WO2005051927A1 - Hiv-1感染末梢血単核球の刺激培養によるcd4陽性t細胞の培養方法、及びhiv-1の増殖阻害剤 - Google Patents
Hiv-1感染末梢血単核球の刺激培養によるcd4陽性t細胞の培養方法、及びhiv-1の増殖阻害剤 Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- 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
- A61P37/04—Immunostimulants
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0636—T lymphocytes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/999—Small molecules not provided for elsewhere
Definitions
- the present invention relates to a method for culturing CD4-positive T cells by stimulating culture of HIV-1-infected peripheral blood mononuclear cells.
- the present invention relates to large-scale culture of CD4 + T cells by R5 / X4 HIV-1-infected PBMC-stimulated culture using a novel chemokine receptor inhibitor.
- HIV infection AIDS treatment is mainly performed by high-drug combination therapy (Highly Active Antiretroviral Therapy, HAART) using a reverse transcriptase inhibitor and a protease inhibitor. Mortality rates have declined significantly. However, even if HAART reduces blood HIV-RNA levels, poor recovery of immunity may result in opportunistic infections or HAART may have to be interrupted due to adverse drug reactions. Not a few.
- high-drug combination therapy High-drug combination therapy
- HAART Highly Active Antiretroviral Therapy
- PBMC peripheral blood mononuclear cells
- CCR5 chemokine receptor
- Non-patent Document 1 After fractionating T cells, expand CD4 + cells by co-stimulation with anti-CD3 + CD28 beads in the presence of IL-2, and repeatedly inject the obtained CD4 + cells into the body It has been reported that the increase in the number of CD4-positive ⁇ cells and the decrease in the proportion of CD4-positive CCR5-positive cells in a patient's body without changing the blood virus concentration (Non-patent Document 1). This study reports previously reported anti-CD4 + cells in vitro.
- HIV-1 includes, in addition to R5 HIV-1, which uses CCR5 as a co-receptor, X4 HIV_1 which uses CXCR4, and R5 / X4 HIV-1, which can use both CCR5 and CXCR4.
- Non-Patent Document 6 PBMCs from end-stage AIDS patients were successfully cultured in the presence of IL-2 by stimulating culture with an immobilized anti-CD3 antibody to successfully expand T cells with virus growth suppressed.
- a method for stably culturing CD4-positive T cells of AIDS patients infected with X4 HIV-1 and R5 / X4 HIV-1 is not known.
- Non-Patent Document 1 Nature Medicine, 8, 47-53, 2002
- Non-Patent Document 2 Science, 272, 1939-1943, 1996
- Non-Patent Document 3 Science, 276, 273-276, 1997
- Non-Patent Document 4 J. Immunol, 158, 5545-5553, 1997
- Non-Patent Document 5 Science, 276, 273-276, 1997
- Non-Patent Document 6 AIDS Research and Human Retroviruses, 16, 611-612, 2000 Disclosure of the Invention
- the present invention relates to not only R5 HIV-1 utilizing CCR5 as a co-receptor, but also X4 HIV-1 utilizing CXCR4, and R5 / X4 HIV-1 infected AIDS capable of utilizing both CCR5 and CXCR4.
- An object of the present invention is to provide a method for stably culturing and proliferating CD4-positive T cells, from which a patient's strength has been collected, and an HIV-1 proliferation inhibitor used for the culturing.
- Certain aromatic amine compounds having MIP-1 ⁇ binding inhibitory effect are effective for the proliferation of HIV-1 with R5, X4, or R5 / X4 tropism in stimulated and activated PBMC, It was found that cell fusion by HIV-1 Env between stained cells was suppressed.
- the present inventors have found that in a stimulated culture of P5MC infected with R5, X4, and R5 / X4 HIV-1, the aromatic amine compound suppresses the proliferation of these HIV-1 viruses, and a large-scale culture of CD4-positive T cells. The inventors have obtained the knowledge that they can achieve the above, and have completed the present invention.
- the present invention provides an HIV-1 proliferation inhibitor comprising a compound of the following formula I or a salt thereof.
- V is a 9- to 24-membered cyclic polyamine moiety having 2 to 6 amine nitrogens, the amine nitrogens being spaced apart from each other by at least 2 carbon atoms. ;
- R 1 to R 7 are each independently a hydrogen atom or a linear, branched or cyclic C alkyl
- R 8 is a monocyclic or polycyclic heterocyclic group, or a monocyclic or polycyclic, and is a substituted or unsubstituted aromatic or heteroaromatic group;
- Ar is an aromatic or heteroaromatic ring, each of which may be substituted in at least one position with an electron-donating or electron-withdrawing group; and X is an integer from 0 to 2 .
