WO2020166729A1 - Vaccin à base de cellules t - Google Patents

Vaccin à base de cellules t Download PDF

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Publication number
WO2020166729A1
WO2020166729A1 PCT/JP2020/006949 JP2020006949W WO2020166729A1 WO 2020166729 A1 WO2020166729 A1 WO 2020166729A1 JP 2020006949 W JP2020006949 W JP 2020006949W WO 2020166729 A1 WO2020166729 A1 WO 2020166729A1
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treatment
cells
antigen
pathogen
vaccine
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PCT/JP2020/006949
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English (en)
Japanese (ja)
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健二郎 松野
祐司 上田
祐介 北沢
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学校法人獨協学園獨協医科大学
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Priority to JP2020536906A priority Critical patent/JP6884450B2/ja
Publication of WO2020166729A1 publication Critical patent/WO2020166729A1/fr

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    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
    • 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
    • A61K39/02—Bacterial antigens
    • 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
    • A61K39/12—Viral antigens
    • 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
    • A61K39/12—Viral antigens
    • A61K39/145—Orthomyxoviridae, e.g. influenza virus
    • 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
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4648—Bacterial antigens
    • 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
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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

Definitions

  • the present invention relates to a T cell vaccine that induces neutralizing antibodies in lymphoid organs in multiple locations.
  • DST (donor specific blood transfusion/donor-specific blood transfusion) is a treatment method of inducing immune tolerance by administering a donor (allo) blood to a host before organ transplantation (Non-patent document 1: Clin Transplant 25:317). , 2011). Performing DST before kidney transplantation since the 1970s suppresses rejection reaction in a donor-specific manner. From clinical practice, antibodies against donor histocompatibility antigen (MHC antigen) can be easily produced by a single blood transfusion. Although it has been reported, side effects may occur, so it has almost disappeared due to the advent of immunosuppressive drugs that can easily treat rejection reactions. Therefore, by what component in the allo antibody response (AFC response) blood, where, how happen, made antibodies is not yet elucidated or with what effects, including immunosuppression ..
  • AFC response allo antibody response
  • Non-patent document 2 Cell Transplant 21:581). , 2012; Non-patent document 3: Cell Transplant 19:765, 2010; Non-patent document 4: Arch Histol Cyto 73:1, 2010; Non-patent document 5: Hepatology 56: 1532, 2012).
  • the allo-immune response is presented by direct sensitization in which donor antigen-presenting dendritic cells (DCs) directly associate with host T cells to present donor MHC antigens, and MHC antigens derived from donor cells are taken up by host DCs and presented. It is said to be caused by indirect sensitization (Non-Patent Document 8: Immunity 14:357, 2001).
  • AFC response (humoral immunity) is induced by Th2 helper T cells and follicular helper T cells (Follicular helper T cells/Tfh), and the GATA-3 gene, which is a cytokine or transcription factor such as IL-4 and IL-10. It has been reported that the expression of the above is dominant (Non-patent document 9: Immunity 30:324, 2009).
  • the antibody production response by DST mainly involves an immune response by indirect sensitization in the spleen.
  • the immune response in the spleen occurs in the periarterial lymphocyte sheath (PALS/T cell region) in the white pulp of the spleen, where DC is localized, and T and B cells are used for immune surveillance. It is known that most of them recirculate throughout the body, always migrate from blood into PALS and stay in PALS for a while, and T cells further associate with DC of PALS to confirm antigen information (Non-Patent Document 10). : Arch Histol Cyto 73:1, 2010).
  • a vaccine against a pathogen is usually administered intramuscularly or subcutaneously to induce the production of neutralizing antibodies mainly in the spleen. Therefore, when the spleen function is low or the spleen is removed, the usual vaccine effect cannot be expected so much.
  • the present inventor has conducted extensive studies to solve the above-mentioned problems, and as a result, by labeling allo-T cells with a pathogen antigen and inoculating this to an individual, not only the spleen but also lymph nodes throughout the body are multifocal.
  • the inventors have found that a neutralizing antibody is induced in Escherichia coli and have completed the present invention.
  • the present invention is as follows.
  • a vaccine against the pathogen antigen in an allogeneic recipient individual which comprises donor-derived T cells that have undergone histocompatibility antigen expression suppression treatment, activation suppression treatment, and pathogen antigen labeling treatment.
  • the vaccine according to (1), wherein the treatment for suppressing the expression of the histocompatibility antigen is RNA interference treatment for the histocompatibility antigen gene or knockout treatment of the gene.
  • the vaccine according to (1) or (2), wherein the activation suppression treatment is an antimetabolite or DNA synthesis inhibitor treatment or irradiation treatment.
  • the vaccine according to any one of (1) to (3), wherein the pathogen is a virus or a bacterium.
  • the vaccine according to (4), wherein the virus is influenza virus.
