WO1997010006A1 - Method for inhibiting cell-mediated killing of target cells - Google Patents
Method for inhibiting cell-mediated killing of target cells Download PDFInfo
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- WO1997010006A1 WO1997010006A1 PCT/US1996/014571 US9614571W WO9710006A1 WO 1997010006 A1 WO1997010006 A1 WO 1997010006A1 US 9614571 W US9614571 W US 9614571W WO 9710006 A1 WO9710006 A1 WO 9710006A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/81—Protease inhibitors
- C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
- C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
- C07K14/8121—Serpins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
Definitions
- Cell-mediated killing of target cells can be undesirable in vivo.
- cell-mediated killing of grafts is thought to be responsible for rejection of a graft by a host
- autoimmune diseases such as diabetes
- Cell-mediated killing has also hampered progress in the field of gene therapy.
- Many gene therapy methods entail the use of a viral vector to express a therapeutic gene in a target cell.
- viral vectors also encode viral antigens that induce the patient's immune system to effectuate cell-mediated killing of target cells that are transfected with the virus and therapeutic gene.
- these examples illustrate that the induction of an immune response can be undesirable.
- CTL cytotoxic T lymphocytes
- cell-mediated killing of a target cell can be inhibited by expressing in the target cell a proteinase inhibitor of an orthopoxvirus (e.g., SPI-1).
- a proteinase inhibitor of an orthopoxvirus e.g., SPI-1
- the invention features a method for inhibiting cell-mediated cell death of a mammalian target cell by expressing in the target cell an orthopoxvirus proteinase inhibitor, thereby inhibiting cell-mediated cell death.
- the invention can be used to inhibit CTL-mediated cell death and apoptosis.
- the invention is thus useful for suppressing the immune system of a patient, e.g., for treating an autoimmune disease, inhibiting graft rejection, or inhibiting the death of cells that are targeted in gene therapy methods.
- Figs. 1A and 1B are histograms representing the inhibition of granule-meditated cytolysis of cells infected with CPV or RPV.
- L1210 (Fig. 1A) or EL4 (Fig. 1B) cells were either mock-infected or infected with CPV or RPV, and cytolysis was assayed by incubation with stimulated CTL21.9 effector cells in a standard 4 hour chromium release assay at an effector to target ratio of 5:1.
- the values for % specific lysis for mock-infected cells were set to 100%, and other data are shown relative to mock-infected cells.
- Each bar represents the mean and standard deviation calculated from 3-5 independent experiments, each performed in triplicate.
- 2C1 1 hybridoma supernatant (anti-CD3 monoclonal antibody - Leo, et al., 1987, Proceedings of the National Academy of Sciences USA 84:1374-4274).
- L1210 cells a murine T lymphoma derived from DBA/2 mice, obtained from Dr.
- EL4 cells a murine T lymphoma cell line
- CPV Biton Red strain
- RPV Utrecht strain
- RPMI RPMI 1640 containing 5% fetal bovine serum (Gibco) and 10 -4 M ⁇ -mercaptoethanol
- Cells were labeled with 51 Cr (100 ⁇ Ci per 2 ⁇ 10 6 cells, Dupont NEN) at 37°C for 90 minutes, washed three times, and added to V-bottomed 96-well plates (1 ⁇ 10 4 cells per well) with stimulated CTL21.9 effector cells (5 ⁇ 10 4 cells per wall). Plates were centrifuged at 500 rpm for 5 minutes to promote cell contact, and then incubated for 4 hours at 37°C in RPMI . Supernatants were then removed and counted in a gamma counter.
- Figs.2A - 2D are a series of histograms representing inhibition of Fas-mediated cytolysis of virus-infected L1210-Fas (Fig. 2A), EL4 (Fig. 2B) and YAC-1 (Fig. 2C) cells.
- L1210-Fas, EL4 and YAC-1 cells were either mock-infected or infected with the indicated virus as described in the legend to figure 1. Cytolysis of target cells was assayed by incubation with stimulated PMM-1 effector cells in a standard 4 hour chromium release assay at an effector to target ratio of 5:1.
- % specific lysis for mock-infected cells were set to 100%, and other data are shown relative to mock infected cells. Each bar represents the mean and standard deviation calculated from 3-5 independent experiments, each performed in triplicate.
- Fig. 2D is the histogram obtained after L1210-FAS and L1210 cells were either mock-infected or infected with CPV or RPV, and incubated with stimulated PMM-1 effector cells at an effector to target ratio of 5:1 and the % specific chromium release was determined. Representative data from a single experiment performed in triplicate are shown. Virus infections, chromium release assays, and calculations were performed as described in the legend to Figs.
