLysS, and expression vectors suitable for them can be selected and used.
- yeasts that may include baker's yeast, fission yeast, and the like include the genus Saccharomyces, the genus Schizosaccharomyces, and the genus Pichia.
- examples include Saccharomyces cerevisiae (Sac charomyces cerevisiae Schicharosaccharomyces pombe), and Hichia pastoris (Pichia pastoris), which can be used by selecting appropriate expression vectors.
- Representative expression vectors include, for example, pBR322, pUC18, pUC19, pUC118, pUC119, pSP64, pSP65, pTZ-18R / -18U, pTZ_19R /-19U, pGEM-3, pGEM-4, pGEM-3Z, pGEM-4Z, pGEM-5Zf (-), pGEMEX-l (Promega), pBC KS (Stratagene), pBC SK (Stratagene), pBluescript SK (Stratagene), pBluescript II SK (Stratagene), Bluescript II KS (Stratagene) ), pBS (Stratagene), pAS, pKK223 ⁇ 3 (Amersham Pharmacia Biotech), pMC1403, pMC931, pKC30, pRSET-B (Invitrogen), pSE280 (Invitrogen), pBTrp2 (Boehringer Mannheim
- BsdCassette Vectors Epitope- Tagged pcDNA Vectors, Eukaryotic TA Expression Kit, Flp-In Expression Vectors and Kits, Flp-In -REx Expression Vectors, Free Style 293 Expression System, GeneSwitch System, pBCl Milk Expression Vector Kit, pBudCE4.1, pcDNA Gateway Vectors, pcDNA 3.1 Dir ectional TOPO Expression Kit, pcDNA 1-E Echo Expression Vector Kit, pc DNA 3.1 / V5- His TOPO Expression Kit, pcDNA 4 / HisMax and pcDNA 4 / His Max TOPO TM TA Expression Kit, pcDNA TM 4 / TO_E Echo TM Vector Expression Kit, pcDNA TM 6 BioEase TM Gateway TM Biotinylation System, pcDNA / V5 — GW / D—TOPO TM Vectors, pCEP4 and pREP4, pDisplay TM Vector, pEF6
- Adenoviral Expression Vectors Creator System Vectors, IRES Bicistronic Expression Vectors, Living Colors Fluorescent Protein Vectors, MATCHMARJER Vectors, Retroviral Expr ession Vectors, Signal Transduction Vectors, Tet Expression System Vectors, BacP ak Baculovirus Expression Vectors, HAT Protein Expression Syste m Vectors), HaloTag TM pHT2 Vector, pACT Vectors, pBIND Vectors, pCAT TM 3 Vectors, pCI V ectors, phRG Vectors, phRL Vectors (Promega Corp.), Novagen vectors for protein expression (for example, TriEX Multisystem Expression Vectors, pBiEX Multisyste m Expression Vectors, pTandem -1 Vector, or known by the force other art cited pTK-neo DNA, etc.) force s, Ru can be appropriately selected and used those commercially available.
- TriEX Multisystem Expression Vectors for example, TriEX Multisystem Expression Vectors,
- the target product contained in cells can be purified by an appropriate combination of per se known separation and purification methods, such as ammonium sulfate precipitation.
- per se known separation and purification methods such as ammonium sulfate precipitation.
- polyacrylamide gel electrophoresis affinity chromatography with immobilized ligand, etc. It can be processed and purified and separated.
- the ligand include an antibody including a monoclonal antibody that specifically recognizes or a fragment thereof, a lectin, a sugar, and one binding pair.
- galactosides including imno 'affinity' chromatography, gelatin agarose affinity chromatography, heparin agarose chromatography, ratatoose agarose chromatography, etc. And chromatography using a carrier such as agarose.
- gene recombination technology is used to produce a fusion protein or polypeptide, and a fusion portion (tag) is used to utilize a specific binding ligand such as an antibody to affinity chromatography. It can be easily purified by chromatography.
- Galectin 9 and its variants may be chemically synthesized.
- a method known in the peptide synthesis field for example, a chemical synthesis method such as a liquid phase synthesis method or a solid phase synthesis method can be used for the synthesis of the protein and a part of the peptide.
- a resin for protein or peptide synthesis is used, and appropriately protected amino acids are sequentially bonded to the desired amino acid sequence on the resin by various condensation methods known per se.
- the ability to use various activation reagents known per se for the condensation reaction As such reagents, for example, calpositimides such as dicyclohexyl carpositimide can be preferably used.
- the desired product can be obtained by removing the protecting group as appropriate.
- the nucleic acid encoding galectin 9 and a selected from the group consisting of variants thereof may be chemically synthesized.
- it can be chemically synthesized by a method such as a phosphophotoreestero method, a phosphodiesterenole method, a phosphite method, a phosphoramidite method, or a phosphonate method. It is known that normal synthesis can be carried out conveniently on a modified solid support, for example using an automated synthesizer, which is commercially available.
- Nucleic acid sequences encoding galectin 9, and variants selected from the group consisting of variants thereof include, for example, modified codons suitable for proper expression in selected host cells (e.g., codon substitutions). ), Restriction enzyme sites may be provided, and target genes such as expression control sequences and regulatory sequences to facilitate expression of the target gene are manipulated. Suitable for use with linkers, adapters, etc. They may also be provided with convenient or useful modifications, including sequences useful for controlling antibiotic resistance, auxotrophic 'metabolism, screening' detection and the like.
- the method of preparing galectin 9 for the conjugates of the present invention is not limited to that described herein.
- the polymer part in the galectin 9_polymer conjugate is derived from a “water-soluble polymer”, and examples of the polymer that gives the polymer part include polyalkylene oxide, phospholipid polymer, polyvinylenopyrrolidone And polysaccharides such as dextran.
- Polymers that are water-soluble at room temperature are widely known and can be selected from, for example, typical examples include polyalkyleneoxide homopolymers, polyoxyethylenated polyols, copolymers thereof, and Examples include block copolymers.
