WO2005054497A1 - Methode de criblage d'un medicament therapeutique immunologique contre le cancer - Google Patents

Methode de criblage d'un medicament therapeutique immunologique contre le cancer Download PDF

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Publication number
WO2005054497A1
WO2005054497A1 PCT/JP2004/017852 JP2004017852W WO2005054497A1 WO 2005054497 A1 WO2005054497 A1 WO 2005054497A1 JP 2004017852 W JP2004017852 W JP 2004017852W WO 2005054497 A1 WO2005054497 A1 WO 2005054497A1
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Prior art keywords
nkt
cancer
cells
perforin
value
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PCT/JP2004/017852
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English (en)
Japanese (ja)
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Akikuni Yagita
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Orient Cancer Therapy Co., Ltd.
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Publication of WO2005054497A1 publication Critical patent/WO2005054497A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • 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
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5011—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing antineoplastic activity

Definitions

  • the present invention relates to a method for screening a novel cancer immunotherapy agent. More specifically, the present invention relates to a method for screening a cancer immunotherapeutic agent containing a component derived from a marine yeast having a ⁇ 1,3 glucan structure. Further, the present invention relates to a novel cancer immunotherapeutic agent containing a component derived from a marine yeast having a j8 1,3 glucan structure screened as described above.
  • cancer malignant neoplasms
  • direct action on cancer cells has been conventionally regarded as important.
  • immunostimulants have been found to be useful in treating cancer, the compounds obtained as immunostimulants all have weak anticancer effects, and are treated with immunotherapy alone or in combination with chemotherapy. According to this, a sufficient therapeutic effect on cancer has been achieved.
  • IL-12 interleukin 12
  • NITC Novel Immunotherapy for cancer
  • IL-12 has TNFa ⁇ IFN ⁇ ⁇ IL-12 ⁇ CTL activation and the killer T cell activating and enhancing effects via the! / ⁇ ⁇ route.
  • IL-12 production is expected to have an anticancer effect by activating and enhancing killer cells.
  • the specific ⁇ cell antigen receptor that 8 11 (TCR) to discover the specific glycolipid antigens recognized, this antigen is alpha-galactosylceramide
  • TCR 8 11
  • Non-Patent Document 1 Yagida has found that NKR-P1 is also involved in the activation of ⁇ cells, and that this activation is more important in anticancer effects.
  • Patent Document 1 Japanese Patent Application Laid-Open No. 10-139670
  • Non-patent document 1 Special issue: Basics and clinical practice of NKT cells: Latest Medicine 55 Vol. 4 2000 818—823 ⁇ 1 ⁇
  • the present invention provides a method of screening for a more useful cancer immunotherapy agent, particularly a more effective cancer immunotherapy agent even in the case of severe progression of cancer (advanced cancer, terminal cancer). , 13 1,3 It is an object of the present invention to provide a method for screening a more effective cancer immunotherapeutic agent derived from a marine yeast having a glucan structure.
  • the present invention has been studied on yeast as a material, and has found a method for screening an unprecedentedly effective cancer immunotherapeutic agent as a component of marine yeast having a j8 1,3 glucan structure.
  • a method for screening for a cancer immunotherapeutic agent containing a component derived from a marine yeast having a ⁇ 1,3 glucan structure characterized by using the dynamics of perforin-producing cells as a marker to determine the efficacy of the immunotherapeutic agent .
  • cancer immunotherapeutic agent is a marine yeast-derived substance having an
  • the dynamics of perforin-producing cells are ⁇ ( ⁇ +) / ⁇ , CD8 + (P +), CD8 + (P +) / CD8 +, NKT (+ P), NKT (P +) / NKT, NKT (8 +) (P +), NKT (8 +) (P +) / NKT (8+), NKT (8-) (P +), and NKT (8-) (P +) / NKT (8-) 3.
  • NK (P +) / NK value is CD3 (-) CD161 (+) perforin (+) / CD3 (-) CD161 (+), and CD8 + (P +) value is CD8 (+) perforin (+).