  • a neutralizing antibody inducer in an allogeneic recipient individual which comprises donor-derived T cells that have undergone histocompatibility antigen expression suppression treatment, activation suppression treatment, and pathogen antigen labeling treatment.
  • the neutralizing antibody inducer according to (7), wherein the treatment for suppressing the expression of the histocompatibility antigen is RNA interference treatment for the histocompatibility antigen gene or knockout treatment of the gene.
  • the present invention provides a T cell vaccine and a neutralizing antibody inducer.
  • the T cell vaccine of the present invention is capable of inducing neutralizing antibodies in multiple points.
  • FIG. 3 is a schematic diagram of a staining method for specific antibody-producing cells in Examples.
  • FIG. 5 is a diagram showing an experimental result of Example 1.
  • semi-allo T cells a system in which parental T cells are administered to a first-generation hybrid F1 recipient
  • a specific antibody against the labeled antigen phycoerythrin (PE) was detected in serum (left graph, red arrow), and cervical lymph node section Antibody-producing cells (blue, right panel) appeared on the top, but alloantibodies did not appear (black arrow).
  • the allo T cells a large amount of alloantibodies appeared, but the PE antibody titer was low.
  • the present inventor has found that donor T cells migrate to the spleen PALS after blood transfusion and, after associating with the host DC, transfer the donor MHCI antigen in some form and cause indirect sensitization most efficiently there, resulting in Th2 and Tfh
  • the inventor has come up with the hypothesis that antigen-specific antibodies are induced and efficiently produced.
  • the present invention relates to a vaccine against a pathogen in an allogeneic recipient individual and a neutralizing antibody inducer, which comprises donor-derived T cells that have undergone histocompatibility antigen expression suppression treatment, activation suppression treatment, and pathogen antigen labeling treatment.
  • Allogeneic (allo) T cells like autologous T cells, have the ability to recirculate to systemic lymphoid organs and undergo hematogenous migration, but efficiently mobilize tissue-resident dendritic cells via T cell receptors. It was found that when stimulated well, alloantibodies against the type I histocompatibility antigen (MHC) of the T cell itself were easily induced. This finding is different from autologous T cells.
  • the present inventor utilizes the above findings to label allo T cells (donor-derived T cells) with a pathogen antigen such as influenza, and administer this to recipients other than self (donor) to obtain only the spleen. It was found that multiple neutralizing antibodies are induced in the normal lymph node. Since there are hundreds of lymph nodes in humans, the vaccine of the present invention capable of inducing neutralizing antibody in systemic lymph nodes is highly efficient and can be used as a vaccine of a new concept.
  • the T cells used in the present invention are collected from one individual. After this T cell is subjected to the above treatment, it is administered to another individual who is the same species as the one individual but is allogeneic. Therefore, the T cells used are referred to herein as "allo T cells.”
  • T cells (allo T cells) collected from donor blood are subjected to histocompatibility antigen expression suppression treatment, activation suppression treatment, and pathogen antigen labeling treatment.
  • the thus treated allo-T cells are administered to an allogeneic individual (recipient) different from the donor.
  • the expression suppressing treatment of the histocompatibility antigen means an alloantigenicity suppressing treatment, and as the treatment for suppressing the expression of the histocompatibility antigen, for example, RNA interference treatment to the histocompatibility antigen gene or knockout treatment of the gene is performed.
  • RNA interference treatment to the histocompatibility antigen gene or knockout treatment of the gene is performed.
  • synthetic nucleic acid molecules capable of suppressing gene expression by RNA interference (RNAi) include siRNA (small interfering RNA), microRNA (miRNA) and shRNA (short hairpin RNA).
  • siRNA can be designed based on criteria well known in the art. For example, as the target segment of the mRNA of the target histocompatibility antigen gene, a continuous 15 to 30 bases, preferably 19 to 25 bases segment starting with AA, TA, GA or CA can be selected.
  • the siRNA has a GC ratio of 30 to 70%, preferably 35 to 55%.
  • siRNA is produced as a single-stranded hairpin RNA molecule that folds on its own nucleic acid to produce a double-stranded portion.
  • siRNA molecules can be obtained by conventional chemical synthesis, but can also be produced biologically using expression vectors containing sense and antisense siRNA sequences.
  • a method of ligating siRNA synthesized in vitro with plasmid DNA and introducing it into cells a method of annealing double-stranded RNA, or the like can be adopted.
  • ShRNA is an RNA molecule having a stem-loop structure in which a part of a single strand forms a complementary strand with another region. Therefore, shRNA is designed such that a part thereof forms a stem-loop structure. For example, if the sequence of a certain region is sequence A and the complementary strand to sequence A is sequence B, sequence A, spacer, sequence B are linked in this order so that these sequences exist in one RNA strand, and It is designed to have a length of 45 to 60 bases. Sequence A is a sequence of a partial region of the target histocompatibility antigen gene, and the target region is not particularly limited, and any region can be used as a candidate. The length of the sequence A is 19 to 25 bases, preferably 19 to 21 bases.