- Polyalkylene oxides may include polyethylene glycol (PE G), polypropylene glycol, etc.
- an unbranched one for example, a linear one can be preferably used, and a substituted one is preferred, but one end of the PEG copolymer is an alkyl group. Also preferred are those substituted with groups.
- the alkyl group present at the terminal is a C to C alkyl group.
- Polyoxyethylenated polyols include polyoxyethylenated glycerol, polyoxyethylenated sorbitol, polyoxyethylenated glucose, and the like.
- Polyoxyethylenation (PEGylation) in polyoxyethylenated glycerol may include, for example, mono PEG ⁇ , di PEG ⁇ , and tri PEGylation.
- Preferred polymers are unsubstituted.
- the polymer is not limited to one having a specific molecular weight as long as a predetermined purpose is obtained, but typically a polymer having a number average molecular weight of about 200 to 100,000 can usually be selected, and about 500 ⁇ 90,000, about 1,000-80,000, about 2,000-70,000, about 3,000-60,000, about 4,000-50,000, about 4,500-45,000 Stuff, about 5,000 to 40,000 can be selected.
- the polymer has, for example, a number average molecular weight of about 2,500 to 7,500, more preferably about 4,000 to 6,000, in other cases about 8,000 to 15,000, About 9,000 to 12,000, and for other purposes, about 15,000 to 25,000, even about 18,000 to 22,000, and in yet another example about 25,000 to 50,000 And about 30,000-45,000 can be selected.
- the bond between the polymer part and the galectin 9 part is selected from the group consisting of a carbon-carbon bond, a carbon-oxygen bond, a carbon-sulfur bond, a carbon-nitrogen bond, and a sulfur-sulfur bond.
- ester bond (_CO-0-), thioester bond, amide bond (_NH-CO-), ether bond, thioether bond, disulfide bond (-SS-), urethane It may have one selected from the group consisting of a bond (-0-CO-NH-) and the like.
- one of the hydroxyl groups of the polymer is a conformation. It can be changed to a reactive functional group as possible. This conversion process is often referred to as activation.
- the product obtained by the activation treatment is called an activated polymer or a functionalized polymer.
- one of the hydroxyl groups of the polymer is replaced with an amino group or a sulfhydryl group (HS-group), and then subjected to an activation treatment. It may be the corresponding activated polymer.
- Activated PEG is also referred to in the art as a PEGylating agent or a PEGylation reagent.
- Reactive groups, ie activated groups (functional groups) on the polymer side For example, a terminal carboxy-N-dicarboximide group such as a succinimidyloxycarbonyl group is preferably used.
- N-dicarboximide group include an N-succinimide group, an N-phthalimide group, an N-glutarimide group, an N-tetrahydrophthalenimide group, and an N-5-norbornene-2,3-dicarboximide group.
- N-succinimide group can be preferably used.
- Various techniques are known to form the terminal carbonyloxy-N-dicarboxyimide group, for example, carbonyl halides or carbonyloxysulfonyl compounds and N-hydroxysuccinimide and other N -Obtained by a method such as reacting with hydroxydicarboximide.
- N-hydroxydicarboximide includes N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxyglutarimide, N-hydroxytetrahydrophthalimide, N-hydroxy-5-norbornene-2,3-dicarboximide, etc. Can be mentioned.
- An activated group (functional group) for example, a terminal carbonyloxy-N-dicarboximide group
- a terminal carbonyloxy-N-dicarboximide group on the polymer side that reacts with the above-described protein nitrogen atom and the main backbone of the polymer (for example, the polymer is PEG).
- mPEG, etc. [-CH -CH _0_] or [-CH -CH -0-]
- the polymer is treated with a coupling agent so as to give the activated carboxylic acid residue moiety present in the carbonyl halide or carbonyloxysulfonyl compound.
- a coupling agent May have been modified or modified to be convenient for treatment with the coupling agent and / or to provide an appropriate interrelationship between the galectin-9 polymers, and some of the spacers derived therefrom may be It exists.
- What exists between the main skeleton of the polymer and galectin 9 can be called a spacer or a spacer arm, and the spacer has a nitrogen atom, an oxygen atom, a sulfur atom, etc.
- the spacer can be appropriately selected from those known to those skilled in the art in the field of protein modification, or modified derivatives thereof.
- Typical spacers include amino acid force-induced lysines such as those linked by a methylene chain, Those derived from oligopeptides such as tides, those derived from bifunctional carboxylic acid anhydrides such as succinic anhydride and dartaric anhydride, those derived from hydroxycarboxylic acid forces such as hydroxybutyric acid, etc.
- -0-CH CH -CO- -0-CH
- the coupling agent examples include those known in the art, particularly those known to be used for protein modification, and those known as linkers may be included.
- PEGylating agents or PEGylating reagents are known in the art, and it is convenient to use commercially available ones such as NE KTAR, San You can use what is available, such as Carlos, CA, USA.
- Examples of the commercially available PEG reagent include mPEG-succinimidyl propionate (mPEG_SPA), branched P A force S that can include EG N-hydroxysuccinimide (mPEG2-NHS), etc.
- conjugation or conjugation (or conjugation reaction).
- this conditioning is called PEGylation or PE Gation reaction.
- this reaction can be carried out in an aqueous solvent, but it can also be carried out in a state attached to a carrier in an aqueous environment.
- the carrier can be appropriately selected from those used in the isolation purification of proteins, and can be selected from among those used for affinity chromatography, for example.
- a typical carrier includes a carrier having a ligand such as a sugar chain. Examples include garose and the like, and carriers such as garose to which 3-galatatoside is immobilized as a ligand.
- the conjugation reaction of the present invention preferably includes performing the modification so as to avoid modifying the amino group present in the lysine residue at a site important for the biological activity of galectin-9.
- it may be included so as to avoid modification of the amino group present in the lysine residue at a site important for the bioactivity of galectin 9, and it may be preferable. is there.
