CN117222426A - Novel treatment and prevention based on novel methods of controlling cellular immunity - Google Patents
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract
The present invention provides a composition for preventing or treating a disease (e.g., an infection, allergy, or autoimmune disease). The present invention provides a composition, medicament or kit for preventing or treating the disease in a subject, or the like, characterized by comprising a non-pathogenic antigen component (which is neither derived from nor cross-reactive with the pathogenic agent of the disease), and being administered in the presence of a pathogenic antigen component (which is derived from and/or cross-reactive with the pathogenic agent of a target disease in the subject).
Description
Technical Field
The present invention relates to novel disease treatment and prevention using novel combination partners for controlling cellular immunity.
Background
2019 coronavirus infection (Covid-19) is a disease caused by severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) and has been widely prevalent worldwide since 2019. Clinical studies are currently being conducted on a variety of coronavirus vaccines, but more effective therapeutic methods (appreach) are becoming a critical issue.
Disclosure of Invention
Means for solving the problems
As a result of intensive studies, the present inventors have developed a technique for treating and preventing a novel disease using a novel composition for controlling cellular immunity. In one embodiment of the invention it is found that: if a pathogenic agent antigen component (which is derived from and/or cross-reacts with a pathogenic agent of a target disease in a subject) is combined with a non-pathogenic agent antigen component (which is neither derived from nor cross-reacts with a pathogenic agent of the disease), then the cellular immune memory useful for preventing or treating the disease can be freely controlled (e.g., primed, upregulated, inhibited, downregulated, etc.), and the disease can be specifically prevented or treated. In a preferred embodiment, the subject has an immunological memory for a non-pathogenic antigen component, whereby by exposure to the subject in combination with a pathogenic antigen component other than the non-pathogenic antigen component, humoral immunity against the pathogenic antigen component can be controlled, effecting prophylaxis or cure of a disease in the subject.
Thus, the present invention provides the following schemes as representative schemes.
(item Y1) a composition for preventing or treating an infectious disease, an allergic reaction (allergy) and/or an autoimmune disease (autoimmune disease), comprising a non-pathogenic antigen component which is neither derived from nor cross-reactive with a pathogenic agent of the infectious disease, allergic reaction and/or autoimmune disease of a subject,
the composition has the following characteristics:
1) Confirming that the subject has an immune response against the non-pathogenic agent;
2) In the event that the subject has the immune response, the composition is administered to the subject.
(item Y2) A composition for preventing or treating an infectious disease, which comprises a non-pathogenic antigen component derived neither from nor cross-reactive with a pathogenic agent of the infectious disease of a subject,
the composition has the following characteristics:
1) Confirming that the subject has an immune response against the non-pathogenic agent;
2) In the event that the subject has the immune response, the composition is administered to the subject.
(item Y3) a composition for preventing or treating an infectious disease other than tuberculosis in a subject, wherein the composition comprises a hot water extract of Bacillus tuberculosis or a part thereof,
The composition has the following characteristics:
1) Confirming that the subject has an immune response against tuberculosis;
2) In the event that the subject has the immune response, the composition is administered to the subject.
The composition according to any one of the above items (Y4), wherein the hot water extract of Mycobacterium tuberculosis or a part thereof is a hot water extract of Mycobacterium tuberculosis Qingshan B strain.
The composition according to any one of the above items (Y5), wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
The composition of any one of the preceding items (item Y6), wherein the composition is administered in an amount effective to produce IL-10.
The composition according to any one of the above items (Y7), wherein the infection is a viral infection.
The composition according to any one of the above items (Y8), wherein the infection is a coronavirus-related viral infection.
The composition according to any one of the above items (item Y9), wherein the immune response is objectively confirmed.
The composition according to any one of the above items (item Y10), wherein the objective confirmation of the immune response is confirmed by a tuberculin reaction test or a test based on a gamma interferon release test, or objective information contained in a mother-son health manual or an equivalent thereof, medical records or other medical information.
(item Y11) the composition according to any one of the above items, wherein the immune response is examined by a tuberculin reaction test or a gamma interferon release test.
(item Y12) the composition according to any one of the above items, wherein the non-pathogenic antigen component, or the hot water extract of tubercle bacillus or a part thereof, is administered to the subject in advance in the case where the subject does not have the immune response, and then the composition is administered to the subject in the case where it is confirmed that the subject has the immune response.
The composition according to any one of the above items (item Y13), wherein the administration is repeated in advance until the subject has the immune response.
The composition according to any one of the above items (item Y14), wherein the previous administration is administration before or after the infection is caused.
The composition according to any one of the above items (item Y15), wherein the previous administration is an administration after the infection is suffering from the infection.
(item Y16) a composition according to any one of the preceding items, wherein the composition is administered in the presence of a pathogenic antigen component derived from and/or cross-reactive with the pathogenic agent.
(item Y17) a composition for preventing or treating a disease comprising a non-pathogenic antigen component that is neither derived from nor cross-reactive with a pathogenic agent of the disease, the composition being administered in the presence of a pathogenic antigen component that is derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject.
The composition according to any one of the above items (item Y18), wherein the pathogenic agent comprises a foreign substance for the subject.
The composition according to any one of the above items (item Y19), wherein the causative agent of the above disease comprises causative agent of infectious disease, causative agent of allergy, causative agent of autoimmune disease, or poison.
The composition according to any one of the above items (Y20), wherein the disease is an infectious disease.
The composition according to any one of the above items (item Y21), wherein the subject has an immunological memory against the non-pathogenic antigen component.
(item Y22) the composition according to any one of the preceding items, wherein the composition comprises the pathogenic agent antigen component described above.
The composition according to any one of the above items (Y23), wherein the composition is for preventing the above-mentioned diseases.
The composition according to any one of the above items (item Y24), wherein the composition prevents or treats the above-described diseases in a form in which an immune excessive reaction is not accompanied or reduced.
The composition according to any one of the above items (item Y25), wherein the composition is administered in a form effective for controlling cellular immunity against a causative agent of the disease.
(item Y26) the composition of any one of the preceding items, wherein the presence or absence of a pathogenic antigenic component in said subject is confirmed, and in the absence, the pathogenic antigenic component is administered together with said non-pathogenic antigenic component, wherein said pathogenic antigenic component is derived from and/or cross-reacts with a pathogenic agent of the target disease.
The composition according to any one of the above items (Y27), wherein the disease is an infection, an allergy or an autoimmune disease.
The composition according to any one of the above items (Y28), wherein the disease is a viral infection or a bacterial infection.
The composition according to any one of the above items (Y29), wherein the disease is a viral infection.
The composition according to any one of the above items (Y30), wherein the disease is an infectious disease associated with coronavirus.
The composition according to any one of the above items (item Y31), wherein the pathogenic antigen component is a molecule having at least a part of its surface on which a pathogenic agent of a target disease appears.
The composition according to any one of the above items (Y32), wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The composition according to any one of the above items (Y33), wherein the non-pathogenic antigen component is a hot water extract of B strain of Mycobacterium tuberculosis or a part thereof.
The composition according to any one of the above items (Y34), wherein the non-pathogenic antigen component is extract A.
(item Y35) the composition according to any one of the preceding items, wherein the non-pathogenic antigen component comprises a STING agonist derived from Bacillus tuberculosis, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, an Mtb-associated antigen, a component capable of biosynthesis of a STING agonist in human cells, or a NOD2 agonist.
(item Y36) the composition of any one of the preceding items, wherein the non-pathogenic antigen component comprises a STING agonist derived from Bacillus tuberculosis, the STING agonist being c-di-AMP, c-di-GM P, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing 2'3' -cGAMP in human cytoplasm mediated by cGA S.
The composition according to any one of the above items (item Y37), wherein the non-pathogenic antigen component is administered twice or more.
(item Y38) the composition according to any one of the above items, wherein the above composition has the following features:
1) Confirming that the subject has an immune response against the non-pathogenic agent;
2) In the case where the subject has the above-described immune response, the above-described composition is administered to the subject.
The composition according to any one of the above items (item Y39), wherein the immune response is objectively confirmed.
The composition according to any one of the above items (item Y40), wherein the objective confirmation of the immune response is confirmed by a tuberculin reaction test or a test based on a gamma interferon release test, or objective information contained in a mother-son health manual or an equivalent thereof, medical records or other medical information.
(item Y41) the composition according to any one of the above items, wherein the immune response is examined by a tuberculin reaction test or a gamma interferon release test.
(item Y42) the composition according to any one of the above items, wherein the non-pathogenic antigen component or the hot water extract of tubercle bacillus or a part thereof is administered to the subject in advance in the case where the subject does not have the immune response, and then the composition is administered to the subject in the case where it is confirmed that the subject has the immune response.
The composition according to any one of the above items (item Y43), wherein the administration is repeated in advance until the subject has the immune response.
The composition according to any one of the above items (item Y44), wherein the previous administration is administration before or after the infection is caused.
The composition according to any one of the above items (item Y45), wherein the previous administration is an administration after the infection is suffering from the infection.
(item Y46) a combination, characterized in that it is a combination of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject, and a non-pathogenic antigen component derived from or cross-reactive with neither the pathogenic agent of the disease.
(item Y47) the combination according to any one of the preceding items, wherein the pathogenic antigen component comprises a pathogenic agent of an infectious disease, a pathogenic agent of an allergic reaction, a pathogenic agent of an autoimmune disease, or a poison.
(item Y48) the combination according to any one of the preceding items, wherein the pathogenic antigen component is a bacterium, a virus or a protozoan or a part thereof.
The combination according to any one of the preceding items (item Y49), wherein the pathogenic antigen component is a virus or a part thereof.
(item Y50) the combination according to any one of the preceding items, wherein the pathogenic antigen component is a virus belonging to the family Coronaviridae or a part thereof.
(item Y51) the combination according to any one of the preceding items, wherein the pathogenic agent is a virus belonging to the family selected from the group consisting of rhinovirus, adenovirus, coronavirus, RS virus, influenza virus, parainfluenza virus and enterovirus.
(item Y52) the combination according to any one of the preceding items, wherein the pathogenic agent is a virus belonging to the genus coronavirus.
(item Y53) the combination according to any one of the preceding items, wherein the pathogenic agent is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2.
(item Y54) the combination according to any one of the preceding items, wherein the pathogenic agent is SARS-CoV-2 virus.
(item Y55) the combination according to any one of the preceding items, wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The combination according to any one of the preceding items (item Y56), wherein the non-pathogenic antigen component is a hot water extract of the B strain of human tubercle bacillus or a part thereof.
The combination according to any one of the preceding items (item Y57), wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The combination according to any one of the preceding items (item Y58), wherein the non-pathogenic antigen component is a hot water extract of the B strain of human tubercle bacillus or a part thereof.
The combination according to any one of the above items (Y59), wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item Y60) the combination according to any one of the preceding items, wherein the hot water extract of tubercle bacillus or a part thereof comprises STING agonist, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, STING agonist, or NOD2 agonist derived from tubercle bacillus.
(item Y61) the combination according to any one of the preceding items, wherein the hot water extract of tubercle bacillus or a portion thereof comprises a STING agonist derived from tubercle bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
(item Y62) the combination according to any one of the preceding items, wherein the non-pathogenic antigen component is administered more than twice.
The combination according to any one of the above items (item Y63), wherein the pathogenic antigen component is a pathogenic agent of an infectious disease, and the non-pathogenic antigen component functions as an adjuvant when the pathogenic antigen component is used as a vaccine.
(item Y64) the combination of any one of the preceding items, wherein the combination has the following features:
1) Confirming that the subject has an immune response against the non-pathogenic agent;
2) In the case where the subject has an immune response as described above, one or both of the combinations described above are administered to the subject.
(item Y65) the combination according to any of the preceding items, wherein the immune response is objectively confirmed.
(item Y66) the combination according to any one of the preceding items, wherein the objective confirmation of the immune response is confirmed by a tuberculin response test or a test based on a gamma interferon release test, or objective information contained in a mother-child health manual or its equivalent, medical record or other medical information.
(item Y67) the combination according to any one of the preceding items, wherein the immune response is examined by a tuberculin response test or a gamma interferon release test.
(item Y68) the combination according to any one of the preceding items, wherein the non-pathogenic antigen component or the hot water extract of tubercle bacillus or a part thereof is administered to the subject in advance in the case where the subject does not have the immune response, and then the combination is administered to the subject in the case where it is confirmed that the subject has the immune response.
(item Y69) the combination according to any one of the preceding items, wherein the prior administration is repeated until the subject has the immune response.
(item Y70) the combination according to any one of the preceding items, wherein the prior administration is administration before or after the infection.
(item Y71) the combination according to any one of the preceding items, wherein the prior administration is an administration after the infection is suffering from.
(item Y72) a medicament for preventing or treating a disease, comprising a combination of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject, and a non-pathogenic antigen component derived from or cross-reactive with neither the pathogenic agent of the disease.
(item Y73) the medicament of any one of the preceding items, wherein the medicament further comprises the features of any one or more of the preceding items.
(item Y74) A kit for preventing or treating a disease, comprising a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject, and a non-pathogenic antigen component neither derived from nor cross-reactive with a pathogenic agent of the disease.
(item Y75) the kit of any one of the preceding items, wherein the kit further comprises the features of any one or more of the preceding items.
(item Y76) a method for preventing or treating a disease in a subject, comprising the steps of:
administering to the subject an effective amount of a non-pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of the disease in the subject in the presence of a pathogenic antigen component that is neither derived from nor cross-reactive with a pathogenic agent of the disease.
(item Y77) the method of any one of the preceding items, wherein the method further comprises the features of any one or more of the preceding items.
(item Y78) a method for preventing or treating a disease in a subject, comprising the steps of:
administering to the subject an effective amount of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of the disease; and administering to the subject an effective amount of a non-pathogenic antigen component that is neither derived from nor cross-reactive with a pathogenic agent of the disease.
(item Y79) the method of any one of the preceding items, wherein the method further comprises the features of any one or more of the preceding items.
(item Y80) a composition for use in relieving or transforming the suppression of regulatory T cells (tregs), wherein the suppression of regulatory T cells (tregs) refers to the suppression of the activity of a pathogenic agent against an infection, allergy and/or autoimmune disease in a subject or the activity of a cell infected with or comprising the pathogenic agent, the non-pathogenic antigen component neither originating nor cross-reacting with the pathogenic agent of the targeted infection, allergy and/or autoimmune disease, the composition comprising a non-pathogenic antigen component.
(item Y81) the composition of any preceding claim, wherein said Treg is transformed into effector T cells (Teff) derived from and/or cross-reactive with a pathogenic agent of a target disease by the presence in said subject of a pathogenic agent antigen component which is directed against a pathogenic agent of the disease or a cell comprising a pathogenic agent of the infection.
(item Y82) the composition of any one of the preceding items, wherein the subject has an immunological memory for the pathogenic agent and/or a factor that cross-reacts with the pathogenic agent.
(item Y83) the composition of any one of the preceding items, wherein the composition further comprises the features of any one or more of the preceding items.
(item Y84) a composition for preventing or treating an infectious disease in a subject, wherein the composition comprises an antigen component specific for a component different from a causative agent of the infectious disease in the subject.
(item Y85) a composition for preventing or treating an infectious disease in a subject, wherein the composition comprises an antigenic component derived from a pathogen of the subject that is different from a past infectious disease of the infectious disease, and is substantially free of a causative agent of the infectious disease or a portion thereof.
(item Y86) A composition for preventing or treating an infection except tuberculosis, which comprises a Bacillus tuberculosis extract.
(item Y87) a composition for controlling immune enhancement against a causative agent of an infectious disease other than tuberculosis in a subject when the subject is exposed to the causative agent, wherein the composition comprises a tubercule bacillus extract.
(item Y88) a composition for preventing or treating an infection, allergy or autoimmune disease in a subject, wherein the composition comprises an antigen component specific in the subject, said antigen component being neither derived from nor cross-reactive with a causative agent of the infection, allergy or autoimmune disease,
the antigenic component is a protein or a portion thereof, or a peptide, and is capable of controlling an immune response mediated by CD4 positive T cells,
the infection, allergy or autoimmune disease includes a disease that can be prevented or treated by an immune response mediated by CD4 positive T cells,
here, it is confirmed whether the subject can control an immune response against an infectious disease, an allergic reaction, or an autoimmune disease mediated by CD4 positive T cells, and the composition is administered in a case where the subject can control an immune response against an infectious disease, an allergic reaction, or an autoimmune disease mediated by CD4 positive T cells.
(item Y89) A composition for preventing or treating an infectious disease in a subject, characterized in that the composition comprises an antigen component specific to a component different from a causative agent of the infectious disease in the subject,
The infection comprises a viral infection and the method comprises,
the antigenic component is a protein or a portion thereof, or a peptide, and is capable of controlling an immune response mediated by CD4 positive T cells,
the viral infections include diseases which can be prevented or treated by an immune response mediated by CD4 positive T cells,
here, it is confirmed whether the subject can control an antiviral immune response mediated by CD4 positive T cells, and the composition is administered in a case where the subject can control an antiviral immune response mediated by CD4 positive T cells.
(item Y90) the composition of any one of the preceding items, wherein the composition further comprises the features of any one or more of the preceding items.
(item Y91) a method of making or otherwise providing a composition for preventing or treating an infection, allergy, or autoimmune disease in a subject, comprising the steps of:
step a) identifying an antigenic component specific to the subject, said antigenic component being neither derived from nor cross-reactive with a causative agent of the infection, allergy or autoimmune disease;
step B), determining whether the antigen component has an immunological memory in the subject, and selecting the antigen component having the immunological memory; and
Step C) manufacturing or otherwise providing the selected antigen component.
(item Y92) a method of determining whether an antigenic component specific to a subject, said antigenic component being neither derived from nor cross-reactive with a causative agent of an infectious disease, allergic reaction or autoimmune disease in the subject, can prevent or treat the infectious disease, allergic reaction or autoimmune disease in the subject, comprising the steps of:
step B) is a step of specifying whether or not the antigen component has an immunological memory in the subject, and in the case of having the immunological memory, is specified to be capable of preventing or treating an infection, an allergy or an autoimmune disease in the subject.
(item Y93) a method for preventing or treating an infectious disease, an allergic reaction, or an autoimmune disease, comprising the steps of:
step a), obtaining an antigen responsiveness profile of the subject;
step b) of specifying an antigen component or a combination of antigen components based on the antigen responsiveness profile, wherein the antigen component or the combination of antigen components is specified based on whether the subject now exhibits an immune responsiveness or has previously exhibited an immune responsiveness; and
Step c) administering to the subject the antigen component or combination of antigen components identified in step b) in an amount sufficient to control an immune response in the subject.
(item Y94) the method of any one of the preceding items, wherein the method further comprises the features of any one or more of the preceding items.
(item Y95) an adjuvant for a vaccine against infectious diseases, wherein the adjuvant comprises a hot water extract of Bacillus tuberculosis or a part thereof.
(item Y96) an adjuvant for a vaccine against an infectious disease, wherein the adjuvant comprises a STING agonist.
(item Y97) an adjuvant for a vaccine against an infectious disease of a viral infection, wherein the adjuvant comprises a STING agonist.
(item Y98) the adjuvant according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof is a hot water extract of human type Bacillus tuberculosis Qingshan B strain or a part thereof.
An adjuvant according to any one of the above items (Y99), wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item Y100) the adjuvant according to any one of the preceding items, wherein the hot water extract of Bacillus tuberculosis or a part thereof comprises a STING agonist, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb-related antigen, STING agonist, or NOD2 agonist derived from Bacillus tuberculosis.
(item Y101) an adjuvant according to any one of the preceding items, wherein the hot water extract of tubercle bacillus or a portion thereof comprises a STING agonist derived from tubercle bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
An adjuvant according to any one of the above items (item Y102), wherein the causative agent of the infection is a bacterium, a virus or a protozoan.
An adjuvant according to any one of the above items (item Y103), wherein the causative agent of the infection is a virus.
An adjuvant according to any one of the above items (item Y104), wherein the causative agent of the infection is a virus belonging to the family Coronaviridae.
(item Y105) the adjuvant according to any one of the above items, wherein the causative agent of the above-mentioned infectious disease is a virus belonging to the family selected from the group consisting of rhinovirus, adenovirus, coronavirus, RS virus, influenza virus, parainfluenza virus and enterovirus.
An adjuvant according to any one of the above items (item Y106), wherein the causative agent of the infection is a virus belonging to the genus coronavirus.
An adjuvant according to any one of the above items (item Y107), wherein the causative agent of the infection is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2.
An adjuvant according to any one of the above items (item Y108), wherein the causative agent of the infection is SARS-CoV-2 virus.
(item Y109) the adjuvant according to any one of the preceding items, wherein the adjuvant further comprises the features of any one or more of the preceding items.
(item Y110) the adjuvant according to any one of the preceding items, wherein the adjuvant converts natural immunity (natural immunity) to acquired immunity (acquired immunity).
(item Y1A) a method for preventing or treating an infectious disease, an allergic reaction and/or an autoimmune disease, comprising administering an effective amount of a non-pathogenic antigen component which is neither derived from nor cross-reactive with a pathogenic agent of the infectious disease, allergic reaction and/or autoimmune disease in a subject,
the method comprises the following steps:
1) Confirming that the subject has an immune response against the non-pathogenic agent;
2) In the event that the subject has the immune response, the non-pathogenic antigen component is administered to the subject.
(item Y2A) a method for preventing or treating an infectious disease, comprising administering an effective amount of a non-pathogenic antigen component that is neither derived from nor cross-reactive with a pathogenic agent of the infectious disease in a subject,
the method comprises the following steps:
1) Confirming that the subject has an immune response against the non-pathogenic agent;
2) In the event that the subject has the immune response, the non-pathogenic antigen component is administered to the subject.
(item Y3A) a method for preventing or treating an infectious disease other than tuberculosis in a subject, comprising administering an effective amount of a hot water extract of Bacillus tuberculosis or a portion thereof,
the method comprises the following steps:
1) Confirming that the subject has an immune response against mycobacterium tuberculosis;
2) In the event that the subject has the immune response, the non-pathogenic antigen component is administered to the subject.
The method according to any one of the above items (Y4A), wherein the hot water extract of Mycobacterium tuberculosis or a part thereof is a hot water extract of Mycobacterium tuberculosis Qingshan B strain.
The method according to any one of the above items (Y5A), wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item Y6A) the method of any one of the preceding items, wherein the method is effective for producing IL-10.
The method according to any one of the above items (Y7A), wherein the infection is a viral infection.
The method according to any one of the above items (Y8A), wherein the infection is a coronavirus-related viral infection.
The method according to any one of the above items (item Y9A), wherein the immune response is objectively confirmed.
The method according to any one of the above items (item Y10A), wherein the objective confirmation of the immune response is confirmed by a tuberculin reaction test or a test based on a gamma interferon release test, or objective information contained in a mother-son health manual or an equivalent thereof, medical records or other medical information.
(item Y11A) the method according to any one of the above items, wherein the immune response is examined by a tuberculin reaction test or a gamma interferon release test.
(item Y12A) the method according to any one of the preceding items, wherein the non-pathogenic antigen component or a hot water extract of tubercle bacillus or a part thereof is administered to the subject in advance in the case where the subject does not have the immune response, and then the non-pathogenic antigen component is administered to the subject in the case where the subject is confirmed to have the immune response.
The method according to any one of the above items (item Y13A), wherein the administration in advance is repeated until the subject has the immune response.
The method according to any one of the preceding items (item Y14A), wherein the previous administration is administration before or after the infection is caused.
The method according to any one of the above items (item Y15A), wherein the previous administration is an administration after the infection is suffering from the infection.
(item Y16A) the method according to any one of the preceding items, wherein the administration is carried out in the presence of a pathogenic antigen component derived from and/or cross-reactive with the pathogenic agent.
(item Y17A) a method for preventing or treating a disease, wherein the method is administered in the presence of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject, the method comprising administering a non-pathogenic antigen component derived from neither the pathogenic agent of the disease nor cross-reactive with the pathogenic agent.
(item Y18A) the method according to any one of the above items, wherein the pathogenic agent comprises a foreign substance for the subject.
The method according to any one of the above items (item Y19A), wherein the causative agent of the disease comprises causative agent of infectious disease, causative agent of allergy, causative agent of autoimmune disease, or poison.
The method according to any one of the above items (Y20A), wherein the disease is an infectious disease.
The method according to any one of the above items (Y21A), wherein the subject has an immunological memory against the non-pathogenic antigen component.
(item Y22A) the method according to any one of the preceding items, wherein the method comprises administering the pathogenic antigen component.
The method according to any one of the above items (Y23A), wherein the method is for preventing the above-mentioned diseases.
(item Y24A) the method according to any one of the above items, wherein the method prevents or treats the above disease in a form that is not accompanied by or reduces immune overreaction.
(item Y25A) the method according to any one of the preceding items, wherein the method is administered in a form effective for controlling cellular immunity, which is cellular immunity against a causative agent of the disease.
(item Y26A) the method according to any one of the preceding items, wherein the presence or absence of a pathogenic antigenic component in said subject is confirmed, and in the absence, the pathogenic antigenic component is administered together with said non-pathogenic antigenic component, said pathogenic antigenic component being derived from and/or cross-reactive with a pathogenic agent of the target disease.
The method according to any one of the above items (Y27A), wherein the disease is an infection, an allergy or an autoimmune disease.
The method according to any one of the above items (Y28A), wherein the disease is a viral infection or a bacterial infection.
The method according to any one of the above items (Y29A), wherein the disease is a viral infection.
The method according to any one of the above items (Y30A), wherein the disease is an infectious disease associated with coronavirus.
The method according to any one of the above items (Y31A), wherein the pathogenic antigen component is a molecule which is at least partially present on the surface of a pathogenic agent of the target disease.
The method according to any one of the above items (Y32A), wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The method according to any one of the above items (Y33A), wherein the non-pathogenic antigen component is a hot water extract of the Qingshan B strain of Mycobacterium tuberculosis or a part thereof.
The method according to any one of the above items (Y34A), wherein the non-pathogenic antigen component is extract A.
(item Y35A) the method according to any one of the preceding items, wherein the non-pathogenic antigen component comprises a STING agonist derived from Bacillus tuberculosis, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, an Mtb-associated antigen, a component capable of biosynthesis of a STING agonist in human cells, or a NOD2 agonist.
(item Y36A) the method of any one of the preceding items, wherein the non-pathogenic antigen component comprises a STING agonist derived from Bacillus tuberculosis, the STING agonist being c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing 2'3' -cGAMP in human cytoplasm mediated by cGAS.
(item Y37A) the method according to any one of the preceding items, wherein the non-pathogenic antigen component is administered more than twice.
(item Y38A) the method according to any one of the preceding items, wherein the method comprises the steps of:
1) Confirming that the subject has an immune response against the non-pathogenic agent;
2) In the case where the subject has the above-described immune response, the above-described composition is administered to the subject.
(item Y39A) the method according to any one of the above items, wherein the immune response is objectively confirmed.
The method according to any one of the above items (item Y40A), wherein the objective confirmation of the immune response is confirmed by a tuberculin reaction test or a test based on a gamma interferon release test, or objective information contained in a mother-son health manual or an equivalent thereof, medical records or other medical information.