  • miRNA is a single-stranded RNA having a length of about 20 to 25 bases existing in cells, and is a kind of ncRNA (non coding RNA) which is considered to have a function of regulating the expression of other genes. .. miRNA exists as a nucleic acid forming a hairpin structure that is generated by being processed when it is transcribed into RNA and suppresses the expression of a target sequence. Since miRNA is also an inhibitory nucleic acid based on RNAi, it can be designed and synthesized according to shRNA or siRNA.
  • a histocompatibility antigen gene can also be knocked out.
  • the knockout method include, but are not limited to, knockout by CRISPR/Cas9.
  • the siRNA treatment, the gene knockout treatment with CRISPR/Cas9, or the like can be performed by a method described in a known document (Cancer Cell Int. 13:112, 2013; Clin Cancer Res 23:2255, 2017).
  • the T cell activation suppressing treatment means a treatment for removing the risk of T cell onset of GvH disease, and the activation suppressing treatment includes an antimetabolite or a DNA synthesis inhibitor treatment, or irradiation treatment.
  • an antimetabolite or a DNA synthesis inhibitor treatment or irradiation treatment.
  • ⁇ Antimetabolite or DNA synthesis inhibitor Folic acid analogs: methotrexate, pemetrexed, pralatrexate, etc. Purine analogs: mercaptopurine, thioguanine, cladribine, fludarabine, etc. Pyrimidine analogs: cytarabine, fluorouracil, tegafur, gemcitabine, etc. Antibiotics: mitomycin C, actinomycin, doxorubicin, etc. Alkylating agents: cyclophosphamide, melphalan, thiotepa, busulfan, etc. Platinum preparations: cisplatin, iproplatin, carboplatin, etc. Topoisomerase inhibitors: irinotecan, nogitecan, etoposide, anthracycline drugs, etc.
  • the amount of the antimetabolite or the DNA synthesis inhibitor to be used is 20 ⁇ g/5 ⁇ 10 7 /ml for mitomycin C, treated at 37° C. for 30 minutes, and other appropriate amount is used. This treatment can be performed by a method described in a known document (Hepatology 56: 1532, 2012).
  • the radiation dose of X-rays, gamma rays, etc. is 10 to 50 Gy, preferably 15 Gy per 10 8 cells. These treatments can be performed by a method described in a known document (Arch Pathol Lab Med 142:662, 2018).
  • the pathogen used as an antigen is not particularly limited and includes viruses, bacteria, protozoa and the like.
  • the antigen labeling is performed by preparing a gene vector of the target antigen and using a gene transfer technique into T cells.
  • influenza virus examples include influenza virus, hepatitis virus, herpes zoster, measles/rubella, papilloma (HPV), human immunodeficiency (HIV) virus and the like.
  • bacteria examples include pneumococcus, meningococcus, diphtheria, tetanus, pertussis, tuberculosis, and the like.
  • protozoa examples include malaria.
  • the allo T cell vaccine is prepared by treating donor-derived T cells with (a) histocompatibility antigen expression suppression treatment, (b) activation suppression treatment, and (c) pathogen antigen labeling treatment, in the order of It is not particularly limited.
  • the above processes may be performed in the order of (a), (b) and (c), or may be performed in another order.
  • a pathogen antigen is bound to an antibody that specifically recognizes T cells such as an anti-CD4 antibody to prepare a complex of the antibody and the pathogen antigen, and the complex is bound to a donor T cell.
  • alloimmunity that causes GvH disease or induction of alloantibody production in the recipient of donor T cells (allo T cells) is lost, but a new function of antigen transporting ability is acquired.
  • cells specialized for antigen transport capable of delivering the pathogen antigen to the recipient dendritic cells of lymphoid organs throughout the body without producing an alloimmune response have been produced.
  • the cells can be administered to any recipient of different MHC and in that sense can be regarded as "standardized" allo-T cells. This standardized allo-T cell can be used as a completely new type of vaccine that is relatively safe and versatile.
  • the allo-T cells that have been subjected to the above treatment are administered to the recipient allogeneic target individual.
  • the vaccine of the present invention can be used as a pharmaceutical composition for a disease associated with the antigen, depending on the antigen used.
  • the pharmaceutical composition of the present invention can be administered according to the form of parenteral administration such as injection.
  • parenteral administration such as injection.
  • local injection into the abdominal cavity and the like are exemplified.
  • the administration method examples include intravenous administration and intraperitoneal administration.
  • the dose is appropriately selected according to the administration route, administration subject, age, body weight, sex of the patient, symptoms and other conditions.
  • the daily dose of allo-T cells used as a vaccine is about 10 7 cells/ml to 10 9 cells/ml in the case of intravenous administration, preferably about 5 ⁇ 10 7 cells/ml to 5 ⁇ 10 8 cells/ml, It can be administered once a day or divided into several times.
  • the vaccine of the present invention can induce neutralizing antibodies systemically and multifocally not only in humans with normal spleen function but also in humans with decreased or splenectomy. Therefore, the allo T cell of the present invention can be used as a neutralizing antibody inducer.
  • the F1 rat system can be said to be a model similar to the system using siRNA.
  • autologous T cells cannot induce an antibody response, it is a necessary condition in the present invention to use allo T cells.

