WO2009104388A1 - Agent prophylactique/thérapeutique pour la collagénose - Google Patents

Agent prophylactique/thérapeutique pour la collagénose Download PDF

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WO2009104388A1
WO2009104388A1 PCT/JP2009/000659 JP2009000659W WO2009104388A1 WO 2009104388 A1 WO2009104388 A1 WO 2009104388A1 JP 2009000659 W JP2009000659 W JP 2009000659W WO 2009104388 A1 WO2009104388 A1 WO 2009104388A1
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trem
seq
amino acid
strem
therapeutic agent
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PCT/JP2009/000659
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Japanese (ja)
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上阪等
村上洋介
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国立大学法人東京医科歯科大学
田辺三菱製薬株式会社
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    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6887—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids from muscle, cartilage or connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • C12N2799/00—Uses of viruses
    • C12N2799/02—Uses of viruses as vector
    • C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
    • C12N2799/022—Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from an adenovirus
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    • C12N2799/00—Uses of viruses
    • C12N2799/02—Uses of viruses as vector
    • C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
    • C12N2799/025—Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from a parvovirus
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    • C12N2799/00—Uses of viruses
    • C12N2799/02—Uses of viruses as vector
    • C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
    • C12N2799/027—Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from a retrovirus
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/10—Musculoskeletal or connective tissue disorders
    • G01N2800/101—Diffuse connective tissue disease, e.g. Sjögren, Wegener's granulomatosis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/10—Musculoskeletal or connective tissue disorders
    • G01N2800/101—Diffuse connective tissue disease, e.g. Sjögren, Wegener's granulomatosis
    • G01N2800/102—Arthritis; Rheumatoid arthritis, i.e. inflammation of peripheral joints
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/10—Musculoskeletal or connective tissue disorders
    • G01N2800/101—Diffuse connective tissue disease, e.g. Sjögren, Wegener's granulomatosis
    • G01N2800/104—Lupus erythematosus [SLE]
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/10—Musculoskeletal or connective tissue disorders
    • G01N2800/107—Crystal induced conditions; Gout

Definitions

  • the present invention relates to a preventive / therapeutic agent for collagen disease and a screening method thereof.
  • Collagen diseases are rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), dermatomyositis (DM), multiple myositis (PM), rheumatic fever (RF), nodular polyposis. It is a general term for a series of diseases such as arteritis (PN) and mixed connective tissue disease (mixed connective tissue disease; MCTD).
  • Collagen disease is an autoimmune disease, in which autoantibodies in the body's blood react with the nuclei of their own cells to form immune complexes and deposit in tissues, such as joints, blood vessels, and internal organs throughout the body. It is thought to be caused by an attack.
  • Rheumatoid arthritis a type of collagen disease, is accompanied by cartilage degeneration and bone erosion, and eventually loses joint function.
  • Rheumatoid arthritis is said to be caused by a large amount of inflammatory cells, including lymphocytes that produce autoantibodies, infiltrating the joint and hyperplasia of the periosteum. More specifically, rheumatoid arthritis is caused by T cells recognizing an unknown self-antigen causing inflammation in synovial tissue, followed by local assembly of macrophages and lymphocytes in the synovial tissue, It is said to be caused by further activation at the site of inflammation (Non-patent Document 1).
  • macrophages greatly contribute to the progression of rheumatoid arthritis because they produce various inflammatory molecules such as inflammatory cytokines, prostaglandins, and nitric oxide.
  • the production of these inflammatory molecules is controlled by the activation of cell surface molecules such as cytokine receptors, complement receptors and ITAM (Immunoreceptor-tyrosine-based activation-motif) -related receptors through their respective ligand involvement.
  • Some receptors such as those mentioned above that are involved in the regulation of the immune system, are associated non-covalently with membrane anchored adapter molecules. In many cases, these receptors cannot be stably expressed on the cell surface without their adapter molecules, and signal transduction into cells via these adapter molecules. .
  • TREM-1 Triggering receptor expressed on myeloidcells-1 has been identified as a transmembrane receptor on bone marrow cells associated with activation of DAP12 (DNAX activationprotein 12), an adapter molecule having ITAM (Non-patent Document 2, 3). TREM-1 is expressed mainly in monocytes / macrophages and neutrophils and is induced by various stimuli such as TLR ligands (LPS, LTA, etc.) and inflammatory cytokines (TNF ⁇ , IL-1 ⁇ , etc.) Patent Documents 2 to 4) have not yet identified their natural ligands.
  • TLR ligands LPS, LTA, etc.