- This compound is a modified galectin 9 [in this specification, since it is a stabilized human galectin 9, a force that may be referred to as “stabilized galectin 9”.
- / 093064 publication date: October 06, 2005.
- the sequence number in the sequence listing of W ⁇ 2005 / 093064 (publication date: October 06, 2005) is For the amino acid sequences shown, including those abbreviated as G9NC (null), the arrangement of 6 lysine residues [WO2005 / 093064 (publication date: October 06, 2005)] Lys 88 , Lys 95 , Lys " 1 , Lys 180 , Lys 238 , and Ly S 259 ] in the amino acid sequence shown in SEQ ID NO: 2 in the column table, and may occur at the amino group at the N-terminus, M Similarly for type galectin 9 (Gal9M), six lysine residues [WO 02/037114 (publication date: May 10, 2002)] Lys 88
- Species species (and may include their positional isomers), molecular species in which PEG molecules are bound at two positions of the lysine residue (and their positional isomers), the lysine residue Molecular species with PEG molecules bound to the three strengths of the group (and may include their positional isomers), and PEG molecules bound to the four strengths of the lysine residue.
- Molecular species (and their positional isomers) can be obtained. If preferred, it may be a molecular species in which a PEG molecule is bound to one of the lysine residues, or a molecular species in which a PEG molecule is bound to two of the lysine residues.
- activated polymer such as PEGylation reagent for galectin 9 is not particularly limited in the amount used, but is selected so as to obtain a required modification, that is, a conjugate. it can.
- PEGylation reagents can be used in a range from a relatively slightly lower molar amount to a relatively slightly excess molar amount.
- the PEGylation reagent can be used in a molar excess of about 0.8 to 8 times relative to galectin 9, and can be used in a molar excess of about 1 to 8 times.
- the PEGylation reagent can be used in a molar excess of about 1.25 to 7 times or in a molar excess of about 1.75 to 6 times.
- the reaction temperature is not particularly limited, but is usually a force that can be carried out at 0 to 50 ° C.
- the reaction can be carried out at about 4 to 40 ° C, typically about 4 ° C or around room temperature. It can be carried out at 15-25 ° C.
- the reaction time may be relatively short, for example, 30 minutes to 3 hours, in some cases, about:! To 2 hours.
- the reaction can be stopped after proceeding for a predetermined time, which is preferable in some cases.
- the pH in the aqueous medium in this reaction is about 7.0 to about 9.0, preferably about 7.5 to about 8.5, and is preferably performed in a buffer solution.
- the buffer solution may contain one selected from phosphate ion, chloride ion, bicarbonate ion, carbonate ion, for example, NaCl, KC1, Na PO, K PO, Na HPO, K ⁇ , ( ⁇ ) ⁇
- aqueous solution containing a salt selected from 4 2 4 2 4 2 3 2 3 3 3 4 4 2 3 and the like is preferably used.
- Preferred and buffer solutions include those using Na HPO -NaH PO system.
- the reaction product solution may be obtained as a heterogeneous mixture containing polymer chains bonded to different sites on 9 molecules of galectin.
- the solution containing these conjugates is useful even when used as is S, Molecules It is also preferable to separate and purify the composite based on the amount or the difference in the position of polymer chain binding on the galectin 9 molecule.
- the properties of the galectin 9-polymer conjugate in the reaction mixture obtained with this mixture can be characterized by cation exchange chromatography, for example, the polymer chain bound to one force on the galectin 9 molecule.
- Those that bind to different sites, or that have polymer chains bound to two sites on the galectin 9 molecule, or those that bind to different sites, such as positional isomers. May be included.
- both a mixture containing positional isomers of galectin 9_polymer conjugate and a mixture of Z or molecular species having different numbers of bonds on galactin 9 molecules of the polymer chain are used. It is possible to do.
- Any of the solutions containing the conjugate are in the form of a mixture containing at least two positional isomers, in some cases in the form of a mixture containing the three positional isomers, or even 4 It may be in the form of a mixture containing more than one species of positional isomers.
- the target product contained in the reaction product solution obtained with this conduit can be purified by an appropriate combination of known separation and purification methods, for example, a salt such as ammonium sulfate precipitation method.
- Gel filtration methods such as analysis, cefadex, etc., for example, using a carrier having a dimethylaminoethyl group, a carboxymethyl group, a —SO— group, etc.
- Ion exchange chromatography for example, hydrophobic chromatography using a carrier having a hydrophobic group such as butyl, octyl, phenyl, etc., dye gel chromatography, electrophoresis, dialysis, ultrafiltration, It can be obtained by purification by a two-tee 'chromatography method, a high performance liquid chromatography method or the like. Preferably, it can be purified and separated by treatment with polyacrylamide gel electrophoresis, affinity 'chromatography with a ligand or the like immobilized.
- the ligand include an antibody including a monoclonal antibody that specifically recognizes or a fragment thereof, a lectin, a sugar, and one of binding pairs.
- ⁇ -galatatoside is immobilized as a ligand, including Imuno'affinity 'chromatography, Gelatin-agarose'affinity chromatography, Heparin-agarose'chromatography, Ratatoose-agarose'chromatography, etc. And chromatography using a carrier such as agarose.
- a carrier such as agarose.
- strong It can also be divided into desired fractions by ion exchange chromatography using an acidic thione exchange resin, a strong acidic thione exchange gel, or the like. In some cases, it is effective to use gel filtration chromatography that can be separated based on the size of the molecule, and in some cases, it is also effective to use anion exchange chromatography.
- a concentration gradient can be used to elute the target complex from the support.
- an aqueous medium is preferably used.
- a buffer solution can be suitably used.
- the buffer solution may contain one selected from phosphate ion, chloride ion, bicarbonate ion, carbonate ion, for example, NaCl, KC1, Na PO, K PO, Na HP ⁇ , K ,, ( ⁇ ) ⁇ ⁇ ⁇
- aqueous solution containing a selected salt is preferably used.
