WO2024100549A1 - Composés destinés à être utilisés dans la reprogrammation de macrophages - Google Patents

Composés destinés à être utilisés dans la reprogrammation de macrophages Download PDF

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Publication number
WO2024100549A1
WO2024100549A1 PCT/IB2023/061229 IB2023061229W WO2024100549A1 WO 2024100549 A1 WO2024100549 A1 WO 2024100549A1 IB 2023061229 W IB2023061229 W IB 2023061229W WO 2024100549 A1 WO2024100549 A1 WO 2024100549A1
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tumor
compound
tam
macrophages
medical use
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PCT/IB2023/061229
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English (en)
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Renzo Dal Monte
Andrea Carpi
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Oncogreen Therapeutics S.A.
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Publication of WO2024100549A1 publication Critical patent/WO2024100549A1/fr

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    • 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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1796—Receptors; Cell surface antigens; Cell surface determinants for hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/82—Vectors or expression systems specially adapted for eukaryotic hosts for plant cells, e.g. plant artificial chromosomes (PACs)
    • C12N15/8241—Phenotypically and genetically modified plants via recombinant DNA technology
    • C12N15/8242—Phenotypically and genetically modified plants via recombinant DNA technology with non-agronomic quality (output) traits, e.g. for industrial processing; Value added, non-agronomic traits
    • C12N15/8257—Phenotypically and genetically modified plants via recombinant DNA technology with non-agronomic quality (output) traits, e.g. for industrial processing; Value added, non-agronomic traits for the production of primary gene products, e.g. pharmaceutical products, interferon
    • 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
    • C12N5/0645—Macrophages, e.g. Kuepfer cells in the liver; Monocytes
    • 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
    • C12N2506/00—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells
    • C12N2506/11—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells from blood or immune system cells
    • C12N2506/115—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells from blood or immune system cells from monocytes, from macrophages