- PMM-1 effector cells (Kaufmann, et al., 1981 , Proceedings of the National Academy of Sciences USA 78:2502) (a BALB/c derived peritoneal exudate lymphocyte CTL hybridoma; obtained from Dr. G. Berke, Weizmann Institute of Science, Rehovot, Israel, were stimulated prior at assay by incubating with PMA (10 ng/ml; Sigma) and lonomy ⁇ n (3# ⁇ g/ml; Sigma) at 37°C for three hours L1210-FAS is an L1210 cell transfectant expressing the murine Fas antigen (Rouvier, et al., 1993, Journal of Experimental Medicine 177:195-200) (obtained from Dr. Pierre Goldstein,
- YAC-1 is murine Lymphoma cell line.
- Figs. 3A-3F are a series of histograms representing Fas-mediated cytolysis of target cells infected with virus mutants in the SPI-1 or SPI-2 genes.
- L1210-FAS Figs. 3A and 3D
- EL4 Figs. 3B and 3E
- YAC-1 Figs. 3C and 3F
- Virus infections, chromium release assays, and calculations were performed as described in the legends to Figs. 1A, 1 B, and 2A-2D.
- RPV mutant in both SPI-1 and SPI-2 was constructed from RPV ⁇ SPI-1 by homologous recombination leading to replacement of a 447 bp region of the SPI-2 open reading frame with the E.coli lacZ gene driven by the vaccinia virus p1 1 promoter.
- Figs. 4A-4D are a series of histograms representing Granule-mediated cytolysis of target cells infected with virus mutants in the SPI-1 or SPI-2 genes.
- L1210 Figs.
- EL4 cells were infected with wild type viruses or virus mutants in either the SPI-1 or SPI-2 genes, or with RPV containing mutations in both the SPI-1 and the SPI-2 genes (RPV ⁇ SPI-1/2, described above). Data are shown as the % specific lysis relative to mock infected cells and represent the mean and standard deviations of three independent experiments. Virus infections, chromium release assays, and calculations were performed as described in the legends to Figs. 1A, 1 B, and 2A-2D.
- Fig. 5 is a listing of the DNA and amino acid sequences for SPI-1 (SEQ ID Nos:
- Fig 6 is a listing of the DNA and amino acid sequences for SPI-2 (SEQ ID NOs: 3 and 4, respectively).
- Cell-mediated killing refers to ability of a cell (e.g., a cytotoxic T lymphocyte (CTL)) to effectuate the death of a target cell, e.g., by cytolysis or apoptosis.
- CTL cytotoxic T lymphocyte
- cell death is inhibited by expressing in the target cell a proteinase inhibitor of a pox virus, such as an orthopoxvirus, thereby inhibiting cell-mediated (e.g., CTL-mediated) killing of the target cell.
- the method can include identifying the target cell as a target of cell-mediated killing.
- Numerous cells are known to be targets of cell-mediated cell death
- the cell is a human cell.
- cells of heterologous or autologous grafts are targets for cell-mediated killing, and such cells can be used in the invention.
- Bone marrow cells are particularly suitable for use in the invention, as such cells can readily be obtained, manipulated in vitro, and then introduced into a patient.
- Other suitable cells include cells that are associated as tissues (e.g., liver tissue) or organs (e.g., hearts) that can be grafted in methods of transplantation.
- CD4 + lymphocytes of patients infected with Human Immunodeficiency Virus are considered target cells in the invention.
- Such CD4 + lymphocytes are thought to be killed by apoptosis that is induced by stimulation of the CD4 molecule on the lymphocytes by a complex of gp120 and antibody.
- the Fas antigen/Fas ligand system is thought to mediate the death of CD4 + cells even though the cells are not thought to be infected with HIV.
- cell-mediated killing of these cells results in the massive depletion of CD4 cells that is observed in AIDS patients.
- the invention can be autologous or heterologous to the patient.
- the invention can be used to inhibit cell-mediated killing of cells that are the targets of conventional gene therapy methods.
- Many conventional gene therapy methods employ viral vectors to express a therapeutic gene in a cell of a mammal.
- a "therapeutic" gene is any gene that, when expressed, confers a beneficial effect on a cell. In vivo, such a gene is one that ameliorates a sign or symptom of a disorder, or confers a desired phenotype on a cell or another cell of the patient.
- Such a therapeutic gene can be, for example, a gene that corrects a deficiency in gene expression (e.g., an insulin gene for correcting a deficiency in insulin expression).