(item Y41A) the method according to any one of the above items, wherein the immune response is examined by a tuberculin reaction test or a gamma interferon release test.
(item Y42A) the method according to any one of the preceding items, wherein the non-pathogenic antigen component or the hot water extract of tubercle bacillus or a part thereof is administered to the subject in advance in the case where the subject does not have the immune response, and then an effective amount of the non-pathogenic antigen component is administered to the subject in the case where the subject is confirmed to have the immune response.
(item Y43A) the method of any one of the above items, wherein the prior administration is repeated until the subject has the immune response.
The method according to any one of the preceding items (item Y44A), wherein the previous administration is before or after the infection is caused.
The method according to any one of the above items (item Y45A), wherein the previous administration is an administration after the infection is suffering from the infection.
(item Y46A) a method for preventing or treating a disease, comprising the steps of: a combination of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject and a non-pathogenic antigen component derived from and cross-reactive with neither the pathogenic agent of the disease is administered.
The method according to any one of the above items (item Y47A), wherein the pathogenic antigen component comprises a pathogenic factor of an infectious disease, a pathogenic agent of an allergic reaction, a pathogenic agent of an autoimmune disease, or a poison.
The method according to any one of the above items (Y48A), wherein the pathogenic antigen component is a bacterium, a virus or a protozoan or a part thereof.
The method according to any one of the above items (Y49A), wherein the pathogenic antigen component is a virus or a part thereof.
The method according to any one of the preceding items (item Y50A), wherein the pathogenic antigen component is a virus belonging to the family Coronaviridae or a part thereof.
(item Y51A) the method according to any one of the above items, wherein the pathogenic agent is a virus belonging to the family selected from the group consisting of rhinovirus, adenovirus, coronavirus, RS virus, influenza virus, parainfluenza virus and enterovirus.
The method according to any one of the above items (Y52A), wherein the pathogenic agent is a virus belonging to the genus coronavirus.
(item Y53A) the method according to any one of the preceding items, wherein the pathogenic agent is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2.
The method according to any one of the above items (Y54A), wherein the pathogenic agent is SARS-CoV-2 virus.
The method according to any one of the above items (Y55A), wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The method according to any one of the above items (Y56A), wherein the non-pathogenic antigen component is a hot water extract of the Qingshan B strain of Mycobacterium tuberculosis or a part thereof.
The method according to any one of the above items (Y57A), wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The method according to any one of the above items (Y58A), wherein the non-pathogenic antigen component is a hot water extract of the Qingshan B strain of Mycobacterium tuberculosis or a part thereof.
The method according to any one of the above items (Y59A), wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item Y60A) the method according to any one of the preceding items, wherein the hot water extract of Bacillus tuberculosis or a part thereof comprises a STING agonist, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, STING agonist, or NOD2 agonist derived from Bacillus tuberculosis.
(item Y61A) the method of any one of the preceding items, wherein the hot water extract of Bacillus tuberculosis or a portion thereof comprises a STING agonist derived from Bacillus tuberculosis, the STING agonist being c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
(item Y62A) the method according to any one of the preceding items, wherein the non-pathogenic antigen component is administered more than twice.
The method according to any one of the above items (item Y63A), wherein the pathogenic antigen component is a pathogenic factor of an infectious disease, and the non-pathogenic antigen component functions as an adjuvant when the pathogenic antigen component is used as a vaccine.
(item Y64A) the method according to any one of the preceding items, wherein the method has the following features:
1) Confirming that the subject has an immune response against the non-pathogenic agent;
2) In the case where the subject has an immune response as described above, one or both of the combinations described above are administered to the subject.
The method according to any one of the above items (item Y65A), wherein the immune response is objectively confirmed.
(item Y66A) the method according to any one of the preceding items, wherein the objective confirmation of the immune response is confirmed by a tuberculin response test or a test based on a gamma interferon release test, or objective information contained in a mother-son health manual or an equivalent thereof, medical records, or other medical information.
(item Y67A) the method according to any one of the preceding items, wherein the immune response is examined by a tuberculin response test or a gamma interferon release test.
(item Y68A) the method according to any one of the preceding items, wherein the non-pathogenic antigen component or the hot water extract of mycobacterium tuberculosis or a part thereof is administered to the subject in advance in the case where the subject does not have the immune response, and then the combination is administered to the subject in the case where it is confirmed that the subject has the immune response.
(item Y69A) the method of any one of the preceding items, wherein the prior administration is repeated until the subject has the immune response.
The method according to any one of the preceding items (item Y70A), wherein the previous administration is administration before or after the infection is caused.
The method according to any one of the above items (item Y71A), wherein the previous administration is after the infection is suffering from.
(item Y72A) a method for preventing or treating a disease, comprising the steps of: administering an effective amount of a combination of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in the subject and a non-pathogenic antigen component that is neither derived from nor cross-reactive with a pathogenic agent of the disease.
(item Y73A) the method of any one of the preceding items, wherein the method further comprises the features of any one or more of the preceding items.
(item Y74A) a method for preventing or treating a disease, comprising the steps of: an effective amount of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject and a non-pathogenic antigen component derived from neither the pathogenic agent nor the pathogenic agent of the disease are administered.
(item Y75A) the method of any one of the preceding items, wherein the method further comprises the features of any one or more of the preceding items.
(item Y76A) a method for preventing or treating a disease in a subject, comprising the steps of: administering to the subject an effective amount of a non-pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of the disease in the subject in the presence of a pathogenic antigen component that is neither derived from nor cross-reactive with a pathogenic agent of the disease.
(item Y77A) the method of any one of the preceding items, wherein the method further comprises the features of any one or more of the preceding items.
(item Y78A) a method for preventing or treating a disease in a subject, comprising the steps of:
administering to the subject an effective amount of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of the disease; and administering to the subject an effective amount of a non-pathogenic antigen component that is neither derived from nor cross-reactive with a pathogenic agent of the disease.
(item Y79A) the method of any one of the preceding items, wherein the method further comprises the features of any one or more of the preceding items.
(item Y80A) a method for disarming or transforming the suppression of regulatory T cells (tregs), wherein the suppression of a regulatory T cell (Treg) refers to the suppression of the activity of a pathogenic agent against an infection, allergy and/or autoimmune disease in a subject or against a cell infected with or comprising the pathogenic agent, the method comprising administering an effective amount of a non-pathogenic antigen component that neither originates from nor cross-reacts with a pathogenic agent of the infection, allergy and/or autoimmune disease that is the target to which the subject has an immune memory.
(item Y81A) the method according to any one of the preceding items, wherein said Treg is transformed into effector T cells (Teff) derived from and/or cross-reactive with a pathogenic agent of a target disease by allowing the presence in said subject of a pathogenic agent antigen component which is directed against a pathogenic agent of the disease or a cell comprising a pathogenic agent of the infectious disease.
(item Y82A) the method of any one of the preceding items, wherein the subject has an immunological memory for the pathogenic agent and/or a factor that cross-reacts with the pathogenic agent.
(item Y83A) the method of any one of the preceding items, wherein the method further comprises the features of any one or more of the preceding items.
(item Y84A) a method for preventing or treating an infectious disease in a subject, comprising administering an effective amount of an antigen component specific for a component different from a causative agent of the infectious disease in the subject.
(item Y85A) a method for preventing or treating an infection in a subject, comprising administering an effective amount of an antigenic component derived from a pathogen of the subject that is different from a past infection of the infection, without substantially comprising administering a causative agent of the infection or a portion thereof.
(item Y86A) a method for preventing or treating an infection other than tuberculosis, comprising administering an effective amount of a Bacillus tuberculosis extract.
(item Y87A) a method for controlling immune enhancement against a causative agent of an infectious disease other than tuberculosis in a subject when the subject is exposed to the causative agent, comprising administering an effective amount of a Bacillus tuberculosis extract.
(item Y88A) a method for preventing or treating an infection, allergy or autoimmune disease in a subject comprising administering an effective amount of an antigenic component specific in the subject, said antigenic component being neither derived from nor cross-reactive with a causative agent of the infection, allergy or autoimmune disease,
the antigenic component is a protein or a portion thereof, or a peptide, and is capable of controlling an immune response mediated by CD4 positive T cells,
the infection, allergy or autoimmune disease includes a disease that can be prevented or treated by an immune response mediated by CD4 positive T cells,
here, it was confirmed whether the subject could control an immune response against an infectious disease, an allergic reaction, or an autoimmune disease mediated by CD4 positive T cells, and the antigen component was administered in a case where the subject could control an immune response against an infectious disease, an allergic reaction, or an autoimmune disease mediated by CD4 positive T cells.
(item Y89A) a method for preventing or treating an infectious disease in a subject, comprising administering an effective amount of an antigen component specific for a component of a causative agent different from the infectious disease in the subject,
the infection comprises a viral infection and the method comprises,
the antigenic component is a protein or a portion thereof, or a peptide, and is capable of controlling an immune response mediated by CD4 positive T cells,
the viral infections include diseases which can be prevented or treated by an immune response mediated by CD4 positive T cells,
here, it is confirmed whether the subject can control an antiviral immune response mediated by CD4 positive T cells, and in the case where the subject can control an antiviral immune response mediated by CD4 positive T cells, an effective amount of the antigen component is administered.
(item Y90A) the method of any one of the preceding items, wherein the method further comprises the features of any one or more of the preceding items.
(item Y91A) a method of making or otherwise providing a composition for preventing or treating an infection, allergy, or autoimmune disease in a subject, wherein the method comprises the steps of:
Step a) identifying an antigenic component specific to the subject, said antigenic component being neither derived from nor cross-reactive with a causative agent of the infection, allergy or autoimmune disease;
step B), determining whether the antigen component has an immunological memory in the subject, and selecting the antigen component having the immunological memory; and
step C) manufacturing or otherwise providing the selected antigen component.
(item Y92A) a method of determining whether an antigenic component specific to a subject, which antigenic component is neither derived from nor cross-reactive with a causative agent of an infectious disease, allergic reaction or autoimmune disease in a subject, can prevent or treat the infectious disease, allergic reaction or autoimmune disease in the subject, comprising the steps of:
step B) is a step of specifying whether or not the antigen component has an immunological memory in the subject, and in the case of having the immunological memory, is specified to be capable of preventing or treating an infection, an allergy or an autoimmune disease in the subject.
(item Y93A) a method for preventing or treating an infectious disease, an allergic reaction, or an autoimmune disease, comprising the steps of:
Step a), obtaining an antigen responsiveness profile of the subject;
step b) of specifying an antigen component or a combination of antigen components based on the antigen responsiveness profile, wherein the antigen component or the combination of antigen components is specified based on whether the subject now exhibits an immune responsiveness or has previously exhibited an immune responsiveness; and
step c) administering to the subject the antigen component or combination of antigen components identified in step b) in an amount sufficient to control an immune response in the subject.
(item Y94A) the method of any one of the preceding items, wherein the method further comprises the features of any one or more of the preceding items.
(item Y95A) an adjuvant for a vaccine against infectious diseases, wherein the adjuvant comprises a hot water extract of Bacillus tuberculosis or a part thereof.
(item Y96A) an adjuvant for a vaccine against an infectious disease, wherein the adjuvant comprises a STING agonist.
(item Y97A) an adjuvant for a vaccine against an infectious disease of a viral infection, wherein the adjuvant comprises a STING agonist.
(item Y98A) the adjuvant according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof is a hot water extract of human type Bacillus tuberculosis Qingshan B strain or a part thereof.
An adjuvant according to any one of the above items (Y99A), wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item Y100A) the adjuvant according to any one of the preceding items, wherein the hot water extract of Bacillus tuberculosis or a part thereof comprises a STING agonist, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, STING agonist, or NOD2 agonist derived from Bacillus tuberculosis.
(item Y101A) an adjuvant according to any one of the preceding items, wherein the hot water extract of tubercule bacillus or a portion thereof comprises a STING agonist derived from tubercule bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
An adjuvant according to any one of the above items (item Y102A), wherein the causative agent of the infection is a bacterium, a virus or a protozoan.
An adjuvant according to any one of the above items (item Y103A), wherein the causative agent of the infection is a virus.
An adjuvant according to any one of the above items (item Y104A), wherein the causative agent of the infection is a virus belonging to the family Coronaviridae.
(item Y105A) the adjuvant according to any one of the above items, wherein the causative agent of the above-mentioned infectious disease is a virus belonging to the family selected from the group consisting of rhinoviruses, adenoviruses, coronaviruses, RS viruses, influenza viruses, parainfluenza viruses and enteroviruses.
An adjuvant according to any one of the above items (item Y106A), wherein the causative agent of the infection is a virus belonging to the genus coronavirus.
(item Y107A) the adjuvant according to any one of the preceding items, wherein the causative agent of the infection is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2.
The adjuvant according to any one of the above items (item Y108A), wherein the causative agent of the infection is SARS-CoV-2 virus.
(item Y109A) the adjuvant according to any one of the preceding items, wherein the adjuvant further comprises the features of any one or more of the preceding items.
(item Y110A) the adjuvant according to any one of the preceding items, wherein the adjuvant converts innate immunity into acquired immunity.
(item Y1B) an antigen component, characterized in that it is a non-pathogenic antigen component for preventing or treating an infectious disease, an allergic reaction and/or an autoimmune disease, which is neither derived from nor cross-reactive with a pathogenic agent of the infectious disease, allergic reaction and/or autoimmune disease in a subject,
The antigen component has the following characteristics:
1) Confirming that the subject has an immune response against the non-pathogenic agent;
2) In the event that the subject has the immune response, the antigenic component is administered to the subject.
(item Y2B) an antigen component, characterized in that it is a non-pathogenic antigen component for preventing or treating an infectious disease, which is neither derived from nor cross-reactive with a pathogenic agent of the infectious disease in a subject,
the antigen component has the following characteristics:
1) Confirming that the subject has an immune response against the non-pathogenic agent;
2) In the event that the subject has the immune response, the antigenic component is administered to the subject.
(item Y3B) a hot water extract of Bacillus tuberculosis or a part thereof, characterized in that it is used for preventing or treating an infectious disease other than tuberculosis in a subject,
the hot water extract of tubercle bacillus or a part thereof has the following characteristics:
1) Confirming that the subject has an immune response against mycobacterium tuberculosis;
2) In the case that the subject has the immune response, the hot water extract of tubercule bacillus, or a portion thereof, is administered to the subject.
(item Y4B) the antigen component, or the hot water extract of Bacillus tuberculosis or a part thereof according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof is a hot water extract of human type Mycobacterium tuberculosis Qingshan B strain.
(item Y5B) the antigen component, or the hot water extract of Bacillus tuberculosis or a part thereof according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item Y6B) the antigen component, or the hot water extract of Bacillus tuberculosis or a part thereof according to any one of the above items, wherein the antigen component, or the hot water extract of Bacillus tuberculosis or a part thereof is administered in an amount effective for producing IL-10.
The antigen component according to any one of the above items, or the hot water extract of tubercle bacillus or a part thereof, wherein the infection is a viral infection.
The antigen component according to any one of the above items, or the hot water extract of tubercle bacillus or a part thereof, wherein the infection is a virus infection associated with coronavirus.
The antigen component according to any one of the above items, or the hot water extract of tubercle bacillus or a part thereof, wherein the immune response is objectively confirmed.
The antigen component according to any one of the above items, or the hot water extract of tubercle bacillus or a part thereof, wherein the objective confirmation of the immune response is confirmed by an examination of tuberculin reaction or an examination based on a gamma interferon release test, or objective information contained in a mother-child health manual or an equivalent thereof, medical records or other medical information.
(item Y11B) the antigen component, or the hot water extract of tubercle bacillus or a part thereof according to any one of the above items, wherein the above immune response is examined by tuberculin reaction examination or gamma interferon release test.
(item Y12B) the antigen component, or the hot water extract of Bacillus tuberculosis or a part thereof according to any one of the above items, wherein the antigen component, or the hot water extract of Bacillus tuberculosis or a part thereof, which is the non-pathogenic factor, is administered to the subject in advance in the case where the subject does not have the above immune response, and then the antigen component, or the hot water extract of Bacillus tuberculosis or a part thereof, is administered to the subject in the case where the subject is confirmed to have the immune response.
The antigen component according to any one of the items described in item Y13B, or the hot water extract of tubercle bacillus or a part thereof, wherein the administration in advance is repeated until the subject has the immune response.
The antigen component according to any one of the items (Y14B), or the hot water extract of tubercle bacillus or a part thereof, wherein the preliminary administration is administration before or after the infection is caused.
The antigen component according to any one of the items (Y15B), or the hot water extract of tubercle bacillus or a part thereof, wherein the preliminary administration is an administration after the infection is suffering from.
(item Y16B) the antigenic component, or the hot water extract of tubercule bacillus, or a part thereof according to any one of the above items, characterized in that the antigenic component, or the hot water extract of tubercule bacillus, or a part thereof, is administered in the presence of a pathogenic agent antigenic component derived from and/or cross-reactive with the pathogenic agent.
(item Y17B) a non-pathogenic antigen component for preventing or treating a disease, wherein the non-pathogenic antigen component is neither derived from nor cross-reactive with a pathogenic agent of the disease, and wherein the non-pathogenic antigen component is administered in the presence of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject.
(item Y18B) the antigen component according to any one of the above items, wherein the pathogenic agent comprises a foreign substance to the subject.
The antigen component according to any one of the above items (item Y19B), wherein the causative agent of the disease comprises causative agent of infectious disease, causative agent of allergy, causative agent of autoimmune disease, or poison.
The antigen component according to any one of the above items (Y20B), wherein the disease is an infectious disease.
The antigen component according to any one of the above items (item Y21B), wherein the subject has an immunological memory against the non-pathogenic antigen component.
(item Y22B) the antigen component according to any one of the above items, wherein the antigen component comprises the above-mentioned pathogenic antigen component.
The antigen component according to any one of the above items (Y23B), wherein the antigen component is used for preventing the above-mentioned diseases.
The antigen component according to any one of the above items (Y24B), wherein the antigen component prevents or treats the disease in a form that does not accompany or reduce an immune excessive reaction.
The antigen component according to any one of the above items (item Y25B), wherein the antigen component is administered in a form effective for controlling cellular immunity against a causative agent of the disease.
(item Y26B) the antigenic component of any one of the preceding items, wherein the presence or absence of a pathogenic antigenic component derived from and/or cross-reactive with a pathogenic agent of a target disease in said subject is confirmed, and in the absence, the pathogenic antigenic component is administered together with said non-pathogenic antigenic component.
The antigen component according to any one of the above items (Y27B), wherein the disease is an infection, an allergy or an autoimmune disease.
The antigen component according to any one of the above items (Y28B), wherein the disease is a viral infection or a bacterial infection.
The antigen component according to any one of the above items (Y29B), wherein the disease is a viral infection.
The antigen component according to any one of the above items (Y30B), wherein the disease is an infectious disease associated with coronavirus.
The antigen component according to any one of the above items (item Y31B), wherein the pathogenic antigen component is a molecule having at least a part of its surface on which a pathogenic agent of a target disease appears.
(item Y32B) the antigen component according to any one of the above items, wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The antigen component according to any one of the above items (item Y33B), wherein the non-pathogenic antigen component is a hot water extract of a strain B of Mycobacterium tuberculosis or a part thereof.
(item Y34B) the antigen component according to any one of the above items, wherein the non-pathogenic antigen component is extract A.
(item Y35B) the antigen component according to any one of the preceding items, wherein the non-pathogenic antigen component comprises a STING agonist derived from Bacillus tuberculosis, lpqH, Y1269, PPD, CMPp 65 overlapping peptide, mtb-related antigen, a component capable of biosynthesis of a STING agonist in human cells, or a NOD2 agonist.
(item Y36B) the antigen component according to any one of the preceding items, wherein the non-pathogenic antigen component comprises a STING agonist derived from Bacillus tuberculosis, the STING agonist being c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing 2'3' -cGAMP in human cytoplasm mediated by cGAS.
(item Y37B) the antigen component according to any one of the above items, wherein the non-pathogenic antigen component is administered twice or more.
(item Y38B) the antigen component according to any one of the above items, wherein the antigen component has the following features:
1) Confirming that the subject has an immune response against the non-pathogenic agent;
2) In the case where the subject has the immune response, the antigen component is administered to the subject.
The antigen component according to any one of the above items (item Y39B), wherein the immune response is objectively confirmed.
The antigen component according to any one of the above items (item Y40B), wherein the objective confirmation of the immune response is confirmed by a tuberculin reaction test or a test based on a gamma interferon release test, or objective information contained in a mother-son health manual or an equivalent thereof, medical records or other medical information.
(item Y41B) the antigen component according to any one of the above items, wherein the above immune response is examined by a tuberculin reaction test or a gamma interferon release test.
(item Y42B) the antigen component according to any one of the above items, wherein the non-pathogenic antigen component or the hot water extract of Bacillus tuberculosis or a part thereof is administered to the subject in advance in the case where the subject does not have the immune response, and then the antigen component is administered to the subject in the case where the subject is confirmed to have the immune response.
The antigen component according to any one of the above items (item Y43B), wherein the administration in advance is repeated until the subject has the immune response.
The antigen component according to any one of the above items (item Y44B), wherein the preliminary administration is administration before or after the infection is caused.
The antigen component according to any one of the above items (item Y45B), wherein the preliminary administration is an administration after the infection is suffering from the infection.
(item Y46B) a combination, characterized in that it is a combination of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject, and a non-pathogenic antigen component derived from or cross-reactive with neither the pathogenic agent of the disease.
(item Y47B) the combination according to any one of the preceding items, wherein the pathogenic antigen component comprises a pathogenic factor of an infectious disease, a pathogenic agent of an allergic reaction, a pathogenic agent of an autoimmune disease, or a poison.
(item Y48B) the combination according to any one of the preceding items, wherein the pathogenic antigen component is a bacterium, a virus or a protozoan or a part thereof.
(item Y49B) the combination according to any one of the preceding items, wherein the pathogenic antigen component is a virus or a part thereof.
(item Y50B) the combination according to any one of the preceding items, wherein the pathogenic antigen component is a virus belonging to the family Coronaviridae or a part thereof.
(item Y51B) the combination according to any one of the preceding items, wherein the pathogenic agent is a virus belonging to the family selected from the group consisting of rhinoviruses, adenoviruses, coronaviruses, RS viruses, influenza viruses, parainfluenza viruses and enteroviruses.
(item Y52B) the combination according to any one of the preceding items, wherein the pathogenic agent is a virus belonging to the genus coronavirus.
(item Y53B) the combination according to any one of the preceding items, wherein the pathogenic agent is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2.
(item Y54B) the combination according to any one of the preceding items, wherein the pathogenic agent is SARS-CoV-2 virus.
(item Y55B) the combination according to any one of the preceding items, wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The combination according to any one of the above items (item Y56B), wherein the non-pathogenic antigen component is a hot water extract of the Qingshan B strain of Mycobacterium tuberculosis or a part thereof.
(item Y57B) the combination according to any one of the preceding items, wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The combination according to any one of the above items (item Y58B), wherein the non-pathogenic antigen component is a hot water extract of the Qingshan B strain of Mycobacterium tuberculosis or a part thereof.
(item Y59B) the combination according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item Y60B) the combination according to any one of the preceding items, wherein the hot water extract of Bacillus tuberculosis or a part thereof comprises a STING agonist, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, STING agonist, or NOD2 agonist derived from Bacillus tuberculosis.
(item Y61B) the combination according to any one of the preceding items, wherein the above tubercule bacillus hot water extract or a portion thereof comprises a STING agonist derived from tubercule bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
(item Y62B) the combination according to any one of the preceding items, wherein the non-pathogenic antigen component is administered more than twice.
The combination according to any one of the above items (item Y63B), wherein the pathogenic antigen component is a pathogenic factor of an infectious disease, and the non-pathogenic antigen component functions as an adjuvant when the pathogenic antigen component is used as a vaccine.
(item Y64B) the combination of any one of the preceding items, wherein the combination has the following features:
1) Confirming that the subject has an immune response against the non-pathogenic agent;
2) In the case where the subject has an immune response as described above, one or both of the combinations described above are administered to the subject.
(item Y65B) the combination according to any of the preceding items, wherein the immune response is objectively confirmed.
(item Y66B) the combination according to any one of the preceding items, wherein the objective confirmation of the immune response is confirmed by a tuberculin response test or a test based on a gamma interferon release test, or objective information contained in a mother-son health manual or an equivalent thereof, medical records, or other medical information.
(item Y67B) the combination according to any one of the preceding items, wherein the immune response is examined by a tuberculin response test or a gamma interferon release test.
(item Y68B) the combination according to any one of the preceding items, wherein the non-pathogenic antigen component or the hot water extract of mycobacterium tuberculosis or a part thereof is administered to the subject in advance in the case where the subject does not have the immune response, and then the combination is administered to the subject in the case where the subject is confirmed to have the immune response.
(item Y69B) the combination according to any one of the preceding items, wherein the prior administration is repeated until the subject has the immune response.
(item Y70B) the combination according to any one of the preceding items, wherein the prior administration is administration before or after the infection.
(item Y71B) the combination according to any one of the preceding items, wherein the prior administration is administration after the infection is suffering from.
(item Y72B) a medicament for preventing or treating a disease, comprising a combination of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject, and a non-pathogenic antigen component derived from or cross-reactive with neither the pathogenic agent of the disease.
(item Y73B) the medicament of any one of the preceding items, wherein the medicament further comprises the features of any one or more of the preceding items.
(item Y74B) A kit for preventing or treating a disease, comprising a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject, and a non-pathogenic antigen component neither derived from nor cross-reactive with a pathogenic agent of the disease.
(item Y75B) the kit of any one of the preceding items, wherein the kit further comprises the features of any one or more of the preceding items.
(item Y76B) an antigen component, characterized in that it is a non-pathogenic antigen component for preventing or treating a disease in a subject, said non-pathogenic antigen component being neither derived from nor cross-reactive with a pathogenic agent of the disease,
the non-pathogenic antigen component is administered to a subject in the presence of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of the disease in the subject.
(item Y77B) the antigen component of any one of the preceding items, wherein the antigen component further comprises the features of any one or more of the preceding items.
(item Y78B) a combination for preventing or treating a disease in a subject, comprising a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of the disease and a non-pathogenic antigen component neither derived from nor cross-reactive with a pathogenic agent of the disease.
(item Y79B) the combination of any one of the preceding items, wherein the combination further comprises the features of any one or more of the preceding items.
(item Y80B) an antigenic component for use in the deregulation or transformation of the suppression of regulatory T cells (tregs), wherein the suppression of regulatory T cells (tregs) refers to the suppression of the activity of a pathogenic agent against an infection, allergy and/or autoimmune disease in a subject or the activity against a cell infected with or comprising the pathogenic agent, said antigenic component being a non-pathogenic antigenic component which neither originates from nor cross-reacts with a pathogenic agent of an infection, allergy and/or autoimmune disease that is the target to which the subject has an immunological memory.
(item Y81B) the antigenic component of any one of the preceding items, wherein said Treg is transformed into effector T cells (Teff) derived from and/or cross-reactive with a pathogenic agent of a target disease by the presence in said subject of a pathogenic agent antigenic component which is directed against a pathogenic agent of the disease or a cell comprising a pathogenic agent of the infection.