  • CD8 + (P +) / CD8 + value force CD8 (+) perforin (+) / CD8 (+)
  • NKT (+ P) value is CD3 (+) CD161 (+) perforin (+)
  • NKT (P +) / NKT value Power CD3 (+) CD161 (+) perforin (+) / CD3 (+) CD161 (+), NKT (8 +) (P +) value is CD3 (+) CD161 (+) CD8 (+) perforin (+),
  • NKT 8 +) (P +) / NKT (8+) Value CD3 (+) CD161 (+) CD8 (+) Perforin
  • a novel cancer immunotherapeutic agent obtained by the method according to any one of items 1 to 4 above. It consists of. The invention's effect
  • a novel means for screening for a cancer immunotherapeutic agent has been provided, and an epoch-making cancer immunotherapy agent has been provided.
  • FIG. 1 shows clinical test data
  • FIG. 2 shows the change in TH1 site force input.
  • FIG. 3 shows changes in IL-10 and VEGF.
  • FIG. 4 shows changes in NK cells and CD8 cells.
  • FIG. 5 shows NKT cell changes.
  • FIG. 6 shows changes in NKT cells.
  • FIG. 7 is a diagram (C57BL / 10) of a tumor growth suppression experiment.
  • FIG. 8 is a diagram (BALB / c) of a tumor growth suppression experiment.
  • the raw material in the screening method of the present invention is a marine yeast, the main component of which has a j8 1,3 glucan structure.
  • yeast used for the study components derived from marine yeast, components derived from practical baker's yeast (using alpenrose), and the like were used.
  • the effectiveness as an immunotherapy can be determined using the effect on perforin-producing cells, that is, the dynamics of the cells as a marker.
  • screening for a stronger cancer immunotherapy agent is possible.
  • the novel cancer immunotherapeutics selected have been found to be potent cancer immunotherapeutics, especially in advanced and terminal cancers. Furthermore, they found that they are cancer immunotherapeutic agents which can be expected to exert the activity of perforin-producing cells by oral administration of a marine yeast component having a ⁇ 1,3 glucan structure.
  • the composition containing the cancer immunotherapeutic agent or the dietary supplement for oral ingestion selected according to the present invention includes lung cancer, lung adenoma, thymoma, thyroid cancer, bladder cancer, colon cancer, rectal cancer, and cecal cancer.
  • Effective for treatment but not limited to these cancers.
  • induction of IL-12 production by AHCC (Amino Inc.) Even if the agent is administered, it is suitably administered to those who have a low level of IL-12 (eg, 7.8 pgZml or less).
  • the cancer immunotherapeutic agent according to the present invention is used in a formulation capable of inducing or enhancing its activity and maintaining its activity, using as its index the immunological ability, particularly the result on perforin-producing cells. That is, based on the index, a dose capable of inducing or enhancing the activity and maintaining the activity and a period of administration are selected and used.
  • the selected cancer immunotherapy is preferably taken orally.
  • parenteral ingestion including intravenous or intramuscular administration
  • parenteral ingestion is also possible by reducing the dosage and preparing them to a quality that can be tolerated parenterally.
  • CT ⁇ sex The ability of CT ⁇ sex to be determined by the ability to produce CD8 (+) perforin
  • This CD8 (+) perforin level includes cytotoxic T cells (CTL) and immunosuppressive T cells (STC; Suppressor T cells).
  • CTL cytotoxic T cells
  • STC immunosuppressive T cells
  • the former damages cancer cells, and the latter results in the growth of cancer. Therefore, the absolute value cannot be evaluated.
  • the ⁇ force is 10 IU / ml or more or the IL-12 value is 7.8 pg / ml or more, it is judged as CTL, and if ⁇ and IL-12 are low, it is judged as STC. Therefore, CTL activity can be evaluated based on the ability to produce IFN ⁇ (IFN ⁇ value) or the ability to produce IL-12 (IL-12 value).
  • NKR-P1 [ ⁇ cell receptor CD161 (+)]
  • the number of NK cells can be measured using the CD3 (-) CD161 (+) surface marker. Its activity can be determined by its ability to produce CD3 (-) CD161 (+) perforin.
  • the latter NKT cells can be measured by CD3 (+) CD161 (+), and the number of the cells can be measured, and the activity of NKT cells can be measured by their perforin-producing ability.