Definitions

  • the present invention finds use in the field of medicine, and in particular in preventing and treating tumors and tumor metastases .
  • Inflammatory cells represent a key component in the regulation of the biological processes which characterize, in the body, the niche in which the tumor develops.
  • the inflammatory microenvironment is now recognized as a fundamental factor in the process of carcinogenesis.
  • the formation of an inflammatory microenvironment in tumors can be the result of aberrations involving onco-genes or oncosuppressor genes.
  • anomalies are responsible not only for the f ormation/progression of the primary tumor, but also for the metastasis process, which is the leading cause of death from disease in patients with cancer.
  • macrophages represent an important component of the immune system.
  • TAMs Tumor-associated macrophages
  • TAMs can polarize into two different classes referred to as Ml and M2.
  • the M1/M2 polarization model has been characterized and studied in many solid tumor study models.
  • the TAM-M1 population is characterized by the expression of high levels of IL12 and IL23, the ability to produce significant amounts of ROS/RNS (reactive oxygen and nitrogen species) , and inflammatory cytokines.
  • ROS/RNS reactive oxygen and nitrogen species
  • TAM-Mls also have an active role in causing the immune system response through This (hl-type T lymphocytes) , which act in an anti-cancer sense.
  • TAM-M2 the macrophages can polarize towards the class referred to as TAM-M2.
  • TAM-M2s acquire different and alternative features, phenotype and activation state with respect to TAM-Mls.
  • the main differences comprise, for example, the variation in the expression of different receptors, the different ability to present the antigen, the variation in metabolic functions such as arginine metabolism and the different production of cytokines.
  • TAM-M2s show pro-tumor, pro-angiogenic activity and strong immuno-inhibitory phenotype.
  • This class of macrophages is characterized by the ability to produce high amounts of IL10 (immuno-inhibitory) and specifically express surface receptors such as CD163 and in particular CD206, which is the main receptor capable of binding carbohydrate molecules characterized by particular structures rich in mannose.
  • TAM-M2s represent a new therapeutic target in treating solid tumors.
  • mAbs monoclonal antibodies
  • Trabectedin interferes with DNA transcription and repair in tumor cells but also causes the TAMs' death through still-unknown molecular mechanisms.
  • drugs capable of blocking the recruitment of monocytes into tumors and their polarization into macrophages are also being tested.
  • Non-specific macrophage population suppression can be risky, also considering the fact that these cells are key effectors in the mechanisms of antibody-mediated cellular cytotoxicity/phagocytosis, which represents a fundamental aspect in the mechanisms of the immune response in healthy subjects.
  • the stimulation of the immune system would thus be obtained, in particular modulating innate immunity and stimulating the cytotoxic cellular component, converting pro-tumor TAM-2s to antitumor TAM-ls without the risk of significantly altering the other components of the immune system, indeed causing them to recognize and fight tumor cells.
  • the inventors of the present patent application have surprisingly found compounds capable of specifically binding TAM- M2 macrophages and reprogramming the phenotype, metabolism, and ability thereof to produce cytokines, restoring the typical features of TAM-Mls ( anti-tumor ) ; such an ability surprisingly results in reducing the growth of the primary tumor and blocking the metastasis process of solid tumors.
  • a compound is described having the amino acid structure of SEQ. ID NO: 1 or 2 for the medical use.
  • such a medical use is described for preventing and/or treating and/or delaying the development of a tumor .
  • TAM-M2 tumor-associated macrophages M2
  • TAM-M1 tumor-associated macrophages Ml
  • TAM-M2 tumor-associated macrophages M2
  • a second object is represented by the process for preparing the compounds of the present invention.
  • a compound having the amino acid structure of SEQ. ID NO: 1 or 2 is also described as such.
  • Figure 1 is a graph reporting the results of the MTT viability assay of the macrophages treated with MANI and MAN2.
  • Figure 2 shows the results of the differentiation assay of M2 macrophages in the Ml line for increased expression of the iNos marker .
  • Figure 3 shows the results of the differentiation assay of M2 macrophages in the Ml line for increased expression of the HLA-DR marker .
  • Figure 4 shows the results of the differentiation assay of M2 macrophages in the Ml line for decreased expression of the CD206 marker .
  • Figure 5 shows the results of the assay on IL10 production in macrophages previously differentiated into M2.
  • Figure 6 shows the results of the assay on IL12 production in macrophages previously differentiated into M2.
  • Figure 7 shows the results of the assay on the anti-metastatic effect of MANI in a mouse model of melanoma.
  • Figure 8 shows the results of the assay on the anti-metastatic effect of MANI in a triple negative mouse model of breast tumor. Detailed description of the invention
  • a compound is described having the amino acid structure of SEQ. ID NO: 1 or 2 for the medical use.
  • such a compound is represented by the compound comprising the structure of the sequence of SEQ. ID No. 2:
  • such a compound has a structure corresponding to the amino acid sequence of SEQ. ID No. 2.
  • such a compound is represented by the compound comprising the structure of the sequence of SEQ. ID No. 1 :
  • such a compound has a structure corresponding to the amino acid sequence of SEQ. ID No. 1.
  • a compound according to the invention is obtained from appropriately transformed plant or mammal cells.