(item Y82B) the antigen component according to any one of the preceding items, wherein the subject has an immunological memory against the pathogenic agent and/or a factor cross-reactive with the pathogenic agent.
(item Y83B) the antigen component of any one of the preceding items, wherein the antigen component further comprises the features of any one or more of the preceding items.
(item Y84B) an antigenic component for use in the prevention or treatment of an infection in a subject, characterized in that it is specific for a component different from the causative agent of the infection in the subject.
(item Y85B) an antigenic component for use in the prevention or treatment of an infection in a subject, wherein said antigenic component is derived from a pathogen of the subject that is different from a past infection of the infection and is substantially free of a causative agent of the infection or a part thereof.
(item Y86B) A tubercle bacillus extract for use in the prevention or treatment of an infection other than tuberculosis.
(item Y87B) a tubercle bacillus extract for controlling immune enhancement against a pathogenic agent in a subject when the subject is exposed to the causative agent of an infection other than tuberculosis.
(item Y88B) an antigenic component for use in the prevention or treatment of an infection, allergy or autoimmune disease in a subject, characterized in that it is an antigenic component specific in the subject, said antigenic component being derived neither from nor cross-reactive with a causative agent of the infection, allergy or autoimmune disease,
the antigenic component is a protein or a portion thereof, or a peptide, and is capable of controlling an immune response mediated by CD4 positive T cells,
the infection, allergy or autoimmune disease includes a disease that can be prevented or treated by an immune response mediated by CD4 positive T cells,
here, it was confirmed whether the subject could control an immune response against an infectious disease, an allergic reaction, or an autoimmune disease mediated by CD4 positive T cells, and the antigen component was administered in a case where the subject could control an immune response against an infectious disease, an allergic reaction, or an autoimmune disease mediated by CD4 positive T cells.
(item Y89B) an antigen component for use in preventing or treating an infectious disease in a subject, characterized in that it has specificity for a component different from a causative agent of the infectious disease in the subject,
the infection comprises a viral infection and the method comprises,
the antigenic component is a protein or a portion thereof, or a peptide, and is capable of controlling an immune response mediated by CD4 positive T cells,
the viral infections include diseases which can be prevented or treated by an immune response mediated by CD4 positive T cells,
here, it was confirmed whether the subject could control an antiviral immune response mediated by CD4 positive T cells, and the antigen component was administered in the case where the subject could control an antiviral immune response mediated by CD4 positive T cells.
(item Y90B) the antigenic component of any one of the preceding items, wherein the antigenic component further comprises the features of any one or more of the preceding items.
(item Y91B) a method of making or otherwise providing a composition for preventing or treating an infection, allergy, or autoimmune disease in a subject, wherein the method comprises the steps of:
step a) identifying an antigenic component specific to the subject, said antigenic component being neither derived from nor cross-reactive with a causative agent of the infection, allergy or autoimmune disease;
Step B), determining whether the antigen component has an immunological memory in the subject, and selecting the antigen component having the immunological memory; and
step C) manufacturing or otherwise providing the selected antigen component.
(item Y92B) a method of determining whether an antigenic component specific to the subject, said antigenic component being neither derived from nor cross-reactive with a causative agent of an infectious disease, allergic reaction or autoimmune disease in the subject, can prevent or treat the infectious disease, allergic reaction or autoimmune disease in the subject, comprising the steps of:
step B) is a step of specifying whether or not the antigen component has an immunological memory in the subject, and in the case of having the immunological memory, is specified to be capable of preventing or treating an infection, an allergy or an autoimmune disease in the subject.
(item Y93B) an antigen component for use in a method for preventing or treating an infectious disease, an allergic reaction, or an autoimmune disease, wherein the method comprises the steps of:
step a), obtaining an antigen responsiveness profile of the subject;
step b) of specifying the antigen component or combination of antigen components based on the antigen responsiveness profile, wherein the antigen component or combination of antigen components is specified based on whether the subject is now or has previously been immunocompetent; and
Step c) administering to the subject the antigen component or combination of antigen components identified in step b) in an amount sufficient to control an immune response in the subject.
(item Y94B) the antigenic component of any one of the preceding items, wherein the antigenic component further comprises the features of any one or more of the preceding items.
(item Y95B) an adjuvant for a vaccine against infectious diseases, wherein the adjuvant comprises a hot water extract of Bacillus tuberculosis or a part thereof.
(item Y96B) an adjuvant for a vaccine against an infectious disease, wherein the adjuvant comprises a STING agonist.
(item Y97B) an adjuvant for a vaccine against an infectious disease of a viral infection, wherein the adjuvant comprises a STING agonist.
(item Y98B) the adjuvant according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof is a hot water extract of the strain B of human type Bacillus tuberculosis or a part thereof.
An adjuvant according to any one of the above items (Y99B), wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item Y100B) the adjuvant according to any one of the preceding items, wherein the hot water extract of Bacillus tuberculosis or a part thereof comprises a STING agonist, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, STING agonist, or NOD2 agonist derived from Bacillus tuberculosis.
(item Y101B) an adjuvant according to any one of the preceding items, wherein the hot water extract of tubercule bacillus or a portion thereof comprises a STING agonist derived from tubercule bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
An adjuvant according to any one of the above items (item Y102B), wherein the causative agent of the infection is a bacterium, a virus or a protozoan.
An adjuvant according to any one of the above items (item Y103B), wherein the causative agent of the infection is a virus.
An adjuvant according to any one of the above items (item Y104B), wherein the causative agent of the infection is a virus belonging to the family Coronaviridae.
(item Y105B) the adjuvant according to any one of the above items, wherein the causative agent of the above-mentioned infectious disease is a virus belonging to the family selected from the group consisting of rhinoviruses, adenoviruses, coronaviruses, RS viruses, influenza viruses, parainfluenza viruses and enteroviruses.
An adjuvant according to any one of the above items (item Y106B), wherein the causative agent of the infection is a virus belonging to the genus coronavirus.
(item Y107B) the adjuvant according to any one of the preceding items, wherein the causative agent of the infection is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2.
The adjuvant according to any one of the above items (item Y108B), wherein the causative agent of the infection is SARS-CoV-2 virus.
(item Y109B) the adjuvant according to any one of the preceding items, wherein the adjuvant further comprises the features of any one or more of the preceding items.
(item Y110B) the adjuvant according to any one of the preceding items, wherein the adjuvant converts natural immunity to acquisition immunity.
(item Y1C) use of a non-pathogenic antigen component for the manufacture of a medicament for preventing or treating an infectious disease, an allergic reaction and/or an autoimmune disease, wherein the non-pathogenic antigen component is neither derived from nor cross-reactive with a pathogenic agent of the infectious disease, allergic reaction and/or autoimmune disease in a subject,
the antigen component has the following characteristics:
1) Confirming that the subject has an immune response against the non-pathogenic agent;
2) In the event that the subject has the immune response, the antigenic component is administered to the subject.
(item Y2C) use of a non-pathogenic antigen component for the manufacture of a medicament for preventing or treating an infectious disease, wherein the non-pathogenic antigen component is neither derived from nor cross-reactive with a pathogenic agent of the infectious disease of a subject,
the antigen component has the following characteristics:
1) Confirming that the subject has an immune response against the non-pathogenic agent;
2) In the event that the subject has the immune response, the antigenic component is administered to the subject.
The use of the hot water extract of Mycobacterium tuberculosis of item Y3C or a part thereof for preventing or treating an infectious disease other than tuberculosis in a subject, wherein,
the hot water extract of tubercle bacillus or a part thereof has the following characteristics:
1) Confirming that the subject has an immune response against tuberculosis;
2) In the case that the subject has the immune response, the hot water extract of tubercule bacillus, or a portion thereof, is administered to the subject.
The use according to any one of the above items (item Y4C), wherein the hot water extract of Mycobacterium tuberculosis or a part thereof is a hot water extract of Mycobacterium tuberculosis Qingshan B strain or a part thereof.
The use according to any one of the above items (Y5C), wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item Y6C) the use according to any one of the preceding items, wherein the above composition is administered in an amount effective to produce IL-10.
The use according to any one of the above items (item Y7C), wherein the infection is a viral infection.
The use according to any one of the above items (Y8C), wherein the infection is a coronavirus-related viral infection.
(item Y9C) the use according to any one of the above items, wherein the immune response is objectively confirmed.
(item Y10C) the use according to any one of the above items, wherein the objective confirmation of the immune response is confirmed by a tuberculin reaction test or a test based on a gamma interferon release test, or objective information contained in a mother-son health manual or an equivalent thereof, medical records, or other medical information.
(item Y11C) the use according to any one of the above items, wherein the immune response is examined by a tuberculin response test or a gamma interferon release test.
(item Y12C) the use according to any one of the above items, wherein the non-pathogenic antigen component or the hot water extract of tubercule bacillus or a part thereof is administered to the subject in advance in the case where the subject does not have the immune response, and then the hot water extract of tubercule bacillus or a part thereof is administered to the subject in the case where the subject is confirmed to have the immune response.
(item Y13C) the use according to any one of the above items, wherein the administration in advance is repeated until the subject has the immune response.
(item Y14C) the use according to any one of the preceding items, wherein the prior administration is administration before or after the infection is suffered.
(item Y15C) the use according to any one of the above items, wherein the prior administration is administration after the infection is suffering from.
(item Y16C) the use according to any one of the preceding items, wherein the administration is carried out in the presence of a pathogenic antigen component derived from and/or cross-reactive with the pathogenic agent.
(item Y17C) use of a non-pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a disease in a subject, in the manufacture of a medicament for preventing or treating the disease, wherein the non-pathogenic antigen component is administered in the presence of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in the subject.
(item Y18C) the use according to any one of the above items, wherein the pathogenic agent comprises a foreign substance for the subject.
(item Y19C) the use according to any one of the above items, wherein the causative agent of the above disease comprises causative agent of infectious disease, causative agent of allergy, causative agent of autoimmune disease, or poison.
The use according to any one of the above items (item Y20C), wherein the disease is an infectious disease.
(item Y21C) the use according to any one of the above items, wherein the subject has an immunological memory against the non-pathogenic antigen component.
(item Y22C) the use according to any one of the above items, wherein the agent comprises the above-mentioned pathogenic antigen component.
The use according to any one of the above items (Y23C), wherein the antigen component is used for preventing the disease.
(item Y24C) the use according to any one of the above items, wherein the above antigen component prevents or treats the above disease in a form that does not accompany or reduce an immune excessive reaction.
The use according to any one of the above items (item Y25C), wherein the antigen component is administered in a form effective for controlling cellular immunity against a causative agent of the disease.
(item Y26C) the use according to any of the preceding items, characterized in that it is confirmed whether a pathogenic antigen component is present in the subject and, in the absence, the pathogenic antigen component is administered together with the non-pathogenic antigen component, which pathogenic antigen component is derived from and/or cross-reacts with the pathogenic agent of the target disease.
(item Y27C) the use according to any one of the above items, wherein the disease is an infection, allergy or autoimmune disease.
The use according to any one of the above items (item Y28C), wherein the disease is a viral infection or a bacterial infection.
The use according to any one of the above items (item Y29C), wherein the disease is a viral infection.
The use according to any one of the above items (item Y30C), wherein the disease is an infectious disease associated with coronavirus.
The use according to any one of the above items (item Y31C), wherein the pathogenic antigen component is a molecule having at least a part of its surface on which a pathogenic agent of a target disease appears.
The use according to any one of the above items (Y32C), wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The use according to any one of the above items (item Y33C), wherein the non-pathogenic antigen component is a hot water extract of the Qingshan B strain of Mycobacterium tuberculosis or a part thereof.
(item Y34C) the use according to any one of the above items, wherein the non-pathogenic antigen component is extract A.
(item Y35C) the use according to any one of the preceding items, wherein the non-pathogenic antigen component comprises a STING agonist derived from Bacillus tuberculosis, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, an Mtb-related antigen, a component capable of biosynthesis of a STING agonist in human cells, or a NOD2 agonist.
(item Y36C) the use according to any one of the preceding items, wherein the non-pathogenic antigen component comprises a STING agonist derived from Bacillus tuberculosis, which is C-di-AMP, C-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing 2'3' -cGAMP in human cytoplasm mediated by cGA S.
(item Y37C) the use according to any one of the above items, wherein the non-pathogenic antigen component is administered twice or more.
(item Y38C) the use according to any one of the above items, wherein the antigen component has the following features:
1) Confirming that the subject has an immune response against the non-pathogenic agent;
2) In the case where the subject has the immune response, the antigen component is administered to the subject.
(item Y39C) the use according to any one of the above items, wherein the above immune response is objectively confirmed.
(item Y40C) the use according to any one of the above items, wherein the objective confirmation of the immune response is confirmed by a tuberculin reaction test or a test based on a gamma interferon release test, or objective information contained in a mother-son health manual or an equivalent thereof, medical records or other medical information.
(item Y41C) the use according to any one of the above items, wherein the immune response is examined by tuberculin reaction examination or gamma interferon release test.
(item Y42C) the use according to any one of the preceding items, wherein the non-pathogenic antigen component or the hot water extract of tubercle bacillus or a part thereof is administered to the subject in advance in the case where the subject does not have the immune response, and then the antigen component is administered to the subject in the case where the subject is confirmed to have the immune response.
(item Y43C) the use according to any one of the above items, wherein the administration in advance is repeated until the subject has the immune response.
(item Y44C) the use according to any one of the preceding items, wherein the prior administration is administration before or after the infection is suffered.
(item Y45C) the use according to any one of the above items, wherein the prior administration is administration after the infection is suffering from.
(item Y46C) use of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject, in combination with a non-pathogenic antigen component neither derived from nor cross-reactive with a pathogenic agent of the disease, for the manufacture of a medicament for the prevention or treatment of the disease.
(item Y47C) the use according to any one of the above items, wherein the pathogenic antigen component comprises a pathogenic factor of an infectious disease, a pathogenic substance of an allergic reaction, a pathogenic substance of an autoimmune disease, or a poison.
(item Y48C) the use according to any one of the above items, wherein the pathogenic antigen component is a bacterium, a virus or a protozoan or a part thereof.
The use according to any one of the above items (item Y49C), wherein the pathogenic antigen component is a virus or a part thereof.
(item Y50C) the use according to any one of the above items, wherein the pathogenic antigen component is a virus belonging to the family Coronaviridae or a part thereof.
(item Y51C) the use according to any one of the above items, wherein the pathogenic agent is a virus belonging to the family selected from the group consisting of rhinovirus, adenovirus, coronavirus, RS virus, influenza virus, parainfluenza virus and enterovirus.
(item Y52C) the use according to any one of the above items, wherein the pathogenic agent is a virus belonging to the genus coronavirus.
(item Y53C) the use according to any one of the preceding items, wherein the pathogenic agent is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2.
(item Y54C) the use according to any one of the above items, wherein the pathogenic agent is SARS-CoV-2 virus.
The use according to any one of the above items (item Y55C), wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The use according to any one of the above items (item Y56C), wherein the non-pathogenic antigen component is a hot water extract of the Qingshan B strain of Mycobacterium tuberculosis or a part thereof.
The use according to any one of the above items (Y57C), wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The use according to any one of the above items (item Y58C), wherein the non-pathogenic antigen component is a hot water extract of the Qingshan B strain of Mycobacterium tuberculosis or a part thereof.
The use according to any one of the above items (Y59C), wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item Y60C) the use according to any one of the preceding items, wherein the hot water extract of Bacillus tuberculosis or a part thereof comprises a STING agonist, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, STING agonist, or NOD2 agonist derived from Bacillus tuberculosis.
(item Y61C) the use according to any one of the preceding items, wherein the hot water extract of tubercle bacillus or a part thereof comprises a STING agonist derived from tubercle bacillus, which is C-di-AMP, C-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
(item Y62C) the use according to any one of the above items, wherein the non-pathogenic antigen component is administered twice or more.
The use according to any one of the above items (item Y63C), wherein the pathogenic antigen component is a pathogenic factor of an infectious disease, and the non-pathogenic antigen component functions as an adjuvant when the pathogenic antigen component is used as a vaccine.
(item Y64C) the use according to any one of the above items, wherein the use has the following features:
1) Confirming that the subject has an immune response against the non-pathogenic agent;
2) In the case where the subject has an immune response as described above, one or both of the combinations described above are administered to the subject.
(item Y65C) the use according to any one of the above items, wherein the immune response is objectively confirmed.
(item Y66C) the use according to any one of the above items, wherein the objective confirmation of the immune response is confirmed by a tuberculin reaction test or a test based on a gamma interferon release test, or objective information contained in a mother-son health manual or an equivalent thereof, medical records or other medical information.
(item Y67C) the use according to any one of the preceding items, wherein the immune response is examined by a tuberculin response test or a gamma interferon release test.
(item Y68C) the use according to any one of the preceding items, wherein the non-pathogenic antigen component or the hot water extract of mycobacterium tuberculosis or a part thereof is administered to the subject in advance in the case where the subject does not have the immune response, and then the combination is administered to the subject in the case where the subject is confirmed to have the immune response.
(item Y69C) the use according to any one of the preceding items, wherein the administration in advance is repeated until the subject has the immune response.
(item Y70C) the use according to any one of the preceding items, wherein the prior administration is administration before or after the infection is suffered.
(item Y71C) the use according to any one of the above items, wherein the prior administration is an administration after the infection is suffering from.
The use of a combination of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject and a non-pathogenic antigen component neither derived from nor cross-reactive with a pathogenic agent of the disease (item Y72C) for the manufacture of a medicament for preventing or treating the disease.
(item Y73C) the use according to any one of the preceding items, wherein the use further comprises the features of any one or more of the preceding items.
(item Y74C) use of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject, and a non-pathogenic antigen component neither derived from nor cross-reactive with a pathogenic agent of the disease, in the manufacture of a kit for preventing or treating the disease.
(item Y75C) the use according to any one of the preceding items, wherein the use further comprises the features of any one or more of the preceding items.
(item Y76C) use of a non-pathogenic antigen component for the manufacture of a medicament for preventing or treating a disease in a subject, wherein the non-pathogenic antigen component is neither derived from nor cross-reactive with a pathogenic agent of the disease,
administering to the subject an effective amount of the non-pathogenic antigen component in the presence of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of the disease in the subject.
(item Y77C) the use according to any one of the preceding items, wherein the use further comprises the features of any one or more of the preceding items.
(item Y78C) use of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a disease and a non-pathogenic antigen component neither derived from nor cross-reactive with a pathogenic agent of the disease in a method for preventing or treating the disease in a subject.
(item Y79C) the use according to any one of the preceding items, wherein the use further comprises the features of any one or more of the preceding items.
The use of the non-pathogenic antigen component of item Y80C for the manufacture of a medicament for relieving or transforming the inhibition of regulatory T cells (tregs) that are neither derived from nor cross-reactive with an infectious, allergic and/or autoimmune disease that is a target in a subject having an immunological memory against the antigen component.
(item Y81C) the use according to any one of the preceding items, characterized in that said Treg is transformed into effector T cells (Teff) derived from and/or cross-reactive with a pathogenic agent of a target disease by the presence in said subject of a pathogenic agent antigen component which is directed against a pathogenic agent of the disease or a cell comprising a pathogenic agent of the infectious disease.
(item Y82C) the use according to any one of the preceding items, wherein the subject has an immunological memory for the pathogenic agent and/or a factor cross-reactive with the pathogenic agent.
(item Y83C) the use according to any one of the preceding items, wherein the use further comprises the features of any one or more of the preceding items.
The use of the antigen component of item Y84C for the manufacture of a medicament for preventing or treating an infection in a subject, wherein the antigen component is specific for a component different from a causative agent of the infection in the subject.
The use of the antigen component of item Y85C for the manufacture of a medicament for preventing or treating an infection of a subject, wherein the antigen component is derived from a pathogen of the subject that is different from a past infection of the infection and is substantially free of a causative agent of the infection or a portion thereof.
(item Y86C) use of a Bacillus tuberculosis extract for the manufacture of a medicament for preventing or treating an infection other than tuberculosis.
(item Y87C) use of a tubercle bacillus extract for the manufacture of a medicament for controlling immune enhancement against a causative agent of an infection other than tuberculosis in a subject when the subject is exposed to the causative agent.
(item Y88C) use of an antigen component specific to a subject for the manufacture of a medicament for preventing or treating an infection, allergy or autoimmune disease in a subject, wherein the antigen component is neither derived from nor cross-reacts with a causative agent of the infection, allergy or autoimmune disease,
the antigenic component is a protein or a portion thereof, or a peptide, and is capable of controlling an immune response mediated by CD4 positive T cells,
the infection, allergy or autoimmune disease includes a disease that can be prevented or treated by an immune response mediated by CD4 positive T cells,
here, it was confirmed whether the subject could control an immune response against an infectious disease, an allergic reaction, or an autoimmune disease mediated by CD4 positive T cells, and the antigen component was administered in a case where the subject could control an immune response against an infectious disease, an allergic reaction, or an autoimmune disease mediated by CD4 positive T cells.
The use of the antigen component of item Y89C for producing a medicament for preventing or treating an infectious disease, an allergic reaction or an autoimmune disease in a subject, characterized in that the antigen component has specificity for a component different from a causative agent of the infectious disease in the subject,
the infection comprises a viral infection and the method comprises,
the antigenic component is a protein or a portion thereof, or a peptide, and is capable of controlling an immune response mediated by CD4 positive T cells,
the viral infections include diseases which can be prevented or treated by an immune response mediated by CD4 positive T cells,
here, it was confirmed whether the subject could control an antiviral immune response mediated by CD4 positive T cells, and the antigen component was administered in the case where the subject could control an antiviral immune response mediated by CD4 positive T cells.
(item Y90C) the use according to any one of the preceding items, wherein the use further comprises the features of any one or more of the preceding items.
(item Y91C) a method of making or otherwise providing a composition for preventing or treating an infection, allergy, or autoimmune disease in a subject, wherein the method comprises the steps of:
Step a) identifying an antigenic component specific to the subject, said antigenic component being neither derived from nor cross-reactive with a causative agent of the infection, allergy or autoimmune disease;
step B), determining whether the antigen component has an immunological memory in the subject, and selecting the antigen component having the immunological memory; and
step C) manufacturing or otherwise providing the selected antigen component.
(item Y92C) a method of determining whether an antigenic component specific to a subject, said antigenic component being neither derived from nor cross-reactive with a causative agent of an infectious disease, allergic reaction or autoimmune disease in the subject, can prevent or treat the infectious disease, allergic reaction or autoimmune disease in the subject, comprising the steps of:
step B) is a step of specifying whether or not the antigen component has an immunological memory in the subject, and in the case of having the immunological memory, is specified to be capable of preventing or treating an infection, an allergy or an autoimmune disease in the subject.
(item Y93C) use of an antigen component or combination of antigen components in the manufacture of a medicament for use in a method for preventing or treating an infectious disease, allergy or autoimmune disease, wherein the method comprises the steps of:
Step a), obtaining an antigen responsiveness profile of the subject;
step b) of specifying an antigen component or a combination of antigen components based on the antigen responsiveness profile, wherein the antigen component or the combination of antigen components is specified based on whether the subject now exhibits an immune responsiveness or has previously exhibited an immune responsiveness; and
step c) administering to the subject the antigen component or combination of antigen components identified in step b) in an amount sufficient to control an immune response in the subject.
(item Y94C) the use according to any one of the preceding items, wherein the use further comprises the features of any one or more of the preceding items.
(item Y95C) use of a hot water extract of Mycobacterium tuberculosis or a part thereof for the manufacture of an adjuvant for a vaccine against infectious diseases.
(item Y96C) use of an STING agonist in the manufacture of an adjuvant for a vaccine against an infectious disease.
(item Y97C) use of an STING agonist in the manufacture of an adjuvant for a vaccine against an infectious disease of a viral infection.
(item Y98C) the use according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof is a hot water extract of the strain B of human type Bacillus tuberculosis or a part thereof.
The use according to any one of the above items (Y99C), wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item Y100C) the use according to any one of the preceding items, wherein the hot water extract of Bacillus tuberculosis or a part thereof comprises a STING agonist, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, STING agonist, or NOD2 agonist derived from Bacillus tuberculosis.
(item Y101C) the use according to any one of the preceding items, wherein the above tubercule bacillus hot water extract or a part thereof comprises a STING agonist derived from tubercule bacillus, which is C-di-AMP, C-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
(item Y102C) the use according to any one of the above items, wherein the causative agent of the infection is a bacterium, a virus or a protozoan.
The use according to any one of the above items (item Y103C), wherein the causative agent of the infection is a virus.
The use according to any one of the above items (item Y104C), wherein the causative agent of the infection is a virus belonging to the family Coronaviridae.
(item Y105C) the use according to any one of the preceding items, wherein the causative agent of the infection is a virus belonging to the family selected from the group consisting of rhinoviruses, adenoviruses, coronaviruses, RS viruses, influenza viruses, parainfluenza viruses and enteroviruses.
The use according to any one of the above items (item Y106C), wherein the causative agent of the infection is a virus belonging to the genus coronavirus.
(item Y107C) the use according to any one of the preceding items, wherein the causative agent of the infection is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2.
The use according to any one of the above items (item Y108C), wherein the causative agent of the infection is SARS-CoV-2 virus.
(item Y109C) the use according to any one of the preceding items, wherein the use further comprises the features of any one or more of the preceding items.
(item Y110C) the use of any one of the preceding items, wherein the adjuvant converts natural immunity to acquisition immunity.
(item X1) a composition for preventing or treating a disease, characterized in that the composition comprises a non-pathogenic antigen component that is neither derived from nor cross-reactive with a pathogenic agent of the disease, the composition being administered in the presence of a pathogenic antigen component that is derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject.
The composition according to any one of the above items (X2), wherein the pathogenic agent comprises a foreign substance for the subject.
The composition according to any one of the above items (X3), wherein the causative agent of the disease comprises causative agent of infectious disease, causative agent of allergy, causative agent of autoimmune disease, or poison.
The composition according to any one of the above items (X4), wherein the disease is an infectious disease.
The composition according to any one of the above items (X5), wherein the subject has an immunological memory against the non-pathogenic antigen component.
(item X6) the composition according to any one of the above items, wherein the composition comprises the above pathogenic antigen component.
(item X7) the composition according to any one of the above items, wherein the composition is for preventing a disease.
The composition according to any one of the above items (X8), wherein the composition prevents or treats the above-mentioned diseases in a form in which the immune excessive reaction is not accompanied or reduced.
The composition according to any one of the above items (item X9), wherein the composition is administered in a form effective for controlling cellular immunity, which is a cellular immunity against a causative agent of the disease.
(item X10) the composition of any one of the preceding items, wherein the presence or absence of a pathogenic agent antigen component in the subject is confirmed, and in the absence, the pathogenic agent antigen component is administered together with the non-pathogenic agent antigen component, wherein the pathogenic agent antigen component is derived from and/or cross-reacts with a pathogenic agent of the target disease.
The composition according to any one of the above items (X11), wherein the disease is an infection, an allergy or an autoimmune disease.
The composition according to any one of the above items (X12), wherein the disease is a viral infection or a bacterial infection.
The composition according to any one of the above items (X13), wherein the disease is a viral infection.
The composition according to any one of the above items (X14), wherein the disease is an infectious disease associated with coronavirus.
