WO2023176896A1 - 糸状菌感染症の治療薬及び糸状菌感染症の治療方法 - Google Patents

糸状菌感染症の治療薬及び糸状菌感染症の治療方法 Download PDF

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WO2023176896A1
WO2023176896A1 PCT/JP2023/010134 JP2023010134W WO2023176896A1 WO 2023176896 A1 WO2023176896 A1 WO 2023176896A1 JP 2023010134 W JP2023010134 W JP 2023010134W WO 2023176896 A1 WO2023176896 A1 WO 2023176896A1
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cells
human
fungal infections
filamentous fungal
γδt cells
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French (fr)
Japanese (ja)
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貴弘 ▲高▼園
哲 古賀
義正 田中
寛 迎
公一 泉川
奈々 中田
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Nagasaki University NUC
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    • 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
    • A61K35/14—Blood; Artificial blood
    • A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
    • 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
    • A61P31/10—Antimycotics

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  • the present invention relates to a therapeutic agent for filamentous fungal infections and a method for treating filamentous fungal infections.
  • Filamentous fungal infections such as aspergillosis and mucormycosis, are diseases with a poor prognosis that are often seen in patients with weakened immune systems, and the standard therapy is the administration of low-molecular antifungal drugs, but cases with a poor prognosis There are many. Furthermore, in recent years, the number of filamentous fungi that are resistant to low-molecular-weight antifungal drugs has been on the rise. In addition, since the proteins that serve as drug discovery targets for filamentous fungi are structurally similar to proteins derived from human cells, it is extremely difficult to develop low-molecular-weight drugs that specifically act against filamentous fungi, resulting in nephrotoxicity. Side effects such as these are also notable. In fact, only one first-in-class drug has been marketed in the past 30 years. Therefore, it is essential to develop new drug modalities different from small molecules.
  • Non-Patent Document 1 describes as follows. NK cells whose proliferation is induced using IL-2 or the like exhibit toxicity to tumor cells and cells infected with pathogenic microorganisms. Therefore, it is possible to develop therapeutic methods for fungal infections by utilizing the immune effector action or killing action of IL-2-induced NK cells. Specifically, it is possible to treat filamentous fungal infections by injecting IL-2-induced NK cells as adoptive immunotherapy into patients who have become susceptible to infection due to immunosuppressants during hematopoietic stem cell transplantation. There is. However, this literature does not explain how IL-2-induced NK cells control invasive fungal infections caused by fungi such as Aspergillus in patients receiving hematopoietic stem cell infusion therapy.
  • NK cells activate innate immune system cells derived from hematopoietic stem cells and their own innate immune system cells, increasing fungal phagocytosis. It is thought that it may enhance sterilization and bactericidal ability, but no scientific evidence has been shown for this. In addition, it is thought that NK cells activate B cells, which are cells of the adaptive immune system, and enhance their antibody production ability, increasing antibody-dependent cytotoxicity and cell phagocytosis, but there is no scientific evidence for this. Nor.
  • NK cells enhance the activation of Th1 type CD4-positive helper T cells, which are cells of the adaptive immune system, and enhance the ability to produce cytokines such as interferon- ⁇ (IFN- ⁇ ) and IL-2. It is thought that this may enhance the antifungal activity of the entire immune system, but there is no scientific evidence for this.
  • NK cells enhance the activation of CD8-positive killer T cells, which are cells of the adaptive immune system, and enhance their ability to produce cytokines such as IFN- ⁇ and tumor necrosis factor- ⁇ (TNF- ⁇ ). , it is also possible that it induces antifungal effects, but no scientific evidence has been shown for this. As described above, there are many unknown points regarding the treatment of filamentous fungal infections using IL-2-induced NK cells.
  • Non-Patent Document 2 describes as follows. The mechanism of immune action mediated by IL-2-induced NK cells against malignant tumors and viruses has been clarified, but IL-2 and filamentous fungi, especially Aspergillus fungi, which are the main cause of invasive aspergillosis. There is little knowledge regarding the -2-induced interaction with NK cells. Therefore, we investigated how NK cells exhibit antifungal effects. First, we investigated the in vitro interaction between human NK cells and Aspergillus fumigatus, and found that only germinated bacterial cells showed high immunogenicity and were able to induce Th1-like responses, including IFN- ⁇ , TNF- ⁇ , etc. It has been shown that this enhances the production of cytokines.
  • NK cells when NK cells were primed with human recombinant IL-2 and brought into direct contact with the pathogen, NK cells showed toxicity against A. fumigatus.
  • the most interesting finding is that NK cells are A. When exhibiting a bactericidal effect on S. fumigutus cells, they did not degranulate and release the cytotoxic proteins perforin, granzyme, and granulysin, but through an alternative mechanism using another soluble factor. However, the mechanism is not completely clear.