- the invention thus provides a method for inhibiting cell-mediated death of these target cells, with inhibition being accomplished by expressing a poxvirus proteinase inhibitor in the target cell.
- the proteinase inhibitor can be expressed from the same vector, or a different vector, as the vector used to express the therapeutic gene. Additional cells that are targeted for cell-mediated cell killing can readily be identified in conventional in vitro CTL cytotoxicity assays, such as chromium release assays.
- a proteinase inhibitor in a cell.
- vectors derived from mammalian viruses such as retrovirus vectors, adeno-associated virus vectors, and herpes simplex virus vectors, are well known in the art and can be used in the invention.
- Other art-known gene delivery and expression techniques can also be used in the invention.
- the proteinase inhibitor can be expressed from a genetic construct (i.e., any nucleic acid, such as a plasmid or cosmid, engineered to express a gene).
- the vector can be engineered to contain a "suicide" gene.
- genes are known in the art for their ability to encode a factor that renders the cell sensitive to a substance that can be administered to the cell in the event that subsequent killing of the target cell should be desired.
- the various genetic constructs can be introduced into a cell by conventional methods, such as liposome-based methods, direct uptake, electroporation, CaCl-based methods, and the like.
- liposome-based methods direct uptake, electroporation, CaCl-based methods, and the like.
- the liposomes can be engineered to have on their surface desired markers, e.g., receptors, antibodies, lectins, or carbohydrates.
- the nucleic acid encoding the proteinase inhibitor is operably linked to a promoter that is active in a mammalian cell (e.g ., a promoter that naturally drives expression of a gene in a mammalian cell or a promoter of a virus that infects a mammalian cell).
- a promoter that is active in a mammalian cell
- the promoter is a promoter of an poxvirus, such as a promoter that naturally drives expression of a proteinase inhibitor.
- the promoter can be a cell-specific promoter, a tissue-specific promoter, or a stage-specific promoter. Such promoters are known in the art and can be used to confer specificity in the practicing the invention.
- tissue or organs are used as the target cells in the invention, conventional organ perfusion methods are well suited for delivering the nucleic acid encoding the proteinase inhibitor to the cells of the tissue or organ.
- the proteinase inhibitor is a serpin proteinase inhibitor, such as SPI-1 (SEQ ID NO: 2; GenBank Accession No. UO7766; Ali et al., supra), SPI-2 (SEQ ID NO: 2; GenBank Accession No. UO7766; Ali et al., supra), SPI-2 (SEQ ID NO: 2; GenBank Accession No. UO7766; Ali et al., supra), SPI-2 (SEQ ID NO: 2; GenBank Accession No. UO7766; Ali et al., supra), SPI-2 (SEQ ID NO: 2; GenBank Accession No. UO7766; Ali et al., supra), SPI-2 (SEQ ID NO: 2; GenBank Accession No. UO7766; Ali et al., supra), SPI-2 (SEQ ID NO: 2; GenBank Accession No. UO7766; Ali et al., supra), SPI-2 (SEQ ID NO: 2; GenBank Accession No. U
- the proteinase inhibitor can be derived from any pox virus, preferably, the virus is an orthopox virus, such as a cowpox virus, rabbitpox virus, smallpox virus, or vaccinia virus. Such virus can be obtained from ATCC.
- Each of these viruses naturally encodes members of the serpin family of proteinase inhibitors, which can be used in the assay. Mutant strains of these viruses that have decreased pathogenicity while nonetheless expressing a proteinase inhibitor can used. In addition, variants (e.g., conservative variants) and mutants of these proteinase inhibitors can be used, provided that the resulting polypeptide retains a detectable ability to inhibit CTL-mediated cell death (e.g., as determined in a CTL cytotoxicity assay as described herein).
- conservative variant is meant a polypeptide having an amino acid substitution where the native amino acid and the substituted amino acid are of approximately the same charge and polarity.
- substitutions typically include, e.g., substitutions within the following groups: glycine, alanine; valine, isoleucine, leucine, methionine, aspartic acid, glutamic acid; asparagine, glutamine, serine, threonine; lysine, arginine; and phenylalanine, tyrosine.
- conservative amino acid substitutions do not significantly affect the function of the polypeptide.
- the ability of a variant or mutant to function as a proteinase inhibitor can be measured in a CTL cytotoxicity assay as described herein, using the wild-type proteinase inhibitor as a standard.
- nucleic acids encoding a protease inhibitor where the nucleic acid is a degenerate variant of the nucleic acid sequences expressly described herein.