  • NITC new immunotherapy
  • NITC new immunotherapy
  • NITC new immunotherapy
  • general immunotherapy it is possible to evaluate each effector cell with the following measurement items.
  • CTL activity can be evaluated by the ability to produce IFNy or IL-12
  • NK cell activation can be assessed by CD3 (-) CD161 (+) or CD3 (-) CD161 (+) perforin levels.
  • NKT cell activation can also be assessed by CD3 (+) CD161 (+) or CD3 (+) CD161 (+) perforin levels. In each case, the significance of the perforin value is particularly important.
  • the method for measuring cells and each marker is exemplified below.
  • the measurement of NKT cells having NKR-P1 can be performed by measuring cell surface antigens (CD3 and CD161) specifically present on the cell surface of NKT cells. Specifically, for lymphocytes in peripheral blood, cells that are positive for CD3 and positive for CD161 [CD3 (+) CD161 (+)] are assayed. That is, CD3 and CD161 which are cell surface antigens of NKT cells are measured by a two-color test using a flow cytometry using a monoclonal antibody.
  • that the NKT cells are activated means that the ratio of NKT cells [CD3 (+) CD161 (+)] in lymphocytes is 10% or more, more preferably 16% or more.
  • the ability to activate NKT cells means a function of increasing the proportion of NKT cells to 10% or more, more preferably 16% or more, or a function of further increasing the proportion of NKT cells before administration of a certain substance.
  • CD3 (-) CD161 (+) refers to assaying cells that are negative for CD3 and positive for CD161. This method is useful for measuring NK cells.
  • CD8 (+) refers to assaying for CD8-positive cells. This method is useful for measuring CTL activity.
  • lymphocytes in peripheral blood two of cell surface antigens, CD3, CD8, and CD161, and perforin are measured in the usual manner by a Three Color test using flow cytometry. Specifically, the cells are fixed by collecting a fixative solution into the collected blood, After adding, an anti-perforin antibody (manufactured by Pharmingen) is added and reacted, and furthermore, a pre-Cy5 labeled secondary antibody (manufactured by DAKO) is added and reacted, and the anti-CD3-PE (Coulter 6604627) antibody and anti-CD161-FITC (BD) antibody are added and reacted, and then measured by flow cytometry. Abbreviations in the figure are indicated as PER or P.
  • a mononuclear cell fraction is separated and prepared from blood.
  • Heparin-added peripheral blood is diluted 2-fold with Phosphate Buffered Saline (PBS), mixed, and then layered on FicoU-Conray solution (specific gravity 1.077), and 400 G for 20 minutes. After centrifugation, the mononuclear cell fraction is collected. After washing, prepare RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS), and adjust the cell number to 1 ⁇ 10 6 .
  • PBS Phosphate Buffered Saline
  • FBS fetal bovine serum
  • Phytohemagglutinin (manufactured by DIFCO) is added to the obtained cell suspension 200 1 to a concentration of gZml, and cultured in a 96-well microplate at 37 ° C for 24 hours in the presence of 5% CO. And in the cultured cell solution
  • the amount of induced IL-12 should be measured indirectly, as in humans, because when using mice as in the examples below, sufficient IL-12 is induced in the serum. It can be measured directly without using an enzyme-linked immunosorbent assay (ELISA). In this system using mice, the ability to induce IL-12 production can be assayed by continuously ingesting the IL-12 production inducer orally and subsequently increasing the amount of IL-12 in the blood.
  • ELISA enzyme-linked immunosorbent assay
  • the amount of IL-12 in blood cannot be measured directly due to the presence of the inhibitor in the blood.
  • the amount of IL-12 induced in a cancer patient can be measured separately from the blood of the cancer patient.
  • the cells After stimulating the peripheral blood mononuclear cells with the stimulant, the cells are centrifuged to remove the cells, and the culture is performed.
  • the number of cells used for culture is 0.5 ⁇ 10 6 / ml—1 ⁇ 10 7 Zml, preferably 1 ⁇ 10 6 Zml.