  • IFN- ⁇ released by NK cells directly damages A. fumigatus, suggesting that human NK cells and IFN- ⁇ may serve as a new therapeutic tool against fungal infections. .
  • IFN- ⁇ acts on the IFN- ⁇ receptor on human cells and exhibits effector action, it is unlikely that such a receptor exists in filamentous fungi. There are many unknowns regarding the details, such as whether it directly acts on filamentous fungi.
  • Non-Patent Document 3 describes as follows. Natural killer (NK) cells exhibit antifungal activity against A. fumigatus and, as a result, can enhance the host's defense function. However, little is known regarding the mechanism of interaction between NK cells and A. fumigatus. In this paper, human NK cells and A. fumigatus hyphae are brought into contact and gene expression and protein concentration of specific molecules are evaluated. The results revealed that when NK cells were exposed to A. fumigatus, the transcription and translation of inflammatory protein molecules within the NK cells was increased. However, the post-translational release of inflammatory proteins from NK cells was suppressed by some mechanism, and these molecules accumulated within NK cells and did not act outside the cells. On the other hand, A.
  • A. fumigatus acted on NK cells and decreased the mRNA level of perforin, but on the contrary, increased its intracellular and extracellular protein concentrations.
  • A. fumigatus also increased gene expression of stress-related molecules such as the heat shock protein HSP90 in human NK cells.
  • NK cells are cells that account for approximately 5% to 30% of mononuclear cells present in human peripheral blood, and are characterized by CD56 (+) and CD3 (-).
  • the name NK derives from the fact that it exhibits toxicity to tumor cells and virus-infected cells both in vivo and in vitro without prior stimulation.
  • NK cells In addition to acting as pure innate immune system cells, NK cells have also been reported to have properties similar to adaptive immune system cells, such as immunological memory, and have been shown to act as host immune cells against various pathogens ( Mainly responsible for antiviral action). Based on previous knowledge, it is predicted that when NK cells are used as a cell preparation for antifungal therapy, the effect will be low unless the effector/target ratio is large.
  • NK cells 1 ⁇ 10 9 to 1 ⁇ 10 10 or more NK cells are required for one treatment.
  • the conventional proliferation method using IL-2 as an activator it is difficult to prepare 1 ⁇ 10 9 to 1 ⁇ 10 10 or more NK cells.
  • methods for proliferating NK cells using genetically modified K562 cells and the like as feeder cells have been devised, a method for preparing NK cells that is compatible with Good Gene, Cellular, and Tissue-based Products Manufacturing Practice (GCTP) has not been established. Therefore, at present, it is extremely difficult to efficiently prepare NK cells as a cell preparation for antifungal therapy.
  • GCTP Good Gene, Cellular, and Tissue-based Products Manufacturing Practice
  • An object of the present invention is to provide a therapeutic agent for filamentous fungal infections and a method for treating filamentous fungal infections, which have no side effects and are less susceptible to drug resistance.
  • the present invention includes the following aspects.
  • the therapeutic agent for filamentous fungal infections according to [2], wherein the patient with decreased immunity is a patient with cellular immunodeficiency.
  • the drug for treating filamentous fungal infections according to [3], wherein the cellular immunodeficiency patient is an adult T-cell leukemia/lymphoma patient.
  • [6] Use of human ⁇ T cells for producing a therapeutic agent for filamentous fungal infections. [7] The use according to [6], wherein the human ⁇ T cells are cultured human ⁇ T cells. [8] Human ⁇ T cells for use in the treatment of fungal infections. [9] Cultured human ⁇ T cells for use in the treatment of fungal infections. [10] A method for treating a filamentous fungal infection, comprising administering a therapeutically effective amount of human ⁇ T cells to a patient in need of treatment.
  • the present invention it is possible to provide a therapeutic drug for filamentous fungal infections and a method for treating filamentous fungal infections, which have no side effects and are less susceptible to drug resistance.
  • FIG. 1 is a graph showing the purity and number of ⁇ T cells in the peripheral blood of a healthy person before culture and after 10 days of culture.
  • FIG. 2 is a graph showing the results of co-culture of Af293 and ⁇ T cells.
  • the filamentous fungal infection is a human filamentous fungal infection.
  • the fungal infections to be treated by the present invention are particularly deep-seated fungal infections, such as aspergillosis and mucormycosis.
  • Aspergillosis is an opportunistic infection caused by inhaling the spores of Aspergillus, a filamentous fungus that is ubiquitous in the environment. The spores germinate, grow, become hyphae, enter blood vessels, and become invasive. The disease causes hemorrhagic necrosis and infarction. They may present with symptoms of asthma, pneumonia, sinusitis, or rapidly progressive systemic disease. Diagnosis is mainly made clinically, but image tests, histopathological tests, and specimen staining and culture may be helpful. Treatment is with voriconazole, amphotericin B (or its lipid formulation), caspofungin, micafungin, or itraconazole. Fungal balls may require surgical removal.