- Preferred examples of the buffer system include those using the Na HPO -NaH PO system. In this fraction processing
- the pH in the aqueous medium is not particularly limited as long as it does not adversely affect the product, but is usually about 5.0 to about 10.0, preferably about 6.0 to about 9.0, more preferably about 7.0 to about 8.0. It is.
- the operating temperature in the case of leaching is not particularly limited, but it can usually be carried out at 0 to 37 ° C, but it can be preferably carried out at about 4 to 30 ° C. It can be performed at 4 ° C or near room temperature, and can be performed at about 4 to 25 ° C.
- a column packed with a cation exchange gel is equilibrated with an aqueous solution of galectin 9 conditioned in a conventional manner and an aqueous buffer solution having the same pH and salt concentration, and then conjugated.
- the solution containing the gate is adsorbed onto the column.
- run a conditioned galectin 9 solution and a buffered aqueous solution with the same pH and salt concentration through the column to elute unadsorbed components.
- the column is then run with elution buffer that gives a gradient that gradually increases the salt concentration, and the eluate is collected in fractions.
- Suitable galectin 9_polymer conjugate fractions include:! ⁇ 6 polymer chains per galectin 9 molecule (for example, when using mPEG2-NHS as the PEGylation reagent, the amino acid residues on galectin 9 When bound to one of the amino groups (one substitution bond), the polymer chain, mPEG, will be introduced two) and may contain a galectin-9 conjugate molecule, In some cases The fraction may contain galectin 9 conjugate molecules with 9 polymer galectins per molecule: and, further, with 2 polymer chains per galectin 9 molecules:! It may contain a galectin-9 conjugate molecule having a galectin-9 conjugate molecule having one polymer chain per galectin9 molecule.
- the galectin 9_polymer conjugate obtained in the present invention can be used as an active ingredient in IJ, which is useful in medicine.
- the galectin 9-polymer conjugate may be separated and purified to a single molecular form, or has an essentially uniform molecular weight and degree of substitution. Fractions containing conjugates, and also in the form of a mixture containing a plurality of galectin 9_polymer conjugate molecular species that are considered to be therapeutically homogeneous. You can select and use.
- the active ingredient of the present invention when used as a medicine, it can be administered as a pharmaceutical composition or a pharmaceutical preparation, usually alone or mixed with various pharmacologically acceptable adjuvants.
- a pharmaceutical composition or a pharmaceutical preparation usually alone or mixed with various pharmacologically acceptable adjuvants.
- it is administered in the form of a preparation suitable for use such as oral administration, topical administration, parenteral administration, etc., and depending on the purpose, any dosage form (including inhalation or rectal administration) may be used.
- Each of the active ingredients of the present invention may be used as a mixture, for example, a mixture of galectin 9-polymer conjugate and native galectin 9, a mixture of galectin 9-polymer conjugate and galectin-9 variant, galectin 9-polymer conjugate A mixture of galectin 9-polymer conjugate and galectin 9-galectin 9 inducer, a mixture of native galectin 9 and galectin 9_polymer conjugate and galectin-9 variant, etc. You may use it.
- the active ingredient of the present invention includes various drugs such as antitumor agents (anticancer agents), antibiotics, tumor transfer inhibitors, thrombus formation inhibitors, joint destruction treatment agents, analgesics, anti-inflammatory agents, antiallergic agents.
- drugs such as antitumor agents (anticancer agents), antibiotics, tumor transfer inhibitors, thrombus formation inhibitors, joint destruction treatment agents, analgesics, anti-inflammatory agents, antiallergic agents.
- mammals including humans (eg, intracellular, tissue, intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intrathoracic, intrathecal, instillation, enema, Can be administered to the rectum, ear drops, eye drops, nose, teeth, skin, mucous membranes, etc.).
- humans eg, intracellular, tissue, intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intrathoracic, intrathecal, instillation, enema, Can be administered to the rectum, ear drops, eye drops, nose, teeth, skin, mucous membranes, etc.
- preparations include solution preparations, dispersion preparations, semi-solid preparations, granular preparations, molded preparations, leaching preparations, etc., for example, microcapsules, carriers, powders, Powder, Granule, Fine Granule, Injection, Solution, Elixir, Emulsion, Irrigation, Water, Emulsion, Suspension, Aerosol, Spray, Inhalation, Spray, Skin Solution, Eye Drop , Nasal drops, ear drops
- powders, lyophilized preparations, gel preparations, etc. for coating agents, infusion solutions, injection solutions and the like.
- the pharmaceutical composition can be formulated according to a usual method.
- physiologically acceptable carriers for example, as needed, physiologically acceptable carriers, pharmaceutically acceptable carriers, adjuvants, excipients, excipients, excipients, diluents, flavoring agents, fragrances, sweeteners, vehicles, preservatives , Stabilizer, binder, pH adjuster, buffer, surfactant, base, solvent, filler, extender, solubilizer, solubilizer, isotonic agent, emulsifier, suspending agent , Dispersants, thickeners, gelling agents, curing agents, absorbents, adhesives, elastic agents, plasticizers, disintegrants, propellants, preservatives, antioxidants, sunscreen agents, moisturizers, relaxation agents, electrification
- an inhibitor, a soothing agent or the like alone or in combination with the compound of the present invention and the like, it can be produced into a unit dosage form required for the practice of a generally accepted formulation.
- Suitable formulations for parenteral use include sterile solutions or suspensions of the active ingredient and water or other pharmaceutically acceptable media such as injections. .
- water, saline, aqueous dextrose solution, other related sugar solutions, glycols such as ethanol, propylene glycol, polyethylene glycol and the like are preferable liquid carriers for injections.
- a carrier such as distilled water, Ringer's solution, physiological saline, an appropriate dispersing agent, wetting agent, suspending agent, etc., and a solution known in the art.
- prepare in an injectable form such as a suspension or emulsion.