  • phytohemadaltune (PHA) which is a conventionally used mitogen, is added and cultured at a final concentration of 0.1 to 100 gZml, and preferably to 120 gZml.
  • the substance that stimulates cells is not limited to PHA, and any substance capable of stimulating cells to produce an immunophysiologically active substance can be used in order to achieve the object of the present invention.
  • MA Phorbol 12— Myristate— 13— Acetate
  • PMA + Ionomycin LPS (Lipo polysaccharide)
  • PWM Poke Weed Mitogen
  • a measurement kit based on enzyme immunoassay (ELISA) available from R & D SYSTEMS or MBL is used, which is a power that can use clinical and biochemical tests known per se.
  • the ability to induce IL-12 production refers to the function of enhancing the amount of IL-12 produced by peripheral blood mononuclear cells upon stimulation to 7.8 pgZml or more, or the amount of IL-12 production before administering a certain substance. It means the function to increase.
  • the active ingredient having a cancer immunotherapeutic agent obtained by the method of the present invention is a marine yeast-derived ingredient having a ⁇ 1,3 glucan structure.
  • a marine yeast-derived component having the ⁇ 1,3 glucan structure as an active ingredient shows sufficient IL-12 production-inducing ability even in the early stage of cancer, and is characteristically advanced advanced terminal cancer. Exerts the same or stronger ability to induce IL-12 production. More characteristically, it has strong and active ability against perforin-producing cells.
  • the dose of the cancer immunotherapeutic agent for oral ingestion containing the active ingredient capable of inducing IL-12 production obtained by the method of the present invention is 11 to 2000 mgZkg body weight per day, more preferably about 10 to 2000 mgZkg body weight. It is preferably taken orally in 10 days, 1 year, 1 day several times on Z days. Of course, parenteral ingestion is also possible by reducing the dose and preparing the compound so that it can be administered parenterally.
  • Oral preparations are prepared into tablets, powders, capsules, syrups and the like.
  • the preparation can of course be prepared by mixing necessary additives such as known excipients, disintegrants, binders, lubricants and the like, and using conventional means. If necessary, flavoring agents, coloring agents, flavors, stabilizers, bactericides, preservatives and the like can be added.
  • the response rate for each type of cancer indicates the proportion of CR, PR, LNC, SNC, and PD in all cases of each type of cancer (for example, PR 71.4% for colon cancer in 7 cases is 5 out of 7 cases show PR).
  • Isolates were identified for their morphological and physiological properties by the method of Van Der Walt and D. Yallow and performed according to The Yeasts (ed. By N.W. Kreger van Rij).
  • a DNA-DNA homology test with a reference strain of S. cerevisiae was performed to confirm that the strain was S. cerevisiae.
  • the cells were shake-cultured at 27 ° C for 24 hours in a 500-ml Sakaro flask containing 150 ml of YPD medium (10 g of yeast extract, 20 g of polypeptone, 20 g of Glucose, 1000 ml of distilled water, pH 5.0) and used as the inoculum. .
  • YPD medium 10 g of yeast extract, 20 g of polypeptone, 20 g of Glucose, 1000 ml of distilled water, pH 5.0
  • the cultured cells were centrifuged (8,000 rpm, 10 min) and separated into a supernatant and a precipitate.
  • the obtained cells were washed twice with 0.85% physiological saline, dried at 70 ° C for 24 hours, and ground in a mortar to obtain cell powder ⁇ (A): about 20 g, (B): about 22g ⁇ .
  • SP-2 (4.5 g / day) was orally administered daily to S.H. (39-year-old, male, colon (cecum) cancer) who had no effect on conventional immunotherapy.
  • the value of the tumor marker (CA19-9) was 406.0 (U / ml) about 1 month after administration, but 283.7 (U / ml) about 2.5 months later and 298.9 (U / ml) 3.5 months later. / ml), which is remarkably effective (Fig. 1)
  • Thl site force-in was examined ( Figure 2).
  • the TNFa, IL-12 and Thl / Th2 ratios showed no significant difference after the administration of SP-2, but tended to increase, although the strength was strong.
  • the ability to produce IFNy was significantly increased (p ⁇ 0.05), compared to an average of 27.1 ⁇ 6.01 (iU / ml) before administration and an average of 35.3 to 7.15 (IU / ml) after administration.