The composition according to any one of the above items (X15), wherein the pathogenic antigen component is a molecule which is at least partially present on the surface of a pathogenic agent of a target disease.
(item X15A) the composition according to any one of the above items, wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The composition according to any one of the above items (X15B), wherein the non-pathogenic antigen component is a hot water extract of the Qingshan B strain of Mycobacterium tuberculosis or a part thereof.
(item X15C) the composition according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item X15D) the composition of any one of the preceding items, wherein the hot water extract of Bacillus tuberculosis or a portion thereof comprises a STING agonist, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, STING agonist, or NOD2 agonist derived from Bacillus tuberculosis.
(item X15E) the composition of any one of the preceding items, wherein the hot water extract of tubercle bacillus or a portion thereof comprises a STING agonist derived from tubercle bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
(item X15F) the composition according to any one of the preceding items, wherein the non-pathogenic antigen component is administered more than twice.
(item X16) a combination, characterized in that it is a combination of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject, and a non-pathogenic antigen component derived from or cross-reactive with neither the pathogenic agent of the disease.
(item X17) the combination according to any one of the preceding items, wherein the pathogenic antigen component comprises a pathogenic agent of an infectious disease, a pathogenic agent of an allergic reaction, a pathogenic agent of an autoimmune disease, or a poison.
(item X18) the combination according to any one of the preceding items, wherein the pathogenic antigen component is a bacterium, a virus or a protozoan or a part thereof.
The combination according to any one of the preceding items (item X19), wherein the pathogenic antigen component is a virus or a part thereof.
(item X20) the combination according to any one of the preceding items, wherein the pathogenic antigen component is a virus belonging to the family Coronaviridae or a part thereof.
(item X21) the combination according to any one of the preceding items, wherein the pathogenic agent is a virus belonging to the family selected from the group consisting of rhinovirus, adenovirus, coronavirus, RS virus, influenza virus, parainfluenza virus and enterovirus.
(item X22) the combination according to any one of the preceding items, wherein the pathogenic agent is a virus belonging to the genus coronavirus.
(item X23) the combination according to any one of the preceding items, wherein the pathogenic agent is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2.
(item X24) the combination according to any one of the preceding items, wherein the pathogenic agent is SARS-CoV-2 virus.
(item X25) the combination according to any one of the preceding items, wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The combination according to any one of the above items (X26), wherein the non-pathogenic antigen component is a hot water extract of the B strain of human tubercle bacillus or a part thereof.
(item X26A) the combination according to any one of the preceding items, wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The combination according to any one of the above items (X26B), wherein the non-pathogenic antigen component is a hot water extract of the Qingshan B strain of Mycobacterium tuberculosis or a part thereof.
(item X26C) the combination according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item X26D) the combination according to any one of the preceding items, wherein the tubercle bacillus hot water extract or a part thereof comprises a STING agonist, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, STING agonist, or NOD2 agonist derived from tubercle bacillus.
(item X26E) the combination according to any one of the preceding items, wherein the above tubercule bacillus hot water extract or a portion thereof comprises a STING agonist derived from tubercule bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
(item X26F) the combination according to any one of the preceding items, wherein the non-pathogenic antigen component is administered more than twice.
The combination according to any one of the above items (item X26G), wherein the pathogenic antigen component is a pathogenic factor of an infectious disease, and the non-pathogenic antigen component functions as an adjuvant when the pathogenic antigen component is used as a vaccine.
(item X27) a medicament for preventing or treating a disease, comprising a combination of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject, and a non-pathogenic antigen component derived from or cross-reactive with neither the pathogenic agent of the disease.
(item X27A) the medicament according to any one of the above items, wherein the pathogenic agent comprises a foreign substance for the subject.
The medicine according to any one of the above items (item X27B), wherein the causative agent of the above-mentioned disease comprises causative agent of infectious disease, causative agent of allergy, causative agent of autoimmune disease, or poison.
The drug according to any one of the above items (X27C), wherein the disease is an infectious disease.
The drug according to any one of the above items (X27D), wherein the subject has an immunological memory against the non-pathogenic antigen component.
(item X27E) the medicament according to any one of the above items, wherein the medicament is for preventing the above diseases.
(item X27F) the medicament according to any one of the above items, wherein the medicament prevents or treats the above diseases in a form not accompanied by or reducing an immune excess reaction.
The drug according to any one of the above items (item X27G), wherein the drug is administered in a form effective for controlling cellular immunity, which is a cellular immunity against a causative agent of the disease.
The drug according to any one of the above items (X27H), wherein the disease is an infection, an allergy or an autoimmune disease.
The drug according to any one of the above items (X27I), wherein the disease is a viral infection or a bacterial infection.
The drug according to any one of the above items (X27J), wherein the disease is a viral infection.
The drug according to any one of the above items (X27K), wherein the disease is an infectious disease associated with coronavirus.
The drug according to any one of the above items (X27L), wherein the pathogenic antigen component is a molecule at least a part of which is present on the surface of the membrane.
The medicament according to any of the above items (X27 AA), wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The drug according to any one of the above items (item X27 AB), wherein the non-pathogenic antigen component is a hot water extract of the Qingshan B strain of Mycobacterium tuberculosis or a part thereof.
(item X27 AC) the medicament according to any one of the preceding items, wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item X27 AD) the medicament according to any one of the preceding items, wherein the hot water extract of tubercle bacillus or a part thereof comprises a STING agonist, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, STING agonist, or NOD2 agonist derived from tubercle bacillus.
(item X27 AE) the medicament of any one of the preceding items, wherein the hot water extract of tubercle bacillus or a portion thereof comprises c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP derived from a STING agonist of tubercle bacillus and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
(item X27 AF) the medicament according to any one of the preceding items, wherein the non-pathogenic antigen component is administered twice or more.
The drug according to any one of the above items (X27 AG), wherein the pathogenic antigen component is a pathogenic factor of an infectious disease, and the non-pathogenic antigen component functions as an adjuvant when the pathogenic antigen component is used as a vaccine.
(item X28) A kit for preventing or treating a disease, comprising a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject, and a non-pathogenic antigen component neither derived from nor cross-reactive with a pathogenic agent of the disease.
(item X28A) the kit according to any one of the above items, wherein the pathogenic agent comprises a foreign substance to the subject.
(item X28B) the kit according to any one of the above items, wherein the causative agent of the above disease comprises causative agent of infectious disease, causative agent of allergy, causative agent of autoimmune disease, or poison.
The kit according to any one of the above items (X28C), wherein the disease is an infectious disease.
The kit according to any one of the above items (X28D), wherein the subject has an immunological memory against the non-pathogenic antigen component.
(item X28E) the kit according to any one of the above items, wherein the above kit is for preventing or treating the above diseases.
The kit according to any one of the above items (X28F), wherein the above kit prevents or treats the above disease in a form in which the immune excess reaction is not accompanied or reduced.
(item X28G) the kit according to any one of the above items, wherein the above kit is administered in a form effective for controlling cellular immunity, which is cellular immunity against a causative agent of the above disease.
The kit according to any one of the above items (X28H), wherein the disease is an infection, an allergy or an autoimmune disease.
The kit according to any one of the above items (X28I), wherein the disease is a viral infection or a bacterial infection.
The kit according to any one of the above items (X28J), wherein the disease is a viral infection.
The kit according to any one of the above items (X28K), wherein the disease is an infectious disease associated with coronavirus.
The kit according to any one of the above items (X28L), wherein the pathogenic antigen component is a molecule at least partially present on the surface of the membrane.
(item X28 AA) the kit according to any one of the above items, wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The kit according to any one of the above items (item X28 AB), wherein the non-pathogenic antigen component is a hot water extract of the Qingshan B strain of Mycobacterium tuberculosis or a part thereof.
(item X28 AC) the kit according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item X28 AD) the kit according to any one of the preceding items, wherein the hot water extract of tubercle bacillus or a part thereof comprises a STING agonist, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, STING agonist, or NOD2 agonist derived from tubercle bacillus.
(item X28 AE) the kit of any one of the preceding items, wherein the hot water extract of tubercle bacillus or a portion thereof comprises a STING agonist derived from tubercle bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
(item X28 AF) the kit according to any one of the above items, wherein the non-pathogenic antigen component is administered twice or more.
The kit according to any one of the above items (X28 AG), wherein the pathogenic antigen component is a pathogenic factor of an infectious disease, and the non-pathogenic antigen component functions as an adjuvant when the pathogenic antigen component is used as a vaccine.
(item X29) a method for preventing or treating a disease in a subject, comprising the steps of:
administering to the subject an effective amount of a non-pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of the disease in the subject in the presence of a pathogenic agent antigen component that is neither derived from nor cross-reactive with a pathogenic agent of the disease.
(item X30) a method for preventing or treating a disease in a subject, comprising the steps of:
administering to the subject an effective amount of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of the disease; and administering to the subject an effective amount of a non-pathogenic antigen component that is neither derived from nor cross-reactive with a pathogenic agent of the disease.
(item X30A) the method according to any one of the above items, wherein the pathogenic agent comprises a foreign substance for the subject.
(item X30B) the method according to any one of the above items, wherein the causative agent of the above disease comprises causative agent of infectious disease, causative agent of allergy, causative agent of autoimmune disease, or poison.
The method according to any one of the above items (X30C), wherein the disease is an infectious disease.
(item X30D) the method according to any one of the above items, wherein the subject has an immunological memory to the non-pathogenic antigen component.
(item X30E) the method according to any one of the above items, for preventing the above-described diseases.
(item X30F) the method according to any one of the above items for preventing or treating the above-described diseases in a form not accompanied by or reduced in immune overreaction.
(item X30G) the method according to any one of the preceding items, wherein the non-pathogenic antigen component is administered in a form effective for controlling cellular immunity against a pathogenic agent of the disease.
The method according to any one of the above items (X30H), wherein the disease is an infection, an allergy or an autoimmune disease.
The method according to any one of the above items (X30I), wherein the disease is a viral infection or a bacterial infection.
The method according to any one of the above items (X30J), wherein the disease is a viral infection.
The method according to any one of the above items (X30K), wherein the disease is an infection associated with coronavirus.
The method according to any one of the above items (X30L), wherein the pathogenic antigen component is a molecule at least a part of which is present on the surface of the membrane.
(item X30 AA) the method according to any one of the above items, wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The method according to any one of the above items (X30 AB), wherein the non-pathogenic antigen component is a hot water extract of the Qingshan B strain of Mycobacterium tuberculosis or a part thereof.
(item X30 AC) the method according to any one of the above items, wherein the above tubercle bacillus hot water extract or a part thereof is extract A.
(item X30 AD) the method according to any one of the preceding items, wherein the hot water extract of Bacillus tuberculosis or a part thereof comprises a STING agonist, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, STING agonist, or NOD2 agonist derived from Bacillus tuberculosis.
(item X30 AE) the method of any one of the preceding items, wherein the hot water extract of tubercle bacillus or a portion thereof comprises a STING agonist derived from tubercle bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
(item X30 AF) the method according to any one of the preceding items, wherein said non-pathogenic antigen component is administered more than twice.
The method according to any one of the above items (X30 AG), wherein the pathogenic antigen component is a pathogenic factor of an infectious disease, and the non-pathogenic antigen component functions as an adjuvant when the pathogenic antigen component is used as a vaccine.
(item X31) a composition for use in relieving or transforming the suppression of regulatory T cells (tregs), wherein the suppression of regulatory T cells (tregs) refers to the suppression of the activity of a pathogenic agent against an infection, allergy and/or autoimmune disease in a subject or against a cell infected with or comprising the pathogenic agent, the composition comprising a non-pathogenic antigen component that is neither derived from nor cross-reacts with a pathogenic agent of an infection, allergy and/or autoimmune disease that is a target to which the subject has an immunological memory.
(item X32) the composition of any one of the preceding items, wherein said Treg is transformed into effector T cells (Teff) derived from and/or cross-reactive with a pathogenic agent of a target disease by the presence in said subject of a pathogenic agent antigen component which is directed against or comprises a cell of a pathogenic agent of the disease (an infectious disease, an allergic reaction and/or an autoimmune disease).
(item X33) the composition of any one of the preceding items, wherein the subject has an immunological memory for the pathogenic agent and/or a factor that cross-reacts with the pathogenic agent.
(item X33A) the composition of any one of the preceding items, wherein suppression of the Treg is released or transformed, thereby imparting a killing ability against the pathogenic agent of the infectious disease, allergy and/or autoimmune disease or against a cell infected with the pathogenic agent or comprising the pathogenic agent, or against immune activation of the pathogenic agent of the infectious disease, allergy and/or autoimmune disease or against a cell infected with the pathogenic agent or comprising the pathogenic agent.
(item X33B) the composition of any one of the above items, wherein the pathogenic agent comprises at least one selected from the group consisting of malaria, yellow fever virus, smallpox virus, vaccinia, measles/rubella, polio, MUMPS (adofurosis)/MUMPS, rotavirus infection, varicella (chicken pox), yellow fever, ebola virus (Ebola), west nile fever, haemophilus influenzae type B infection, pneumococcal infection, pertussis, japanese encephalitis, meningococcal infection, salmonella infection, pathogenic escherichia coli, toxoplasmosis (Toxoplasma gondii), zika virus (Zika virus), herpes virus type 1, EBV (Epstein Barr virus)/epstein-barr virus (herpes virus type 4), CMV/cytomegalovirus (herpes virus type 5), influenza, MARS, rabies, diphtheria.
The composition according to any one of the above items (item X33C), wherein the pathogenic agent is a virus.
(item X33D) the composition of any one of the preceding items, wherein the pathogenic agent is a virus belonging to the family selected from the group consisting of rhinovirus, adenovirus, coronavirus, RS virus, influenza virus, parainfluenza virus and enterovirus.
(item X33E) the composition according to any one of the above items, wherein the pathogenic agent is a virus belonging to the genus coronavirus.
(item X33F) the composition of any one of the preceding items, wherein the pathogenic agent is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2.
(item X33G) the composition of any one of the above items, wherein the pathogenic agent is SARS-CoV-2 virus.
The composition according to any one of the above items (X33H), wherein the antigen component comprises a protein, a part thereof or a peptide.
(item X33I) the composition according to any one of the preceding items, wherein the antigen component comprises an antigen selected from the group consisting of a pathogen of an infectious disease or a part thereof, an antigen related to a past history, and an antigen related to a vaccination history.
The composition according to any one of the above items (item X33J), wherein the antigen component comprises an antigen derived from a pathogen of a past infectious disease.
(item X33K) the composition of any one of the preceding items, wherein the antigen component comprises an antigen component capable of controlling an immune response mediated by CD4 positive T cells.
(item X33L) the composition according to any one of the above items, wherein the antigen component comprises a hot water extract of Mycobacterium tuberculosis.
The composition according to any one of the above items (item X33M), wherein the subject is a subject having a history of BCG vaccination, a history of tuberculosis infection or an antigen responsiveness against tubercle bacillus, and the antigen component comprises a hot water extract of human tubercle bacillus.
(item X33N) the composition of any one of the preceding items, wherein the Treg is CD4 positive.
(item X33O) the composition of any one of the preceding items, wherein the Treg releases activation inhibition of killer T cells (killer T cells) that are specific for a causative agent of the infectious disease.
(item X33P) the composition according to any one of the above items, wherein the composition is for preventing the above-described infectious disease.
(item X33Q) the composition according to any one of the above items, wherein the composition is used for deactivating inhibition of activation of killer cells (killer cells) that kill cells infected with the above-mentioned pathogenic agent.
(item X33R) the composition according to any one of the preceding items, wherein the composition is for use in a method comprising the steps of: investigating whether the antigen component has immune memory of tregs in the subject; and administering the antigen component to the subject in the event that the subject has an immunological memory for the antigen component.
(item X33S) the composition of any one of the preceding items, wherein it is confirmed whether the subject can control an antiviral immune response mediated by CD4 positive T cells, and the composition is administered in a case where the subject can control an antiviral immune response mediated by CD4 positive T cells.
(item X33 AA) the composition according to any one of the preceding items, wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The composition according to any one of the above items (item X33 AB), wherein the non-pathogenic antigen component is a hot water extract of the B strain of Mycobacterium tuberculosis or a part thereof.
(item X33 AC) the composition according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item X33 AD) the composition of any one of the preceding items, wherein the hot water extract of tubercle bacillus or a portion thereof comprises a STING agonist, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, STING agonist, or NOD2 agonist derived from tubercle bacillus.
(item X33 AE) the composition of any one of the preceding items, wherein the hot water extract of tubercle bacillus or a portion thereof comprises a STING agonist derived from tubercle bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
(item X33 AF) the composition according to any one of the preceding items, wherein said non-pathogenic antigen component is administered more than twice.
The composition according to any one of the above items (item X33 AG), wherein the pathogenic antigen component is a pathogenic factor of an infectious disease, and the non-pathogenic antigen component functions as an adjuvant when the pathogenic antigen component is used as a vaccine.
(item X34) a composition for preventing or treating an infectious disease in a subject, wherein the composition comprises an antigen component specific for a component different from a causative agent of the infectious disease in the subject.
(item X35) a composition for preventing or treating an infection of a subject, comprising an antigenic component derived from a pathogen of the subject that is different from a past infection of the infection, substantially free of a causative agent of the infection or a portion thereof.
(item X35A) the composition of any one of the preceding items, wherein the pathogenic agent is a virus belonging to the family selected from the group consisting of rhinovirus, adenovirus, coronavirus, RS virus, influenza virus, parainfluenza virus, and enterovirus.
The composition according to any one of the above items (X35B), wherein the pathogenic agent is a virus belonging to the genus coronavirus.
(item X35C) the composition of any one of the preceding items, wherein the pathogenic agent is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2.
The composition according to any one of the above items (X35D), wherein the pathogenic agent is SARS-CoV-2 virus.
(item X35E) the composition according to any one of the above items, wherein the antigen component is specific to the memory T cells of the subject.
(item X35F) the composition of any one of the above items, wherein the memory T cells are memory regulatory T cells (IL-2 producing).
The composition according to any one of the above items (X35G), wherein the antigen component has an immunopotentiating effect.
The composition according to any one of the above items (item X35H), wherein the antigen component acts on memory CD 4-positive T cells in an antigen-dependent manner.
(item X35I) the composition of any one of the preceding items, wherein the antigen component has an activity of biasing the presence ratio of Foxp 3-positive Treg cells and IFN- γ -producing T cells.
(item X35J) the composition of any one of the preceding items, wherein the bias is an increase in IFN- γ producing T cells compared to Foxp3 positive Treg cells.
(item X35K) the composition of any one of the preceding items, wherein the antigen component has an activity that biases the ratio of the presence of Foxp3 positive Treg cells and type 1 helper T cells.
(item X35L) the composition of any one of the preceding items, wherein the IFN-gamma producing T cells comprise type 1 helper T cells.
The composition according to any one of the above items (item X35M), wherein the antigen component has an activity of biasing the presence ratio of Th1 cells.
(item X35N) the composition of any one of the above items, wherein the IFN-gamma producing T cells are T-bet positive Th1 cells.
The composition according to any one of the above items (item X35O), wherein the antigen component having specificity has an ability to cause at least one selected from the group consisting of IFN-gamma producing ability, IL-2 producing ability and TNF-alpha producing ability to be increased in a sample derived from the subject.
The composition according to any one of the above items (X35P), wherein the antigen component is a protein.
(item X36) A composition for preventing or treating an infection other than tuberculosis, which comprises a Bacillus tuberculosis extract.
(item X37) A composition for controlling immunopotentiation against a causative agent of an infectious disease other than tuberculosis in a subject when the subject is exposed to the causative agent, wherein the composition comprises a Bacillus tuberculosis extract.
(item X37A) the composition of any one of the preceding items, wherein the immune enhancement comprises enhancement of cytokines and/or enhancement of immune cells associated with immune enhancement.
(item X37B) the composition of any one of the preceding items, wherein the immune cells comprise IL-10 producing cells.
(item X38) a composition for preventing or treating an infection, allergy or autoimmune disease in a subject, wherein the composition comprises an antigen component specific in the subject, said antigen component being neither derived from nor cross-reactive with a causative agent of the infection, allergy or autoimmune disease,
the antigenic component is a protein or a portion thereof, or a peptide, and is capable of controlling an immune response mediated by CD4 positive T cells,
The infection, allergy or autoimmune disease includes a disease that can be prevented or treated by an immune response mediated by CD4 positive T cells,
here, it is confirmed whether the subject can control an immune response against an infectious disease, an allergic reaction, or an autoimmune disease mediated by CD4 positive T cells, and the composition is administered in a case where the subject can control an immune response against an infectious disease, an allergic reaction, or an autoimmune disease mediated by CD4 positive T cells.
(item X39) A composition for preventing or treating an infectious disease in a subject, characterized in that the composition comprises an antigen component specific to a component different from a causative agent of the infectious disease in the subject,
the infection comprises a viral infection and the method comprises,
the antigenic component is a protein or a portion thereof, or a peptide, and is capable of controlling an immune response mediated by CD4 positive T cells,
the viral infections include diseases which can be prevented or treated by an immune response mediated by CD4 positive T cells,
here, it is confirmed whether the subject can control an antiviral immune response mediated by CD4 positive T cells, and the composition is administered in a case where the subject can control an antiviral immune response mediated by CD4 positive T cells.
(item X40) a method of making or otherwise providing a composition for preventing or treating an infection, allergy, or autoimmune disease in a subject, wherein the method comprises the steps of:
step a) identifying an antigenic component specific to the subject, said antigenic component being neither derived from nor cross-reactive with a causative agent of the infection, allergy or autoimmune disease;
step B), determining whether the antigen component has an immunological memory in the subject, and selecting the antigen component having the immunological memory; and
step C) manufacturing or otherwise providing the selected antigen component.
(item X41) a method of determining whether an antigenic component specific to the subject, which antigenic component is neither derived from nor cross-reactive with a causative agent of an infectious disease, allergic reaction or autoimmune disease in a subject, can prevent or treat the infectious disease, allergic reaction or autoimmune disease, comprising the steps of:
step B) is a step of specifying whether or not the antigen component has an immunological memory in the subject, and in the case of having the immunological memory, is specified to be capable of preventing or treating an infection, an allergy or an autoimmune disease in the subject.
(item X42) a method for preventing or treating an infectious disease, an allergic reaction, or an autoimmune disease, comprising the steps of:
step a), obtaining an antigen responsiveness profile of the subject;
step b) of specifying an antigen component or a combination of antigen components based on the antigen responsiveness profile, wherein the antigen component or the combination of antigen components is specified based on whether the subject now exhibits an immune responsiveness or has previously exhibited an immune responsiveness; and
step c) administering to the subject the antigen component or combination of antigen components identified in step b) in an amount sufficient to control an immune response in the subject.
(item X42A) the method according to any one of the preceding items, wherein the obtaining of the antigen responsiveness profile comprises: confirming a past physical state of the subject; confirming whether one or more antigen candidates are responsive in a sample derived from the subject; or both.
(item X42B) the method according to any one of the preceding items, wherein the obtaining of the antigen responsiveness profile comprises: an antigen component or combination of antigen components is specified that controls an immune response mediated by CD4 positive T cells.
(item X42C) the method of any one of the above items, wherein i) the antigenic response profile comprises at least one selected from the group consisting of a past medical history based on a consultation, a mother-son health manual or an equivalent thereof, and a vaccination history, and combinations thereof; and/or ii) whether the above-described acknowledgement is responsive comprises: body fluid (e.g., blood) is collected from the subject, peripheral blood cells are isolated, and then it is determined whether the peripheral blood cells react with antigens associated with the antigen profile to produce cytokines, and other biomarkers are measured.
(item X42D) the method according to any one of the preceding items, wherein the method further comprises the steps of: the responsiveness of the antigen was periodically checked, and maintenance of the responsiveness was confirmed.
(item X42E) the method according to any one of the preceding items, wherein the a) and b) are performed by:
step i) obtaining a past physical state of the subject;
step ii) collecting blood from the subject, separating peripheral blood cells, determining whether the peripheral blood cells react with an antigen corresponding to the physical state to produce cytokines, and determining other biomarkers; and
Step iii) specifies the appropriate antigen component or combination of antigen components based on the results of ii).
(item X42F) the method of any one of the preceding items, wherein the method further comprises the features of any one or more of the preceding items.
(item X42G) the method of any one of the preceding items, wherein the past physical state comprises a past medical history and a vaccination history.
(item X42H) the method according to any one of the preceding items, wherein the physical state comprises a history of non-coronavirus infection and the antigen component comprises an antigen component or a combination of antigen components directed against the non-coronavirus infection.
(item X42I) the method according to any one of the above items, wherein the physical state comprises a history of BCG vaccination, a history of tuberculosis infection or an antigen responsiveness to tubercule bacillus, and the antigen component or combination of antigen components comprises a hot water extract of human tubercule bacillus.
(item X42J) the method of any one of the preceding items, wherein the administering comprises subcutaneous, intradermal, or intramuscular administration.
(item X42K) the method of any one of the preceding items, wherein step ii) above comprises assaying for induction of cells that produce IFN-gamma, IL-2, TNF-alpha, or simultaneously produce multiple cytokines of these cytokines.
(item X42L) the method according to any one of the above items, wherein the antigen responsiveness profile is obtained by performing a concomitant diagnosis in advance based on a past medical history and a vaccination history.
(item X42M) the method according to any one of the above items, wherein the past physical state and the antigen component or combination of antigen components are a history of tuberculosis infection and a hot water extract of human type tubercle bacillus.
(item X42N) the method according to any one of the preceding items, characterized in that,
the above subjects were subjects who had confirmed a history of BCG vaccination, a history of tuberculosis infection or antigen responsiveness,
the extract of Bacillus tuberculosis is obtained by conventional methods, and is administered prophylactically before or at the beginning of infection onset, and subcutaneously or intradermally or intramuscularly at the beginning of infection onset.
(item X42O) A method for preventing or treating viral infection according to any one of the above items, which comprises re-inoculating the above antigen component or combination of antigen components.
(item X42P) a method for preventing or treating an infection in a subject using an antigenic component different from the causative agent of the infection, wherein the antigenic component is an antigen or extract identified by interrogation and/or by reference to the past medical history and vaccination history of the subject, the subject is a person having a history of infection or a person having a history of vaccination with an infection associated with the antigenic component, the component is administered to the subject prophylactically for a relapse after treatment, prophylactically before onset, or at an initial stage of onset of the infection, and the component is administered at an initial stage of onset of the infection as desired.
(item X42Q) the method according to any one of the preceding items, wherein the responsiveness is determined specifically for the past history of infection, vaccination, and induction of cells using IFN-gamma production, IL-2 production, TNF-alpha production or simultaneous production of a plurality of cytokines of these cytokines.
(item X42R) the method according to any one of the above items, wherein the above tubercle bacillus extract is a hot water extract of human tubercle bacillus or an extract derived from other tubercle bacillus (extract with high safety).
The method according to any one of the above items (X42S), wherein the antigen component is a protein.
(item X42T) a vaccine formulation comprising the antigen component of any one of the preceding items and an adjuvant-based agent.
(item X42U) the vaccine formulation of any one of the preceding items, wherein the adjuvant-based agent comprises a substance that promotes a Th 1-type immune response.