  • the process for preparing the compound of the invention represents a second object of the present patent application.
  • the preparation of the compound of the invention can be obtained for production in both plant cells and mammal cells, as further detailed in the following Experimental Section.
  • plant cells can be appropriately transformed by means of the sequence of SEQ. ID No. 3:
  • Nicotiana benthamiana cells can be transformed.
  • the process can comprise the use of Agrobacterium tumefaciens .
  • the cultivation of the transformed plant cells is carried out in suspension.
  • mammal cells can be appropriately transformed by means of the sequence of SEQ. ID No. 4 :
  • CHO cells Choinese hamster ovary cells ⁇ can for example be transformed.
  • the process can for example comprise the use of Lipof ectamine technology .
  • the compound obtainable or the compound obtained by means of the transformation process in plant cells or in mammal cells as described herein represent a third object of the present invention .
  • said tumor form is represented, for example, by: breast tumor, ovarian tumor, melanoma, neuroblastoma (also in pediatric age) , pancreatic tumor, colon tumor, uterine tumor, liver tumor, prostate tumor, kidney tumor, lung tumor.
  • breast tumor includes triple negative breast tumor, i.e., the cells of which do not have estrogen (ER) or progesterone (PR) receptors and without an increase in HER2 expression .
  • ER estrogen
  • PR progesterone
  • preventing the tumor comprises preventing the development of a not yet-diagnosed neoplasm.
  • treating the tumor comprises reducing the tumor mass, even until the disappearance thereof .
  • delaying tumor development comprises slowing tumor development.
  • said medical use is for preventing and/or treating and/or delaying the development of tumor metastases.
  • preventing the tumor comprises preventing the development of a not yet-diagnosed neoplasm.
  • treating a metastasis comprises reducing the metastatic tumor mass, even until the disappearance thereof.
  • delaying the development of a metastasis comprises slowing the development of the metastatic tumor mass.
  • the compounds of the invention thus have anti-metastatic activity.
  • TAM-M2 tumor-associated macrophages M2
  • TAM-M1 tumor-associated macrophages Ml
  • TAM-M2 tumor-associated macrophages M2
  • tumor niche refers to the microenvironment where the tumor forms and grows. It is characterized by the presence of particular cytokines produced by tumor cells and healthy cells which are caused to modify the phenotype thereof, producing a series of essential factors for tumor development. These factors affect the neo-vascularization process, depress the immune system and make the surrounding tissues easily infiltratable by tumor cells .
  • cytokines produced by tumor cells and healthy cells which are caused to modify the phenotype thereof, producing a series of essential factors for tumor development. These factors affect the neo-vascularization process, depress the immune system and make the surrounding tissues easily infiltratable by tumor cells .
  • a compound having the amino acid structure of SEQ. ID No. 1 or 2 is also described as such.
  • such a method comprises administering to a subject in need thereof a pharmaceutically effective amount of a compound of the present invention.
  • a macrophage viability assay was conducted by means of MTT assay.
  • Nicotian benthamiana plant cells were grown in MS (Murashige and Skoog) culture medium and binary plasmids derived from pGreen II were used for the transformation thereof.
  • the transformation occurred using the classic process which includes using Agrobacterium tumefaciens to make the exogenous DNA enter the plant cell.
  • the plant cells were transformed by inserting the sequence of SEQ. ID No. 3.
  • the mammal cells are cultured in suspension in ProCHO-4 culture medium (added with 4% L-Gln, 2% HT Supplement and 0.5% antibiotics) and pcDNA 3.1 plasmids were used for the transformation thereof .
  • ProCHO-4 culture medium added with 4% L-Gln, 2% HT Supplement and 0.5% antibiotics
  • pcDNA 3.1 plasmids were used for the transformation thereof .
  • the chemical approach based on Lipof ectamine was used following the manufacturer' s instructions .
  • the mammal cells were transformed by inserting the sequence of SEQ. ID No. 4 .
  • the transformed plant cells are harvested and separated from the culture medium, then lysed in the buffer: 50 mM Na2HPCO4, 150 mM NaCl, 20 mM citric acid, 40 mM ascorbic acid, 1 mM ethylenediaminetetraacetic acid (EDTA) , 1 mM phenylmethanesulfonyl fluoride (PMSF) , 2 mM potassium metabisulfite, 0.1% (w/v) benzoic acid, 0.05% (v/v) Tween-20, pH 6.5 added with 1% (w/v) XAD-4 and 1% (w/v) polyvinylpolypyrrolidone (PVPP) for 1 h at 4°C under continuous stirring. The extract is then centrifuged at 18000 g for 20 min at 4 °C to recover the supernatant.
  • the extract is then centrifuged at 18000 g for 20 min at 4 °C to recover the supernatant.
  • Ammonium sulfate is added to the extract until a saturation concentration of 70% is obtained. After centrifugation at 18000 g for 20 min at 4°C, the precipitate is resuspended in 400 ml of buffer (20 mN Na2HPO4, 200 mM NaCl, 10 mM imidazole, 0.1% (w/v) benzoic acid, pH 8.0) suitable for promoting the interaction between the His-tag-derivatized protein and the IMAC resin.
  • buffer (20 mN Na2HPO4, 200 mM NaCl, 10 mM imidazole, 0.1% (w/v) benzoic acid, pH 8.0
  • the MANI protein is then purified from the centrifuged and filtered solution (0.22 pm) through subsequent chromatographies.
  • the product eluted from the first affinity chromatography (IMAC binding HisTag) on HiTrap Chelating HP column (following the manufacturer's instructions, GE Healthcare) is desalted using Sephadex G-25 Medium resin (GE Healthcare) equilibrated and eluted with a buffer of 50 mM sodium acetate, 150 mM NaCl, 60 pM Tween-
  • the eluate from the desalting column is loaded on a column with SP Sepharose HP resin (GE Healthcare) equilibrated with a buffer of 50 mM sodium acetate, 150 mM NaCl, 60 pM Tween-