  • TNF ⁇ , IL-1 ⁇ , etc. inflammatory cytokines
  • TREM-1 Although the detailed function of TREM-1 is not yet clear, treatment of neutrophils and monocytes with an agonistic monoclonal antibody against TREM-1 causes various inflammation in neutrophils and monocytes. It is known that production of sex cytokines and expression of cell surface molecules are caused (Non-patent Document 2). Further, soluble TREM-1 (sTREM-1) is known as a substance that inhibits the function of TREM-1 (Non-patent Document 5). This sTREM-1 is a soluble polypeptide obtained by proteolytic cleavage of membrane-bound TREM-1, and has a property of inhibiting the function of TREM-1 by competing with TREM-1 itself.
  • TREM-1 Bacterial infection is known as a disease involving the action of TREM-1.
  • TREM-1 plays an important role in the pathophysiology of bacterial infections.
  • administration of a “sTREM-1-Fc recombinant fusion protein” or “sTREM-1 synthetic peptide” that competes with TREM-1 to septic shock model mice results in administration of lethal amounts of LPS or septic bacteria. It was confirmed that mice were protected from infection (Non-Patent Documents 6 and 7).
  • Inflammatory colitis is a disease in which bacterial damage in the intestine is known to play an important role in its pathogenesis, and a TREM-1 antagonist peptide was administered to experimental inflammatory colitis model mice.
  • TREM-1 is known to play an important role in disease-related bacterial infections.
  • the present inventors introduced the adenovirus-sTREM-1-Ig gene to inhibit the function of TREM-1, thereby causing the progression of collagen-induced arthritis (CIA) It was found that the onset was significantly suppressed without impairing the immune response of T cells or B cells, and the present invention was completed based on this finding.
  • the present invention relates to (1) a preventive / therapeutic agent for collagen disease containing a TREM-1 inhibitor, and (2) the TREM-1 inhibitor is a soluble TREM-1 or a soluble TREM-1 expression vector
  • the preventive / therapeutic agent for collagen disease according to (1) above (3) a polypeptide comprising the amino acid sequence represented by amino acid numbers 1 to 194 in SEQ ID NO: 1, and the amino acid number in SEQ ID NO: 5
  • the above (2) which is a polypeptide consisting of the amino acid sequence shown by 1 to 200, a polypeptide consisting of the amino acid sequence shown by SEQ ID NO: 3 or 7, or a polypeptide comprising the amino acid sequence shown by SEQ ID NO: 3 or 7
  • Soluble TREM-1 is represented by amino acid numbers 1 to 194 in SEQ ID NO: 1.
  • the preventive / therapeutic agent for collagen disease according to (2) above which is a polypeptide having an inserted or added amino acid sequence and having TREM-1 inhibitory activity, and (5) a TREM-1 inhibitor
  • the preventive / therapeutic agent for collagen disease according to (1) above which is an immunoglobulin binding-soluble TREM-1 (sTREM-1-Ig), or (6) an immunoglobulin binding-soluble TREM-1 (sTREM-1-Ig) ) Is a polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 1 or 5, the preventive / therapeutic agent for collagen disease according to (5) above, or (7) soluble TR
  • the M-1 expression vector is a polynucleotide consisting of the nucleotide sequence shown in nucleotide numbers 1 to 582 in SEQ ID NO: 2, a
  • a therapeutic agent, or (8) a soluble TREM-1 expression vector is a nucleotide sequence represented by nucleotide numbers 1 to 582 in SEQ ID NO: 2, a nucleotide sequence represented by nucleotide numbers 1 to 600 in SEQ ID NO: 6, and SEQ ID NO: 4 Or the number 8 A recombinant vector comprising a polynucleotide that hybridizes under stringent conditions with a polynucleotide comprising a sequence complementary to a nucleotide sequence selected from a nucleotide sequence and encodes a polypeptide having TREM-1 inhibitory activity
  • the preventive / therapeutic agent for collagen disease according to (2) above, or (9) the soluble TREM-1 expression vector is a recombinant viral vector expressing soluble TREM-1 And (10) the preventive / therapeutic agent for collagen disease according to any one of the above (1) to (9), wherein the collagen disease is rheumatoid arthritis.
  • the present invention also includes (11) a screening method for a prophylactic / therapeutic agent for collagen disease comprising a step of searching for a TREM-1 inhibitor, and (12) a step of searching for a TREM-1 inhibitor.
  • the method according to (11) above which is a step of culturing cells containing TREM-1 in the presence or absence of a substance, measuring the TNF ⁇ concentration in the culture supernatant, and comparing the TNF ⁇ concentrations.
  • the present invention relates to a screening method for a preventive / therapeutic agent for collagen disease.
  • A It is a figure which shows the result of having measured the sTREM-1 density
  • B It is a figure which shows the result of having double-stained the synovial cell of RA patient about TREM-1 and CD14 (macrophage marker).