- V is 14 to 20 members and contains 4 nitrogen atoms, and it is particularly preferable that V is 1,4,8,11-tetraazacyclodecane. ! / ,.
- R 4 are preferably hydrogen atoms, and is preferably a hydrogen atom or a CH group.
- the Ar force is 1,3 or 1,4 unsubstituted phenylene, and particularly preferably, the Ar force is 1,3 or 1,4 unsubstituted phenylene.
- R 4 is preferably a hydrogen atom
- R 5 is a hydrogen atom or a CH group
- X is preferably 0.
- R 8 represents (1) It is preferably any one group of (5).
- the above-mentioned HIV-1 proliferation inhibitor wherein the compound of the formula 1 is a compound having the following formula 2, is preferred.
- the above-mentioned HIV-1 proliferation inhibitor wherein the compound of the formula 1 is a compound having the following formula 2, is preferred.
- A represents a group having any one of the following (1) to (5).
- the present invention provides a method for culturing HIV-1-infected peripheral blood mononuclear cells in a medium containing the HIV-1 proliferation inhibitor and a growth stimulant, comprising the steps of: Provided is a method for culturing CD4-positive T cells contained in monocytes.
- the HIV-1 infection of the peripheral blood mononuclear cells is due to a subtype HIV-1 selected from the group consisting of R5 HIV-1, X4 HIV-1, and R5 / X4 HIV-1.
- the culturing method is provided.
- the present invention provides a kit for culturing CD4-positive T cells contained in HIV-1-infected peripheral blood mononuclear cells, comprising the HIV-1 proliferation inhibitor.
- the activated CD4-positive T cells obtained by the culture method were collected. Provided are methods of treating HIV-1 infection, including returning to a patient.
- the present invention includes the use of the activated CD4-positive T cells obtained by the above-described culture method for producing a pharmaceutical composition for treating HIV-1 infection.
- the HIV-1 proliferation inhibitor of the present invention suppressed all HIV-1 proliferation having R5, X4, or R5 / X4 tropism in ActiviDani PBMC from which AIDS patients were also collected.
- the culture method using the HIV-1 proliferation inhibitor of the present invention enables large-scale culture of CD4 + T cells collected from AIDS patients, and enables infection with R5, X4, or R5 / X4 HIV-1. Adoptive immunotherapy for AIDS patients has become possible.
- A represents a group having any one of the following (1) to (5); [0021] [Formula 11]
- the compound is a compound of the following formula (3) or a salt thereof:
- Compound 1 a compound of the formula 1 wherein R is a group of the formula (1)
- Compound 2 a compound of Formula 1 wherein R is a group of (2)
- Compound 4 a compound of Formula 1 wherein R is a group of (4)
- Compound 5 a compound of the formula 1 wherein R is a group of the formula (5)
- compound 15 can be used as an HIV-1 proliferation inhibitor, but compound 2 is particularly preferable. These compounds can be used alone or in combination.
- the present inventors have assigned T-1113 to Compound 2 as an experimental control number. The specific method for producing these compounds 115 is described in Production Example 115 following the examples.
- Compound 15 of the present invention can be used as a HIV-1 proliferation inhibitor in the form of a salt.
- the salt is not particularly limited as long as it is harmless to the patient when the cultured CD4 + T cells are returned to the PBMC of the original patient.
- the compounds 115 of the present invention which are preferably used in the form of a pharmaceutically acceptable salt, can be addition salts of organic acids or inorganic acids.
- the inorganic acid addition salts include, for example, hydrofluoric acid, hydrochloride, hydrobromide, nitrate, sulfate, hydrogen sulfate, dihydrogen phosphate, dihydrogen phosphate, Acetate and the like.
- a salt can also be formed using a basic compound, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate, or the like.
- these salts for example, hydrochloride, nitrate, monohydrogen phosphate, dihydrogen phosphate and the like are preferable.
- Organic acid addition salts include fatty acids such as monocarboxylic acids, dicarboxylic acids, hydroxyalkanoic acids, hydroxyalkanediacids, and amino acids, and aromatic acids, fatty acids, and aromatic sulfonic acids.