  • Major risk factors for aspergillosis include long-term neutropenia (typically >7 days), long-term high-dose steroid therapy, and organ transplantation (particularly bone marrow transplantation with graft-versus-host disease [GVHD]). , and genetic disorders related to neutrophil function (eg, chronic granulomatous disease). Aspergillus fungi tend to infect open spaces such as lung cavities, sinuses, and ear canals (e.g., ear canal mycosis) caused by previous lung disease (eg, bronchiectasis, tumors, tuberculosis).
  • Mucormycosis refers to infectious diseases caused by various fungal species belonging to the order Mucorales, such as the genera Rhizopus, Rhizomucor, and Mucor. Symptoms most frequently result from aggressive necrotic lesions of the nose and palate, resulting in pain, fever, orbital cellulitis, proptosis, and purulent nasal discharge. This may be followed by central nervous system symptoms. Pulmonary symptoms are severe and include a productive cough, high fever, and difficulty breathing. Disseminated infection may occur in severely immunocompromised patients. Diagnosis is mainly made clinically, but it is necessary to strongly suspect this condition, and it is confirmed by histopathological examination and culture. Treatment consists of intravenous amphotericin B and surgery to remove necrotic tissue. Despite aggressive treatment, mortality is high. Mucormycosis is most common in immunocompromised individuals, patients with poorly controlled diabetes (particularly those with ketoacidosis), and patients receiving the iron chelator deferoxamine.
  • One embodiment of the present invention is a therapeutic agent for filamentous fungal infections containing human ⁇ T cells as the main active ingredient.
  • Human ⁇ T cells which are the active ingredients of the therapeutic agent of this embodiment, are ⁇ T cells isolated from human peripheral blood or cultured cells thereof. Human ⁇ T cells may be autologous or allogeneic. In other words, as human ⁇ T cells, both ⁇ T cells and cultured cells thereof isolated from a subject to whom the therapeutic drug is administered, as well as ⁇ T cells and cultured cells thereof isolated from a donor other than the subject to whom the therapeutic drug is administered, may be used. I can do it.
  • Human ⁇ T cells have the following characteristics. ⁇ Accounts for 1-5% of T cells in peripheral blood. -Characterized by CD4 (-), CD8 (-) (some ⁇ T cells express CD8 ⁇ chain dimer and therefore become weakly positive for CD8), and CD3 (+). - Expresses the T cell receptor (TCR), which is composed of ⁇ and ⁇ chains. -Unlike human ⁇ T cells, they are not restricted by major histocompatibility complex (MHC). - As described below, ex vivo expansion culture is possible using human peripheral blood (proliferation/activation by recognition of phosphoantigen). ⁇ The results of a phase II study in the field of human solid tumors confirmed that there are no major safety concerns.
  • MHC major histocompatibility complex
  • human ⁇ T cells expressing a V ⁇ 9V ⁇ 2-positive T cell receptor (there are two nomenclatures for V ⁇ , so V ⁇ 9 is also written as V ⁇ 2) are preferred.
  • the culture method is not particularly limited, but the nitrogen-containing bisphosphonic acid prodrug tetrakis-pivaloyloxymethyl 2-(thiazole-2-
  • a method of producing highly enriched human ⁇ T cells using ylamino)ethylidene-1,1-bisphosphonate (PTA) and IL-2 is preferred.
  • PTA ylaminoethylidene-1,1-bisphosphonate
  • IL-18 it is also possible to enhance the proliferation of ⁇ T cells by adding IL-18 or mutant IL-18 to the expansion culture system.
  • a specific cell proliferation method for example, Tanaka et al. Vol., No. 3, p.587-599), Okuno et al.
  • peripheral blood ⁇ T cells can be efficiently proliferated to about 500 to 10,000 times the number of cells with a purity of 90% to 99% or more in 8 to 11 days of culture.
  • one or more of pyrophosphate monoester, phosphoric acid monoester, nitrogen-containing bisphosphonic acid, nitrogen-containing bisphosphonic acid prodrug, alkyl amine, or alkenyl amine is selected instead of PTA, and IL-2 or A combination of one or more of IL-15, IL-18, or their mutants having equivalent effects may be added and cultured.
  • IL-2 variants are disclosed in US 2014/0046026 A1
  • IL-18 variants are disclosed in EP 0 692 536 A2, EP 0 712 931 A2, EP 0 767 178 A1, and WO 1997/002441 A1, etc.
  • it is disclosed in WO 2022/172944 A1 (PCT/JP2022/005051), but is not limited thereto.
