EP3641805A1 - Vaccin pour traiter une tumeur maligne - Google Patents

Vaccin pour traiter une tumeur maligne

Info

Publication number
EP3641805A1
EP3641805A1 EP18732746.5A EP18732746A EP3641805A1 EP 3641805 A1 EP3641805 A1 EP 3641805A1 EP 18732746 A EP18732746 A EP 18732746A EP 3641805 A1 EP3641805 A1 EP 3641805A1
Authority
EP
European Patent Office
Prior art keywords
cells
expression pattern
hla
malignancy
cell membranes
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP18732746.5A
Other languages
German (de)
English (en)
Inventor
Wolfgang Würfel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Intellexon GmbH
Original Assignee
Intellexon GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Intellexon GmbH filed Critical Intellexon GmbH
Publication of EP3641805A1 publication Critical patent/EP3641805A1/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C40B40/14—Libraries containing macromolecular compounds and not covered by groups C40B40/06 - C40B40/12
    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56966—Animal cells
    • G01N33/56977—HLA or MHC typing
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/70—Mechanisms involved in disease identification
    • G01N2800/7023—(Hyper)proliferation
    • G01N2800/7028—Cancer

Definitions

  • the present invention relates to the field of providing vaccines for the treatment of malignancies.
  • neoantigens can be used as a target for immunological therapy.
  • proteins or protein-like molecules that have an antigenic character (and thus cause a reaction of immunocompetent cells) and are based on new mutations in the genome in the context of malignant degeneration.
  • neoantigens which cause a reaction of T cells, in particular CD8 + T cells in the case of MHC-I (Major Histocompatibility Complex, class I) presented neoantigens or of CD4 + T cells in the case of the MHC II (Major Histocompatibility Complex, class II) presented neoantigens.
  • RNA analysis for example by RNA analysis, mass spectrometry or
  • an individual vaccine can be developed and, e.g. by in vitro culture with dendritic cells.
  • this detection can be cumbersome and error-prone, in particular due to the uncertainty of which new mutations are expressed to neoantigens, and due to neoantigens produced by
  • Oncogenic or Splicingtinen be evoked without the new mutations are based.
  • the high individuality and partially chaotic cell organization leads even within a tumor disease to differences, such as neoantigens of metastases compared to neoantigens of the primary tumor.
  • Histocompatibility antigen human leucocyte antigen, HLA
  • HLA human leucocyte antigen
  • HLA groups which serves the cellular dialogue in humans.
  • HLA designates genes coding in the literature or proteins expressed by them.
  • HLA groups used below is intended to denote the surface proteins expressed by the genes on the cell surface.
  • HLA groups can be divided into the following four classes:
  • HLA groups A. B and C (MHC I), which identify essentially all adult and somatic cells;
  • HLA groups D (DRB, DQB, etc., MHC-II), which play an important role in antigen presentation for immunocompetent cells;
  • HLA groups E, F and G the embryonic cells, in particular at the
  • Malignant cells can express typical "embryonic" HLA groups (i.e., HLA-E, HLA-F and / or HLA-G) on their surface.
  • "Embryonic" HLA groups can help to prevent malignant cells from attacking the nonspecific and / or specific immune system of their own organism.
  • these typical HLA groups By expressing these typical HLA groups on the surface of the cells, they are able to activate corresponding receptors on immunocompetent cells.
  • they are receptors that, upon activation, inhibit the function of these immunocompetent cells, such as the killer immunoglobulin-like receptors (KIR) on the natural killer cells, or the leukocyte immunoglobulin-like receptors (LILR) on the lymphocytes.
  • KIR killer immunoglobulin-like receptors
  • LILR leukocyte immunoglobulin-like receptors
  • the antigens HLA-E, -F and -G on the embryonic (mainly on placental or trophoblastic) cells prevent the immune system of the Mother attacks the cells. In this way, embryos can escape the immune response.
  • This escape mechanism provides the backbone of the immunological
  • a method of the invention for providing a medicament for treating a malignancy comprises determining the individual communication structure between the malignancy and the immune system, and providing an individual vaccine to elicit a specific immune response.
  • HLA histocompatibility antigens
  • Chemotherapeutics or hormone antagonists may further influence expression patterns. A determination of the individual expression patterns addresses these differences.
  • malignant cell also includes metastatic cells of the primary malignancy.
  • the method according to the invention is carried out individually for preferably several, particularly preferably for all metastases, in order to check for any individual differences in the metastases, in particular their individual expression patterns
  • Tissue sample masked or removed existing expression pattern, which is able to exert an inhibitory effect on immunocompetent cells.