- Non-toxic organic acid power Derived salts such as sulfonic acid, methanesulfonic acid, sulfamic acid, tartaric acid, fumaric acid, hydrobromic acid, glycolic acid, citric acid, maleic Acid, phosphoric acid, succinic acid, acetic acid, benzoic acid, ascorbic acid, P-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, propionic acid, lactic acid, pyruvic acid, oxalic acid, stearic acid, cinnamate, and asparagine Acids, salicylic acid, dalconic acid and the like.
- sulfonic acid such as sulfonic acid, methanesulfonic acid, sulfamic acid, tartaric acid, fumaric acid, hydrobromic acid, glycolic acid, citric acid, maleic Acid, phosphoric acid, succinic acid, ace
- Such an acid addition salt generally has advantageous properties when culturing PBMC having good dispersibility and absorbability.
- the acid addition salts are well known in the technical field of the present invention, and can be easily prepared by a conventional method by contact with a suitable acid or base conjugate.
- the HIV-1 proliferation inhibitor of the present invention imparts favorable characteristics to T cell culture, and can be added with an appropriate component for preparation or the like to facilitate handling and the like.
- an appropriate component for preparation or the like for example, bulking agents, buffers, pH adjusters, dispersants, stabilizers, surfactants, absorption promoters, and the like, which are components for pharmaceutical preparations such as commonly used carriers, can be used.
- additives such as a coloring agent and a preservative may be used as necessary.
- the culture method of the present invention uses a medium containing the HIV-1 growth inhibitor and a growth stimulant.
- a method for culturing CD4-positive T cells contained in HIV-1-infected peripheral blood mononuclear cells which comprises culturing HIV-1-infected peripheral blood mononuclear cells.
- CD4-positive T cells are immunologically activated and expanded using HIV-1-infected peripheral blood mononuclear cells collected from patients. What is cultured here is mainly peripheral blood mononuclear cells including T cells, macrophages and B cells.
- peripheral blood mononuclear cells includes not only the original peripheral blood mononuclear cells but also epithelial lymphocytes including CD4 + T cells, tumor-infiltrating lymphocytes, and cancerous ascites pleural effusion-infiltrating lymphocytes. This is a concept that includes a sphere.
- the use of fresh peripheral mononuclear cells immediately after blood collection is preferred in terms of physical burden on the blood collection patient, ease of lymphocyte separation, and good survival of lymphocytes after separation.
- the amount of blood collected during the immunological activation and expansion of the CD4-positive T cells and the number of lymphocytes at the start of culture are not particularly limited. Considering the burden on the patient and the ease of processing such as lymphocyte separation, first, a small amount of fresh peripheral blood with a patient strength of about 5 to 50 ml is collected, and the peripheral blood mononuclear cells separated therefrom are collected. It is preferable to start with about 1 one 100 X 10 6 cells spheres.
- the cell density at the start of culture is preferably 1 ⁇ 10 5 to 1 ⁇ 10 6 Zml. If the number of cells increases with culturing, use appropriate cells if necessary. A desired amount of activated CD4-positive T cells can be obtained by subculturing to a cell density. In addition, if the number of cells increases during culture, plastic flasks for cell culture, CO gas permeable gas 'permeable' bags, etc. can be used.
- the peripheral blood mononuclear cells are infected with HIV-1 by a subgroup selected from the group consisting of R5 HIV-1, X4 HIV-1 and R5 / X4 HIV-1. It is particularly effective if it is due to -1.
- the HIV-1 growth inhibitory power of the present invention is the power to suppress the proliferation of these subtype viruses, particularly during the culture of peripheral blood mononuclear cells.
- a synthetic medium in which amino acids, vitamins, nucleobases, and the like are added to a culture solution derived from an organism such as serum or a balanced salt solution can be used.
- examples include RPM 1640, AIM-V, DMEM, IMDM, etc., with RPMI-1640 being particularly preferred.
- fetal bovine serum, bovine serum albumin, human serum and the like are added to the medium. In particular, the addition of normal human serum to the culture often yields excellent growth effects.
- Examples of the growth stimulating agent include anti-CD3 antibody, interferon, interleukin 2 (IL-2), interleukin 12 (IL-12), and interleukin 15 (IL-15).
- immunostimulants such as cytokins, PSK, OK-432, and lentinan. These can be used alone or in combination. In the present invention, for example, it is preferable to use a combination of an anti-CD3 antibody and interleukin 2.
- an anti-CD3 antibody is particularly preferred. This is because an anti-CD3 antibody, which is a specific antibody against the CD3 molecule, stimulates CD3 molecules present on the surface of T cells to initiate T cell proliferation.