  • C TREM-1 of all synovial cells of RA patients is stimulated with an anti-TREM-1 agonist antibody for 24 hours, and the inflammatory cytokine (TNF ⁇ ) concentration in the culture supernatant is measured by ELISA. . Note that * indicates p ⁇ 0.01, and ** indicates p ⁇ 0.001.
  • AC Results of immunohistochemical analysis of synovial cells of CIA mice.
  • A is a diagram stained with hematoxylin and eosin
  • B is a diagram stained with a normal rabbit IgG antibody as an isotype-matched control antibody
  • C is a diagram stained with a rat anti-mouse TREM-1 antibody.
  • D It is a figure which shows the result of having double-stained the synoviocyte of a CIA mouse
  • sTREM-1-Ig an expression product of AxCA-sTREM-1-Ig, have on TNF ⁇ production by resident peritoneal macrophages (RPM) stimulated with an anti-TREM-1 agonist antibody? It is a figure which shows the result of having investigated.
  • B It is a figure which shows the time-dependent transition of the ankle width
  • C It is a figure which shows the time-dependent transition of the thickness of a hind limb when AxCA-sTREM-1-Ig is introduce
  • A It is a figure which shows the result of having dye
  • B It is a figure which shows the result of having dye
  • C shows histological scores of arthritis of knee joints of mice introduced with CIA induction and AxCA-LacZ (control), and knee joints of mice introduced with CIA induction and AxCA-sTREM-1-Ig .
  • A Proliferation of T cells in spleen cells of mice introduced with CIA and AxCA-sTREM-1-Ig.
  • B It is a figure which shows the result analyzed about the anti- CII antibody (IgG1, IgG2a, and IgG2b) in the serum of the mouse
  • the preventive / therapeutic agent for collagen disease of the present invention is not particularly limited as long as it is a composition containing a TREM-1 inhibitor.
  • the “TREM-1 inhibitor” refers to a TREM-1 A substance having an activity of inhibiting all signal transduction, such as TREM-1 inhibitory substance, soluble TREM-1, a recombinant vector expressing soluble TREM-1 (sTREM-1), and a TREM-1 antagonist Can be preferably exemplified.
  • TREM-1 inhibitors inhibit the function of TREM-1 (signal transduction via TREM-1).
  • TREM-1 inhibitors are advantageous as active ingredients for preventive and therapeutic agents for collagen disease. Can be used.
  • TREM-1 is not particularly limited, but is preferably derived from animals, such as human, mouse, rat, guinea pig, rabbit, bird, sheep, pig, cow, horse, cat, dog, monkey, chimpanzee, etc. More preferably, it is derived from a mammal, and more preferably, it is derived from a mammal targeted for prevention / treatment of collagen disease.
  • TREM-1 in these mammals is mouse TREM-1 (Genbank accession No. AK089439), human TREM-1 (Genbank accession No. AF287008), bovine TREM-1 (Genbank accession No.
  • porcine TREM-1 Obtain a polynucleotide encoding TREM-1 using a genetic engineering technique (PCR, Southern hybridization, etc.) using sequence information such as Genbank accession No. AY382476) and express the polynucleotide using an appropriate expression system. By doing so, various origins of TREM-1 can be obtained.
  • soluble TREM-1 As the above-mentioned soluble TREM-1, (1) a polypeptide comprising the amino acid sequence represented by SEQ ID NO: 3 or a polypeptide comprising the amino acid sequence represented by SEQ ID NO: 3 (mouse LP17); (2) a polypeptide (mouse sTREM-1) comprising an amino acid sequence represented by amino acid numbers 1 to 194 in SEQ ID NO: 1; (3) including the amino acid sequence represented by amino acid numbers 1-194 in SEQ ID NO: 1 or the amino acid sequence represented by SEQ ID NO: 3, wherein one or several amino acid substitutions, deletions, insertions, or additions are added.
  • polypeptide having a TREM-1 inhibitory activity (mouse sTREM-1 mutant); (4) Amino acid substitutions, deletions, insertions or additions of one or several amino acids in the amino acid sequences shown in amino acid numbers 1-102 and 120-194 among amino acid numbers 1-194 in SEQ ID NO: 1
  • a polypeptide comprising a sequence and having TREM-1 inhibitory activity (mouse sTREM-1 mutant); (5) a polypeptide comprising the amino acid sequence represented by SEQ ID NO: 7 or a polypeptide comprising the amino acid sequence represented by SEQ ID NO: 7 (human LP17); (6) a polypeptide comprising the amino acid sequence represented by amino acid numbers 1 to 200 in SEQ ID NO: 5 (human sTREM-1); (7) including the amino acid sequence represented by amino acid numbers 1 to 200 in SEQ ID NO: 5 or the amino acid sequence represented by SEQ ID NO: 7 in which one or several amino acid substitutions, deletions, insertions, or additions are added
  • a linker sequence (amino acid sequence represented by amino acid numbers 195 to 199 in SEQ ID NO: 1; amino acid numbers 201 to 205 in SEQ ID NO: 5 is provided on the C-terminal side of these soluble TREM-1s.