  • those cells are lysed on which a part of the expression pattern has been masked or removed to obtain cell membranes or fragments of cell membranes for injection. At the same time, this lysis leads to the danger that the destroyed malignant cell can no longer pose a danger.
  • the histocompatibility antigens whose expression pattern is determined comprise "embryonic" HLA groups, in particular HLA-E, -F and / or -G.
  • the part of the expression pattern to be masked or removed comprises the embryonic HLA groups, in particular HLA-E, -F and / or -G.
  • the at least part of the embryonic HLA groups in particular HLA-E, -F and / or -G.
  • Antibody masking may inhibit binding of the masked histocompatibility antigens
  • antibodies Prevent receptors of immunocompetent cells and thus break the escape mechanism of the malignancy.
  • examples of such antibodies include anti-HLA-E antibodies, anti-HLA-F antibodies or anti-HLA-G antibodies.
  • combined or multi-valent antibodies can be used.
  • Removal by genetic manipulation may remove the binding of the removed
  • the cells are lysed by means of mechanical or biochemical cell disruption methods, in particular by means of hypotonic lysis.
  • the cells may be burst in hypo-osmolar solution.
  • the cell assemblage of the tissue sample is dissolved to obtain a single cell suspension.
  • the dissolution can, for example, be carried out enzymatically by means of trypsin or collagenase.
  • the invention provides cell membranes which have been provided by a method according to the invention.
  • the cell membrane may have an expression pattern of
  • the provided cell membranes are suitable to be used as a vaccine in the treatment of a malignancy for specific activation of the immune system.
  • the invention provides the use of cell membranes of the invention as a medicament in the treatment of a malignancy.
  • the cell membranes can serve as a vaccine for specific activation of the immune system in vivo.
  • the cell membranes may be used to "train" immunocompetent cells, particularly T cells, in vitro, i. to activate at the neoantigens, and to re-inject the trained or activated immunocompetent cells into the organism.
  • immunocompetent cells may be withdrawn, exposed to cell membranes or the vaccine, and backfused after activation.
  • Embodiments according to claim 10 include the use of the cell membranes as a vaccine containing the cell membranes or at least fragments of the
  • the use may include injection of the vaccine.
  • the use of cell membranes may be local or systemic. Local use includes, for example, injection into or near the malignancy.
  • systemic use includes administration in one of the following ways: oral, nasal, sublingual, rectal, subcutaneous, intravenous, percutaneous, etc.
  • the use may also include the use of checkpoint inhibitors and / or classical adjuvants to enhance the
  • FIG. 1 is a flowchart of a method for providing a medicament according to an embodiment
  • FIG. 2 shows a schematic view of a performance of a method according to an embodiment
  • Fig. 3 is a schematic view of an implementation of a method according to another embodiment
  • FIG. 4 is a schematic view of a cell membrane according to an embodiment
  • FIG. 5 shows a use of a cell membrane according to an embodiment
  • FIG. 1 shows a flowchart of a method 10 for providing a
  • the method 10 is preceded by a removal 12 of a tissue sample.
  • the method 10 includes determining 14 a
  • Expression pattern masking or removing 16 an immune-inhibiting part of the expression pattern, and providing 18 cell membranes by lysing the cells.
  • Upon removal 12 of a tissue sample at least cells of the malignant to be treated are removed.
  • the removal of the tissue sample may include, for example, surgery or biopsy.
  • a malignoma-specific expression pattern a malignoma-specific
  • Expression pattern of histocompatibility antigens determined on the tissue sample.
  • the determination of the expression pattern can be based on the known
  • Histocompatibility antigens may be restricted, i. comprise only a limited number of predetermined proteins.
  • the determination of the expression pattern can be made more specific and less expensive than the determination of neoantigens whose number and composition are not limited or known a priori.
  • the determination of the expression pattern comprises the quantitative
  • expression patterns or expression levels can be determined by known methods such as R A sequencing, DNA microarrays, quantitative PCR (PCR), expression profiling, SAGE (serial analysis of gene expression, etc.).
  • Expression pattern is masked or removed at least such a part of the existing on the cells of the tissue sample expression pattern, which is able to exert an inhibitory effect on immunocompetent cells.
  • Expression pattern also other parts of the expression pattern can be masked or removed. If they are not masked or removed, histocompatibility antigens with an inhibitory effect can be found, for example, on KIR receptors (Killer immunoglobulin-like receptors), NKG2 receptors, LIL-R receptors
  • ⁇ immunoglobulin-like receptors from immunocompetent cells.
  • histocompatibility antigens with an inhibitory effect are, in particular, the embryonic groups HLA-E, HLA-F and HLA-G.