(item X42V) a method for preventing or treating an infection, allergy, or autoimmune disease in a subject, comprising the steps of:
step a) of identifying, based on an antigenic response profile, an antigenic component specific to the subject, said antigenic component being neither derived from nor cross-reactive with a causative agent of the infection, allergy or autoimmune disease;
Step b) identifying whether the subject has an immunological memory for the antigenic component and identifying the subject having the immunological memory; and
step c) administering the antigenic component to the subject specified as having the immunological memory.
(item X42W) the method of any one of the preceding items, wherein the antigenic response profile comprises a vaccination history and/or a infection history.
(item X43) an adjuvant for a vaccine against infectious diseases, wherein the adjuvant comprises a hot water extract of Bacillus tuberculosis or a part thereof.
(item X43A) an adjuvant for a vaccine against an infectious disease, comprising a STING agonist.
(item X43B) an adjuvant for a vaccine against an infectious disease of a viral infection, wherein the adjuvant comprises a STING agonist.
(item X44) the adjuvant according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof is a hot water extract of strain B of human type Bacillus tuberculosis or a part thereof.
An adjuvant according to any one of the above items (X45), wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
An adjuvant according to any one of the above items (item X46), wherein the hot water extract of Bacillus tuberculosis or a part thereof comprises a metabolite such as a STING agonist, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb-related antigen, STING agonist c-di-AMP, or a NOD2 agonist derived from Bacillus tuberculosis or a part other than the same.
(item X47) an adjuvant according to any one of the preceding items, wherein the hot water extract of tubercle bacillus or a portion thereof comprises a STING agonist derived from tubercle bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
An adjuvant according to any one of the above items (item X48), wherein the causative agent of the infection is a bacterium, a virus or a protozoan.
An adjuvant according to any one of the above items (item X49), wherein the causative agent of the infection is a virus.
(item X50) the adjuvant according to any one of the above items, wherein the causative agent of the infection is a virus belonging to the family Coronaviridae.
(item X51) the adjuvant according to any one of the above items, wherein the causative agent of the above-mentioned infectious disease is a virus belonging to the family selected from the group consisting of rhinovirus, adenovirus, coronavirus, RS virus, influenza virus, parainfluenza virus and enterovirus.
An adjuvant according to any one of the above items (item X52), wherein the causative agent of the infection is a virus belonging to the genus coronavirus.
(item X53) the adjuvant according to any one of the preceding items, wherein the causative agent of the infection is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SA RS-CoV-2.
An adjuvant according to any one of the above items (X54), wherein the causative agent of the infection is SARS-CoV-2 virus.
(item X1A) a method for preventing or treating a disease, comprising the steps of:
administering an effective amount of a non-pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject in the presence of a pathogenic antigen component, the non-pathogenic antigen component being neither derived from nor cross-reactive with a pathogenic agent of the disease.
(item X2A) the method according to any one of the above items, wherein the pathogenic agent comprises a foreign substance for the subject.
The method according to any one of the above items (item X3A), wherein the causative agent of the disease comprises causative agent of infectious disease, causative agent of allergy, causative agent of autoimmune disease, or poison.
The method according to any one of the above items (X4A), wherein the disease is an infectious disease.
The method according to any one of the above items (X5A), wherein the subject has an immunological memory against the non-pathogenic antigen component.
(item X6A) the method according to any one of the above items, wherein the method comprises administering the above pathogenic antigen component.
(item X7A) the method according to any one of the above items, wherein the method is for preventing the above-described diseases.
(item X8A) the method according to any one of the above items, wherein the method is for preventing or treating the above-described diseases in a form not accompanied by or reducing immune overreaction.
The method according to any one of the above items (item X9A), wherein the administration is in a form effective for controlling cellular immunity, which is a cellular immunity against a causative agent of the disease.
(item X10A) the method according to any one of the preceding items, wherein the method comprises the steps of:
identifying the presence or absence of a pathogenic antigenic component in said subject, and administering said pathogenic antigenic component together with said non-pathogenic antigenic component in the absence of said pathogenic antigenic component, said pathogenic antigenic component being derived from and/or cross-reactive with a pathogenic agent of the target disease.
The method according to any one of the above items (X11A), wherein the disease is an infection, an allergy or an autoimmune disease.
The method according to any one of the above items (X12A), wherein the disease is a viral infection or a bacterial infection.
The method according to any one of the above items (X13A), wherein the disease is a viral infection.
The method according to any one of the above items (X14A), wherein the disease is an infectious disease associated with coronavirus.
The method according to any one of the above items (X15A), wherein the pathogenic antigen component is a molecule which is at least partially present on the surface of a pathogenic agent of the target disease.
(item X15 AA) the method according to any one of the preceding items, wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The method according to any one of the above items (item X15 AB), wherein the non-pathogenic antigen component is a hot water extract of the Qingshan B strain of Mycobacterium tuberculosis or a part thereof.
(item X15 AC) the method according to any one of the above items, wherein the above tubercle bacillus hot water extract or a part thereof is extract A.
(item X15 AD) the method according to any one of the preceding items, wherein the hot water extract of tubercle bacillus or a part thereof comprises a STING agonist, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, STING agonist, or NOD2 agonist derived from tubercle bacillus.
(item X15 AE) the method of any one of the preceding items, wherein the tubercle bacillus hot water extract or a portion thereof comprises a STING agonist derived from tubercle bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
(item X15 AF) the method according to any one of the preceding items, wherein said non-pathogenic antigen component is administered more than twice.
(item X16A) a method, comprising the steps of:
a combination of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject and a non-pathogenic antigen component derived from and cross-reactive with neither the pathogenic agent of the disease is administered.
The method according to any one of the above items (item X17A), wherein the pathogenic antigen component comprises a pathogenic factor of an infectious disease, a pathogenic agent of an allergic reaction, a pathogenic agent of an autoimmune disease, or a poison.
The method according to any one of the above items (X18A), wherein the pathogenic antigen component is a bacterium, a virus or a protozoan or a part thereof.
The method according to any one of the above items (X19A), wherein the pathogenic antigen component is a virus or a part thereof.
The method according to any one of the above items (X20A), wherein the pathogenic antigen component is a virus belonging to the family Coronaviridae or a part thereof.
(item X21A) the method according to any one of the preceding items, wherein the pathogenic agent is a virus belonging to the family selected from the group consisting of rhinovirus, adenovirus, coronavirus, RS virus, influenza virus, parainfluenza virus and enterovirus.
The method according to any one of the above items (X22A), wherein the pathogenic agent is a virus belonging to the genus coronavirus.
(item X23A) the method according to any one of the preceding items, wherein the pathogenic agent is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2.
The method according to any one of the above items (X24A), wherein the pathogenic agent is SARS-CoV-2 virus.
The method according to any one of the above items (X25A), wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The method according to any one of the above items (X26A), wherein the non-pathogenic antigen component is a hot water extract of the Qingshan B strain of Mycobacterium tuberculosis or a part thereof.
The method according to any one of the above items (X26 AA), wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The method according to any one of the above items (X26 AB), wherein the non-pathogenic antigen component is a hot water extract of the Qingshan B strain of Mycobacterium tuberculosis or a part thereof.
(item X26 AC) the method according to any one of the above items, wherein the above tubercle bacillus hot water extract or a part thereof is extract A.
(item X26 AD) the method according to any one of the preceding items, wherein the hot water extract of tubercle bacillus or a part thereof comprises a STING agonist, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, STING agonist, or NOD2 agonist derived from tubercle bacillus.
(item X26 AE) the method of any one of the preceding items, wherein the hot water extract of tubercle bacillus or a portion thereof comprises a STING agonist derived from tubercle bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
(item X26 AF) the method according to any one of the preceding items, wherein said non-pathogenic antigen component is administered more than twice.
The method according to any one of the above items (X26 AG), wherein the pathogenic antigen component is a pathogenic factor of an infectious disease, and the non-pathogenic antigen component functions as an adjuvant when the pathogenic antigen component is used as a vaccine.
(item X27A) a method for preventing or treating a disease, comprising the steps of: a combination of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject and a non-pathogenic antigen component derived from and cross-reactive with neither the pathogenic agent of the disease is administered.
(item X27 AA) the method according to any one of the above items, wherein the pathogenic agent comprises a foreign substance to the subject.
(item X27 BA) the method according to any one of the preceding items, wherein the causative agent of the disease comprises causative agent of an infectious disease, causative agent of allergy, causative agent of autoimmune disease or poison.
The method according to any one of the above items (X27 CA), wherein the disease is an infection.
(item X27 DA) the method according to any one of the preceding items, wherein the subject has an immunological memory for the non-pathogenic antigen component.
(item X27 EA) the method according to any one of the above items, wherein the method is for preventing the above-described diseases.
(item X27 FA) the method according to any one of the above items, wherein the method is for preventing or treating the above-described diseases in a form that is not accompanied by or reduces immune overreaction.
(item X27 GA) the method of any one of the preceding items, wherein the administering is in a form effective for controlling cellular immunity that is a cellular immunity against a causative agent of the disease.
(item X27 HA) the method according to any one of the preceding items, wherein the disease is an infection, allergy or autoimmune disease.
The method according to any one of the above items (X27 IA), wherein the disease is a viral infection or a bacterial infection.
The method according to any one of the above items (X27 JA), wherein the disease is a viral infection.
(item X27 KA) the method according to any one of the above items, wherein the disease is an infection associated with coronavirus.
The method according to any one of the above items (X28 LA), wherein the pathogenic antigen component is a molecule having at least a part thereof present on the surface of the membrane.
The method according to any one of the above items (X28 AA), wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The method according to any one of the above items (X28 AB), wherein the non-pathogenic antigen component is a hot water extract of the Qingshan B strain of Mycobacterium tuberculosis or a part thereof.
(item X28 AC) the method according to any one of the above items, wherein the above tubercle bacillus hot water extract or a part thereof is extract A.
(item X28 AD) the method according to any one of the preceding items, wherein the hot water extract of Bacillus tuberculosis or a part thereof comprises a STING agonist, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, STING agonist, or NOD2 agonist derived from Bacillus tuberculosis.
(item X28 AE) the method of any one of the preceding items, wherein the hot water extract of tubercle bacillus or a portion thereof comprises a STING agonist derived from tubercle bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
(item X28 AF) the method according to any one of the preceding items, wherein said non-pathogenic antigen component is administered more than twice.
The method according to any one of the above items (X28 AG), wherein the pathogenic antigen component is a pathogenic factor of an infectious disease, and the non-pathogenic antigen component functions as an adjuvant when the pathogenic antigen component is used as a vaccine.
(item X31A) a method for relieving or transforming the inhibition of regulatory T cells (tregs), wherein said inhibition of regulatory T cells (tregs) refers to inhibition of activity against cells of a subject, said method comprising administering an effective amount of a non-pathogenic antigen component that is neither derived from nor cross-reactive with a pathogenic agent of an infectious disease, allergic reaction, and/or autoimmune disease that is a target, wherein the subject has an immune memory for the antigen component and the pathogenic agent or the pathogenic agent is infected or the pathogenic agent is contained in the subject that comprises the infectious disease, allergic reaction, and/or the autoimmune disease.
(item X32A) the method according to any one of the preceding items, characterized in that said Treg is transformed into effector T cells (Teff) derived from and/or cross-reactive with the causative agent of the target disease by allowing the presence in said subject of a causative agent antigen component derived from or comprising the causative agent of the disease (infectious disease, allergic reaction and/or autoimmune disease).
(item X33A) the method of any one of the preceding items, wherein the subject has an immunological memory for the pathogenic agent and/or a factor that cross-reacts with the pathogenic agent.
(item X33 AA) the method according to any one of the preceding items, wherein suppression of the Treg is released or transformed, thereby conferring a killing ability against the pathogenic agent of the infectious disease, allergy and/or autoimmune disease or against a cell infected with the pathogenic agent or comprising the pathogenic agent, or against an immune activation of the pathogenic agent of the infectious disease, allergy and/or autoimmune disease or against a cell infected with the pathogenic agent or comprising the pathogenic agent.
(item X33 BA) the method of any one of the preceding items, wherein the pathogenic agent comprises at least one selected from the group consisting of malaria, yellow fever virus, smallpox virus, vaccinia, measles/rubella, polio, MUMPS (adofurosis)/MUMPS, rotavirus infection, varicella (chicken pox), yellow fever, ebola virus (Ebola), west nile fever, haemophilus influenzae type b infection, pneumococcal infection, pertussis, japanese encephalitis, meningococcal infection, salmonella infection, pathogenic escherichia coli, toxoplasmosis (Toxoplasma gondii), zika virus (Zika virus), herpes virus type 1, EBV (EPSTEIN BARR VIRUS)/epstein-barr virus (herpes virus type 4), CMV/cytomegalovirus (herpes virus type 5), influenza, MARS, rabies, diphtheria.
The method according to any one of the above items (X33 CA), wherein the pathogenic agent is a virus.
(item X33 DA) the method according to any one of the preceding items, wherein the pathogenic agent is a virus belonging to the family selected from the group consisting of rhinoviruses, adenoviruses, coronaviruses, RS viruses, influenza viruses, parainfluenza viruses and enteroviruses.
(item X33 EA) the method according to any one of the above items, wherein the pathogenic agent is a virus belonging to the genus coronavirus.
(item X33 FA) the method according to any one of the preceding items, wherein the pathogenic agent is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2.
(item X33 GA) the method according to any one of the above items, wherein the above-mentioned pathogenic agent is SARS-CoV-2 virus.
(item X33 HA) the method according to any one of the preceding items, wherein the antigen component comprises a protein, a portion thereof, or a peptide.
The method according to any one of the preceding items (item X33 IA), wherein the antigen component comprises an antigen selected from the group consisting of a pathogen of an infectious disease or a part thereof, an antigen related to a past history of disease, and an antigen related to a history of vaccination.
(item X33 JA) the method according to any one of the above items, wherein the antigen component comprises an antigen derived from a pathogen of a past infectious disease.
(item X33 KA) the method of any one of the above items, wherein the antigen component comprises an antigen component capable of controlling an immune response mediated by CD4 positive T cells.
The method according to any one of the above items (X33 LA), wherein the antigen component comprises a hot water extract of Mycobacterium tuberculosis.
The method according to any one of the above items (item X33 MA), wherein the subject is a subject having a history of BCG vaccination, a history of tuberculosis infection or an antigen responsiveness against tubercle bacillus, and the antigen component comprises a hot water extract of human tubercle bacillus.
(item X33 NA) the method of any one of the preceding items, wherein the Treg is CD4 positive.
(item X33 OA) the method of any one of the preceding items, wherein the Treg releases inhibition of activation of killer T cells that are specific for the causative agent of the infection.
(item X33 PA) the method according to any one of the preceding items, wherein the method is for preventing the above-described infectious disease.
(item X33 QA) the method according to any one of the preceding items, wherein said method is for deactivating the activation inhibition of killer cells that kill cells infected with said pathogenic agent.
(item X33 RA) the method according to any one of the preceding items, wherein the method comprises the steps of: checking whether the antigenic component has immune memory of tregs in the subject; and administering the antigen component to the subject in the event that the subject has an immunological memory for the antigen component.
(item X33 SA) the method according to any one of the preceding items, wherein the method comprises the steps of: confirming whether the subject is capable of controlling an antiviral immune response mediated by CD4 positive T cells; and administering the above composition in the event that the subject is capable of controlling an antiviral immune response mediated by CD4 positive T cells.
The method according to any one of the above items (X33 XAA), wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The method according to any one of the above items (X33 XAB), wherein the non-pathogenic antigen component is a hot water extract of the Qingshan B strain of Mycobacterium tuberculosis or a part thereof.
(item X33 XAC) the method according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item X33 XAD) the method according to any one of the preceding items, wherein the hot water extract of Bacillus tuberculosis or a part thereof comprises a STING agonist, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, STING agonist, or NOD2 agonist derived from Bacillus tuberculosis.
(item X33 XAE) the method according to any one of the preceding items, wherein the hot water extract of tubercule bacillus or a portion thereof comprises a STING agonist derived from tubercule bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
(item X33 XAF) the method according to any one of the preceding items, wherein the non-pathogenic antigen component is administered more than twice.
The method according to any one of the above items (X33 XAG), wherein the pathogenic antigen component is a pathogenic factor of an infectious disease, and the non-pathogenic antigen component functions as an adjuvant when the pathogenic antigen component is used as a vaccine.
(item X34A) a method for preventing or treating an infectious disease in a subject, comprising administering an effective amount of an antigen component specific for a component different from a causative agent of the infectious disease in the subject.
(item X35A) a method for preventing or treating an infection in a subject, comprising administering an effective amount of an antigenic component derived from a pathogen of the subject that is different from a past infection of the infection, without substantially comprising administering a causative agent of the infection or a portion thereof.
(item X35 AA) the method according to any one of the preceding items, wherein the pathogenic agent is a virus belonging to the family selected from the group consisting of rhinovirus, adenovirus, coronavirus, RS virus, influenza virus, parainfluenza virus and enterovirus.
(item X35 BA) the method according to any one of the preceding items, wherein the pathogenic agent is a virus belonging to the genus coronavirus.
(item X35 CA) the method according to any one of the preceding items, wherein the pathogenic agent is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2.
(item X35 DA) the method according to any one of the preceding items, wherein the pathogenic agent is SARS-CoV-2 virus.
(item X35 EA) the method according to any one of the above items, wherein the antigen component is specific for the memory T cells of the subject.
(item X35 FA) the method according to any one of the above items, wherein the memory T cells are memory regulatory T cells (IL-2 production).
The method according to any one of the above items (item X35 GA), wherein the antigen component has an immunopotentiating effect.
(item X35 HA) the method according to any one of the preceding items, wherein the antigen component acts on memory CD 4-positive T cells in an antigen-dependent manner.
(item X35 IA) the method of any one of the preceding items, wherein the antigen component has an activity of biasing the presence ratio of Foxp 3-positive Treg cells and IFN- γ -producing T cells.
(item X35 JA) the method of any one of the preceding items, wherein the bias is an increase in IFN- γ producing T cells compared to Foxp3 positive Treg cells.
(item X35 KA) the method of any one of the preceding items, wherein the antigen component has an activity that biases the ratio of the presence of Foxp3 positive Treg cells and type 1 helper T cells.
(item X35 LA) the method of any one of the above items, wherein the IFN-gamma producing T cells comprise type 1 helper T cells.
The method according to any one of the above items (X35 MA), wherein the antigen component has an activity of biasing the presence ratio of Th1 cells.
(item X35 NA) the method according to any of the preceding items, wherein the IFN-gamma producing T cells are T-bet positive Th1 cells.
(item X35 OA) the method according to any one of the above items, wherein the antigen component having specificity has an ability to cause at least one selected from the group consisting of IFN-gamma producing ability, IL-2 producing ability and TNF-alpha producing ability to be increased in a sample derived from the subject.
The method according to any one of the above items (X35 PA), wherein the antigen component is a protein.
(item X36A) A method for preventing or treating an infection other than tuberculosis, comprising administering an effective amount of a Bacillus tuberculosis extract.
(item X37A) a method for controlling immune enhancement against a causative agent of an infectious disease other than tuberculosis in a subject when the subject is exposed to the causative agent, comprising administering an effective amount of a Bacillus tuberculosis extract.
(item X37 AA) the method according to any one of the preceding items, wherein the immunopotentiation comprises an enhancement of a cytokine associated with the immunopotentiation and/or an enhancement of an immune cell.
(item X37 BA) the method of any one of the above items, wherein the immune cells comprise IL-10 producing cells.
(item X38A) a method for preventing or treating an infectious disease, an allergic reaction, or an autoimmune disease in a subject, wherein the method comprises administering an effective amount of an antigen component having specificity in the subject, said antigen component being neither derived from nor cross-reactive with a causative agent of the infectious disease, allergic reaction, or autoimmune disease,
The antigenic component is a protein or a portion thereof, or a peptide, and is capable of controlling an immune response mediated by CD4 positive T cells,
the infection, allergy or autoimmune disease includes a disease that can be prevented or treated by an immune response mediated by CD4 positive T cells,
here, it was confirmed whether the subject could control an immune response against an infectious disease, an allergic reaction, or an autoimmune disease mediated by CD4 positive T cells, and the antigen component was administered in a case where the subject could control an immune response against an infectious disease, an allergic reaction, or an autoimmune disease mediated by CD4 positive T cells.
(item X39A) a method for preventing or treating an infectious disease in a subject, wherein the method comprises administering an effective amount of an antigen component specific for a component of a causative agent different from the infectious disease in the subject,
the infection comprises a viral infection and the method comprises,
the antigenic component is a protein or a portion thereof, or a peptide, and is capable of controlling an immune response mediated by CD4 positive T cells,
the viral infections include diseases which can be prevented or treated by an immune response mediated by CD4 positive T cells,
Here, it was confirmed whether the subject could control an antiviral immune response mediated by CD4 positive T cells, and the antigen component was administered in the case where the subject could control an antiviral immune response mediated by CD4 positive T cells.
(item X40A) a method of making or otherwise providing a composition for preventing or treating an infection, allergy, or autoimmune disease in a subject, wherein the method comprises the steps of:
step a) identifying an antigenic component specific to the subject, said antigenic component being neither derived from nor cross-reactive with a causative agent of the infection, allergy or autoimmune disease;
step B), determining whether the antigen component has an immunological memory in the subject, and selecting the antigen component having the immunological memory; and
step C) manufacturing or otherwise providing the selected antigen component.
(item X41A) a method of determining whether an antigenic component specific to a subject, said antigenic component being neither derived from nor cross-reactive with a causative agent of an infectious disease, allergic reaction or autoimmune disease in the subject, can prevent or treat the subject's infectious disease, allergic reaction or autoimmune disease, comprising the steps of:
Step B) is a step of specifying whether or not the antigen component has an immunological memory in the subject, and in the case of having the immunological memory, is specified to be capable of preventing or treating an infection, an allergy or an autoimmune disease in the subject.
(item X42A) a method for preventing or treating an infectious disease, an allergic reaction, or an autoimmune disease, comprising the steps of:
step a), obtaining an antigen responsiveness profile of the subject;
step b) of specifying an antigen component or a combination of antigen components based on the antigen responsiveness profile, wherein the antigen component or the combination of antigen components is specified based on whether the subject now exhibits an immune responsiveness or has previously exhibited an immune responsiveness; and
step c) administering to the subject the antigen component or combination of antigen components identified in step b) in an amount sufficient to control an immune response in the subject.
(item X42 AA) the method of any one of the preceding items, wherein the obtaining of the antigen responsiveness profile comprises: confirming a past physical state of the subject; confirming whether one or more antigen candidates are responsive in a sample derived from the subject; or both.
(item X42 BA) the method of any one of the preceding items, wherein the obtaining of the antigen responsiveness profile comprises: an antigen component or combination of antigen components is specified that controls an immune response mediated by CD4 positive T cells.
(item X42 CA) the method of any one of the above items, wherein i) the antigenic response profile comprises at least one selected from the group consisting of a past medical history based on a consultation, a mother-son health manual or an equivalent thereof, and a vaccination history, and combinations thereof; and/or ii) whether the above-described acknowledgement is responsive comprises: body fluid (e.g., blood) is collected from the subject, peripheral blood cells are isolated, and then it is determined whether the peripheral blood cells react with antigens associated with the antigen profile to produce cytokines, and other biomarkers are measured.
(item X42 DA) the method according to any one of the preceding items, wherein the method further comprises the steps of: the responsiveness of the antigen was periodically checked, and maintenance of the responsiveness was confirmed.
(item X42 EA) the method according to any one of the above items, wherein the above a) and b) are performed by:
step i) obtaining a past physical state of the subject;
Step ii) collecting blood from the subject, separating peripheral blood cells, determining whether the peripheral blood cells react with an antigen corresponding to the physical state to produce cytokines, and determining other biomarkers; and
step iii) specifies the appropriate antigen component or combination of antigen components based on the results of ii).
(item X42 FA) the method of any one of the preceding items, wherein the method further comprises the features of any one or more of the preceding items.
(item X42 GA) the method of any one of the preceding items, wherein the past physical state comprises a past medical history and a vaccination history.
(item X42 HA) the method of any one of the preceding items, wherein the physical state comprises a history of non-coronavirus infection and the antigen component comprises an antigen component or combination of antigen components directed against the non-coronavirus infection.
(item X42 IA) the method according to any one of the preceding items, wherein the physical condition comprises a history of BCG vaccination, a history of tuberculosis infection or an antigen responsiveness to tubercule bacillus, and the antigen component or combination of antigen components comprises a hot water extract of human tubercule bacillus.
(item X42 JA) the method of any one of the preceding items, wherein the administering comprises subcutaneous administration, intradermal administration, or intramuscular administration.
(item X42 KA) the method of any one of the preceding items, wherein step ii) above comprises assaying for induction of cells that produce IFN-gamma, IL-2, TNF-alpha, or simultaneously produce multiple cytokines of these cytokines.
(item X42 LA) the method according to any one of the above items, wherein the antigen responsiveness profile is obtained by performing a concomitant diagnosis in advance based on a past medical history and a vaccination history.
(item X42 MA) the method according to any one of the preceding items, wherein the past physical state and the antigen component or combination of antigen components are a history of tuberculosis infection and a hot water extract of human tubercle bacillus.
(item X42 NA) the method according to any of the preceding items, characterized in that,
the above subjects were subjects who had confirmed a history of BCG vaccination, a history of tuberculosis infection or antigen responsiveness,
the extract of Bacillus tuberculosis is obtained by conventional methods, and is administered prophylactically before or at the beginning of infection onset, and subcutaneously or intradermally or intramuscularly at the beginning of infection onset.
(item X42 OA) A method for preventing or treating viral infection according to any one of the above items, wherein the method comprises re-inoculating the above antigen component or combination of antigen components.
(item X42 PA) a method for preventing or treating an infection in a subject using an antigenic component different from the causative agent of the infection, wherein the antigenic component is an antigen or extract identified by interrogation and/or by reference to the past medical history and vaccination history of the subject, the subject is a person having a history of infection or a person having a history of vaccination with an infection associated with the antigenic component, the component is administered to the subject prophylactically for a relapse after treatment, prophylactically before onset, or at the beginning of an onset of an infection, and the component is administered at the beginning of an onset of an infection as desired.
(item X42 QA) the method according to any one of the preceding items, wherein said specificity of responsiveness is determined with respect to past infection history, vaccination history, and induction of cells using IFN-gamma production, IL-2 production, TNF-alpha production or simultaneous production of a plurality of cytokines of these cytokines in peripheral blood.
(item X42 RA) the method according to any one of the above items, wherein the above tubercle bacillus extract is a hot water extract of human tubercle bacillus or an extract derived from other tubercle bacillus (extract with high safety).
The method according to any one of the above items (X42 SA), wherein the antigen component is a protein.
(item X42 TA) a vaccine formulation comprising the antigen component of any one of the above items and an adjuvant-based agent.
(item X42 UA) the vaccine formulation of any one of the preceding items, wherein the adjuvant-based agent comprises a substance that promotes a Th 1-type immune response.
(item X42 VA) a method for preventing or treating an infection, allergy or autoimmune disease in a subject, comprising the steps of:
step a) of identifying, based on an antigenic response profile, an antigenic component specific to the subject, said antigenic component being neither derived from nor cross-reactive with a causative agent of the infection, allergy or autoimmune disease;
step b) identifying whether the subject has an immunological memory for the antigenic component and identifying the subject having the immunological memory; and
Step c) administering the antigenic component to the subject specified as having the immunological memory.