  • the transformed cells are harvested by centrifugation, the culture medium is removed and then lysed at 4°C for 1 h in a buffer of 50 mM Na2HPO4, 1 M NaCl, 1 mM ethylenediaminetetraacetic acid (EDTA) , 1 mM phenylmethanesulfonyl fluoride (PMSF) , 0.05% (v/v) Tween-20, pH 7.2 at 4 °C under continuous stirring. The extract is then centrifuged at 18000 g for 20 min at 4°C to recover the supernatant.
  • EDTA ethylenediaminetetraacetic acid
  • PMSF phenylmethanesulfonyl fluoride
  • the sample is loaded onto HiTrap Chelating HP column (GE Healthcare) previously loaded with 0.1 M NiC12 solution and equilibrated with a buffer of 50 mM potassium phosphate, pH 7.2, 1 M NaCl, 20 mW imidazole.
  • the protein was eluted from the chromatographic column by means of step gradient of elution buffer (50 mM potassium phosphate, pH 7.2, imidazole) .
  • the purified MAN2 protein is loaded onto Sephadex G-25 column equilibrated in PBS buffer, pH 7.4, so as to remove the imidazole.
  • the monocytes needed for the trial were isolated from human peripheral blood.
  • the fresh plasma (buffy coat) was centrifuged at 3000 x g for 15 minutes at room temperature.
  • the monocytes were prepared with the batch gradient centrifugation technique.
  • 35 ml of buffy coat are deposited on a 15 ml cushion of Ficoll solution (1.077 g /ml) and then centrifuged at 400 x g for 30 min at room temperature.
  • the white ring of mononuclear cells is harvested and transferred to a new tube to which an excess of PBS-EDTA (1 mM) is added and centrifuged at 300 x g for 10 min at room temperature.
  • the cell pellet is then resuspended in RPMI-1640 medium without phenol red, added with 10% complement-inactivated FCS.
  • the second density gradient consists of a Percoll cushion (23.13 ml of Percoll solution (density 1.131 g /ml) mixed with 1.87 ml of 10X PBS diluted 1:2 in RPMI-1640) . 25 ml of this solution are placed in a 50 ml tube, PBMCs (Peripheral Blood Mononuclear Cells) are deposited above such a solution and centrifuged at 550 x g for 30 min at room temperature. The white ring between the two phases of different density consists of monocytes, and is taken and resuspended in PBS-EDTA (1 mW) . Centrifuge at 400 x g for 10 min, the cell pellet is then resuspended in RPMI-1640 medium with phenol red added with 10% complement-inactivated FCS.
  • PBMCs Peripheral Blood Mononuclear Cells
  • the isolated monocytes are seeded into culture dishes using medium consisting of RPMI-1640, 2% human serum, and 1% penicillin/streptomycin .
  • the plates are kept in incubator (37°C with 5% CO) for 4-5 days before causing differentiation.
  • Cell differentiation is caused by treating the cells for 10 days with 2 ng/ml GM-CSF (Ml differentiation) or 2 ng/ml M-CSF (M2 differentiation) .
  • MANI and MAN2 ligands were assessed through the analysis of the IL12 and IL10 production, which are produced in different amounts from the type Ml or M2 macrophages.
  • the interleukins were measured in the culture media of the treated cells using specific ELISA kits and following the manufacturer's instructions.
  • CD68 co-marking
  • Flow cytof luorimetry was used for this purpose.
  • the cells (macrophages differentiated and treated with the different molecules) were harvested from the culture flasks and kept on ice in flow cytometry tubes throughout the experimentation period.
  • the cells were incubated with several primary antibodies, each specific for a given receptor among those listed above. The detection is made possible by virtue of the use of secondary antibodies conjugated with different fluorophores so that multiplex analysis can be performed on the cytof luorimeter .
  • figure 2 shows a significant increase in the expression of the iNOs marker, characteristic for Mis.
  • HLA-DR marker characteristic for Mis.
  • CD206 marker characteristic for M2s.
  • Figure 5 shows the blockage of the production of the IL10 marker characteristic for M2s following inflammatory stimulus (LPS) typical of M2 macrophages in macrophages previously differentiated into M2s and treated with MANI or MAN2.
  • LPS inflammatory stimulus
  • Figure 6 shows the results of incubation of the M2-dif f erentiated macrophages with MANI or MAN2 ligands, leading to increased expression of the IL12 marker, typical of Mis.
  • B16F10 cells (murine melanoma model) were used, inoculated into the animals in the suprascapular sub-skin.
  • the cells generate a very aggressive primary tumor, which quickly generates many metastases which lead to the death of the host.
  • the metastases originate very early in the peritoneum and lungs.
  • the metastases can be easily detected, as the melanin-rich cells are easily identified.
  • the experiment includes the comparison between two experimental groups: one control group (not treated with MANI) and the group treated with MANI.
  • the ligand was administered to the animals intraperitoneally at a dosage of 2 mg/kg twice a week for the entire duration of the experiment (3 weeks) .
  • the administration of MANI was initiated immediately after inoculation of the tumor cells into the animal.
  • the presence of metastases was assessed through necroscopic examination.
  • E0771 cells (mouse model of triple negative breast tumor) were used, inoculated in animals into the fat of the mammary gland (orthotopic model) .
  • the MANI ligand was administered to the animals intraperitoneally at a dosage of 2 mg/kg twice weekly for the entire duration of the experiment (8 weeks) , until the time of animal sacrifice.
  • the administration of MANI was initiated immediately after inoculation of the tumor cells into the animal.
  • the animals are monitored daily to verify the growth of the primary tumor. When the tumor reaches the appropriate size (10x10 mm) , it is surgically removed. The animals are then reared for 45 days after removal of the primary tumor and then euthanized.
  • the search for metastases at the pulmonary level is carried out through necropsy analysis.