- the anti-CD3 antibody can be produced by immunizing an animal or a cell, but a commercially available OKT-3 antibody (manufactured by Osofam Massical) having excellent stability, cost, and quality can also be obtained. .
- the amount of the growth stimulant used is not particularly limited as long as the effect can be obtained. For example, 5-20 units (U) of IL-2, preferably 15-20 U / ml,
- the concentration is 5-100 / z gZml, preferably 40-60 ⁇ g Zml.
- the anti-CD3 antibody is preferably immobilized on the surface of an insoluble carrier before use. Immobilization Alternatively, it can be carried out by allowing the insoluble carrier to stand in a diluent such as a phosphate buffered saline solution (PBS) containing 50 gZml of the anti-CD3 antibody for a certain time at a certain temperature.
- a diluent such as a phosphate buffered saline solution (PBS) containing 50 gZml of the anti-CD3 antibody for a certain time at a certain temperature.
- the reaction temperature at the time of immobilization is usually preferably 4-1400 ° C., and the immobilization time is preferably 30 minutes 24 hours.
- the HIV-1 proliferation inhibitor used in the culture of the present invention contains the compound 115 or a salt thereof, and particularly preferably contains the compound 2 or a salt thereof.
- the HIV-1 proliferation inhibitor may contain these compounds alone or in combination.
- the concentration of the compound in the medium of the present invention is not particularly limited as long as appropriate peripheral blood mononuclear cell culture and proliferation can be obtained, but it is usually 10 nMol / 1-l mMol / U. Is 100 nMol / 1-500 ⁇ Mol / U, particularly preferably 1 ⁇ Mol / 1-100 ⁇ MolZl.
- the culture of the present invention can be performed using the above-described medium according to a general cell culture method.
- it can be performed in a CO incubator that maintains a humid environment.
- the number of days for the culture is not particularly limited, but it is generally preferable to carry out for 2 to 20 days, particularly 3 to 7 days, since it is premised that information of a growth stimulant such as an anti-CD3 antibody is transmitted to cells. During this culture period, it is preferable to observe the state of the cells under a microscope and appropriately add or replace the culture medium while appropriately counting the number of cells. When the required amount of peripheral blood mononuclear cells is obtained by the above culture, these are collected by a conventional method such as centrifugation, and part of the culture is continued if necessary.
- peripheral blood mononuclear cells obtained by the culture method of the present invention or the isolated CD4-positive T cells are administered to an HIV-1 infected patient from which the peripheral blood mononuclear cells have been collected, and the immunity of the patient is increased.
- the dose of the T cells as an immunotherapeutic agent is once Preferably, the number of cells per cell is 10 6 -10 12 .
- the dosage form may be a liquid such as an injection or a drip, particularly an injection prepared by dispersing the T cells in a physiological saline solution containing 0.01-5% of human serum albumin. Propellants or drops are preferred.
- intravenous infusion intravenous infusion into veins, arteries, and local areas, particularly intravenous infusion is preferable.
- the volume of the liquid to be administered is preferably 50 to 500 ml depending on the administration method, the place of administration, and the like. It is preferable that this liquid volume contains 10 6 to 10 12 T cells.
- the administration frequency is preferably once / day once / month / month, and the number of administrations is preferably at least once, preferably 5 or more.
- the following experiment was performed as a model system for stimulation and expansion culture of PBMC that also collected AIDS patient power.
- RPMI-1640 medium in which 1 ⁇ 10 6 Zml of fresh PBMC collected from an HIV seronegative healthy person, was suspended, was spread on a 12 ml plate (3 ml Zell) coated with immobilized anti-CD3 antibody, and moistened. The cells were stimulated and cultured at 37 ° C in a 5% CO environment.
- the RPMI medium used for this culture was
- RPMI-1640 medium (Sigma, Inc.) containing 10% fetal bovine serum (FBS), 50 U / ml human recombinant IL-2 (Shionogi Pharmaceutical Co., Ltd.), 100 U / mU benicillin and 100 ⁇ g ZuZml streptomycin. Sigma, St. Louis, Mo., USA: RPMI-1640 medium).
- the PBMC was exposed to a virus suspension having a multiplicity of infection (MOI) of 0.001.
- MOI multiplicity of infection
- the virus used was obtained from HIV-1 NL4-3 (1) and HIV-1 JR-CSF (2) virus stocks prepared using 293T cells transfected with the HIV-1 molecular clone plasmid by the calcium phosphate method. It is a thing.
- the 50% tissue culture infection dose of the virus was determined by an endpoint assay using a PBMC culture activated with a fixed anti-CD3 antibody.