  • a polypeptide to which an IgG1 Fc region (amino acid sequence represented by amino acid numbers 200 to 430 in SEQ ID NO: 1; amino acid sequence represented by amino acid numbers 206 to 436 in SEQ ID NO: 5) is added is preferable. It can be illustrated. Therefore, mouse or human immunoglobulin-binding-soluble TREM-1 (sTREM-1-Ig) can also be advantageously used as a preventive / therapeutic agent for collagen disease.
  • Soluble TREM-1 is thought to inhibit the function of TREM-1 by trapping the natural ligand of TREM-1, and is a mouse LP17 polypeptide (polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 3). ) Inhibits the function of mouse TREM-1 is disclosed in Non-Patent Document 7.
  • the “several” in the sTREM-1 mutant is, for example, 2 to 60, preferably 2 to 40, more preferably 2 to 30, further preferably 2 to 20, and even more preferably 2 to 10. Examples thereof are 2 to 5, particularly preferably 2 to 5, and most preferably 2 to 3.
  • the amino acid sequence of the sTREM-1 variant is 50% or more, preferably 60% of the amino acid sequence represented by amino acid numbers 1 to 194 in SEQ ID NO: 1 or 5 or the amino acid sequence represented by SEQ ID NO: 3 or 7. Examples thereof include amino acid sequences having homology of 70% or more, more preferably 80% or more, even more preferably 90% or more, and most preferably about 95% or more.
  • soluble TREM-1 can be prepared by deleting a part of the C-terminal of TREM-1 (membrane type TREM-1).
  • TREM-1 membrane type TREM-1
  • soluble TREM-1 sTREM-1
  • sTREM-1 can be produced by deleting the C-terminal 36 amino acids
  • Soluble TREM-1 sTREM-1
  • the sTREM-1 mutant can also be prepared by chemical synthesis, or by applying any method known to those skilled in the art, such as genetic engineering techniques and mutagenesis.
  • a polynucleotide comprising the nucleotide sequence represented by nucleotide numbers 1 to 582 in SEQ ID NO: 2 (polynucleotide encoding mouse sTREM-1), or the nucleotide sequence represented by nucleotide numbers 1 to 600 in SEQ ID NO: 6
  • a polynucleotide comprising (a polynucleotide encoding human sTREM-1), a method of contacting a sTREM-1 polynucleotide derived from another organism with a drug that is a mutagen, a method of irradiating ultraviolet rays, a genetic engineering method
  • a sTREM-1 mutant can be obtained by introducing mutations into these polynucleotides using various techniques and expressing the mutant polynucleotides using an appropriate expression system.
  • the above TREM-1 antagonist can be obtained from an appropriate compound library by using, for example, the screening method for a preventive / therapeutic agent for collagen disease of the present invention described later.
  • a substance expressed on the plasma plate can also be used as a candidate substance.
  • the soluble TREM-1 expression vector is not particularly limited as long as it can express the above-mentioned soluble TREM-1 in the living body of any animal, but the above-mentioned soluble TREM-1 expression vector in the living body of any mammal
  • a recombinant vector expressing TREM-1 can be mentioned, preferably a recombinant viral vector.
  • recombinant vectors expressing these soluble TREM-1 (1) a polynucleotide comprising the nucleotide sequence shown in SEQ ID NO: 4 or a recombinant vector (mouse LP17 vector) in which a polynucleotide containing the nucleotide sequence is integrated; (2) a recombinant vector (mouse sTREM-1 vector) in which a polynucleotide comprising the nucleotide sequence represented by nucleotide numbers 1 to 582 in SEQ ID NO: 2 is integrated; (3) hybridizes under stringent conditions with a polynucleotide consisting of a nucleotide sequence shown in SEQ ID NO: 4 or a nucleotide sequence complementary to the nucleotide sequence shown in nucleotide numbers 1 to 582 in SEQ ID NO: 2, and TREM- A recombinant vector in which a polynucleotide encoding a polypeptide having
  • polynucleotide hybridizing under stringent conditions uses a polynucleotide such as DNA or RNA as a probe, and uses a colony hybridization method, a plaque hybridization method, a Southern blot hybridization method, or the like. Specifically, using a filter on which a polynucleotide derived from a colony or plaque or a fragment thereof is immobilized, the polynucleotide is obtained at 65 ° C. in the presence of 0.7 to 1.0 M NaCl. After hybridization, the filter is washed under conditions of 65 ° C.