Abstract

L'invention concerne un vaccin contre un pathogène chez un individu receveur allogénique, ledit vaccin contenant des cellules T dérivées d'un donneur et qui ont été soumises à un traitement pour supprimer l'expression d'un antigène d'histocompatibilité, un traitement pour supprimer l'activation de celui-ci et un traitement pour marquer l'antigène cible.
PCT/JP2020/006949 2019-02-14 2020-02-14 Vaccin à base de cellules t WO2020166729A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6503503B1 (en) * 1997-05-13 2003-01-07 Duke University Allogeneic cellular vaccine
US20110052554A1 (en) * 2008-01-30 2011-03-03 Memorial Sloan-Kettering Cancer Center Methods for off-the- shelf tumor immunotherapy using allogeneic t-cell precursors
WO2015152429A1 (fr) * 2014-04-03 2015-10-08 学校法人獨協学園獨協医科大学 Méthode de suppression de la réponse immunitaire lors d'une transplantation
WO2019178006A2 (fr) * 2018-03-12 2019-09-19 Sqz Biotechnologies Company Administration intracellulaire de biomolécules pour modifier une réponse immunitaire

Family Cites Families (4)

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Publication number Priority date Publication date Assignee Title
GB0224442D0 (en) * 2002-10-21 2002-11-27 Molmed Spa A delivery system
US20070036773A1 (en) * 2005-08-09 2007-02-15 City Of Hope Generation and application of universal T cells for B-ALL
MX2017006408A (es) * 2014-11-17 2018-03-23 Adicet Bio Inc Linfocitos t gamma delta modificados geneticamente.
CN107847524A (zh) * 2015-03-27 2018-03-27 哈佛学院校长同事会 经过修饰的t细胞及其制备和使用方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6503503B1 (en) * 1997-05-13 2003-01-07 Duke University Allogeneic cellular vaccine
US20110052554A1 (en) * 2008-01-30 2011-03-03 Memorial Sloan-Kettering Cancer Center Methods for off-the- shelf tumor immunotherapy using allogeneic t-cell precursors
WO2015152429A1 (fr) * 2014-04-03 2015-10-08 学校法人獨協学園獨協医科大学 Méthode de suppression de la réponse immunitaire lors d'une transplantation
WO2019178006A2 (fr) * 2018-03-12 2019-09-19 Sqz Biotechnologies Company Administration intracellulaire de biomolécules pour modifier une réponse immunitaire

Non-Patent Citations (2)

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Title
KITAZAWA, Y. ET AL.: "Novel Targeting to XCR1+ Dendritic Cells Using Allogeneic T Cells for Polytopical Antibody Responses in the Lymph Nodes", FRONTIERS IN IMMUNOLOGY, vol. 10, May 2019 (2019-05-01), pages 1 - 22, XP055733582 *
UEDA, YUJI ET AL., ANNUAL MEETING PROCEEDINGS OF THE JAPANESE SOCIETY FOR IMMUNOLOGY, no. 35, 2015, pages 191 *

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JPWO2020166729A1 (ja) 2021-02-25

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