  • the inhibitory effect is mediated by receptor-ligand binding between the histocompatibility antigens (ligand) and receptors on the immunocompetent cells.
  • ligand histocompatibility antigens
  • receptors on the immunocompetent cells By masking or removing the inhibitory part of the expressed histocompatibility antigens is prevented or at least reduced its inhibitory effect on immunocompetent cells.
  • HLA-A to -C histocompatibility antigens
  • HLA-D histocompatibility antigens
  • MHC-I HLA groups -A, -B and -C
  • MHC-II HLA groups DQB, DRB etc.
  • Histocompatibility antigens should be removed or masked.
  • the steps of the tissue sampling 12 and the expression pattern determination 14 serve to determine the individual communication structure between the malignant and the immune system. In particular, this may identify any escape mechanisms that the malignancy uses to target one
  • the steps of masking or removal 16 and lysis 18 serve to provide an individual vaccine for eliciting a specific immune response.
  • the delivery of the vaccine occurs in vitro, i. before injection of the cell membranes. Based on the previous determination of the individual
  • Neoantigens respond to the immune system - due to the masking without inhibitory effect of the inhibitory histocompatibility antigens - especially on these neoantigens and initiates an immune response.
  • Fig. 2 shows a schematic representation of a performance of a method. Clockwise, beginning at the top left corner, a sequence of schematic views at different times of carrying out the method are shown.
  • An individual 20 has a malignancy 22.
  • it is a primary tumor, although other embodiments of metastases can be performed.
  • the malignant tumor 22 may be a malignant melanoma.
  • Malignant melanomas typically have a large number of neoantigens.
  • a tissue sample 24 was taken comprising cells 26 of the malignant 22.
  • an expression pattern 28 of histocompatibility antigens is determined. This determination indicates that a cell 26 of the tissue sample 24 expresses the expression pattern 28 with, for example, three different groups of histocompatibility antigens in the illustrated case.
  • the three histocompatibility antigens in this case are proteins of the groups HLA-E, HLA-A and HLA-F.
  • the proteins of the HLA-E and HLA-F groups are capable of exerting an inhibitory effect on immunocompetent cells.
  • HLA-F is able to bind to LIL receptors of the lymphocytes and to attenuate the activity of the lymphocytes.
  • HLA-E is also able to bind to NKG2 receptors, for example, and to attenuate the activity of natural killer cells.
  • the groups HLA-E and HLA-F thus form a part 29 of the expression pattern 28, which can weaken or prevent the immune response.
  • Inhibitory action is intended here to denote the immunomodulatory effect which reduces or prevents the cytotoxic activity of immunocompetent cells.
  • This signaling pathway may be, for example, via the immunoreceptor tyrosine-based inhibitory motif (ITIM), i. cytoplasmic phosphorylation.
  • ITIM immunoreceptor tyrosine-based inhibitory motif
  • the proteins of the HLA-A group are essentially unable to
  • the malignant cells 26 on their surfaces also include typical neoantigens 33 that are based on new mutations in the course of malignant degeneration.
  • the neoantigens 33 are shown schematically here, although a determination of these neoantigens is not necessary.
  • the inhibiting part 29 is thus the histocompatibility antigens of the groups HLA-E and HLA-F, but not HLA-A.
  • HLA groups of classes I or II such as HLA-A, for example
  • HLA-A HLA-A
  • MHC-I MHC-I
  • HLA groups -A, -B and -C MHC-I
  • HLA-E groups can be masked by anti-HLA-E antibodies.
  • HLA-F groups can be masked by anti-HLA-F antibody.
  • bivalent antibodies (anti-HLA-E / F) may be used. After masking by the antibodies 36, the HLA-E and HLA-F groups can no longer be linked to the corresponding LIL or NKG2 receptors of bind immunocompetent cells and thus exert no inhibitory effect on the immunocompetent cells.
  • the antibodies Prevents or reduces histocompatibility antigens on receptors present on immunocompetent cells.
  • the antibodies Preferably, have a high affinity for the histocompatibility antigens, in particular comparable to, greater than or substantially greater than the affinity of the immune receptors.
  • the affinity is high enough to prevent diffusion and / or competitive displacement of the antibodies.
  • the cells 26 After masking the immuno-inhibitory portion 29 of the expression pattern 28, the cells 26 (at which a portion of the expression pattern has been masked) are lysed to obtain cell membranes 32 for injection.
  • the cell membranes 32 In addition to the expression pattern 28 of histocompatibility antigens, the cell membranes 32 also have the malignant-typical neoantigens 33, as well as the antibodies 36 which mask the inhibitory part 29 of the expression pattern 28. Injection (not shown) of the cell membranes 32 may be made to the individual 20 from which the tissue sample 24 has been taken with malignant cells 26.
  • FIG. 3 shows a schematic view of an implementation of a further method.