  • stringent conditions refer to conditions under which so-called specific hybrids are formed and non-specific hybrids are not formed.
  • polynucleotides having a homology of 50 to 70% or more are hybridized and polynucleotides having lower homology (particularly DNA) are not hybridized with each other, or are washing conditions for normal Southern hybridization at 65 ° C., 1 ⁇ SSC, 0.1% SDS Or a condition of hybridizing at a salt concentration corresponding to 0.1 ⁇ SSC and 0.1% SDS.
  • the polynucleotide that can hybridize under stringent conditions can include a polynucleotide having a certain homology with the base sequence of the polynucleotide used as a probe, for example, 60% or more, preferably Is preferably a polynucleotide having a homology of 70% or more, more preferably 80% or more, more preferably 85% or more, even more preferably 90% or more, particularly preferably 95% or more, and most preferably 98% or more. It can be illustrated.
  • the recombinant vector of the present invention preferably a recombinant virus vector, can be constructed by appropriately integrating the aforementioned polynucleotide encoding sTREM-1 into an expression vector.
  • the expression vector is preferably one that can replicate autonomously in the animal cell to be administered, or one that can be integrated into the chromosome of the aforementioned animal cell, and a promoter or enhancer at a position where sTREM-1 can be expressed.
  • Those containing a control sequence such as a terminator can be preferably used.
  • an expression vector for animal cells for example, an adenovirus vector (Science, 252, 431-434, 1991) used for transient expression in all cells including non-sorted cells (other than blood cells) And retroviral vectors (Microbiology ⁇ and Immunology, 158, 1-23, 1992) used for long-term expression in dividing cells and adeno-associated viruses that can be introduced into non-pathogenic, non-dividing cells and used for long-term expression Virus vectors such as vectors (Curr. Top. Microbiol. Immunol., 158, 1992 97-129, 1992) can be mentioned, among which adenovirus vectors can be preferably exemplified.
  • a procedure and method for constructing an expression vector that can be used in the present invention those commonly used in the field of genetic engineering can be used.
  • the preventive / therapeutic agent for collagen disease of the present invention may be a TREM-1 inhibitor alone, or may be formulated with a physiologically recognized carrier such as an adjuvant for promoting intake. . Further, a prophylactic / therapeutic agent for collagen disease other than a TREM-1 inhibitor may be used in combination.
  • the dosage form of the prophylactic / therapeutic agent for collagen disease of the present invention is not particularly limited, but is an oral agent such as a tablet, capsule, powder, syrup, water or other pharmaceutically acceptable liquid.
  • An injection such as a sterile solution or suspension can be exemplified, and when the TREM-1 inhibitor is a substance expressing TREM-1 or soluble TREM-1, the injection can be preferably exemplified it can.
  • intravenous administration and subcutaneous administration can be preferably exemplified.
  • the preventive / therapeutic agent for collagen disease of the present invention includes, for example, the above-described TREM-1 inhibitor in the present invention, a physiologically acceptable carrier, flavoring agent, excipient, vehicle, preservative, stabilizer, It can be produced by mixing in a unit dosage form that is generally required for the practice of the formulation together with a binder and the like. The amount of active ingredient in these preparations is such that an appropriate dose within the indicated range can be obtained.
  • additives that can be mixed into tablets, capsules and the like include binders such as gelatin, corn starch, tragacanth and gum arabic, excipients such as crystalline cellulose, swelling agents such as corn starch, gelatin and alginic acid, Lubricants such as magnesium stearate, sweeteners such as sucrose, lactose or saccharin, flavoring agents such as peppermint, red mono oil or cherry can be used.
  • a liquid carrier such as fats and oils can be further contained in the above-mentioned type material.
  • the injection can be prepared by dissolving, suspending or emulsifying the polypeptide of the present invention in a sterile aqueous or oily liquid usually used for injection.
  • a sterile aqueous or oily liquid usually used for injection.
  • aqueous solution for injection for example, physiological saline, isotonic solution containing glucose and other adjuvants, and the like can be used.
  • suitable solubilizers such as alcohol (eg, ethanol), Alcohol (eg, propylene glycol, polyethylene glycol), nonionic surfactant [eg, polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adductadof hydrogenated castor oil)] or the like may be used in combination.
  • oily liquid for example, sesame oil, soybean oil and the like can be used, and benzyl benzoate, benzyl alcohol and the like may be used in combination as a solubilizing agent.
  • Buffers eg, phosphate buffer, sodium acetate buffer, etc.
  • soothing agents eg, benzalkonium chloride, procaine hydrochloride, etc.
  • stabilizers eg, human serum albumin, polyethylene glycol, etc.