- aqueous solutions for injection examples include isotonic solutions containing physiological saline, glucose and other adjuvants (eg, D-sorbitol, D-mannitol, sodium chloride sodium salt, etc.).
- Suitable pharmacologically acceptable solubilizers such as alcohol (eg ethanol), polyalcohol (eg propylene glycol, polyethylene glycol etc.)
- Can also be used in combination with nonionic surfactants eg, polysorbate 80 TM, HCO-50, etc.
- nonionic surfactants eg, polysorbate 80 TM, HCO-50, etc.
- oily liquids include sesame oil and soybean oil, which may be used in combination with benzyl benzoate or benzyl alcohol as a solubilizer.
- buffers eg, phosphate buffer, sodium acetate buffer, etc.
- reagents for adjusting osmotic pressure eg, phosphate buffer, sodium acetate buffer, etc.
- soothing agents eg, benzanolonium chloride, pro-hydrochlorin hydrochloride, etc.
- stable You may mix
- the prepared injection solution is usually filled in a suitable ampoule.
- a sterile pharmaceutically acceptable liquid such as water, ethanol or oil
- surfactants and other pharmaceutically acceptable auxiliaries In the form of a solution or suspension.
- the oily vehicle or solvent used in the formulation includes natural, synthetic or semi-synthetic mono-, di- or triglycerides, natural, semi-synthetic or synthetic fats and fatty acids, such as peanut oil. , Vegetable oils such as corn oil, soybean oil and sesame oil.
- this injectable preparation can usually be prepared so as to contain about 0.1 to 10% by weight of the compound of the present invention.
- the active ingredient of the present invention is used as an antitumor agent (anticancer agent), antiallergic agent, immunosuppressant, autoimmune disease agent, antiallergic agent, antiinflammatory agent, corticosteroid substitute agent, etc. Promising.
- the active ingredient of the present invention exhibits an activity of inducing apoptosis in activated T cells and is useful for applications utilizing this.
- the active ingredients of the present invention include immunomodulators, antitumor agents, such as brain tumors (such as glioblastoma multiforme), spinal cord tumors, maxillary sinus cancer, salivary gland cancer, gingival cancer, tongue cancer, lip cancer, upper Pharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, thyroid cancer, parathyroid cancer, lung cancer, pleural tumor, cancerous peritonitis, cancerous pleurisy, esophageal cancer, stomach cancer, colon cancer, bile duct cancer, gallbladder cancer , Knee cancer, liver cancer, kidney cancer, bladder cancer, prostate cancer, penis cancer, testicular tumor, adrenal cancer, cervical cancer, uterine body cancer, vaginal cancer, vulvar cancer, ovarian cancer, ciliated epithelioma, Malignant bone tumor, soft tissue sarcoma, breast cancer, skin cancer
- antitumor agents such as brain tumors (such as glioblast
- A an inflammatory disease selected from the group consisting of various acute and chronic inflammations, allergic and autoimmune inflammations, infections, etc. occurring in each organ;
- lung diseases including acute mediastinitis, epicarditis, endocarditis, myocarditis, Stomatitis, stomatitis, tonsillitis, pharyngitis, laryngitis, esophagitis, peritonitis, acute gastritis, chronic gastritis, acute enteritis
- (C) selected from the group consisting of neurogenic inflammation (eg, neurogenic gastritis, neurocysticitis, etc.), pain associated with cancer and inflammation;
- neurogenic inflammation eg, neurogenic gastritis, neurocysticitis, etc.
- autoimmune disease Autoimmune inflammation (autoimmune disease), systemic (rheumatoid arthritis, systemic lupus erythematosus, polyarteritis nodosa, scleroderma, polymyositis dermatomyositis, Siegren's syndrome , Behcet's disease), nervous system (multiple sclerosis, myasthenia gravis, HAM (H TLV-1 myelopathy), amyotrophic lateral sclerosis, etc.), endocrine (Graves' disease, Hashimoto's disease, type 1) Glycemia), blood (idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, aplastic anemia, etc.), respiratory tract (sarcoidosis, pulmonary fibrosis, etc.), gastrointestinal tract (ulcerative colitis, cough) Loan's disease), liver (autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis,
- coli infections, etc. spirochete infections (lebutospiosis, etc.), chlamydia infections (e.g., omme disease), rickettsial infections (typhoid typhus, tetanus, etc.), viral infections (Such as herpes zoster, viral hemorrhagic fever, rabies), mycosis (such as penaldosis, taryptococcosis, and aspergius), protozoal diseases (amebic dysentery, malaria, toxoplasmosis) ), Parasites (such as fluke and nematode), other mycoplasma infections (such as mycoplasma pneumonia), and mycobacterial infections (such as tuberculosis and atypical mycobacteriosis);
- Lifestyle-related diseases selected from those including hyperlipidemia, arteriosclerosis, hypertension, diabetes, etc .;
- (J) selected from those including amyloidosis, Alzheimer's disease, osteoporosis, fractures;
- PBS Phosphate-buffered saline or phosphate-buffered saline
- Galectin 9 used in the following examples is a stable galectin 9, G9NC (null) [WO2005 / 093064 (published) manufactured and obtained in Example 1 of WO2005 / 093064 (published date: October 06, 2005) A polypeptide having the amino acid sequence represented by SEQ ID NO: 2 and encoded by the nucleotide sequence represented by SEQ ID NO: 1) was used.
- the stable galectin 9 (galectin 9 variant), that is, G9NC (null) can also be prepared as follows.
- G9NC (null) expression induction was performed using 2% (w / v) glucose and 100 ⁇ g / g of E. coli (BL21 (DE3)) transformed with pET-G9NC (null) by the electroboration method.
- ml The cells were cultured in ampicillin-containing 2X YT medium, and when the absorbance at 600 nm reached 0.7, isopylpyr- ⁇ -D-thiogalatatopyranoside was added to a final concentration of 0.15 mM. After culturing at 20 ° C. for 22.5 hours, the cells were collected by centrifugation and stored at ⁇ 80 ° C. until purification.