(item X42 WA) the method of any one of the preceding items, wherein the antigenic response profile comprises a history of vaccination and/or a history of infection.
(item X43A) a method for treating or preventing an infection in a subject, comprising the steps of: an effective amount of a hot water extract of tubercle bacillus or a portion thereof is administered to the subject together with a vaccine against the infection.
(item X43 AA) a method for treating or preventing an infection in a subject, comprising the steps of: an effective amount of a STING agonist is administered to the subject with a vaccine against the infection.
(item X43 AB) a method for treating or preventing a viral infection in a subject, comprising the steps of: an effective amount of a STING agonist is administered to the subject with a vaccine against the viral infection.
The method according to any one of the above items (X44A), wherein the hot water extract of Mycobacterium tuberculosis or a part thereof is a hot water extract of Mycobacterium tuberculosis Qingshan B strain or a part thereof.
The method according to any one of the above items (X45A), wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item X46A) the method according to any one of the preceding items, wherein the hot water extract of Bacillus tuberculosis or a part thereof comprises a metabolite such as a STING agonist, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb-related antigen, STING agonist c-di-AMP, or a NOD2 agonist derived from Bacillus tuberculosis or a part other than the same.
(item X47A) the method of any one of the preceding items, wherein the hot water extract of Bacillus tuberculosis or a portion thereof comprises a STING agonist derived from Bacillus tuberculosis, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
The method according to any one of the above items (X48A), wherein the causative agent of the infection is a bacterium, a virus, or a protozoan.
The method according to any one of the above items (X49A), wherein the causative agent of the infection is a virus.
The method according to any one of the above items (X50A), wherein the causative agent of the infection is a virus belonging to the family Coronaviridae.
(item X51A) the method according to any one of the preceding items, wherein the causative agent of the infection is a virus belonging to the family selected from the group consisting of rhinovirus, adenovirus, coronavirus, RS virus, influenza virus, parainfluenza virus and enterovirus.
The method according to any one of the above items (X52A), wherein the causative agent of the infection is a virus belonging to the genus coronavirus.
(item X53A) the method according to any one of the preceding items, wherein the causative agent of the infection is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2.
The method according to any one of the above items (X54A), wherein the causative agent of the infection is SARS-CoV-2 virus.
(item X1B) a non-pathogenic antigen component for use in preventing or treating a disease, wherein the non-pathogenic antigen component is administered in the presence of a pathogenic antigen component in a subject, said pathogenic antigen component being derived from and/or cross-reactive with a pathogenic agent of a target disease, the non-pathogenic antigen component being neither derived from nor cross-reactive with a pathogenic agent of the disease.
(item X2B) the antigen component according to any one of the above items, wherein the pathogenic agent comprises a foreign substance to the subject.
(item X3B) the antigen component according to any one of the above items, wherein the causative agent of the above disease comprises causative agent of infectious disease, causative agent of allergy, causative agent of autoimmune disease, or poison.
The antigen component according to any one of the above items (X4B), wherein the disease is an infectious disease.
The antigen component according to any one of the above items (X5B), wherein the subject has an immunological memory against the non-pathogenic antigen component.
(item X6B) the antigen component according to any one of the above items, wherein the pathogenic agent antigen component is further administered.
(item X7B) the antigen component according to any one of the above items, wherein the antigen component is for preventing the above-mentioned diseases.
(item X8B) the antigen component according to any one of the above items, wherein the antigen component is used for preventing or treating the above-described diseases in a form not accompanied by or reducing an immune excess reaction.
(item X9B) the antigen component according to any one of the above items, wherein the antigen component is administered in a form effective for controlling cellular immunity against a causative agent of the disease.
(item X10B) the antigen component according to any one of the preceding items, wherein the presence or absence of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease is confirmed in the subject, and in the absence, the pathogenic antigen component is administered together with the non-pathogenic antigen component.
The antigen component according to any one of the above items (X11B), wherein the disease is an infection, an allergy or an autoimmune disease.
The antigen component according to any one of the above items (X12B), wherein the disease is a viral infection or a bacterial infection.
The antigen component according to any one of the above items (X13B), wherein the disease is a viral infection.
The antigen component according to any one of the above items (X14B), wherein the disease is an infectious disease associated with coronavirus.
The antigen component according to any one of the above items (X15B), wherein the pathogenic antigen component is a molecule having at least a part of its surface on which a pathogenic agent of a target disease appears.
(item X15 BA) the antigen component according to any one of the above items, wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
(item X15 BB) the antigen component of any one of the above items, wherein said non-pathogenic antigen component is a hot water extract of Qingshan B strain of human tubercle bacillus or a part thereof.
(item X15 BC) the antigen component according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item X15 BD) according to any one of the preceding items, wherein the hot water extract of Bacillus tuberculosis or a part thereof comprises a STING agonist, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, STING agonist, or NOD2 agonist derived from Bacillus tuberculosis.
(item X15 BE) the antigen component according to any one of the preceding items, wherein the above-mentioned hot water extract of tubercle bacillus or a part thereof contains a STING agonist derived from tubercle bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
(item X15 BF) the antigen component according to any one of the preceding items, characterized in that the non-pathogenic antigen component is administered twice or more.
(item X16B) a combination, characterized in that it is a combination of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject, and a non-pathogenic antigen component neither derived from nor cross-reactive with a pathogenic agent of the disease.
(item X17B) the combination according to any one of the preceding items, wherein the pathogenic antigen component comprises a pathogenic factor of an infectious disease, a pathogenic agent of an allergic reaction, a pathogenic agent of an autoimmune disease, or a poison.
(item X18B) the combination according to any one of the preceding items, wherein the pathogenic antigen component is a bacterium, a virus or a protozoan or a part thereof.
(item X19B) the combination according to any one of the preceding items, wherein the pathogenic antigen component is a virus or a part thereof.
(item X20B) the combination according to any one of the preceding items, wherein the pathogenic antigen component is a virus belonging to the family Coronaviridae or a part thereof.
(item X21B) the combination according to any one of the preceding items, wherein the pathogenic agent is a virus belonging to the family selected from the group consisting of rhinovirus, adenovirus, coronavirus, RS virus, influenza virus, parainfluenza virus and enterovirus.
(item X22B) the combination according to any one of the preceding items, wherein the pathogenic agent is a virus belonging to the genus coronavirus.
(item X23B) the combination according to any one of the preceding items, wherein the pathogenic agent is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2.
(item X24B) the combination according to any one of the preceding items, wherein the pathogenic agent is SARS-CoV-2 virus.
(item X25B) the combination according to any one of the preceding items, wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The combination according to any one of the above items (X26B), wherein the non-pathogenic antigen component is a hot water extract of the Qingshan B strain of Mycobacterium tuberculosis or a part thereof.
(item X26 BA) the combination according to any one of the preceding items, wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
(item X26 BB) the combination of any one of the above items, wherein said non-pathogenic antigen component is a hot water extract of Qingshan B strain of Mycobacterium tuberculosis or a part thereof.
(item X26 BC) the combination according to any one of the above items, wherein the hot water extract of tubercle bacillus or a part thereof is extract A.
(item X26 BD) the combination according to any preceding item, wherein the hot water extract of tubercle bacillus or a portion thereof comprises a STING agonist derived from tubercle bacillus, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, a component capable of biosynthesis of STING agonist in human cells, or a NOD2 agonist.
(item X26 BE) the combination according to any one of the preceding items, wherein the above tubercule bacillus hot water extract or a part thereof comprises a STING agonist derived from tubercule bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
(item X26 BF) a combination according to any of the preceding items, characterized in that the non-pathogenic antigen component is administered more than twice.
(item X26 BG) the combination of any of the above items, wherein the pathogenic antigen component is a pathogenic factor of an infectious disease, and the non-pathogenic antigen component functions as an adjuvant when the pathogenic antigen component is used as a vaccine.
(item X27B) a medicament for preventing or treating a disease, comprising a combination of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject, and a non-pathogenic antigen component derived from or cross-reactive with neither the pathogenic agent of the disease.
(item X27 AB) the medicament according to any one of the above items, wherein the pathogenic agent comprises a foreign substance to the subject.
(item X27 BB) the medicament of any one of the above items, wherein the causative agent of the above-mentioned diseases comprises causative agent of infection, causative agent of allergy, causative agent of autoimmune disease, or poison.
The drug according to any one of the above items (X27 CB), wherein the disease is an infectious disease.
(item X27 DB) the medicament according to any one of the above items, wherein the subject has an immunological memory against the non-pathogenic antigen component.
(item X27 EB) the medicament according to any preceding item, wherein said medicament is for preventing said disease.
(item X27 FB) the medicament according to any one of the preceding items, wherein the medicament prevents or treats the disease in a form that does not accompany or reduce an immune excess reaction.
(item X27 GB) the medicament according to any one of the preceding items, wherein the medicament is administered in a form effective for controlling cellular immunity, which is cellular immunity against a causative agent of the disease.
(item X27 HB) the medicament according to any one of the above items, wherein the above disease is an infection, an allergy or an autoimmune disease.
(item X27 IB) the medicament according to any one of the preceding items, wherein the disease is a viral infection or a bacterial infection.
(item X27 JB) the medicament according to any of the above items, wherein the above diseases are viral infections.
(item X27 KB) the medicament according to any one of the preceding items, wherein the disease is an infectious disease associated with coronavirus.
The drug according to any one of the above items (X27 LB), wherein the pathogenic antigen component is a molecule at least a part of which is present on the surface of the membrane.
(item X27 BAA) the medicament according to any one of the preceding items, wherein said non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The medicament according to any of the preceding items (item X27 BAB), wherein the non-pathogenic antigen component is a hot water extract of the Qingshan B strain of Mycobacterium tuberculosis or a part thereof.
The drug according to any one of the above items (X27 BAC), wherein the above-mentioned hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item X27 BAD) the medicament according to any one of the preceding items, wherein said hot water extract of Bacillus tuberculosis or a part thereof comprises a STING agonist derived from Bacillus tuberculosis, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, a component capable of biosynthesis of STING agonist in human cells, or a NOD2 agonist.
(item X27 BAE) the medicament according to any one of the preceding items, wherein the hot water extract of tubercle bacillus or a portion thereof comprises a STING agonist derived from tubercle bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
(item X27 BAF) the medicament according to any one of the preceding items, wherein the non-pathogenic antigen component is administered more than twice.
(item X27 BAG) the medicament according to any one of the preceding items, wherein said pathogenic antigen component is a pathogenic factor of an infectious disease, and said non-pathogenic antigen component functions as an adjuvant when said pathogenic antigen component is used as a vaccine.
(item X28B) A kit for preventing or treating a disease, comprising a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject, and a non-pathogenic antigen component neither derived from nor cross-reactive with a pathogenic agent of the disease.
(item X28 AB) the kit according to any one of the above items, wherein the pathogenic agent comprises a foreign substance to the subject.
(item X28 BB) the kit of any one of the above items, wherein the causative agent of the above-mentioned disease comprises causative agent of infection, causative agent of allergy, causative agent of autoimmune disease, or poison.
The kit according to any one of the above items (X28 CB), wherein the disease is an infectious disease.
(item X28 DB) the kit according to any one of the above items, wherein the subject has an immunological memory for the non-pathogenic antigen component.
(item X28 EB) the kit according to any one of the preceding items, wherein said kit is for preventing or treating said disease.
(item X28 FB) the kit according to any one of the preceding items, wherein the aforementioned kit prevents or treats the aforementioned diseases in a form that does not accompany or reduce an immune excessive reaction.
(item X28 GB) the kit according to any one of the above items, wherein the above kit is administered in a form effective for controlling cellular immunity, which is cellular immunity against a causative agent of the above disease.
(item X28 HB) the kit according to any of the preceding items, wherein the above-mentioned disease is an infectious disease, an allergic reaction or an autoimmune disease.
(item X28 IB) the kit according to any one of the preceding items, wherein the disease is a viral infection or a bacterial infection.
(item X28 JB) the kit according to any of the above items, wherein the above disease is viral infection.
(item X28 KB) the kit according to any one of the preceding items, wherein the disease is an infectious disease associated with coronavirus.
The kit according to any one of the above items (X28 LB), wherein the pathogenic antigen component is a molecule at least a part of which is present on the surface of the membrane.
(item X28 BAA) the kit according to any one of the preceding items, wherein said non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The kit according to any one of the above items (item X28 BAB), wherein the non-pathogenic antigen component is a hot water extract of a strain B of Mycobacterium tuberculosis or a part thereof.
(item X28 BAC) the kit according to any one of the above items, wherein the above hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item X28 BAD) the kit according to any one of the preceding items, wherein said hot water extract of Bacillus tuberculosis or a part thereof comprises a STING agonist derived from Bacillus tuberculosis, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, a component capable of biosynthesis of STING agonist in human cells, or a NOD2 agonist.
(item X28 BAE) the kit of any one of the preceding items, wherein the hot water extract of tubercle bacillus or a portion thereof comprises a STING agonist derived from tubercle bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
(item X28 BAF) the kit according to any one of the above items, wherein the non-pathogenic antigen component is administered more than twice.
The kit according to any one of the above items, wherein the pathogenic antigen component is a pathogenic factor of an infectious disease, and the non-pathogenic antigen component functions as an adjuvant when the pathogenic antigen component is used as a vaccine.
(item X31B) an antigenic component for use in relieving or transforming the inhibition of regulatory T cells (tregs), said inhibition of regulatory T cells (tregs) meaning inhibition of activity against cells, said antigenic component being a non-pathogenic antigenic component which neither originates from nor cross-reacts with a pathogenic agent of an infectious, allergic and/or autoimmune disease that is a target, wherein the subject has an immunological memory for the antigenic component and comprises or infects or comprises the pathogenic agent of the infectious, the allergic and/or the autoimmune disease in the subject.
(item X32B) the antigenic component of any one of the preceding items, wherein said Treg is transformed into effector T cells (Teff) derived from and/or cross-reactive with a pathogenic agent of a target disease by the presence in said subject of a pathogenic agent antigenic component which is directed against or comprises a cell of a pathogenic agent of the disease (an infectious disease, an allergic reaction and/or an autoimmune disease).
(item X33B) the antigen component according to any one of the above items, wherein the subject has an immunological memory against the pathogenic agent and/or a factor cross-reactive with the pathogenic agent.
(item X33 AB) the antigen component according to any one of the preceding items, wherein suppression of the Treg is released or converted, whereby killing by a pathogenic agent against the infectious disease, allergy and/or autoimmune disease or killing by a cell infected with the pathogenic agent or comprising the pathogenic agent, or immune activation by a pathogenic agent against the infectious disease, allergy and/or autoimmune disease or immune activation by a cell infected with the pathogenic agent or comprising the pathogenic agent is imparted.
(item X33 BB) the antigen component according to any one of the preceding items, wherein the aforementioned pathogenic agent comprises at least one selected from the group consisting of malaria, yellow fever virus, smallpox virus, vaccinia, measles/rubella, polio, MUMPS (adofurosis)/MUMPS, rotavirus infection, varicella (chicken pox), yellow fever, ebola virus (Ebola), west nile fever, haemophilus influenzae type b infection, pneumococcal infection, pertussis, japanese encephalitis, meningococcal infection, salmonella infection, pathogenic escherichia coli, toxoplasmosis (Toxoplasma gondii), zika virus (Zika virus), herpes virus type 1, EBV (EPSTEIN BARR VIRUS)/epstein-barr virus (herpes virus type 4), CMV/cytomegalovirus (herpes virus type 5), influenza, MARS, rabies, diphtheria.
The antigen component according to any one of the above items (item X33 CB), wherein the pathogenic agent is a virus.
(item X33 DB) the antigen component according to any one of the above items, wherein the above pathogenic agent is a virus belonging to the family selected from the group consisting of rhinovirus, adenovirus, coronavirus, RS virus, influenza virus, parainfluenza virus and enterovirus.
(item X33 EB) the antigen component according to any one of the preceding items, wherein said pathogenic agent is a virus belonging to the genus coronavirus.
(item X33 FB) the antigenic component of any one of the preceding items, wherein said pathogenic agent is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2.
(item X33 GB) the antigen component according to any one of the above items, wherein the pathogenic agent is SARS-CoV-2 virus.
(item X33 HB) the antigen component according to any one of the above items, wherein the antigen component comprises a protein, a portion thereof, or a peptide.
(item X33 IB) the antigen component according to any one of the preceding items, wherein the antigen component comprises an antigen selected from the group consisting of a pathogen of an infectious disease or a part thereof, an antigen associated with a past history of disease, and an antigen associated with a history of vaccination.
(item X33 JB) the antigen component according to any one of the above items, wherein the antigen component comprises an antigen derived from a pathogen of a past infectious disease.
(item X33 KB) the antigen component according to any one of the preceding items, wherein the antigen component comprises an antigen component capable of controlling an immune response mediated by CD 4-positive T cells.
(item X33 LB) the antigen component according to any one of the above items, wherein the antigen component comprises a hot water extract of Mycobacterium tuberculosis.
(item X33 MB) the antigen component according to any one of the preceding items, wherein the subject is a subject having a history of BCG vaccination, a history of tuberculosis infection, or an antigen responsiveness to tubercle bacillus, and the antigen component comprises a hot water extract of human tubercle bacillus.
(item X33 NB) the antigen component according to any one of the preceding items, wherein the Treg is CD4 positive.
(item X33 OB) the antigen component according to any one of the preceding items, wherein the Treg releases activation inhibition of killer T cells specific for a causative agent of the infectious disease.
(item X33 PB) the antigen component according to any one of the preceding items, wherein the antigen component is for use in the prevention of the aforementioned infections.
(item X33 QB) the antigen component according to any one of the above items, wherein the antigen component is used for releasing activation inhibition of killer cells that kill cells infected with the above-mentioned pathogenic agent.
(item X33 RB) the antigen component according to any preceding item, characterized in that the antigen component is used in a method comprising the steps of: checking whether the antigenic component has immune memory of tregs in the subject; and administering the antigen component to the subject in the event that the subject has an immunological memory for the antigen component.
(item X33 SB) the antigen component according to any one of the preceding items, wherein it is confirmed whether the subject can control an antiviral immune response mediated by CD 4-positive T cells, and the antigen component is administered in a case where the subject can control an antiviral immune response mediated by CD 4-positive T cells.
(item X33 XAA) the antigen component according to any one of the above items, wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
(item X33 XAB) the antigen component according to any one of the above items, wherein the non-pathogenic antigen component is a hot water extract of a strain B of Mycobacterium tuberculosis or a part thereof.
(item X33 XAC) the antigen component according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item X33 XAD) the antigen component according to any one of the preceding items, wherein the hot water extract of Bacillus tuberculosis or a part thereof comprises a STING agonist derived from Bacillus tuberculosis, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb-related antigen, a component capable of biosynthesis of STING agonist in human cells, or a NOD2 agonist.
(item X33 XAE) the antigenic component of any one of the preceding items, wherein said hot water extract of tubercule bacillus or part thereof comprises a STING agonist derived from tubercule bacillus, said STING agonist being c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing said STING agonist in human cytoplasm mediated by cGAS.
(item X33 XAF) the antigen component according to any one of the above items, wherein the non-pathogenic antigen component is administered twice or more.
(item X33 XAG) the antigen component according to any one of the above items, wherein the pathogenic antigen component is a pathogenic factor of an infectious disease, and the non-pathogenic antigen component functions as an adjuvant when the pathogenic antigen component is used as a vaccine.
(item X34B) an antigen component for preventing or treating an infectious disease in a subject, wherein the antigen component comprises an antigen component specific for a component different from a causative agent of the infectious disease in the subject.
(item X35B) an antigenic component for use in the prevention or treatment of an infection in a subject, comprising an antigenic component derived from a pathogen of the subject that is different from a past infection of the infection, substantially free of a causative agent of the infection or a portion thereof.
(item X35 AB) the antigen component according to any one of the above items, wherein the above pathogenic agent is a virus belonging to the family selected from the group consisting of rhinovirus, adenovirus, coronavirus, RS virus, influenza virus, parainfluenza virus and enterovirus.
(item X35 BB) the antigen component of any one of the above items, wherein said pathogenic agent is a virus belonging to the genus coronavirus.
(item X35 CB) the antigen component according to any one of the above items, wherein the pathogenic agent is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SA RS-CoV-2.
(item X35 DB) the antigen component according to any one of the above items, wherein the pathogenic agent is SARS-CoV-2 virus.
(item X35 EB) the antigen component according to any one of the preceding items, wherein said antigen component is specific for memory T cells of said subject.
(item X35 FB) the antigen component according to any one of the preceding items, wherein the memory T cell is a memory regulatory T cell (IL-2 producing).
(item X35 GB) the antigen component according to any one of the above items, wherein the antigen component has an immunopotentiating effect.
(item X35 HB) the antigen component according to any one of the above items, wherein the above antigen component acts on memory CD 4-positive T cells in an antigen-dependent manner.
(item X35 IB) the antigen component according to any one of the preceding items, wherein the antigen component has an activity of biasing the presence ratio of Foxp 3-positive Treg cells and IFN-gamma producing T cells.
(item X35 JB) the antigen component of any one of the preceding items, wherein the bias is an increase in IFN- γ producing T cells compared to Foxp3 positive Treg cells.
(item X35 KB) the antigen component according to any one of the preceding items, wherein the antigen component has an activity of biasing the presence ratio of Foxp3 positive Treg cells to type 1 helper T cells.
(item X35 LB) the antigen component according to any one of the above items, wherein the IFN-gamma producing T cells comprise type 1 helper T cells.
(item X35 MB) the antigen component according to any one of the above items, wherein the antigen component has an activity of biasing the presence ratio of Th1 cells.
(item X35 NB) according to any one of the preceding items, wherein the IFN-. Gamma.producing T cells are T-bet positive Th1 cells.
(item X35 OB) the antigen component according to any one of the above items, wherein the antigen component having specificity has an ability to cause at least one selected from the group consisting of IFN-gamma producing ability, IL-2 producing ability and TNF-alpha producing ability to be increased in a sample derived from the subject.
The antigen component according to any one of the above items (X35 PB), wherein the antigen component is a protein.
(item X36B) an antigenic component for the prevention or treatment of an infection other than tuberculosis, which comprises a Bacillus tuberculosis extract.
(item X37B) an antigen component for controlling immune enhancement against a causative agent of an infectious disease other than tuberculosis in a subject when the subject is exposed to the causative agent, wherein the antigen component comprises a Bacillus tuberculosis extract.
(item X37 AB) the antigen component according to any one of the above items, wherein the immunopotentiation comprises an enhancement of cytokines and/or an enhancement of immune cells associated with immunopotentiation.
(item X37 BB) the antigen component of any one of the above items, wherein said immune cells comprise IL-10-producing cells.
(item X38B) an antigen component for preventing or treating an infection, allergy or autoimmune disease in a subject, wherein the antigen component comprises an antigen component specific in the subject, said antigen component being neither derived from nor cross-reactive with a causative agent of the infection, allergy or autoimmune disease,
the antigenic component is a protein or a portion thereof, or a peptide, and is capable of controlling an immune response mediated by CD4 positive T cells,
the infection, allergy or autoimmune disease includes a disease that can be prevented or treated by an immune response mediated by CD4 positive T cells,
here, it was confirmed whether the subject could control an immune response against an infectious disease, an allergic reaction, or an autoimmune disease mediated by CD4 positive T cells, and the antigen component was administered in a case where the subject could control an immune response against an infectious disease, an allergic reaction, or an autoimmune disease mediated by CD4 positive T cells.
(item X39B) an antigen component for preventing or treating an infectious disease in a subject, characterized in that the antigen component comprises an antigen component specific for a component different from a causative agent of the infectious disease in the subject,
The infection comprises a viral infection and the method comprises,
the antigenic component is a protein or a portion thereof, or a peptide, and is capable of controlling an immune response mediated by CD4 positive T cells,
the viral infections include diseases which can be prevented or treated by an immune response mediated by CD4 positive T cells,
here, it was confirmed whether the subject could control an antiviral immune response mediated by CD4 positive T cells, and the antigen component was administered in the case where the subject could control an antiviral immune response mediated by CD4 positive T cells.
(item X40B) a method of manufacturing or otherwise providing an antigenic component for use in preventing or treating an infection, allergy or autoimmune disease in a subject, wherein the method comprises the steps of:
step a), identifying an antigenic component specific to the subject, said antigenic component being neither derived from nor cross-reactive with a causative agent of the infection, allergy or autoimmune disease;
step B), determining whether the antigen component has an immunological memory in the subject, and selecting the antigen component having the immunological memory; and
step C) manufacturing or otherwise providing the selected antigen component.
(item X41B) a method of determining whether an antigenic component specific to a subject, said antigenic component being neither derived from nor cross-reactive with a causative agent of an infectious disease, allergic reaction or autoimmune disease in the subject, can prevent or treat the infectious disease, allergic reaction or autoimmune disease in the subject, comprising the steps of:
step B) is a step of specifying whether or not the antigen component has an immunological memory in the subject, and in the case of having the immunological memory, is specified to be capable of preventing or treating an infection, an allergy or an autoimmune disease in the subject.
(item X42B) an antigen component for use in a method for preventing or treating an infection, allergy or autoimmune disease, wherein the method comprises the steps of:
step a), obtaining an antigen responsiveness profile of the subject;
step b) of specifying the antigen component or the combination of antigen components based on the antigen responsiveness profile, wherein the antigen component or the combination of antigen components is specified based on whether the subject now exhibits an immune responsiveness or has previously exhibited an immune responsiveness to the antigen component or the combination of antigen components; and
Step c) administering to the subject the antigen component or combination of antigen components identified in step b) in an amount sufficient to control an immune response in the subject.
(item X42 AB) the antigen component according to any one of the above items, wherein, in the above method, the obtaining of the above antigen-responsiveness profile comprises: confirming a past physical state of the subject; confirming whether one or more antigen candidates are responsive in a sample derived from the subject; or both.
(item X42 BB) the antigen component of any one of the above items, wherein said obtaining of an antigen-responsiveness profile comprises: an antigen component or combination of antigen components is specified that controls an immune response mediated by CD4 positive T cells.
(item X42 CB) the antigen component according to any one of the preceding items, wherein i) the antigenic response profile comprises at least one selected from the group consisting of a past medical history based on a consultation, a mother-son health manual or an equivalent thereof, a vaccination history, and a combination thereof; and/or ii) whether the above-described acknowledgement is responsive comprises: body fluid (e.g., blood) is collected from the subject, peripheral blood cells are isolated, and then it is determined whether the peripheral blood cells react with antigens associated with the antigen profile to produce cytokines, and other biomarkers are measured.
(item X42 DB) the antigen component according to any one of the above items, wherein the above method further comprises the steps of: the responsiveness of the antigen was periodically checked, and maintenance of the responsiveness was confirmed.
(item X42 EB) the antigen component according to any one of the preceding items, wherein the above a) and b) are carried out by the steps of:
step i) obtaining a past physical state of the subject;
step ii) collecting blood from the subject, separating peripheral blood cells, determining whether the peripheral blood cells react with an antigen corresponding to the physical state to produce cytokines, and determining other biomarkers; and
step iii) specifies the appropriate antigen component or combination of antigen components based on the results of ii).