  • a preservative for example, benzyl alcohol, phenol, etc.
  • an antioxidant and the like may be blended.
  • the prepared injection solution can usually be filled into a suitable ampoule. The dose varies depending on the type of TREM-1 inhibitor, the weight and age of the patient, the administration method, etc., but those skilled in the art can appropriately select an appropriate dose.
  • Preferred examples of the target for the administration of a prophylactic / therapeutic agent for collagen disease include mammals such as humans, mice, rats, guinea pigs, rabbits, birds, sheep, pigs, cows, horses, cats, dogs, monkeys, chimpanzees, etc. Can do.
  • the collagen disease to be targeted by the preventive / therapeutic agent for collagen disease of the present invention is not particularly limited as long as it is a collagen disease, but rheumatoid arthritis (RA), gout, systemic lupus erythematosus (SLE), Sjogren's syndrome (SjS), Systemic sclerosis (SSc), polymyositis (PM), dermatomyositis (DM), polyarteritis nodosa (PN), rheumatic fever (RF), mixed connective tissue disease (mixed connective tissue disease; MCTD) , Microscopic polyangitis (MPA), Wegener's granulomatosis (WG), allergic granulomatous vasculitis (AGA), hypersensitivity vasculitis, Behcet's disease, Kogan syndrome RS3PE can be exemplified, among which rheumatoid arthritis, systemic lupus erythematosus (SLE), and Sjogren's syndrome
  • the screening method for a preventive / therapeutic agent for collagen disease of the present invention comprises a step of searching for a TREM-1 inhibitor.
  • a step of searching for a TREM-1 inhibitor for example, cells containing TREM-1 are cultured in the presence or absence of a test substance, the TNF ⁇ concentration in the culture supernatant is measured, and the TNF ⁇ concentrations are compared. The process of performing can be illustrated. When the TNF ⁇ concentration in the presence of the test substance is lower than the TNF ⁇ concentration in the absence of the test substance, the test substance can be evaluated as a TREM-1 inhibitor.
  • the collagen disease prevention / treatment method of the present invention comprises a step of administering the collagen disease prevention / treatment agent of the present invention to an animal.
  • the animal the aforementioned mammals can be preferably exemplified.
  • a preventive / therapeutic agent for collagen disease other than the preventive / therapeutic agent for collagen disease of the present invention may be used in combination.
  • Examples 2 to 7 described later are as follows. ⁇ 15. The materials and methods described in 1 were used. [Materials and methods] 1. Reagents Rat anti-mouse TREM-1 antibody, mouse anti-human TREM-1 antibody, phycoerythrin (PE) -labeled anti-mouse TREM-1 antibody, PE-labeled anti-human TREM-1 monoclonal antibody (mAb), anti-mouse IgG 1 antibody, anti-rat IgG antibodies, mouse TREM-1 duo set, and mouse tumor necrosis factor ⁇ (TNF ⁇ ) duo set were obtained from R & D (Minneapolis, MN).
  • PE phycoerythrin
  • mAb PE-labeled anti-human TREM-1 monoclonal antibody
  • anti-mouse IgG 1 antibody anti-rat IgG antibodies
  • mouse TREM-1 duo set mouse tumor necrosis factor ⁇ duo set
  • TNF ⁇ mouse tumor necrosis factor ⁇
  • Fluorescein isothiocyanate (FITC) labeled anti-human CD14 monoclonal antibody was purchased from Beckman-Coulter (Fullerton, Calif.). Allophycocyanin (APC) labeled anti-mouse CD11b monoclonal antibody was purchased from e-Bioscience (San Diego, Calif.). Rabbit anti-rat IgG antibody, streptavidin-horseradish peroxidase (HRP), and diaminobenzidine (Envision kit) were purchased from Dako Cytomation Co. Ltd. (Kyoto). Reagents for specific enzyme immunoassay (ELISA) used for human TNF ⁇ were obtained from Biosource International (Camarillo, CA).
  • LPS and collagenase A were purchased from Sigma (St. Louis, MO).
  • Rabbit anti-mouse IgG1, IgG2a, and IgG2b antibodies labeled with HRP were purchased from Zymed (Burlingame, Calif.).
  • sTREM-1 concentration in synovial fluid was measured by a conventional enzyme immunoassay (ELISA).
  • Quantitative real-time PCR was performed by the method described in Non-Patent Document 4. That is, total RNA was extracted from cell lysates using RNeasy Mini kit (Qiagen, Tokyo). This RNA was treated with DNase I (Qiagen), and cDNA was synthesized using Omniscript reverse transcriptase (Qiagen). HTREM-1 and rRNA were examined by quantitative real-time PCR (TaqMan) using specific oligonucleotide primers and probes. TaqMan PCR was performed by QuantiTect Probe PCR (Qiagen). PCR amplification was monitored in real time by quantitative analysis of emitted fluorescence using a 7900 sequence detection system. The amount of control sample was 1 arbitrary unit, and each mRNA sample was quantified relative to the amount of control sample.