  • IL-10 Thicken2 site force-in
  • VEGF angiogenesis promoting substance
  • CD8 + perforin-producing cells CD8 + (P +)
  • CD8 (+) perforin (+) ZCD8 + CD8 (+) perforin (+) ZCD8 (+)
  • NKT cells Changes in NKT cells before and after administration of SP-2 were examined (FIG. 5).
  • a significant increase was also observed for the percentage of perforin-producing cells, NKT (P +) / NKT (CD3 (+) CD161 (+) perforin (+) ZCD3 (+) CD161 (+)). (P ⁇ 0.001).
  • CD8-positive (CD8 (+)) cells and CD8-negative (CD8 (-)) cells were examined before and after administration of SP-2.
  • NKT (8+) cells the total lymphocyte count
  • the percentage of CD3 + CD161 + CD8 + [CD3 (+) CD161 (+) CD8 (+)] cells (hereinafter referred to as NKT (8+) cells) was examined, the average before the administration was 3.65 ⁇ 0.39 (%), The mean was significantly increased to 4.63 ⁇ 0.56 (%), and the percentage of perforin-producing (P (+)) cells in NKT (8+) cells was 49.3 ⁇ 2.98 (%) before The mean significantly increased to 54.2 ⁇ 3.44 (%) (p ⁇ 0.01).
  • perforin-producing NKT (8+) cells showed a remarkable increase (p ⁇ 0.001), compared with 1.88 ⁇ 0.28 (%) before administration and 2.64 ⁇ 0.41 (%) after administration.
  • the immunological anti-tumor effect was examined with live marine yeast.
  • the dose was adjusted so that the content of ⁇ 1,3 glucan was the same in each group.
  • 3LL tumors were transplanted into B10 mice (C57BL / 10) or colon26 tumors were transplanted into BALB / c mice, and the tumor volumes were compared over time (FIGS. 7 and 8).
  • control to which gavage water was administered after tumor transplantation, had a tumor volume of 1099 532 mm 3 (day 16), whereas the control group with SP-2 yeast (300 mgZkg) selected in the present invention had a volume of 700

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Abstract

L'invention concerne une méthode de criblage d'un médicament thérapeutique immunologique plus efficace contre le cancer ainsi qu'une méthode de criblage d'un médicament thérapeutique immunologique plus efficace contre le cancer comprenant un composant d'origine marine issu de la levure présentant une structure β-1,3-glucane. D'une manière plus spécifique, l'invention concerne un médicament thérapeutique immunologique contre le cancer comprenant un composant d'origine marine issu de la levure présentant une structure β-1,3-glucane caractérisée en ce qu'elle consiste à utiliser la cinétique de cellules productrices de perforine en tant que marqueur afin d'estimer l'efficacité du médicament thérapeutique immunologique. Le composant d'origine marine issu de la levure obtenu au moyen de cette méthode de criblage peut être utilisé en tant que médicament thérapeutique immunologique efficace contre le cancer.
PCT/JP2004/017852 2003-12-02 2004-12-01 Methode de criblage d'un medicament therapeutique immunologique contre le cancer WO2005054497A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003030938A1 (fr) * 2001-10-09 2003-04-17 Orient Cancer Therary Co.,Ltd. Agents immunotherapeutiques contre le cancer
WO2003031969A1 (fr) * 2001-10-09 2003-04-17 Orient Cancer Therary Co., Ltd. Nouveau procede de determination d'une activite immune
WO2003039568A1 (fr) * 2001-11-06 2003-05-15 Orient Cancer Therary Co.,Ltd. Compositions anticancereuses

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003030938A1 (fr) * 2001-10-09 2003-04-17 Orient Cancer Therary Co.,Ltd. Agents immunotherapeutiques contre le cancer
WO2003031969A1 (fr) * 2001-10-09 2003-04-17 Orient Cancer Therary Co., Ltd. Nouveau procede de determination d'une activite immune
WO2003039568A1 (fr) * 2001-11-06 2003-05-15 Orient Cancer Therary Co.,Ltd. Compositions anticancereuses

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