- G9NC (null) prepared in this manner does not show a contaminating band by protein polyacrylamide electrophoresis, and the amount of endotoxin is 0.5 EU / ml or less. Stable to freezing and thawing and retains biological activity stably for more than half a year even at 4 ° C storage.
- Galectin 9 is a recombinant body obtained by expressing native L-type galectin 9, M-type galectin 9 and S-type galectin 9 using “gene recombination technology” in host cells. May be.
- mPEG- SPA methoxy poly (ethylene glycol) succinimidyl propionate
- El and E2 are mixed and dialyzed against 1 L of 20 mM MES-NaOH (pH 6.0) (first time, 4 hours; second time, 12 hours; third time, 6 hours).
- MES 2-Morpholinoethanesulfonic acid
- the dialyzed solution is centrifuged (15,000 X g, 20 minutes), and the supernatant is collected. Filter the supernatant through a 0.2 ⁇ m finolator and collect the filtrate.
- Ion exchange column RESOURCE S (6 mL) (GE Healthcare, 17-1180-01) was used, and AKTAprime (GE Healthcare) was used as the purifier.
- Half of the sample obtained in step d) above is applied to the column in several batches (using a 5 mL sample loop).
- FIG. 1 shows the data for stabilized galectin 9 [mPEG2_NHS (20K) PEGylated G9NC (null)] that has been PEGylated with mPEG2-NHS molecular weight 20,000 (the solid line shows the absorbance at 280 ⁇ , The broken line is electrical conductivity).
- SE1 Mainly includes molecular species with PEG molecules attached at two or more locations
- SE2 mainly includes molecular species with PEG molecules attached at one place
- SE3, SE4 mainly PEGylated, including nare, molecular species
- G9NC In stabilized galectin 9 (G9NC (null)), there are 6 lysine residues (WO2005 / 093064 (publication date: October 06, 2005) in the amino acid sequence shown in SEQ ID NO: 2 in the sequence listing, Lys 88 , Lys 95 , Lys m , Lys 180 , Lys 238 , and Lys 259 ), there are seven potential sites where the PEG molecule may bind, including the N-terminal amino group.
- SE1 and SE2 are thought to contain a mixture of molecular species with different PEG sites.
- SE3 and SE4 might contain molecules modified with impurities (such as a low molecular weight modifying reagent) present in the PEGylation reagent.
- Proliferation inhibition (proliferation inhibition: cytotoxicity) against PC-3 (human prostate cancer cell line) and MOLT-4 (human T-cell leukemia line) is examined.
- the growth inhibitory effect on PC-3 was determined by a test in which the absorbance was measured after adding WST-8 (1-Methoxy PMS). Addition of WST-1 (4- [3_ (4-Chodophenyl) -2- (4-nitrophenyl) -2H-5-tetrazolio] -1,3-benzene, disulfonate) for growth inhibition against MOLT-4 Later, a test for measuring and evaluating the absorbance is performed.
- FIGS. 2 to 5 show the results of measuring the growth inhibitory action of the purified PEG-stabilized galectin 9 preparation on PC-3 cells.
- Figure 2 shows stabilized galectin 9 PEGylated with mPE G-SPA molecular weight 5,000 (G9Null PEG 5K SE2) and mPEG2-NHS molecular weight 10,000 (G9Null ⁇ G 10K SE2), namely G9Null-PEG-5K-SE 2
- the results of examining the activities of (G9NC (null) -PEG-5K-SE2) and G9NulNPEG-10K-SE2 (G9NC (null) -PEG_10K-SE2) are shown.
- G9Null PEG 5K SE2 (hereinafter referred to as 5K SE2) showed almost the same activity as stabilized galectin 9, and G9Null PEG 10K SE2 (hereinafter referred to as 10K SE2) exhibited slightly higher activity (specific activity) than stabilized galectin 9. Since this activity measurement examines the inhibitory effect on cell proliferation, it may have an apparently high activity if the sample contains toxic substances for cultured cells. As with stabilized galactin 9, the activity of 5K SE2 and 10K SE2 was inhibited by ratatoses. The possibility that it is due to the mixing of specific toxic substances is denied.
- FIG. 4 shows a comparison of the SE1 and SE2 fractions (G9Null PEG 5K and G9Null PEG 10K).
- the SE1 and SE2 fractions were compared. In both 5K and 10K, the activity of the SE1 fraction was found to be reduced by modification with several lower PEG molecules. Even in the case of stabilized galectin 9 modified with one PEG molecule, the activity may vary depending on the modification site.
- Figure 5 shows a comparison of the SE1 and SE2 fractions (G9Null PEG 20K and G9Null PEG 40K). In the case of 20K and 40mm, the same results as 5K and 10K were obtained.
- the hemagglutination activity on rabbit erythrocytes and human erythrocytes was examined. The test was performed by a visual evaluation of the agglutination reaction on erythrocytes. Stabilized galectin 9 and PEG-stabilized galectin 9 were measured simultaneously, and the results were compared to evaluate the activity.
- Bovine serum albumin adjusted to a final concentration of 0.25% (w / v) and red blood cell concentration adjusted to a final concentration of 1% (v / v) was added so that the liquid volume in the tool was 100 zL.
- the reaction mixture was incubated for 1 hour at room temperature. The minimum concentration required for aggregation was determined visually.
- the rabbit blood (purchased from Shimizu Experimental Materials, lOOmL) was centrifuged at 2000 rpm for 15 minutes, the supernatant was removed, and the precipitate was washed with 0.15 M NaCl. Calorie 0.1M Na-phosphate / 0.05M NaCl so that the erythrocyte concentration was 4%. Add trypsin (final concentration lmg / mL) (SIGMA) 37. C, 1 hour incubation. The supernatant was removed by centrifugation at 2300 rpm for 15 minutes, and the precipitate was washed with 0.15 M NaCl.