- the cells After performing the virus infection treatment, the cells were absorbed at 37 ° C. for 3 hours, and the cells were serum-free.
- the cells were further treated twice every three days by the above procedure. The number of surviving cells was determined by a dye exclusion method using Eosin Y dye. In order to examine HIV-1 infection, the concentration of HIV-1 ⁇ 24 antigen in the culture supernatant was measured using a commercially available HIV-lp24 ELISA kit (Zepto Metrix). And the remaining cells were cultured under the same conditions (initial cell concentration: 2.5 ⁇ 10 5 cellsZml).
- FIG. 1 is a graph showing the effect of T-1113 on the growth of HIV-1 infected and uninfected T cells stimulated with IL2 and anti-CD3 antibodies.
- Fig. 2 is a distribution chart showing the ratio of CD4 and CD8-positive T cells in HIV-1 infected and uninfected T cells stimulated with IL2 and the effect of T-1113.
- (1) is a control
- (2) is a case where T-1113 is added to a medium containing normal T cells
- (3) is a case where cells infected with NL4-3 HIV-1 are cultured
- (4) was obtained by culturing cells infected with JR-CSF HIV-1
- (5) was cultured by adding T-1113 (10 awake) to a medium containing cells infected with NL4-3 HIV-1
- (6) show data obtained when T-1113 (10 um) was added to a medium containing cells infected with JR-CSF HIV-1 and cultured.
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JP2013512694A (ja) * | 2009-12-08 | 2013-04-18 | ウィルソン ウォルフ マニュファクチャリング コーポレイション | 養子細胞療法のための細胞を培養する方法 |
US9567565B2 (en) | 2009-12-08 | 2017-02-14 | Juan F. Vera | Methods of cell culture for adoptive cell therapy |
JP2022028677A (ja) * | 2016-07-08 | 2022-02-16 | アメリカン ジーン テクノロジーズ インターナショナル インコーポレイテッド | Hiv予備免疫化および免疫療法 |
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WO1989005657A1 (en) * | 1987-12-17 | 1989-06-29 | Browning's Clinical Pathology Services Limited | Lymphokine activation of cells for adoptive immunotherapy, e.g. of hiv infection |
JP2002520323A (ja) * | 1998-07-08 | 2002-07-09 | アノーメド インコーポレイテッド | 抗ウイルス性大環状化合物 |
JP2002543126A (ja) * | 1999-05-03 | 2002-12-17 | スミスクライン・ビーチャム・コーポレイション | Cxcr−4受容体アンタゴニスト−トロンボポエチン模倣物 |
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WO1989005657A1 (en) * | 1987-12-17 | 1989-06-29 | Browning's Clinical Pathology Services Limited | Lymphokine activation of cells for adoptive immunotherapy, e.g. of hiv infection |
JP2002520323A (ja) * | 1998-07-08 | 2002-07-09 | アノーメド インコーポレイテッド | 抗ウイルス性大環状化合物 |
JP2002543126A (ja) * | 1999-05-03 | 2002-12-17 | スミスクライン・ビーチャム・コーポレイション | Cxcr−4受容体アンタゴニスト−トロンボポエチン模倣物 |
JP2004043324A (ja) * | 2002-07-09 | 2004-02-12 | Kureha Chem Ind Co Ltd | 芳香族アミン化合物及びその用途 |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013512694A (ja) * | 2009-12-08 | 2013-04-18 | ウィルソン ウォルフ マニュファクチャリング コーポレイション | 養子細胞療法のための細胞を培養する方法 |
US9567565B2 (en) | 2009-12-08 | 2017-02-14 | Juan F. Vera | Methods of cell culture for adoptive cell therapy |
US10533156B2 (en) | 2009-12-08 | 2020-01-14 | Baylor College Of Medicine | Methods of cell culture for adoptive cell therapy |
US11268066B2 (en) | 2009-12-08 | 2022-03-08 | Wilson Wolf Manufacturing | Methods of cell culture for adoptive cell therapy |
US11999969B2 (en) | 2009-12-08 | 2024-06-04 | Wilson Wolf Manufacturing | Methods of cell culture for adoptive cell therapy |
JP2022028677A (ja) * | 2016-07-08 | 2022-02-16 | アメリカン ジーン テクノロジーズ インターナショナル インコーポレイテッド | Hiv予備免疫化および免疫療法 |
US11911458B2 (en) | 2016-07-08 | 2024-02-27 | American Gene Technologies International Inc. | HIV pre-immunization and immunotherapy |
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