- degenerate variants of a nucleotide sequence is meant nucleotide sequences that encode the same amino acid sequence as a given nucleotide sequence, but in which at least one codon in the nucleotide sequence is different. Degenerate variants occur due to the degeneracy of the genetic code, whereby two or more different codons can encode the same amino acid. Applicants have discovered that the presence of nucleotide encoding SP-1 polypeptide and nucleotide encoding SP-2 polypeptide provide enhanced inhibition of cell-mediated killing.
- an isolated target cell that is resistant to cell-mediated killing.
- Such cells contain a nucleic acid that consists essentially of a nucleic acid that expresses a poxvirus SPI-1 polypeptide, as described herein.
- Such cells can also include a nucleic acid that consists essentially of a nucleic acid that expresses an SPI-2 polypeptide. If desired, these cells can also express a therapeutic gene.
- isolated target cell means that a gene is delivered to a cell and expressed non-systemically in a population of cells (e.g., in liver cells or pancreatic islet cells).
- Such cells can be in the form of a cell suspension (e.g., bone marrow cells) or they can be in the form of a tissue or organ (e.g., a liver) for use in organ transplantation methods.
- a cell suspension e.g., bone marrow cells
- tissue or organ e.g., a liver
- cell populations of a mammal that are targeted for SPI-1 expression without systemic expression of SPI-1 in the mammal.
- liver cells of a mammal that are targeted for SPI-1 expression are considered "isolated," even when the cells are contained within the mammal.
- the invention also provides a method for determining whether a nucleic acid (i.e., a "test" nucleic acid) encodes a polypeptide that inhibits cell-mediated killing of a target cell.
- a nucleic acid i.e., a "test” nucleic acid
- this aspect of the invention provides a method for identifying additional proteinase inhibitors that can be used in the methods described above.
- One method entails introducing into a target cell a mutant poxvirus that does not express a functional SPI-2 polypeptide; expressing in the target cell the "test" nucleic acid; and detecting inhibition of cell-mediated killing of the target cell as an indication that the test nucleic acid encodes a polypeptide that inhibits cell-mediated killing. In this sense, the "test" nucleic acid is tested for its ability to complement the SPI-2 deletion.
- Mutant viruses that fail to encode functional SPI-2 are known in the art (Ali et al., infra), and additional viruses can be produced using conventional mutagenesis methods.
- polypeptides will be proteinase inhibitors that, like SPI-2, belong to the serpin family of proteinase inhibitors .
- the polypeptide encoded by the "test" nucleic acid is further characterized by testing its ability to confer resistance to cell-mediated killing in the presence of a poxvirus that does not encode a functional SPI-1 polypeptide.
- SPI-1 mutant has been described (Thompson et al., infra), and additional mutant viruses can be produced using conventional gene manipulation techniques.
- a "test" nucleic acid encoding a polypeptide that confers resistance to cell-mediated killing in both of the aforementioned genetic settings is considered a new inhibitor of cell-mediated killing.
- nucleic acid encoding such a polypeptide can then be used in the invention to confer on a target cell resistance to cell-mediated killing.
- Example I Cowpox Virus and Rabbitpox Virus Inhibit CTL-Mediated Cytolysis This example shows that cells infected with an orthopoxvirus are resistant to
- target cells were infected with wild-type cowpox virus (CPV (Brighton Red strain) or rabbbitpox virus (RPV (Utrecht strain)), (American Type Culture Collection, Rockville, MD.), at a multiplicity of infection (moi) of ten plaque forming units (pfu)/cell for twelve hours. Each of these viruses expresses a serpin proteinase inhibitor in the infected cells.
- the target cells were then assayed for cytolysis by CTL21.9 effector cells in a conventional chromium release assay.
- the target cells were L1210 (ATCC) and EL4 cells (thymoma cells).
- PMM-1 cytolytic hybrdi oma cell line that does not express perform or granzymes (Kaufmann et al., 1981 , PNAS 78:2502 and
- SPI-2 and SPI-1 are responsible for the ability of CPV and RPV to inhibit CTL-mediated cytolysis.
- Mutated versions of SPI-1 and SPI-2 were used in these experiments to demonstrate the role of SPI-1 and SPI-2.
- the SPI-1 mutant, CPV ⁇ SPI-1 has been described previously (Thompson et al., 1993, Virology 197:328-338).
- the SPI-2 mutant, CPV ⁇ SPI-1 has been described previously (Thompson et al., 1993, Virology 197:328-338).
- the SPI-2 mutant has been described previously (Thompson et al., 1993, Virology 197:328-338).