  • Cytokine production assay 5 ⁇ g / ml of anti-human TREM-1 monoclonal antibody, anti-mouse TREM-1 monoclonal antibody, or isotype matched control antibody (IgG antibody) was precoated at 4 ° C. overnight at 4 ° C.
  • Cells washed with PBS were added to each well of the flat bottom plate at 1 ⁇ 10 5 cells / well, and this was centrifuged at 1200 rpm for a short time to bind TREM-1 to the antibody. After incubation for 24 hours, the culture medium was collected by centrifugation and stored at ⁇ 20 ° C. until the TNF ⁇ concentration in the culture medium supernatant was measured by specific ELISA.
  • anti-human TREM-1 monoclonal antibody and anti-mouse TREM-1 monoclonal antibody also have agonistic properties against human TREM-1 and mouse TREM-1, respectively. Also referred to as “TREM-1 agonist antibody”.
  • a replication-deficient adenovirus containing a recombinant adenovirus mouse sTREM-1-Ig gene (SEQ ID NO: 1) (hereinafter also referred to as “AxCA-sTREM-1-Ig”) or a replication-deficient adenovirus containing a LacZ gene (hereinafter referred to as “AxCA-sTREM-1-Ig”) “AxCA-LacZ”) was prepared by the method described in the literature (Arthritis Rheum. 54: 2074-2083).
  • a recombinant adenovirus was grown in HEK293 cells to prepare a high-titer recombinant adenovirus, and the recombinant adenovirus was purified from HEK239 cells by cesium chloride density gradient centrifugation.
  • RPM TREM-1-expressing cells
  • STREM-1 Concentration in Serum To examine the sTREM-1 concentration in serum after intravenous administration of AxCA-sTREM-1-Ig, on day 0, 10 9 pfu of AxCA-sTREM-1-Ig or AxCA- LacZ was administered to non-immunized mice. Blood samples were collected from mice at 0, 2, 4, and 7 days after adenovirus administration and stored at -20 ° C. The stored blood sample was subjected to ELISA, and the sTREM-1 concentration in the serum was measured.
  • CII specific antibody CII specific antibody in mouse serum was measured by ELISA. Specifically, it measured by the following methods. Flat bottom plates were coated with 2 ⁇ g / ml bovine type II collagen denatured by boiling in phosphate buffered saline (PBS). The plate was washed in PBS containing 0.05% Tween 20 (PBST), blocked with PBS containing 2% bovine serum albumin (BSA), and incubated with 1000-fold diluted mouse serum.
  • PBS phosphate buffered saline
  • Splenocytes were isolated from each group of mice 14 days after the second immunization. These spleen cells (5 ⁇ 10 5 cells) were cultured in RPMI 1640 medium supplemented with penicillin / streptomycin and 10% fetal calf serum while being stimulated with denatured CII (0-100 ⁇ g / ml). Cultures were cultured with [ 3 H] thymidine (0.037 MBq / well) for the last 16 hours of the 72 hour culture period and splenocytes were collected on a micro 96 harvester (PerkinElmer, Yokohama) to proliferate. evaluated. Incorporated radiation was measured by a microplate beta counter (“Micro ⁇ Plus”; PerkinElmer).
  • Example 1 in order to examine the sTREM-1 concentration in rheumatoid arthritis, the sTREM-1 concentration in the synovial fluid of 23 rheumatoid arthritis (RA) patients and 9 osteoarthritis (OA) patients was described in Example 1 above. It was measured by ELISA according to the method of “Measurement of sTREM-1 concentration in synovial fluid”. The result is shown in FIG. As can be seen from the results in FIG.
  • the sTREM-1 concentration in the synovial fluid of RA patients was 1763.2 ⁇ 1180.2 pg / ml
  • the sTREM-1 concentration in the synovial fluid of OA patients was 162.2 ⁇ 220.2 pg / ml
  • the sTREM-1 concentration in the synovial fluid of RA patients was significantly higher than that of OA patients. This indicates that sTREM-1 is highly expressed in RA with inflammation than OA without inflammation.
  • TREM-1 of all synovial cells of RA patients in Example 2 (1) above was According to the method of “cytokine production assay” described in Example 1 above, stimulation with an anti-TREM-1 monoclonal antibody (anti-TREM-1 agonist antibody) for 24 hours, and the concentration of inflammatory cytokine (TNF ⁇ ) in the culture supernatant was measured by ELISA. The result is shown in FIG. TNF ⁇ secretion itself has already been detected in synovial cells obtained from RA inflamed joints, but as can be seen from the results in FIG.