(item X42 FB) the antigen component of any one of the preceding items, wherein the antigen component further comprises the features of any one or more of the preceding items.
(item X42 GB) the antigen component according to any one of the above items, wherein the past physical state comprises a past medical history and a vaccination history.
(item X42 HB) the antigen component according to any one of the preceding items, wherein the physical state comprises a history of non-coronavirus infection, and the antigen component comprises an antigen component or a combination of antigen components for the non-coronavirus infection.
(item X42 IB) the antigen component according to any one of the above items, wherein the physical state comprises a history of BCG vaccination, a history of tuberculosis infection or an antigen responsiveness to tubercule bacillus, and the antigen component or combination of antigen components comprises a hot water extract of human tubercule bacillus.
(item X42 JB) the antigen component of any one of the above items, wherein the administration comprises subcutaneous administration, intradermal administration, or intramuscular administration.
(item X42 KB) the antigenic component of any one of the preceding items, wherein step ii) above comprises assaying for induction of cells producing IFN-gamma, IL-2, TNF-alpha or a combination of cytokines from these.
(item X42 LB) the antigen component according to any one of the above items, wherein the antigen responsiveness profile is obtained by performing a concomitant diagnosis in advance based on a past medical history and a vaccination history.
(item X42 MB) the antigen component according to any one of the above items, wherein the past physical state and the antigen component or combination of antigen components are a history of tuberculosis infection and a hot water extract of human type tubercle bacillus.
(item X42 NB) the antigen component according to any one of the above items, characterized in that,
the above subjects were subjects who had confirmed a history of BCG vaccination, a history of tuberculosis infection or antigen responsiveness,
the extract of Bacillus tuberculosis is obtained by conventional methods, and is administered prophylactically before or at the beginning of infection onset, and subcutaneously or intradermally or intramuscularly at the beginning of infection onset.
(item X42 OB) an antigenic component based on any one of the above items for use in the prevention or treatment of a viral infection, characterized in that the above antigenic component or combination of antigenic components is re-inoculated.
(item X42 PB) an antigen component for use in preventing or treating an infection in a subject using an antigen component different from a causative agent of the infection, characterized in that the antigen component is an antigen or an extract identified by interrogation and/or by reference to a past history of the subject and a history of vaccination, the subject is a human having a history of infection or a human having a history of vaccination of an infection associated with the antigen component, the component is administered to the subject in a prophylactic administration for recurrence after treatment, a prophylactic administration before onset, or at an early stage of onset of the infection, and the component is administered at an early stage of onset of the infection as needed.
(item X42 QB) the antigen component according to any one of the above items, wherein the responsiveness is specifically determined with respect to the past infection history, vaccination history, and induction of cells using IFN-gamma production, IL-2 production, TNF-alpha production or simultaneous production of a plurality of cytokines among these cytokines.
(item X42 RB) the antigen component according to any one of the above items, wherein the Bacillus tuberculosis extract is a hot water extract of human type Bacillus tuberculosis or an extract derived from other Bacillus tuberculosis (extract with high safety).
(item X42 SB) the antigen component according to any one of the above items, wherein the antigen component is a protein.
(item X42 TB) a vaccine formulation comprising the antigen component of any one of the preceding items and an adjuvant base.
(item X42 UB) the vaccine formulation according to any one of the preceding items, wherein the adjuvant-based agent comprises a substance that promotes a Th1 type immune response.
(item X42 VB) an antigenic component for use in a method for preventing or treating an infection, allergy or autoimmune disease in a subject, wherein the method comprises the steps of:
Step a) of identifying, based on an antigenic response profile, an antigenic component specific to the subject, said antigenic component being neither derived from nor cross-reactive with a causative agent of the infection, allergy or autoimmune disease;
step b) identifying whether the subject has an immunological memory for the antigenic component and identifying the subject having the immunological memory; and
step c) administering the antigenic component to the subject specified as having the immunological memory.
(item X42 WB) the antigenic component of any one of the above items, wherein the above antigenic response profile comprises a history of vaccination and/or a history of infection.
(item X43B) a hot water extract of Mycobacterium tuberculosis or a part thereof, characterized in that it is used as an adjuvant for a vaccine against infectious diseases.
(item X43 AB) a STING agonist, characterized in that it is for use as an adjuvant for a vaccine against an infectious disease.
(item X43 BB) a STING agonist, characterized in that it is for use as an adjuvant for a vaccine against an infectious disease of a viral infection.
(item X44B) the hot water extract of Bacillus tuberculosis or a part thereof or an agonist thereof according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof is a hot water extract of human type Bacillus tuberculosis Qingshan B strain or a part thereof.
(item X45B) the hot water extract of Bacillus tuberculosis or a part thereof or an agonist thereof according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item X46B) the hot water extract of Bacillus tuberculosis or a part or an agonist thereof according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof comprises a STING agonist derived from Bacillus tuberculosis, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, a component capable of synthesizing a STING agonist in human cells, or a NOD2 agonist or a part other than the same.
(item X47B) the hot water extract of tubercule bacillus, or a part or agonist thereof according to any one of the preceding items, wherein the hot water extract of tubercule bacillus, or a part thereof, comprises STING agonists derived from tubercule bacillus, which are c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonists in human cytoplasm mediated by cGAS.
(item X48B) the hot water extract of Mycobacterium tuberculosis or a part or agonist thereof according to any one of the above items, wherein the causative agent of the infection is bacteria, viruses or protozoa.
(item X49B) the hot water extract of Bacillus tuberculosis or a part or agonist thereof according to any one of the above items, wherein the causative agent of the infection is a virus.
(item X50B) the hot water extract of Mycobacterium tuberculosis or a part or agonist thereof according to any one of the above items, wherein the causative agent of the infection is a virus belonging to the family Coronaviridae.
(item X51B) the hot water extract of Mycobacterium tuberculosis or a part or agonist thereof according to any one of the above items, wherein the causative agent of the above infection is a virus belonging to the family selected from the group consisting of rhinovirus, adenovirus, coronavirus, RS virus, influenza virus, parainfluenza virus and enterovirus.
(item X52B) the hot water extract of Mycobacterium tuberculosis or a part or agonist thereof according to any one of the above items, wherein the causative agent of the infection is a virus belonging to the genus coronavirus.
(item X53B) the hot water extract of Mycobacterium tuberculosis or a part or agonist thereof according to any one of the above items, wherein the causative agent of the infection is a virus selected from the group consisting of HCoV-HKU1, HCo V-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2.
(item X54B) the hot water extract of Mycobacterium tuberculosis or a part or agonist thereof according to any one of the above items, wherein the causative agent of the infection is SARS-CoV-2 virus.
(item X1C) use of a non-pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a disease in a subject, in the manufacture of a medicament for preventing or treating the disease, wherein the non-pathogenic antigen component is administered in the presence of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in the subject.
(item X2C) the use according to any one of the above items, wherein the pathogenic agent comprises a foreign substance for the subject.
(item X3C) the use according to any one of the above items, wherein the causative agent of the above disease comprises causative agent of infectious disease, causative agent of allergy, causative agent of autoimmune disease, or poison.
The use according to any one of the above items (X4C), wherein the disease is an infectious disease.
(item X5C) the use according to any one of the above items, wherein the subject has an immunological memory against the non-pathogenic antigen component.
(item X6C) the use according to any one of the above items, wherein the agent comprises the above-mentioned pathogenic antigen component.
(item X7C) the use according to any one of the above items, wherein the above drug is for preventing the above diseases.
(item X8C) the use according to any one of the above items, wherein the above drug prevents or treats the above disease in a form that does not accompany or reduce an immune excessive reaction.
(item X9C) the use according to any one of the preceding items, wherein the medicament is administered in a form effective for controlling cellular immunity, which is a cellular immunity against a causative agent of the disease.
(item X10C) the use according to any one of the preceding items, wherein for the medicament, the presence or absence of a pathogenic antigen component in the subject is confirmed, and in the absence, the pathogenic antigen component is administered together with the non-pathogenic antigen component, which pathogenic antigen component is derived from and/or cross-reacts with a pathogenic agent of the target disease.
(item X11C) the use according to any one of the above items, wherein the disease is an infection, allergy or autoimmune disease.
(item X12C) the use according to any one of the above items, wherein the disease is a viral infection or a bacterial infection.
The use according to any one of the above items (X13C), wherein the disease is a viral infection.
(item X14C) the use according to any one of the above items, wherein the disease is an infectious disease associated with coronavirus.
(item X15C) the use according to any one of the above items, wherein the pathogenic antigen component is a molecule having at least a part of its surface on which a pathogenic agent of a target disease appears.
(item X15 CA) the use according to any one of the above items, wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
(item X15 CB) the use according to any one of the preceding items, wherein the non-pathogenic antigen component is a hot water extract of a strain B of Mycobacterium tuberculosis or a part thereof.
(item X15 CC) the use according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item X15 CD) the use according to any one of the preceding items, wherein the hot water extract of tubercle bacillus or a part thereof comprises a STING agonist derived from tubercle bacillus, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, a component capable of biosynthesis of STING agonist in human cells, or a NOD2 agonist.
(item X15 CE) the use according to any one of the preceding items, wherein the hot water extract of tubercle bacillus or a part thereof comprises a STING agonist derived from tubercle bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
(item X15 CF) the use according to any one of the preceding items, wherein the non-pathogenic antigen component is administered more than twice.
(item X16C) use of a combination of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject, and a non-pathogenic antigen component derived from or cross-reactive with a pathogenic agent of the disease, in the manufacture of a medicament.
(item X17C) the use according to any one of the above items, wherein the pathogenic antigen component comprises a pathogenic factor of an infectious disease, a pathogenic substance of an allergic reaction, a pathogenic substance of an autoimmune disease, or a poison.
(item X18C) the use according to any one of the above items, wherein the pathogenic antigen component is a bacterium, a virus or a protozoan or a part thereof.
The use according to any one of the above items (item X19C), wherein the pathogenic antigen component is a virus or a part thereof.
(item X20C) the use according to any one of the above items, wherein the pathogenic antigen component is a virus belonging to the family Coronaviridae or a part thereof.
(item X21C) the use according to any one of the preceding items, wherein the pathogenic agent is a virus belonging to the family selected from the group consisting of rhinovirus, adenovirus, coronavirus, RS virus, influenza virus, parainfluenza virus and enterovirus.
(item X22C) the use according to any one of the above items, wherein the pathogenic agent is a virus belonging to the genus coronavirus.
(item X23C) the use according to any one of the preceding items, wherein the pathogenic agent is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2.
(item X24C) the use according to any one of the above items, wherein the pathogenic agent is SARS-CoV-2 virus.
(item X25C) the use according to any one of the above items, wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
The use according to any one of the above items (X26C), wherein the non-pathogenic antigen component is a hot water extract of a strain B of Mycobacterium tuberculosis or a part thereof.
(item X26 CA) the use according to any one of the above items, wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
(item X26 CB) the use according to any one of the preceding items, wherein the non-pathogenic antigen component is a hot water extract of a strain B of Mycobacterium tuberculosis or a part thereof.
(item X26 CC) the use according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item X26 CD) the use according to any one of the preceding items, wherein the hot water extract of tubercle bacillus or a part thereof comprises a STING agonist, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, STING agonist, or NOD2 agonist derived from tubercle bacillus.
(item X26 CE) the use according to any one of the preceding items, wherein the hot water extract of tubercle bacillus or a part thereof comprises a STING agonist derived from tubercle bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
(item X26 CF) the use according to any one of the preceding items, wherein the non-pathogenic antigen component is administered more than twice.
The use according to any one of the above items (item X26 CG), wherein the pathogenic antigen component is a pathogenic factor of an infectious disease, and the non-pathogenic antigen component functions as an adjuvant when the pathogenic antigen component is used as a vaccine.
(item X27C) use of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject, in combination with a non-pathogenic antigen component neither derived from nor cross-reactive with a pathogenic agent of the disease, for the manufacture of a medicament for the prevention or treatment of the disease.
(item X27 AC) the use according to any one of the above items, wherein the pathogenic agent comprises a foreign substance for the subject.
(item X27 BC) the use according to any one of the above items, wherein the causative agent of the disease comprises causative agent of an infectious disease, causative agent of an allergic reaction, causative agent of an autoimmune disease, or poison.
(item X27 CC) the use according to any one of the above items, wherein the disease is an infectious disease.
(item X27 DC) the use according to any one of the above items, wherein the subject has an immunological memory to the non-pathogenic antigen component.
(item X27 EC) the use according to any one of the above items, wherein the above drug is for preventing the above diseases.
(item X27 FC) the use according to any one of the above items, wherein the above drug prevents or treats the above disease in a form that does not accompany or reduce an immune excessive reaction.
(item X27 GC) the use according to any one of the preceding items, wherein the medicament is administered in a form effective for controlling cellular immunity, which is a cellular immunity against a causative agent of the disease.
(item X27 HC) the use according to any one of the above items, wherein the disease is an infection, allergy or autoimmune disease.
(item X27 IC) the use according to any one of the above items, wherein the disease is a viral infection or a bacterial infection.
(item X27 JC) the use according to any of the above items, wherein the disease is a viral infection.
(item X27 KC) the use according to any preceding item, wherein the above-mentioned disease is an infectious disease associated with coronavirus.
(item X27 LC) the use according to any one of the above items, wherein the pathogenic antigen component is a molecule at least a part of which is present on the surface of a membrane.
(item X27 CAA) the use according to any one of the preceding items, wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
(item X27 CAB) the use according to any one of the preceding items, wherein the non-pathogenic antigen component is a hot water extract of the Qingshan B strain of Mycobacterium tuberculosis or a part thereof.
(item X27 CAC) the use according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item X27 CAD) the use according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof comprises a STING agonist derived from Bacillus tuberculosis, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, a component capable of biosynthesis of STING agonist in human cells, or a NOD2 agonist.
(item X27 CAE) the use according to any one of the preceding items, wherein the hot water extract of tubercle bacillus or a part thereof comprises a STING agonist derived from tubercle bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
(item X27 CAF) for use according to any one of the preceding items, wherein the non-pathogenic antigen component is administered more than twice.
(item X27 CAG) the use according to any one of the preceding items, wherein the pathogenic antigen component is a pathogenic factor of an infectious disease, and the non-pathogenic antigen component functions as an adjuvant when the pathogenic antigen component is used as a vaccine.
(item X28C) use of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject, and a non-pathogenic antigen component neither derived from nor cross-reactive with a pathogenic agent of the disease, in the manufacture of a kit for preventing or treating the disease.
(item X28 AC) the use according to any one of the above items, wherein the pathogenic agent comprises a foreign substance for the subject.
(item X28 BC) the use according to any one of the preceding items, wherein the causative agent of the disease comprises causative agent of an infectious disease, causative agent of an allergic reaction, causative agent of an autoimmune disease, or poison.
(item X28 CC) the use according to any one of the above items, wherein the disease is an infectious disease.
(item X28 DC) the use according to any one of the above items, wherein the subject has an immunological memory for the non-pathogenic antigen component.
(item X28 EC) the use according to any one of the above items, wherein the above kit is for preventing or treating the above diseases.
(item X28 FC) the use according to any one of the above items, wherein the above kit prevents or treats the above disease in a form that does not accompany or reduce an immune excess reaction.
(item X28 GC) the use according to any one of the preceding items, wherein the kit is administered in a form effective for controlling cellular immunity, which is a cellular immunity against a causative agent of the disease.
(item X28 HC) the use according to any one of the above items, wherein the disease is an infection, allergy or autoimmune disease.
(item X28 IC) the use according to any one of the above items, wherein the disease is a viral infection or a bacterial infection.
(item X28 JC) the use according to any of the above items, wherein the disease is a viral infection.
(item X28 KC) the use according to any preceding item, wherein the above-mentioned disease is an infectious disease associated with coronavirus.
(item X28 LC) the use according to any one of the above items, wherein the pathogenic antigen component is a molecule at least a part of which is present on the surface of a membrane.
(item X28 CAA) the use according to any one of the preceding items, wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
(item X28 CAB) the use according to any one of the preceding items, wherein the non-pathogenic antigen component is a hot water extract of the Qingshan B strain of Mycobacterium tuberculosis or a part thereof.
(item X28 CAC) the use according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item X28 CAD) the use according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof comprises a STING agonist derived from Bacillus tuberculosis, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, a component capable of biosynthesis of STING agonist in human cells, or a NOD2 agonist.
(item X28 CAE) for use according to any of the preceding items, wherein the hot water extract of tubercle bacillus or a part thereof comprises a STING agonist derived from tubercle bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing said STING agonist in human cytoplasm mediated by cGAS.
(item X28 CAF) for use according to any one of the preceding items, wherein said non-pathogenic antigen component is administered more than twice.
(item X28 CAG) the use according to any one of the preceding items, wherein the pathogenic antigen component is a pathogenic factor of an infectious disease, and the non-pathogenic antigen component functions as an adjuvant when the pathogenic antigen component is used as a vaccine.
(item X31C) use of a non-pathogenic antigen component that is neither derived from an infectious disease, allergy, and/or autoimmune disease that is a target nor cross-reactive with a pathogenic agent in the manufacture of a medicament for relieving or transforming the inhibition of regulatory T cells (tregs), which refers to inhibiting activity against a cell, wherein the subject has an immune memory against the antigen component and the subject comprises the pathogenic agent of the infectious disease, allergy, and/or autoimmune disease.
(item X32C) the use according to any one of the preceding items, characterized in that said Treg is transformed into effector T cells (Teff) derived from and/or cross-reactive with the causative agent of the target disease by the presence in said subject of a pathogenic agent antigen component which is directed against or comprises the causative agent of the disease (infectious disease, allergic reaction and/or autoimmune disease).
(item X33C) the use according to any one of the preceding items, wherein the subject has an immunological memory for the pathogenic agent and/or a factor cross-reactive with the pathogenic agent.
(item X33 AC) the use according to any one of the preceding items, wherein suppression of the Treg is released or transformed, thereby imparting a killing ability against a pathogenic agent of the infectious disease, allergy and/or autoimmune disease or against a cell infected with the pathogenic agent or comprising the pathogenic agent, or an immunopotentiation against a pathogenic agent of the infectious disease, allergy and/or autoimmune disease or against a cell infected with the pathogenic agent or comprising the pathogenic agent.
(item X33 BC) the use according to any one of the preceding items, wherein the pathogenic agent comprises at least one selected from the group consisting of malaria, yellow fever virus, smallpox virus, vaccinia, measles/rubella, polio, MUMPS (adofurosis)/MUMPS, rotavirus infection, varicella (chicken pox), yellow fever, ebola virus (Ebola), west nile fever, haemophilus influenzae type b, pneumococcal infection, pertussis, japanese encephalitis, meningococcal infection, salmonella infection, pathogenic escherichia coli, toxoplasmosis (Toxoplasma gondii), zika virus (Zika virus), herpes virus type 1, EBV (EPSTEIN BARR VIRUS)/epstein-barr virus (herpes virus type 4), CMV/cytomegalovirus (herpes virus type 5), influenza, MARS, rabies, diphtheria.
(item X33 CC) the use according to any one of the above items, wherein the pathogenic agent is a virus.
(item X33 DC) the use according to any one of the preceding items, wherein the pathogenic agent is a virus belonging to the family selected from the group consisting of rhinoviruses, adenoviruses, coronaviruses, RS viruses, influenza viruses, parainfluenza viruses and enteroviruses.
(item X33 EC) the use according to any one of the above items, wherein the pathogenic agent is a virus belonging to the genus coronavirus.
(item X33 FC) the use according to any one of the preceding items, wherein the pathogenic agent is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2.
(item X33 GC) the use according to any one of the above items, wherein the pathogenic agent is SARS-CoV-2 virus.
(item X33 HC) the use according to any one of the above items, wherein the antigen component comprises a protein, a part thereof or a peptide.
(item X33 IC) the use according to any one of the preceding items, wherein the antigen component comprises an antigen selected from the group consisting of a pathogen of an infectious disease or a part thereof, an antigen related to a past history, and an antigen related to a vaccination history.
(item X33 JC) the use according to any one of the above items, wherein the antigen component comprises an antigen derived from a pathogen of past infection.
(item X33 KC) the use according to any preceding item, wherein the antigen component comprises an antigen component capable of controlling an immune response mediated by CD4 positive T cells.
(item X33 LC) the use according to any one of the above items, wherein the antigen component comprises a hot water extract of Mycobacterium tuberculosis.
(item X33 MC) the use according to any one of the preceding items, wherein the subject is a subject having a history of BCG vaccination, a history of tuberculosis infection or an antigenic response against tubercle bacillus, and the antigenic component comprises a hot water extract of human tubercle bacillus.
(item X33 NC) the use according to any one of the preceding items, wherein the Treg is CD4 positive.
(item X33 OC) the use according to any of the preceding items, wherein the Treg releases the activation inhibition of killer T cells specific for the causative agent of the infection.
(item X33 PC) the use according to any one of the above items, wherein the above drug is for preventing the above infection.
(item X33 QC) the use according to any one of the above items, wherein the above drug is used for relieving activation inhibition of killer cells that kill cells infected with the above pathogenic agent.
(item X33 RC) use according to any one of the preceding items, characterized in that it is used in a method comprising the steps of: checking whether the medicament has immune memory of tregs in the subject; and administering the antigen component to the subject in the event that the subject has an immunological memory for the antigen component.
(item X33 SC) the use according to any one of the preceding items, wherein it is confirmed whether the subject can control an antiviral immune response mediated by CD4 positive T cells, and the medicament is administered in a case where the subject can control an antiviral immune response mediated by CD4 positive T cells.
(item X33 CAA) the use according to any one of the preceding items, wherein the non-pathogenic antigen component is a hot water extract of Bacillus tuberculosis or a part thereof.
(item X33 CAB) the use according to any one of the preceding items, wherein the non-pathogenic antigen component is a hot water extract of the Qingshan B strain of Mycobacterium tuberculosis or a part thereof.
(item X33 CAC) the use according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item X33 CAD) the use according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof comprises a STING agonist derived from Bacillus tuberculosis, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, a component capable of biosynthesis of STING agonist in human cells, or a NOD2 agonist.
(item X33 CAE) the use according to any one of the preceding items, wherein the hot water extract of tubercle bacillus or a part thereof comprises a STING agonist derived from tubercle bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
(item X33 CAF) for use according to any one of the preceding items, wherein the non-pathogenic antigen component is administered twice or more.
(item X33 CAG) the use according to any one of the preceding items, wherein the pathogenic antigen component is a pathogenic factor of an infectious disease, and the non-pathogenic antigen component functions as an adjuvant when the pathogenic antigen component is used as a vaccine.
The use of the antigen component of item X34C for the manufacture of a medicament for preventing or treating an infection in a subject, wherein the antigen component is specific for a component different from a causative agent of the infection in the subject.
The use of the antigen component of item X35C for the manufacture of a medicament for preventing or treating an infection of a subject, wherein the antigen component is derived from a pathogen of the infection that is different from a past infection of the infection, the medicament being substantially free of a causative agent of the infection or a portion thereof.
(item X35 AC) the use according to any one of the preceding items, wherein the pathogenic agent is a virus belonging to the family selected from the group consisting of rhinoviruses, adenoviruses, coronaviruses, RS viruses, influenza viruses, parainfluenza viruses and enteroviruses.
(item X35 BC) the use according to any one of the above items, wherein the pathogenic agent is a virus belonging to the genus coronavirus.
(item X35 CC) the use according to any one of the preceding items, wherein the pathogenic agent is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2.
(item X35 DC) the use according to any one of the above items, wherein the pathogenic agent is SARS-CoV-2 virus.
(item X35 EC) the use according to any one of the above items, wherein the antigen component has specificity for the memory T cells of the subject.
(item X35 FC) the use according to any one of the above items, wherein the memory T cells are memory regulatory T cells (IL-2 producing).
(item X35 GC) the use according to any one of the above items, wherein the antigen component has an immunopotentiating effect.
(item X35 HC) the use according to any one of the above items, wherein the antigen component acts on memory CD 4-positive T cells in an antigen-dependent manner.
(item X35 IC) the use according to any one of the preceding items, wherein the antigen component has an activity of biasing the presence ratio of Foxp3 positive Treg cells and IFN-gamma producing T cells.
(item X35 JC) the use of any one of the preceding items, wherein the bias is an increase in IFN- γ producing T cells compared to Foxp3 positive Treg cells.
(item X35 KC) the use according to any preceding item, wherein the antigen component has an activity of biasing the presence ratio of Foxp3 positive Treg cells and type 1 helper T cells.
(item X35 LC) the use according to any one of the preceding items, wherein the IFN-gamma producing T cells comprise type 1 helper T cells.
(item X35 MC) the use according to any one of the above items, wherein the antigen component has an activity of biasing the presence ratio of Th1 cells.
(item X35 NC) the use according to any one of the above items, wherein the IFN-gamma producing T cells are T-bet positive Th1 cells.
(item X35 OC) the use according to any one of the above items, wherein the antigen component having specificity has an ability to cause at least one selected from the group consisting of IFN-gamma producing ability, IL-2 producing ability and TNF-alpha producing ability to be enhanced in a sample derived from the subject.
The use according to any one of the above items (item X35 PC), wherein the antigen component is a protein.
(item X36C) use of a Bacillus tuberculosis extract for the manufacture of a medicament for preventing or treating an infection other than tuberculosis.
(item X37C) use of a tubercle bacillus extract for controlling immune enhancement against a pathogenic agent of a non-tubercular infection in a subject when the subject is exposed to the pathogenic agent.
(item X37 AC) the use according to any one of the preceding items, wherein the immune enhancement comprises enhancement of cytokines and/or enhancement of immune cells associated with immune enhancement.
(item X37 BC) the use according to any one of the preceding items, wherein the immune cells comprise IL-10 producing cells.
(item X38C) use of an antigen component specific to a subject for the manufacture of a medicament for preventing or treating an infection, allergy or autoimmune disease in a subject, wherein the antigen component is neither derived from nor cross-reactive with a causative agent of the infection, allergy or autoimmune disease,
The antigenic component is a protein or a portion thereof, or a peptide, and is capable of controlling an immune response mediated by CD4 positive T cells,
the infection, allergy or autoimmune disease includes a disease that can be prevented or treated by an immune response mediated by CD4 positive T cells,
here, it was confirmed whether the subject could control an immune response against an infectious disease, an allergic reaction, or an autoimmune disease mediated by CD4 positive T cells, and the drug was administered in a case where the subject could control an immune response against an infectious disease, an allergic reaction, or an autoimmune disease mediated by CD4 positive T cells.
The use of the antigen component of item X39C for producing a medicament for preventing or treating an infectious disease in a subject, characterized in that the antigen component has specificity for a component different from a causative agent of the infectious disease in the subject,
the infection comprises a viral infection and the method comprises,
the antigenic component is a protein or a portion thereof, or a peptide, and is capable of controlling an immune response mediated by CD4 positive T cells,
the viral infections include diseases which can be prevented or treated by an immune response mediated by CD4 positive T cells,
here, it was confirmed whether the subject could control an antiviral immune response mediated by CD4 positive T cells, and the antigen component was administered in the case where the subject could control an antiviral immune response mediated by CD4 positive T cells.