- CPV ⁇ SPI-2 has been described (Ali et al., 1994, Virology 202:305-314). Cells infected with CPV containing a mutation in the SPI-2 gene were lysed by PMM-1 effectors at a level comparable to the level of lysis obtained with mock-infected cells (Figs. 3A-3C). Cells infected with a CPV mutant having a mutation in the SPI01 gene showed comparable inhibition to wild-type CPV-infected cells. Similarly, mutation of the RPV SPI-2 gene almost completely relieved virus-mediated inhibition of cytolysis of infected L1210-FAS cells.
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Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP96932206A EP0859638A1 (en) | 1995-09-11 | 1996-09-11 | Method for inhibiting cell-mediated killing of target cells |
AU71084/96A AU7108496A (en) | 1995-09-11 | 1996-09-11 | Method for inhibiting cell-mediated killing of target cells |
JP51207497A JP2001519644A (en) | 1995-09-11 | 1996-09-11 | Method of inhibiting cell-mediated killing of target cells |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US366595P | 1995-09-11 | 1995-09-11 | |
US60/003,665 | 1995-09-11 |
Publications (2)
Publication Number | Publication Date |
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WO1997010006A1 true WO1997010006A1 (en) | 1997-03-20 |
WO1997010006A9 WO1997010006A9 (en) | 1997-09-04 |
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ID=21706977
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/US1996/014571 WO1997010006A1 (en) | 1995-09-11 | 1996-09-11 | Method for inhibiting cell-mediated killing of target cells |
Country Status (5)
Country | Link |
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EP (1) | EP0859638A1 (en) |
JP (1) | JP2001519644A (en) |
AU (1) | AU7108496A (en) |
CA (1) | CA2231804A1 (en) |
WO (1) | WO1997010006A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002026245A2 (en) * | 2000-09-29 | 2002-04-04 | Zhong Z Robert | Use of serp-1 in combination with an immunosuppressant for influencing inflammatory and immune reactions |
US6391612B1 (en) | 1998-02-11 | 2002-05-21 | Genvec, Inc. | Vectors, cells, and methods for the production of deleterious adenoviral, herpes viral and adeno-associated viral vectors |
US7514405B2 (en) | 1999-10-27 | 2009-04-07 | Viron Therapeutics Inc. | Methods for treating transplant rejection |
US7745396B2 (en) | 2004-10-21 | 2010-06-29 | Viron Therapeutics Inc. | Use of SERP-1 as an antiplatelet agent |
-
1996
- 1996-09-11 AU AU71084/96A patent/AU7108496A/en not_active Abandoned
- 1996-09-11 CA CA002231804A patent/CA2231804A1/en not_active Abandoned
- 1996-09-11 EP EP96932206A patent/EP0859638A1/en not_active Withdrawn
- 1996-09-11 WO PCT/US1996/014571 patent/WO1997010006A1/en not_active Application Discontinuation
- 1996-09-11 JP JP51207497A patent/JP2001519644A/en active Pending
Non-Patent Citations (5)
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6391612B1 (en) | 1998-02-11 | 2002-05-21 | Genvec, Inc. | Vectors, cells, and methods for the production of deleterious adenoviral, herpes viral and adeno-associated viral vectors |
US7514405B2 (en) | 1999-10-27 | 2009-04-07 | Viron Therapeutics Inc. | Methods for treating transplant rejection |
US7906483B2 (en) | 1999-10-27 | 2011-03-15 | Viron Therapeutics Inc. | Method for treating transplant rejection |
WO2002026245A2 (en) * | 2000-09-29 | 2002-04-04 | Zhong Z Robert | Use of serp-1 in combination with an immunosuppressant for influencing inflammatory and immune reactions |
WO2002026245A3 (en) * | 2000-09-29 | 2003-10-09 | Z Robert Zhong | Use of serp-1 in combination with an immunosuppressant for influencing inflammatory and immune reactions |
US7419670B2 (en) | 2000-09-29 | 2008-09-02 | Viron Therapeutics, Inc. | Method of treating arthritis with SERP-1 and an immunosuppressant |
US7745396B2 (en) | 2004-10-21 | 2010-06-29 | Viron Therapeutics Inc. | Use of SERP-1 as an antiplatelet agent |
Also Published As
Publication number | Publication date |
---|---|
AU7108496A (en) | 1997-04-01 |
EP0859638A1 (en) | 1998-08-26 |
JP2001519644A (en) | 2001-10-23 |
CA2231804A1 (en) | 1997-03-20 |
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