  • TNF ⁇ crosslinking by anti-TREM-1 agonist antibody Secretion was significantly higher than when stimulated with IgG antibody (control antibody). From this, it was shown that the disease in patients with rheumatoid arthritis worsens and tissue destruction progresses by increasing the inflammatory process via TREM-1.
  • mice [Expression of mouse TREM-1 in synovial cells of collagen arthritis (CIA) mice]
  • results of immunohistochemical analysis on synovial cells of CIA mice In order to examine whether TREM-1 expression in bone marrow cells contributes to inflammatory reaction in synovial tissue, in synovial tissue of CIA mice The expression of mouse TREM-1 was examined by the “immunohistochemical analysis” method described in Example 1 above. The results are shown in FIGS. As can be seen from the results of FIGS. 2A to 2C, cells expressing TREM-1 (mononuclear cells) were abundantly observed in the inflamed synovial tissue (FIG. 2C).
  • TREM-1 TREM-1 expression.
  • the expression level (Day 7) of TREM-1 in the early inflammatory joint (7 days after the second collagen immunization) was higher than that in the chronic inflammatory joint (16 days after the second collagen immunization) (Day 16). This indicates that TREM-1 plays a more important role in early inflammatory joints than in chronic inflammatory joints.
  • the concentration of sTREM-1 in mouse serum was measured by ELISA.
  • the result is shown in FIG.
  • the sTREM-1 concentration reached its maximum value 2 days after intravenous administration of AxCA-sTREM-1-Ig, and gradually decreased until the 7th day thereafter.
  • mice administered with AxCA-LacZ instead of AxCA-sTREM-1-Ig no increase in serum sTREM-1 concentration was observed (data not shown). From these results, it was shown that sTREM-1-Ig was efficiently produced in vivo by intravenous administration of AxCA-sTREM-1-Ig.
  • FIG. Of C the time course of the hind limb thickness of CIA mice is shown in FIG. Of C.
  • FIGS. 4A to 4C when 1 ⁇ 10 9 pfu of AxCA-sTREM-1-Ig was intravenously administered, the progression of arthritis was compared to when AxCA-LacZ (control) was administered. Was significantly suppressed.
  • arthritis when 1 ⁇ 10 8 pfu of AxCA-sTREM-1-Ig was administered intravenously, arthritis was significantly suppressed compared to the control, although not as much as when 1 ⁇ 10 9 pfu was administered. That is, it was revealed that AxCA-sTREM-1-Ig inhibits arthritis in a dose-dependent manner.
  • the joints of AxCA-LacZ-introduced mice are unique to collagen arthritis in all four parameters: prominent infiltration of inflammatory cells, degeneration of synovial intima, cartilage destruction, and pannus formation. The characteristics were shown.
  • the infiltration of inflammatory cells was remarkably reduced, and the degree of intimal hyperplasia and bone and cartilage destruction were low.
  • AxCA-sTREM-1-Ig or AxCA-LacZ various adenoviruses (AxCA-sTREM-1-Ig or AxCA-LacZ) were introduced 2 days and 9 days after the second immunization of CIA-induced mice, and 4 spleens per group were introduced on the 16th day. Removed and co-cultured with type II collagen. The observation result is shown in FIG. As can be seen from the results in FIG. 6A, each group was introduced with 10 8 pfu of AxCA-sTREM-1-Ig, 10 9 pfu of AxCA-sTREM-1-Ig, or AxCA-LacZ (control). No significant difference in response was observed. This result indicated that inhibition of TREM-1 did not impair the antigen-specific T cell response.
  • a TREM-1 inhibitor is effective for preventing or treating a collagen disease.
  • a prophylactic / therapeutic agent for collagen disease can be screened by searching for a TREM-1 inhibitor.

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Abstract

L'invention porte sur un agent prophylactique/thérapeutique pour la collagénose, qui permet d'inhiber la fonction de TREM-1 pour présenter un effet prophylactique/thérapeutique sur la collagénose. L'invention porte également sur un procédé pour le criblage d'un agent prophylactique/thérapeutique pour la collagénose qui permet d'inhiber la fonction de TREM-1 pour prévenir ou traiter la collagénose. De façon spécifique, l'agent prophylactique/thérapeutique pour la collagénose comprend un inhibiteur de TREM-1. Des exemples préférés de l'inhibiteur de TREM-1 comprennent TREM-1 soluble et un vecteur capable d'exprimer TREM-1 soluble.
PCT/JP2009/000659 2008-02-20 2009-02-18 Agent prophylactique/thérapeutique pour la collagénose WO2009104388A1 (fr)

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