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Abstract

La présente invention concerne des composés destinés à être utilisés pour traiter et/ou prévenir des tumeurs grâce à la capacité de reprogrammer des macrophages associés à une tumeur M2 (TAM-M2) en macrophages associés à une tumeur M1 (TAM-M1).
PCT/IB2023/061229 2022-11-08 2023-11-07 Composés destinés à être utilisés dans la reprogrammation de macrophages WO2024100549A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012016576A1 (fr) * 2010-08-04 2012-02-09 Glycotope Gmbh Hormone folliculostimulante humaine recombinante améliorée
WO2018069831A2 (fr) * 2016-10-11 2018-04-19 Abresearch S.R.L. Ligands du récepteur de l'hormone fsh dans le diagnostic et le traitement de tumeurs

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012016576A1 (fr) * 2010-08-04 2012-02-09 Glycotope Gmbh Hormone folliculostimulante humaine recombinante améliorée
WO2018069831A2 (fr) * 2016-10-11 2018-04-19 Abresearch S.R.L. Ligands du récepteur de l'hormone fsh dans le diagnostic et le traitement de tumeurs

Non-Patent Citations (4)

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Title
ANNA-MARIA GEORGOUDAKI ET AL: "Reprogramming Tumor-Associated Macrophages by Antibody Targeting Inhibits Cancer Progression and Metastasis", CELL REPORTS, vol. 15, no. 9, 1 May 2016 (2016-05-01), US, pages 2000 - 2011, XP055530643, ISSN: 2211-1247, DOI: 10.1016/j.celrep.2016.04.084 *
LIU KEVIN X. ET AL: ""Re-educating" Tumor Associated Macrophages as a Novel Immunotherapy Strategy for Neuroblastoma", FRONTIERS IN IMMUNOLOGY, vol. 11, 1 January 2020 (2020-01-01), pages 1947, XP093042308, DOI: 10.3389/fimmu.2020.01947 *
MALYSHEV IGOR ET AL: "Current Concept and Update of the Macrophage Plasticity Concept: Intracellular Mechanisms of Reprogramming and M3 Macrophage "Switch" Phenotype", BIOMED RESEARCH INTERNATIONAL, vol. 2015, 1 January 2015 (2015-01-01), pages 1 - 22, XP093120350, ISSN: 2314-6133, Retrieved from the Internet <URL:https://downloads.hindawi.com/journals/bmri/2015/341308.pdf?_gl=1*1spbah9*_ga*MTI1NjEyMTc4OC4xNzA1NDI0Njc1*_ga_NF5QFMJT5V*MTcwNTQyNDY3NS4xLjAuMTcwNTQyNDY3NS42MC4wLjA.&_ga=2.139654067.1693895953.1705424675-1256121788.1705424675> DOI: 10.1155/2015/341308 *
SHNYRA ALEXANDER ET AL: "Reprogramming of Lipopolysaccharide-Primed Macrophages Is Controlled by a Counterbalanced Production of IL-10 and IL-12", THE JOURNAL OF IMMUNOLOGY, vol. 160, no. 8, 15 April 1998 (1998-04-15), US, pages 3729 - 3736, XP093120352, ISSN: 0022-1767, Retrieved from the Internet <URL:https://watermark.silverchair.com/im089803729o.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAABewwggXoBgkqhkiG9w0BBwagggXZMIIF1QIBADCCBc4GCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMh8Nyr6Ch8Zok5NxcAgEQgIIFn1W4MN9Cm4bRvParvhxvlb7YkJcUa9aVuqPPX0SHA5ZKGsbHhgV2AxS-SO6D2HYaDi5XMlrsbEoUEa38Rqiu5ZT> DOI: 10.4049/jimmunol.160.8.3729 *

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