- Hemagglutination atsey hemocyte-aggregation activity was performed according to the method of Nowak et al. (Biochem. Biophys. Res. Commun., 68: 650-657 (1976)). Prepared with 96-uenore (FALCON) stabilized galectin 9 or PEG stabilized galectin 9 (5K, 10K: 100-0.05 ig / mL, 20K, 40K: 100-0 ⁇ ⁇ g / mL) did.
- FALCON 96-uenore
- PEG stabilized galectin 9 5K, 10K: 100-0.05 ig / mL, 20K, 40K: 100-0 ⁇ ⁇ g / mL
- the volume of trypsin-treated Usagi erythrocytes immobilized with bovine serum albumin to a final concentration of 0.25% (w / v) and the aforementioned dartalaldehyde to a final concentration of i% ( v / v) was added to 100 ⁇ L.
- the reaction mixture was incubated for 1 hour at room temperature. The minimum concentration required for aggregation was judged visually.
- 10K SE2, 20K SE2, and 40 K SE2 which are 9 fractions of PEGylated and stabilized galectin, show no aggregation activity even at 12.8 ⁇ M, and are considered to be substantially inactive in this assembly.
- 5 ⁇ SE2 showed approximately 1/4 the activity of stabilized galectin 9 (the lowest concentration showing agglutination activity: 50-100 nM).
- the reason why the aggregation activity of 5K 'SE2 is not detected on the high concentration side (approximately 1.6 ⁇ M or more) is not clear, but the same phenomenon is observed with stabilized galectin-9.
- the concentration of galectin is high, the sugar chain ligand on the erythrocyte membrane is saturated by galectin, so that the cross-linking between blood cells does not occur.
- stabilized galectin 9 showed an agglutinating activity at 100-200 nM, while 10K SE2, 20K SE2, 40K ⁇ £ 2 showed no agglutinating activity even at 12.8 ⁇ .
- 10K SE2, 20 ⁇ SE2, 40 ⁇ SE2 showed virtually no agglutinating activity against rabbits and human erythrocytes.
- 5 ⁇ SE2 showed about 1/4 the activity of stabilized galectin 9, ie, the following results were obtained.
- PEGylated galectin-9 variant PEG-Gal9-10K (PEG-Stable Gal9 (10K)
- PEG_Gal9_20K PEG-Stable Gal9 (20K)
- PEG- Gal9-40K PEG-Stable Gal9 (40K)
- 0.6 mg / kg was intravenously administered 3 times a week until 31st.
- the foot volume of the left and right hind limbs was measured on the first day of collagen sensitization (day 0) and three times a week (month, water, and gold) after the first sensitization.
- PEG-stabilized galectin 9 PEG-modified galectin-9 variant
- PEGylated and stabilized galectin-9 is a chronic joint that has been shown to be therapeutically effective against systems used as a model of human rheumatoid arthritis. It is considered useful as a therapeutic agent for rheumatism.
- PEGylated galectin-9 and PEGylated galectin-9 variants can be expected to be expected as anti-inflammatory agents, antiallergic agents, immunomodulators and the like.
- Stabilized galectin 9 conjugated with PEG (5K, 10K, 20K, 40K) has been shown to increase the elimination half-life of stabilized galectin 9 by PEG binding.
- PEG-stabilized galectin 9 Enhanced growth inhibitory activity against PC-3 (prostate cancer) cells and MOLT-4 cells, and disappearance of hemagglutination, and is superior in terms of solubility of stabilized galectin 9 and prolonged half-life elimination. It was something that could be evaluated.
- a product in which the hemagglutination action disappears was obtained, and it was confirmed that the disappearance of the hemagglutination action was proportional to the length of the PEG chain bound to the stabilized galectin-9.
- galectin-9 (PEGylated galectin-9 variant) is a substance with enhanced utility as a therapeutic agent.
- the galectin 9_polymer conjugate of the present invention is an excellent drug candidate substance.
- PEGylated and stabilized galectin-9 (PEGylated galectin-9 variant) is a substance with enhanced utility as a therapeutic agent, and has antiproliferative activity (or antiproliferative activity) against cancer cells.
- Anti-tumor agent, anti-cancer agent, anti-inflammatory agent, anti-allergic agent, immunomodulator, anti-viral disease agent It can be used as a reagent for elucidating the function of galectin-9.