  • a sequence of schematic views at various times in the implementation of the method are shown in the clockwise direction, starting at the top left.
  • tissue sample 24 containing cells 26 of a malignant 22 is taken from an individual 20 and the expression pattern 28 of FIG.
  • Histocompatibility antigens determined at least one cell 26.
  • the cells 26 have malignoma-typical neoantigens 33.
  • the part 29 of the expression pattern capable of exerting an inhibitory effect on immunocompetent cells is removed by means of gene manipulation methods.
  • HLA-A was not removed in the case shown here, since some neoantigens require the MHC-I. Thus, in the illustrated embodiment, not all cells are all
  • Histocompatibility antigens removed to ensure specific activation of the immune system by the presented neoantigens.
  • this removal can be achieved by means of a Crispr / CAS method in which the DNA segments coding for the histocompatibility antigens of groups HLA-E and HLA-F are excised from the genome of cells 26 and the cells thus modified are cultured ,
  • This provides cells 26 which are substantially identical to the sampled malignant cells without, however, expressing the immuno-inhibiting portion 29 of the histocompatibility antigens (shown schematically by dashed outlines of part 29).
  • the cells in any case express the malignoma-typical neoantigens 33.
  • Those cells 26 whose inhibitory part 29 has been removed are lysed to obtain cell membranes for injection.
  • the cell membranes 29 exert no or at least a reduced inhibitory effect on the immune system due to the removal of the part 29. However, they still include neoantigens 33 to be able to trigger an immune response after injection.
  • FIG. 4 shows a schematic view of a vaccine 34 from a cell membrane 32 provided by a method according to the invention, starting from a malignancy (not shown).
  • a malignancy not shown
  • it may be a cell membrane provided according to the embodiment of FIG. 2.
  • the cell membrane 32 has an expression pattern 28 of histocompatibility antigens. A portion 29 of the expression pattern 28 capable of inhibiting Immune system response was masked by antibodies 36. In this way, the inhibitory effect of the part 29 of the expression pattern 28 on the immune system can be avoided or at least reduced.
  • the cell membrane 32 further comprises neoantigens 33.
  • the neoantigens are proteins based on new mutations of the genome of malignant cells in the course of malignant degeneration. The neoantigens are characteristic of the malignancy and are capable of eliciting an immune system response (if the immune response is not inhibited).
  • the illustrated cell membrane 32 is capable of being used as a vaccine 34 in the treatment of a malignancy for specific activation of the immune system.
  • FIG. 5 shows a schematic representation of a use of a cell membrane 32 according to FIG. 4 as a vaccine 34 for the treatment of a malignancy.
  • the cell membrane 32 was provided from a tissue sample with cells of the malignant tumor to be treated.
  • the cell membrane 32 is injected with bound antibodies 36 which mask an inhibitory part 29 of the expression pattern of histocompatibility antigens and with neoantigens 33 in the organism affected by the malignancy.
  • the immunocompetent cells of the organism recognize some of the
  • Cell membranes neoantigens 33 are expressed and presented, which the organism does not know, it comes to the development of a corresponding immune response, e.g. Formation of antibodies and / or activation of T cells. Since no immuno-inhibitory histocompatibility antigens are "visible", this immune response is not blocked.
  • the cell membranes 32 provided according to the invention have, in particular, two interactions with the immune system 30.
  • the neoantigens 33 which are typical of the malignancy, evoke an adaptive immune response against these malignoma-typical neoantigens.
  • the part 29 of the histocompatibility antigens can not inhibit the immune response due to its masking by antibodies 36 or at least reduced. In the unmasked state, the part 29 would be able to inhibit a response of the immune system 30, in particular to the neo-antigens 33.
  • the immune system 30 of the organism triggers an immune reaction.
  • the immune system 30 comprises, in the schematic representation, immunocompetent cells 30a, 30b, namely, antigen presenting cells (APC) 30a and CD8 + T cells 30b.
  • APC antigen presenting cells
  • the immune system 30 can recognize any cells 38 with the underlying neoantigens 33. These include in particular the cells of the malignancy, from the tissue sample of the vaccine in the form of
  • Neuterutationen or neoantigens for example by means of complex sequencing.
  • the immune response can be carried out, for example, by means of CD8 + T cells 30b with T cell receptors.
  • the cytotoxic T cells 30b may be replaced by antigen presenting cells 30a containing the neoantigen 33 or a partial peptide of the
  • Neoantigens 33 present have been activated.
  • the activated T-cells 30b recognize a malignant cell 38 from the neo-antigen 33, they initiate apoptosis (represented by dashed outlines of the malignant cell 38) of the malignant cells.