  • the subject to whom the therapeutic agent of this embodiment is administered is not particularly limited as long as it is a patient who has developed a filamentous fungal infection, but patients with weakened immunity are preferred.
  • the patient with decreased immunity is preferably a patient with cellular immunodeficiency.
  • the cell-mediated immunodeficiency patient is preferably an adult T-cell leukemia/lymphoma patient.
  • the method for administering the therapeutic agent of this embodiment is not particularly limited, but it is preferable to intravenously infuse a cell suspension containing human ⁇ T cells. Although the detailed mechanism of intravenously infused ⁇ T cells is unknown, they tend to accumulate in the lungs and are particularly effective against pulmonary mycosis such as pulmonary aspergillosis.
  • Mechanism of action The mechanism of action of the therapeutic agent of this embodiment is not particularly limited, but it is thought to be due to direct damaging activity due to contact between ⁇ T cells and hyphae of filamentous fungi.
  • Human ⁇ T cells to produce a therapeutic drug for fungal infections
  • Another embodiment of the invention is the use of human ⁇ T cells to produce a medicament for the treatment of fungal infections.
  • Human ⁇ T cells are as described above.
  • Human ⁇ T cells for use in the treatment of fungal infections Yet another embodiment of the invention is human ⁇ T cells for use in treating fungal infections.
  • Human ⁇ T cells are as described above.
  • Yet another embodiment of the invention is a method of treating a fungal infection comprising administering a therapeutically effective amount of human ⁇ T cells to a patient in need of treatment.
  • Human ⁇ T cells are as described above.
  • the therapeutically effective amount of human ⁇ T cells is not particularly limited, but is preferably 10 3 to 10 12 cells per infusion.
  • V ⁇ 9V ⁇ 2-positive ⁇ T cells Peripheral blood V ⁇ 9V ⁇ 2-positive ⁇ T cells from healthy individuals or patients infected with filamentous fungi were induced to proliferate/activated ex vivo in the presence of PTA and IL-2 by the method described above (Tanaka et al. (2017)).
  • Aspergillus fumigatus Af293 wild strain provided by the filamentous fungus American Type Culture Collection (ATCC).
  • FIG. 1 shows the purity and number of ⁇ T cells in the peripheral blood of healthy subjects before culture and 10 days after culture.
  • Figure 2 shows the results of co-culture of Af293 and ⁇ T cells. A bactericidal effect on Af293 of V ⁇ 9V ⁇ 2 T cells was observed.
  • the advantage of the present invention is that cell medicine is developed as a new pharmaceutical modality for treating filamentous fungal infections. Specifically, human peripheral blood mononuclear cells are purified, stimulated with the nitrogen-containing bisphosphonic acid prodrug PTA, and IL-2 is added to expand and culture V ⁇ 9V ⁇ 2-positive ⁇ T cells for use. This disease occurs in patients with immunodeficiency, and the concept of activating the immune system is very logical and is thought to have a therapeutic effect that cannot be expected with antifungal drugs. Not affected.

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006500373A (ja) * 2002-08-26 2006-01-05 ランバクシー ラボラトリーズ リミテッド 抗真菌剤としてのアゾール誘導体
WO2007020936A1 (ja) * 2005-08-17 2007-02-22 Daiichi Sankyo Company, Limited 抗真菌作用二環性複素環化合物
JP2010540522A (ja) * 2007-09-28 2010-12-24 メルク シャープ アンド ドーム コープ． 抗真菌剤
JP2016501013A (ja) * 2012-11-08 2016-01-18 アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル γδＴ細胞の無ＩＬ−２増殖を誘導するための方法
JP2018533373A (ja) * 2015-10-30 2018-11-15 キャンサー・リサーチ・テクノロジー・リミテッド 非造血組織常在性γδ Ｔ細胞の増幅および該細胞の使用

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* Cited by examiner, † Cited by third party
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JP2006500373A (ja) * 2002-08-26 2006-01-05 ランバクシー ラボラトリーズ リミテッド 抗真菌剤としてのアゾール誘導体
WO2007020936A1 (ja) * 2005-08-17 2007-02-22 Daiichi Sankyo Company, Limited 抗真菌作用二環性複素環化合物
JP2010540522A (ja) * 2007-09-28 2010-12-24 メルク シャープ アンド ドーム コープ． 抗真菌剤
JP2016501013A (ja) * 2012-11-08 2016-01-18 アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル γδＴ細胞の無ＩＬ−２増殖を誘導するための方法
JP2018533373A (ja) * 2015-10-30 2018-11-15 キャンサー・リサーチ・テクノロジー・リミテッド 非造血組織常在性γδ Ｔ細胞の増幅および該細胞の使用

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