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Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP07790899A EP2042513A4 (en) | 2006-07-25 | 2007-07-18 | Galectin-9-POLYMER CONJUGATE |
US12/309,583 US20100009908A1 (en) | 2006-07-25 | 2007-07-18 | Galectin 9-Polymer Conjugates |
JP2008526732A JPWO2008013082A1 (ja) | 2006-07-25 | 2007-07-18 | ガレクチン9−ポリマーコンジュゲート |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2006-202305 | 2006-07-25 | ||
JP2006202305 | 2006-07-25 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2008013082A1 true WO2008013082A1 (fr) | 2008-01-31 |
Family
ID=38981394
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2007/064144 WO2008013082A1 (fr) | 2006-07-25 | 2007-07-18 | Conjugué galectine 9/polymère |
Country Status (4)
Country | Link |
---|---|
US (1) | US20100009908A1 (ja) |
EP (1) | EP2042513A4 (ja) |
JP (1) | JPWO2008013082A1 (ja) |
WO (1) | WO2008013082A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3348275A2 (en) | 2009-03-31 | 2018-07-18 | East Carolina University | Cytokines and neuroantigens for treatment of immune disorders |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007061936A2 (en) | 2005-11-18 | 2007-05-31 | New England Medical Center Hospitals, Inc. | Clearance of abnormal iga1 in iga1 deposition diseases |
WO2010123885A2 (en) * | 2009-04-20 | 2010-10-28 | Tufts Medical Center, Inc. | Iga1 protease polypeptide agents and uses thereof |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5623587A (en) | 1979-08-03 | 1981-03-05 | Mitsuwa Seiki Co Ltd | Vane type compressor |
WO2002037114A1 (fr) | 2000-11-01 | 2002-05-10 | Galpharma Co., Ltd. | Agent permettant de detecter l'aptitude d'une tumeur cancereuse a se metastaser |
JP2002541832A (ja) * | 1999-04-21 | 2002-12-10 | ヒューマン ジノーム サイエンシーズ, インコーポレイテッド | ガレクチン11 |
WO2004064857A1 (ja) | 2003-01-24 | 2004-08-05 | Galpharma Co., Ltd. | ガレクチン9含有医薬 |
JP2004244411A (ja) * | 2003-01-24 | 2004-09-02 | Galpharma Co Ltd | ガレクチン9含有医薬 |
WO2005093064A1 (ja) | 2004-03-29 | 2005-10-06 | Galpharma Co., Ltd. | 新規ガレクチン9改変体タンパク質及びその用途 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005033144A2 (en) * | 2003-10-03 | 2005-04-14 | Brigham And Women's Hospital | Tim-3 polypeptides |
AU2005245918A1 (en) * | 2004-05-19 | 2005-12-01 | F. Hoffmann-La Roche Ag | Interferon-alpha polypeptides and conjugates |
-
2007
- 2007-07-18 WO PCT/JP2007/064144 patent/WO2008013082A1/ja active Application Filing
- 2007-07-18 EP EP07790899A patent/EP2042513A4/en not_active Withdrawn
- 2007-07-18 JP JP2008526732A patent/JPWO2008013082A1/ja active Pending
- 2007-07-18 US US12/309,583 patent/US20100009908A1/en not_active Abandoned
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5623587A (en) | 1979-08-03 | 1981-03-05 | Mitsuwa Seiki Co Ltd | Vane type compressor |
JP2002541832A (ja) * | 1999-04-21 | 2002-12-10 | ヒューマン ジノーム サイエンシーズ, インコーポレイテッド | ガレクチン11 |
WO2002037114A1 (fr) | 2000-11-01 | 2002-05-10 | Galpharma Co., Ltd. | Agent permettant de detecter l'aptitude d'une tumeur cancereuse a se metastaser |
WO2004064857A1 (ja) | 2003-01-24 | 2004-08-05 | Galpharma Co., Ltd. | ガレクチン9含有医薬 |
JP2004244411A (ja) * | 2003-01-24 | 2004-09-02 | Galpharma Co Ltd | ガレクチン9含有医薬 |
WO2005093064A1 (ja) | 2004-03-29 | 2005-10-06 | Galpharma Co., Ltd. | 新規ガレクチン9改変体タンパク質及びその用途 |
Non-Patent Citations (31)
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"DNA Cloning", vol. 1-4, 1995, IRL PRESS |
"Gene Transfer Vectors for Mammalian Cells", 1987, COLD SPRING HARBOR LABORATORY |
"Handbook of Experimental Immunology", vol. 1, 2, 3,, 1986, BLACKWELL SCIENTIFIC PUBLICATIONS |
"Immunochemical Methods in Cell and Molecular Biology", 1987, ACADEMIC PRESS |
"Methods in Enzymology", vol. 204, 1991, ACADEMIC PRESS |
"Methods in Enzymology", vol. 218, 1993, ACADEMIC PRESS |
"Methods in Enzymology", vol. 303, 1999, ACADEMIC PRESS |
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"Methods in Enzymology", vol. 326-328, 2000, ACADEMIC PRESS |
"Methods in Enzymology", vol. 392, 2005, ACADEMIC PRESS |
"Nucleic Acid Hybridization, A Practical Approach", 1985, IRL PRESS LTD. |
"Oligonucleotide Synthesis", 1984, IRL PRESS |
"Protein Purification: Principles and Practice", 1987, SPRINGER-VERLAG |
"Recombinant DNA", vol. 68, 1980, ACADEMIC PRESS, article "Methods in Enzymology" |
"Recombinant DNA, Part B", vol. 100, article "Methods in Enzymology" |
"Recombinant DNA, Part C", vol. 101, 1983, ACADEMIC PRESS |
"Recombinant DNA, Part D", vol. 153, article "Methods in Enzymology" |
"Recombinant DNA, Part F", vol. 155, 1987, ACADEMIC PRESS |
"Shin-Seikagaku Jikken Kouza 2, Kakusan III (Kumikae DNA Gijutsu", 1992, TOKYO KAGAKU DOJIN |
"Transcription and Translation: A Practical Approach", 1984, IRL PRESS LTD. |
"Vaccines new approaches to immunological problems", 1992 |
"Weir's Handbook of Experimental Immunology", vol. 1, 2, 3,, 1997, BLACKWELL SCIENCE LTD. |
"Zoku-Seikagaku Jikken Kouza 1, Idenshi Kenkyuho II", 1986, TOKYO KAGAKU DOJIN |
B. PERBAL: "A Practical Guide to Molecular Cloning", 1988, JOHN WILEY & SONS |
J. BIOL. CHEM., vol. 275, no. 12, 2000, pages 8355 - 8360 |
J. SAMBROOK ET AL.: "Molecular Cloning: A Laboratory Manual", 1989, COLD SPRING HARBOR LABORATORY PRESS |
MATSUMOTO R. ET AL., J. BIOL. CHEM., vol. 273, 1998, pages 16976 - 84 |
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RECOMBINANT DNA, PART E, vol. 154 |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3348275A2 (en) | 2009-03-31 | 2018-07-18 | East Carolina University | Cytokines and neuroantigens for treatment of immune disorders |
Also Published As
Publication number | Publication date |
---|---|
EP2042513A4 (en) | 2010-07-07 |
US20100009908A1 (en) | 2010-01-14 |
JPWO2008013082A1 (ja) | 2009-12-17 |
EP2042513A1 (en) | 2009-04-01 |
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