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Abstract

L'invention concerne des procédés permettant de préparer un médicament pour traiter une tumeur maligne ainsi que des membranes cellulaires ainsi obtenues et leur utilisation. Selon l'invention, la structure de communication individuelle entre la tumeur maligne et le système immunitaire est établie sur la base d'un échantillon de tissu contenant des cellules de la tumeur maligne par détermination d'un profil d'expression génique d'antigènes d'histocompatibilité (antigène des leucocytes humains, HLA), lequel est spécifique de la tumeur maligne, au niveau dudit échantillon de tissu, au moins une partie du profil d'expression génique présente sur les cellules de l'échantillon de tissu et en mesure d'exercer une action inhibitrice sur des cellules immunocompétentes est masquée ou éliminée et un vaccin est individuel, destiné à induire une réaction immunitaire spécifique par lyse des cellules au niveau desquelles une partie du profil d'expression a été masquée ou éliminée, est préparé.
EP18732746.5A 2017-06-20 2018-06-19 Vaccin pour traiter une tumeur maligne Pending EP3641805A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102017005815.6A DE102017005815A1 (de) 2017-06-20 2017-06-20 Vakzine zur Behandlung eines Malignoms
PCT/EP2018/066211 WO2018234287A1 (fr) 2017-06-20 2018-06-19 Vaccin pour traiter une tumeur maligne

Publications (1)

Publication Number Publication Date
EP3641805A1 true EP3641805A1 (fr) 2020-04-29

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ID=62684808

Family Applications (1)

Application Number Title Priority Date Filing Date
EP18732746.5A Pending EP3641805A1 (fr) 2017-06-20 2018-06-19 Vaccin pour traiter une tumeur maligne

Country Status (6)

Country Link
US (1) US20200129602A1 (fr)
EP (1) EP3641805A1 (fr)
JP (2) JP2020525440A (fr)
CA (1) CA3066339A1 (fr)
DE (1) DE102017005815A1 (fr)
WO (1) WO2018234287A1 (fr)

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4470007B2 (ja) * 1998-02-20 2010-06-02 コミサリア・ア・レネルジー・アトミーク Ｈｌａ−ｇを発現する、抗癌治療に感受性な腫瘍を選択する方法およびその使用
DE102011111631A1 (de) * 2011-08-25 2013-02-28 Wolfgang Würfel Verfahren zur Herstellung von Medikamenten zur Tumorbekämpfung
US10656156B2 (en) * 2012-07-05 2020-05-19 Mepur Ravindranath Diagnostic and therapeutic potential of HLA-E monospecific monoclonal IgG antibodies directed against tumor cell surface and soluble HLA-E
US20160045594A1 (en) * 2013-03-27 2016-02-18 Fred Hutchinson Cancer Research Center Directed immune stimulation
EP3659625A1 (fr) * 2014-10-23 2020-06-03 Innate Pharma Traitement de cancers à l'aide d'agents anti-nkg2a
US10758567B2 (en) * 2015-09-16 2020-09-01 Immune Ventures LLC In vivo priming of natural killer cells

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US20200129602A1 (en) 2020-04-30
DE102017005815A1 (de) 2018-12-20
WO2018234287A1 (fr) 2018-12-27
JP2023113854A (ja) 2023-08-16
CA3066339A1 (fr) 2018-12-27
JP2020525440A (ja) 2020-08-27

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