(item X40C) a method of making or otherwise providing a composition for preventing or treating an infection, allergy, or autoimmune disease in a subject, wherein the method comprises the steps of:
step a) identifying an antigenic component specific to the subject, said antigenic component being neither derived from nor cross-reactive with a causative agent of the infection, allergy or autoimmune disease;
step B), determining whether the antigen component has an immunological memory in the subject, and selecting the antigen component having the immunological memory; and
step C) manufacturing or otherwise providing the selected antigen component.
(item X41C) a method of determining whether an antigenic component specific to the subject, said antigenic component being neither derived from nor cross-reactive with a causative agent of an infectious disease, allergic reaction or autoimmune disease in the subject, can prevent or treat the infectious disease, allergic reaction or autoimmune disease in the subject, comprising the steps of:
step B) is a step of specifying whether or not the antigen component has an immunological memory in the subject, and in the case of having the immunological memory, is specified to be capable of preventing or treating an infection, an allergy or an autoimmune disease in the subject.
(item X42C) use of the manufacture of a medicament for use in a method for preventing or treating an infectious disease, allergy or autoimmune disease, wherein the method comprises the steps of:
step a), obtaining an antigen responsiveness profile of the subject;
step b) of specifying an antigen component or a combination of antigen components based on the antigen responsiveness profile, wherein the antigen component or the combination of antigen components is specified based on whether the subject now exhibits an immune responsiveness or has previously exhibited an immune responsiveness; and
step c) administering to the subject the antigen component or combination of antigen components identified in step b) in an amount sufficient to control an immune response in the subject.
(item X42 AC) the use according to any one of the preceding items, wherein the obtaining of the antigen responsiveness profile comprises: confirming a past physical state of the subject; confirming whether one or more antigen candidates are responsive in a sample derived from the subject; or both.
(item X42 BC) the use according to any one of the preceding items, wherein the obtaining of the antigen responsiveness profile comprises: an antigen component or combination of antigen components is specified that controls an immune response mediated by CD4 positive T cells.
(item X42 CC) the use according to any one of the preceding items, wherein i) the antigenic response profile comprises at least one selected from the group consisting of a past medical history based on a consultation, a mother-son health manual or an equivalent thereof, etc., a vaccination history and combinations thereof; and/or ii) whether the above-described acknowledgement is responsive comprises: body fluid (e.g., blood) is collected from the subject, peripheral blood cells are isolated, and then it is determined whether the peripheral blood cells react with antigens associated with the antigen profile to produce cytokines, and other biomarkers are measured.
(item X42 DC) the use according to any one of the preceding items, wherein the method further comprises the steps of: the responsiveness of the antigen was periodically checked, and maintenance of the responsiveness was confirmed.
(item X42 EC) the use according to any of the above items, wherein the above a) and b) are carried out by:
step i) obtaining a past physical state of the subject;
step ii) collecting blood from the subject, separating peripheral blood cells, determining whether the peripheral blood cells react with an antigen corresponding to the physical state to produce cytokines, and determining other biomarkers; and
Step iii) specifies the appropriate antigen component or combination of antigen components based on the results of ii).
(item X42 FC) the use according to any one of the preceding items, wherein the use further comprises the features of any one or more of the preceding items.
(item X42 GC) the use according to any one of the preceding items, wherein the past physical state comprises a past medical history and a vaccination history.
(item X42 HC) the use according to any one of the preceding items, wherein the physical state comprises a history of non-coronavirus infection and the antigen component comprises an antigen component or a combination of antigen components against the non-coronavirus infection.
(item X42 IC) the use according to any one of the above items, wherein the physical state comprises a history of BCG vaccination, a history of tuberculosis infection or an antigen responsiveness to tubercule bacillus, and the antigen component or combination of antigen components comprises a hot water extract of human tubercule bacillus.
(item X42 JC) the use according to any one of the preceding items, wherein the administration comprises subcutaneous administration, intradermal administration or intramuscular administration.
(item X42 KC) for use according to any preceding item, wherein step ii) above comprises assaying induction of cells producing IFN-gamma, IL-2, TNF-alpha or a plurality of these cytokines simultaneously.
(item X42 LC) the use according to any one of the above items, wherein the antigen responsiveness profile is obtained by performing a concomitant diagnosis in advance based on a past medical history and a vaccination history.
(item X42 MC) the use according to any one of the above items, wherein the past physical state and the antigen component or combination of antigen components are a history of tuberculosis infection and a hot water extract of human type tubercle bacillus.
(item X42 NC) the use according to any one of the above items, characterized in that,
the above subjects were subjects who had confirmed a history of BCG vaccination, a history of tuberculosis infection or antigen responsiveness,
the extract of Bacillus tuberculosis is obtained by conventional methods, and is administered prophylactically before or at the beginning of infection onset, and subcutaneously or intradermally or intramuscularly at the beginning of infection onset.
(item X42 OC) use of any one of the above items for the manufacture of a medicament for use in the prevention or treatment of a viral infection, characterized in that the above antigen component or combination of antigen components is re-inoculated.
(item X42 PC) use of an antigenic component other than a causative agent of an infectious disease, for the manufacture of a medicament for preventing or treating an infectious disease in a subject, characterized in that the antigenic component is an antigen or extract identified by interrogation and/or reference to the past medical history and vaccination history of the subject, the subject is a person having a history of infection or a person having a vaccination history of an infectious disease associated with the antigenic component, the component is administered to the subject prophylactically for a relapse after treatment, prophylactically for a pre-onset period, or at an initial onset period of an infectious disease, and the component is administered at an initial onset period of an infectious disease, as desired.
(item X42 QC) the use according to any one of the preceding items, wherein the responsiveness is determined specifically for the past history of infection, vaccination, and induction of cells using IFN-gamma production, IL-2 production, TNF-alpha production or simultaneous production of a plurality of cytokines of these cytokines.
(item X42 RC) the use according to any one of the above items, wherein the above tubercle bacillus extract is a hot water extract of human tubercle bacillus or an extract derived from other tubercle bacillus (extract with high safety).
(item X42 SC) the use according to any one of the above items, wherein the antigen component is a protein.
(item X42 TC) the use according to any one of the preceding items, wherein the medicament is a vaccine formulation comprising an adjuvant base.
(item X42 UC) the use according to any preceding item wherein said adjuvant-based agent comprises a substance that promotes a Th1 type immune response.
Use of the (item X42 VC) antigen component for the manufacture of a medicament for use in a method for preventing or treating an infection, allergy or autoimmune disease in a subject, wherein the method comprises the steps of:
Step a) of identifying, based on an antigenic response profile, an antigenic component specific to the subject, said antigenic component being neither derived from nor cross-reactive with a causative agent of the infection, allergy or autoimmune disease;
step b) identifying whether the subject has an immunological memory for the antigenic component and identifying the subject having the immunological memory; and
step c) administering the antigenic component to the subject specified as having the immunological memory.
(item X42 WC) the use according to any one of the preceding items wherein the antigenic response profile comprises a history of vaccination and/or a history of infection.
(item X43C) use of a hot water extract of tubercle bacillus or a part thereof for the manufacture of a medicament for use as an adjuvant for a vaccine against infectious diseases.
Use of (item X43 CA) STING agonist for the manufacture of a medicament for use as an adjuvant for a vaccine against an infectious disease.
Use of (item X43 CB) STING agonist for the manufacture of a medicament for an adjuvant for a vaccine against an infectious disease of a viral infection.
(item X44C) the use according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof is a hot water extract of the strain B of human type Bacillus tuberculosis or a part thereof.
(item X45C) the use according to any one of the above items, wherein the hot water extract of Bacillus tuberculosis or a part thereof is extract A.
(item X46C) the use according to any one of the preceding items, wherein the hot water extract of Bacillus tuberculosis or a part thereof comprises a STING agonist derived from Bacillus tuberculosis, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, a component capable of biosynthesis of STING agonist in human cells, or a NOD2 agonist or a part other than the same.
(item X47C) the use according to any one of the preceding items, wherein the above tubercule bacillus hot water extract or a part thereof comprises a STING agonist derived from tubercule bacillus, which is C-di-AMP, C-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
(item X48C) the use according to any one of the above items, wherein the causative agent of the infection is a bacterium, a virus or a protozoan.
(item X49C) the use according to any one of the above items, wherein the causative agent of the infection is a virus.
(item X50C) the use according to any one of the above items, wherein the causative agent of the infection is a virus belonging to the family Coronaviridae.
(item X51C) the use according to any one of the above items, wherein the causative agent of the above-mentioned infectious disease is a virus belonging to the family selected from the group consisting of rhinovirus, adenovirus, coronavirus, RS virus, influenza virus, parainfluenza virus and enterovirus.
(item X52C) the use according to any one of the above items, wherein the causative agent of the infection is a virus belonging to the genus coronavirus.
(item X53C) the use according to any one of the preceding items, wherein the causative agent of the infection is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2.
(item X54C) the use according to any one of the above items, wherein the causative agent of the infection is SARS-CoV-2 virus.
In the present invention, it is intended that: in addition to the combinations specified, 1 or more of the features described above may be provided in further combinations. Still other embodiments and advantages of the present invention will be appreciated to those of ordinary skill in the art upon reading and understand the following detailed description as desired.
Effects of the invention
The present invention provides a technique capable of effectively preventing or treating diseases such as infection, allergy, autoimmune disease, etc.
In one embodiment, the present invention unexpectedly finds that: by combining a pathogenic antigen of an infectious disease with a non-pathogenic antigen different from the cause of the infectious disease, it has specific and potent effects in the prevention and treatment against infectious disease. Although immunotherapy using a non-pathogenic antigen in the present invention has been conventionally considered as "nonspecific" immunotherapy (i.e., natural immunity), the present invention has found that it is one aspect of "specific" immunotherapy and provides a novel immunotherapy using this mechanism.
Drawings
FIG. 1 shows the combination of extract A and SARS CoV2 antigenGraph of induced characteristic T cell populations in non-infected Peripheral Blood Mononuclear Cells (PBMCs). FIG. 1A shows the protocol for human PBMC culture. In FIG. 1B, human PBMC from 3 healthy individuals were labeled with cell trace amounts of purple (Cell Trace Violet, CTV), stimulated with extract A (30. Mu.g/ml), SARS CoV-2 RBD (1. Mu.g/ml), or a combination thereof for 3 days, and the medium was replaced with fresh medium containing IL-2 for a further 3 days. Cells were re-stimulated with SARS CoV-2 Receptor Binding Domain (RBD) antigen for 18 hours on day 6, during which time protein transport inhibitors were added to the medium during the last 4 hours. Intracellular staining was performed and cell proliferation, intracellular cytokines, and transcription factors were analyzed by FACS. After all samples from 3 individuals were joined, they survived CD14/19/56 - In cells, by FlowJo TM tSNE (t-Distributed Stochastic Neighbor Embedding, t-distribution random neighborhood embedding) analysis was performed, and a representative tSNE plot derived from 1 individual was shown along with tSNE plots for all joined samples. FIG. 1C shows a heat map showing expression of surface and intracellular markers including cytokines and transcription factors in specific populations. Color scale bar (scale bar) indicates the expression level of each marker from low level (dark blue) to high level (red).
FIG. 2 shows the strategy of intracellular staining for transcription factors and cytokines on day 7 (gating strategy). After cell sorting based on forward scattered light (FSC) and side scattered light (SSC), viable CD14/19/56 is sorted out of a single cell circle - And (3) cells. From CD3 + The cells were circled to select for CD4 and CD8 positive T cells, and the proliferated CD 4T cells and CD 8T cells were circled based on CTV intensity (e.g., CTV diluted cells represent proliferated cells). Tbet is selected from the circle of proliferated CD 4T cells and CD 8T cells + Cells and ifnγ + And (3) cells. Foxp3 and IL-10 were selected from the expanded CD 4T cells.
FIG. 3 shows the expanded proliferation of the unique T cell population induced by the combination of extract A and SARS CoV-2 antigen in non-infected PBMC (tSNE plots for donors 2 and 3). In FIG. 3A, human PBMC derived from 3 healthy individuals were labeled with CTV After 3 days of stimulation with extract A (30. Mu.g/ml), SARS CoV-2 RBD (1. Mu.g/ml), or a combination thereof, the medium was replaced with fresh medium containing IL-2 and further cultured for 3 days. Cells were re-stimulated with SARS CoV-2 RBD antigen for 18 hours on day 6, during which time protein transport inhibitors were added to the medium during the last 4 hours. Intracellular staining was performed and cell proliferation, intracellular cytokines, and transcription factors were analyzed by FACS. After all samples from 3 individuals were joined, they survived CD14/19/56 - In cells, tSNE analysis was performed by FlowJo, and representative tSNE plots derived from donor 2 and donor 3 were shown along with tSNE plots for all the linked samples (FIG. 3A). Fig. 3B is a graph showing the presence ratio of Foxp3 MFI and foxp3+ cells in total CD 4T cells in the form of a box plot using data derived from 3 individuals. * P is p<0.05。
Fig. 4 shows: in non-infected PBMC, the anti-SARS CoV-2 specific T cell response is accelerated by modulating the balance of Treg/Th1 by extract A. In FIG. 4A, human PBMC from 3 healthy individuals were labeled with CTV, stimulated with extract A (30. Mu.g/ml), SARS CoV-2 RBD (1. Mu.g/ml), or a combination thereof for 3 days, and the medium was replaced with fresh medium containing IL-2 for further 3 days. Cells were re-stimulated with SARS CoV-2 RBD antigen for 18 hours on day 6, during which time protein transport inhibitors were added to the medium during the last 4 hours. Ifnγ levels in supernatants after 6 days of antigen re-stimulation were determined by ELISA and their data were represented as box line plots. * P is p <0.05，**p<0.01. In fig. 4B, intracellular staining was performed, and cell proliferation, intracellular cytokines, and transcription factors were analyzed by FACS. After all samples from 3 individuals were joined, they survived CD14/19/56 - In cells, tSNE analysis was performed by FlowJo, and a representative tSNE plot derived from 1 individual was shown along with tSNE plots for all the linked samples. Fig. 4C shows: the presence ratio of the C1 group obtained by the tSNE analysis was plotted as a box plot by using data derived from all 3 individuals. * P is p<0.05，**p<0.01，***p<0.001. FIG. 4D is a representation ofCD4 and CD 8T Cells (CTV) derived from proliferation Low/negative Circle) Tbet expression and ifnγ production. Fig. 4E shows: by using data from all 3 individuals, the presence ratio of the C2 population obtained by tSNE analysis, and the proliferated CD 4T cells (CTV Low/negative Circle) Foxp3 MFI is plotted as a box plot. * P is p<0.05，**p<0.01。
Fig. 5 shows: in non-infected PBMC, the anti-SARS CoV-2 specific T cell response is accelerated by modulating the balance of Treg/Th1 by extract A. In FIG. 5A, human PBMC from 3 healthy individuals were labeled with CTV, stimulated with extract A (30. Mu.g/ml), SARS CoV-2 RBD (1. Mu.g/ml), or a combination thereof for 3 days, and the medium was replaced with fresh medium containing IL-2 for further 3 days. Cells were re-stimulated with SARS CoV-2 RBD antigen for 18 hours on day 6, during which time protein transport inhibitors were added to the medium during the last 4 hours. Intracellular staining was performed and cell proliferation, intracellular cytokines, and transcription factors were analyzed by FACS. FACS plots show proliferation of CD 4T cells and CD 8T cells, tbet expression and IFNγ production (CTV) from the proliferated CD 4T cells and CD 8T cells Low/negative A circle).
FIG. 6 is a graph showing that extract A induces proliferation of MDSC-like innate immune cells that can produce IL-10 with inhibitory effects at an earlier time point. In FIG. 6A, human PBMC from 3 healthy individuals were labeled with CTV, stimulated with extract A (30. Mu.g/ml), SARS CoV-2 RBD (1. Mu.g/ml), or a combination thereof for 3 days, and the medium was replaced with fresh medium containing IL-2 for further 3 days. Cells were restimulated with SARS CoV-2 RBD antigen in the presence of protein transport inhibitor for 6 hours on day 3. Intracellular staining was performed and cell proliferation, intracellular cytokines, and transcription factors were analyzed by FACS. After all samples from 3 individuals were joined, they survived CD14/19/56 - In cells, tSNE analysis was performed by FlowJo, and a representative tSNE plot derived from 1 individual was shown along with tSNE plots for all the linked samples. FIG. 6B illustrates inclusion in particular clustersHeat map of expression of surface and intracellular markers, including cytokines and transcription factors. The color scale indicates the expression level of each marker from low level (dark blue) to high level (red). Fig. 6C shows: the presence ratios of the P1 and P2 groups obtained by the tSNE analysis were plotted as a box plot using data derived from all 3 individuals. * P is p <0.05，**p<0.01. FIG. 6D is a graph showing the data in the form of a box plot of IL-10 levels in supernatants from day 3 as determined by ELISA. SD (secure digital). * P is p<0.05，**p<0.01。
FIG. 7 shows a round-robin strategy for intracellular staining of transcription factors and cytokines. After cell sorting based on FSC and SSC, viable CD14/19/56 is sorted out from a single cell circle - And (3) cells. From CD3 + The cells are circled to select for CD 4T cells and CD 8T cells, and the proliferated CD 4T cells and CD 8T cells are circled based on CTV intensity (e.g., CTV diluted cells represent proliferated cells). Tbet is selected from the circle of proliferated CD 4T cells and CD 8T cells + Cells and ifnγ + And (3) cells. Foxp3 and IL-10 were selected from the expanded CD 4T cells. In addition, the memory expression pattern was determined from CCR7 and CD45RA expression in the proliferated CD 4T cells and CD 8T cells.
In FIG. 8A, FIG. 8 is a graph showing that the enhancement of SARS CoV-2-specific T cells mediated by extract A is not solely due to adjuvant effects. In FIG. 8A, human PBMC from healthy individuals were labeled with CTV, stimulated with extract A (30. Mu.g/ml), SARS CoV-2 RBD (1. Mu.g/ml), or a combination thereof for 3 days, and the medium was replaced with fresh medium containing IL-2 for further 3 days. Cells were re-stimulated with SARS CoV-2 RBD antigen for 18 hours on day 6. Intracellular staining was performed and the transcription factor was analyzed by FACS. After cell sorting based on FSC and SSC, viable CD14/56 is sorted out from a single cell circle - And (3) cells. From surviving CD14/56 based on CD3 and CD19 expression - In the circle and from CD3 + T cells and B cells are selected from the cells. From CD3 + CD 4T cells and CD 8T cells are selected from the cells. For the other 2 transcription factors, the gene is expressed from CD 4T cells or CD 8T cells as negative (e.g., fromGata3 - Foxp3 - Tbet is selected by cell circle + Cell) in which Tbet is selected + Cells, IFN gamma + Cells and Gata3 + And (3) cells. In addition, the memory expression pattern was determined from CCR7 and CD45RA expression in the proliferated CD 4T cells and CD 8T cells.
In fig. 8B-D, fig. 8B is: after all samples were ligated, the samples were subjected to surviving CD14/56 - In cells, by FlowJo TM A tSNE analysis was performed, a tSNE plot was shown with the tSNE plots for all the linked samples. FIG. 8C is a diagram showing a heat map showing expression of surface markers and transcription factors in each group. The color scale indicates the expression level of each marker from low level (dark blue) to high level (red). FIG. 8D shows the Foxp3/Tbet ratio in effector memory CD 4T cells as a bar graph.
In FIGS. 9A-D, FIG. 9 is a graph showing that the enhancement of SARS CoV-2-specific T cells mediated by extract A is not solely due to adjuvant effects. In FIG. 9A, human PBMC from 2 healthy individuals were labeled and after stimulation with extract A (30. Mu.g/ml), SARS CoV-2 RBD (1. Mu.g/ml), or a combination thereof for 3 days, the medium was replaced with fresh medium containing IL-2 and further cultured for 3 days. Cells were re-stimulated with SARS CoV-2 RBD antigen for 18 hours on day 6. Ifnγ levels in the supernatants were determined by ELISA. In fig. 9B, cytokine production was analyzed by FACS after intracellular staining. After all samples from 2 individuals were joined, they were isolated by FlowJo in surviving CD 14/56-cells TM A tSNE analysis was performed and a representative tSNE plot derived from 1 individual is shown along with the tSNE plots for all the linked samples. FIG. 9C is a diagram showing a heat map showing expression of surface markers and transcription factors in each group. The color scale indicates the expression level of each marker from low level (dark blue) to high level (red). Fig. 9D is a graph showing the results of plotting the presence ratios of P1 group and P2 group obtained by tSNE analysis of a representative healthy control as a bar chart.
In 9E-F, FIG. 9E shows a schematic representation of a population of CD 4T cells diluted with CTV-based pigment, and proliferated CD 4T Cells (CTV) Low/negative Circle) FACS plots of tnfα and ifnγ production. Fig. 9F shows FACS plots representing tnfα and ifnγ production from CTV pigment-based diluted CD 8T cell populations, and proliferated CD 8T cells 8.
FIG. 10 is a graph showing Bio-Plex analysis of PBMC stimulation over time. Human PBMC from 3 healthy individuals were labeled with CTV and stimulated with extract A (30. Mu.g/ml), SARS CoV-2 RBD (1. Mu.g/ml), or a combination thereof for 3 days, after which the medium was replaced with fresh medium containing IL-2 for a further 3 days. Cells were restimulated with SARS CoV-2 RBD antigen for 18 hours on day 6 (last 4 hours with protein delivery inhibitor), supernatants before and after restimulation were recovered, and cytokine levels were determined by 48-Plex Bio-Plex analysis.
FIG. 11 is a graph showing that existing Mtb-specific T cell memory is necessary to promote the anti-SARS CoV-2-specific T cell response mediated by extract A. In FIG. 11A, human PBMC derived from healthy individuals with high/low PPD/CMV reactivity were labeled with CTV and after 3 days of stimulation with CMVpp65, PPD (1 μg/ml), extract A (30 μg/ml), SARS CoV-2 RBD (1 μg/ml), or a combination thereof, the medium was replaced with fresh medium containing IL-2 and further cultured for 3 days. Cells were re-stimulated with SARS CoV-2 RBD antigen for 18 hours on day 6, during which time protein transport inhibitors were added to the medium during the last 4 hours. Ifnγ levels in supernatants were measured by ELISA, intracellular staining was performed, and cell proliferation, intracellular cytokines, and transcription factors were analyzed by FACS. The percentage of ifnγ -producing RBD/CMV proliferating CD 4T cells is plotted against the percentage of ifnγ -producing rbd+ extract a proliferating CD 4T cells, or the Foxp3: tbet ratio in rbd+ extract a proliferating CD 4T cells. R is R 2 And p values are shown on the linear regression graph. * P is p<0.05，**p<0.01. FIG. 11B is a graph showing the percentage of PPD/CMV points relative to the proliferation of CD4T cells or CD 8T cells by IFNγ -producing RBD+ extract A. R is R 2 And p values are shown on the linear regression graph. * P is p<0.05。
FIG. 12 is a circle selection showing intracellular staining of cytokinesA map of policies. After cell selection based on FSC and SSC, viable CD14/56 is selected by the selection - And (3) cells. From surviving CD14/56 based on CD3 and CD19 expression - T cells and B cells are selected from the circle. From CD3 + CD19 - The cells are circled to select for CD 4T cells and CD 8T cells, and then the expanded CD 4T cells and CD 8T cells are circled based on CTV intensity (e.g., CTV diluted cells indicate expanded cells). The IFNγ is selected from the proliferation of CD 4T cells or CD 8T cells + 、IL-10 + Or TNF alpha + And (3) cells. And, memory expression type was determined based on CCR7 and CD45RA expression in proliferated CD 4T cells and CD 8T cells.
Fig. 13 is a graph showing that extract a exerts an antitumor effect only in mice immunized in advance. B16-BL6 cells were injected subcutaneously into the lower back of blank mice (naive mice) on day 0. From day 2, mice were given intratumoral administration of normal saline (fig. 13A), extract a (20 μg) (fig. 13B) or K3 CpG (20 μg) (fig. 13C) every other day, and tumor growth was measured using digital vernier calipers for 2 weeks. On day 0, B16-BL6 cells (FIG. 13D) or B16-F10 cells (FIG. 13G) were inoculated subcutaneously into the lower back of blank mice. From day 2, mice were subcutaneously injected with normal saline or extract a (20 μg) every other day, and tumor growth was measured using a digital vernier caliper for 2 weeks. Before 5 weeks and before 2 weeks of tumor inoculation, B16-BL6 cells (fig. 13E), B16-F10 cells (fig. 13H) or LLC cells (fig. 13J) were inoculated subcutaneously into the lower back of BCG immunized blank mice. Subcutaneous administration of extract a was performed every other day for 2 weeks starting 8 days prior to tumor injection, and tumor growth was measured using digital vernier calipers for 2 weeks. On day 0, B16-BL6 cells (fig. 13F) or B16-F10 cells (fig. 13I) were inoculated subcutaneously into the lower back of mice immunized by intradermal administration of extract a emulsified with Incomplete Freund's Adjuvant (IFA) in the tail root 4 weeks and 2 weeks before tumor inoculation. Next, from 8 days before tumor inoculation, mice were injected with extract a or physiological saline until euthanized, and tumor growth was measured using a digital vernier caliper for 2 weeks. On day 0, B16-BL6 cells were inoculated subcutaneously into the lower back of mice immunized with extract a+k3+cgamp (fig. 13K) or extract a+k3+alum extract a (fig. 13L) at the tail root 4 weeks and 2 weeks before tumor inoculation. Next, from 8 days before tumor inoculation, mice were injected with extract a or physiological saline until euthanized, and tumor growth was measured using a digital vernier caliper for 2 weeks. Data are expressed as mean ± SE. * p <0.05, < p <0.01 (student t assay).
Fig. 14 shows: in BCG immunized tumor-bearing mice, anti-tumor immunity was induced by activating Interferon (IFN) gamma secreting CD 4T cells, and STING pathways induced by STING agonists derived from mycobacterium tuberculosis (Mtb). B16-BL6 cells were inoculated subcutaneously into the lower back of BCG-immunized mice 5 weeks and 2 weeks before tumor inoculation. Subcutaneous administration of extract a was performed every other day starting 8 days prior to tumor inoculation, and tumor growth was measured in Wild Type (WT), isotype control antibody treated mice, rag2 Knockout (KO) mice (fig. 14A), CD4 positive cell depleted mice (fig. 14B), CD8 positive cell depleted mice (fig. 14C), CD4 positive KO mice (fig. 14D), MHC II KO mice (fig. 14E), ifny depleted mice (fig. 14G), or STING heteroconjugate or KO mice (fig. 14J), respectively. (FIG. 14F) spleen cells isolated from BCG-immunized WT tumor-bearing mice and WT tumor-bearing mice treated with extract A or physiological saline were stimulated with physiological saline or extract A, and intracellular staining was performed for IFNγ, IL-13 and IL-17. The proportion of CD 44-positive CD 4-positive cells producing each cytokine is plotted as a bar graph, with each point in the graph corresponding to each mouse. Spleen cells isolated from BCG immunized WT, CD4 KO or MHC class II KO tumor bearing mice, and WT, CD4 KO or MHC class II KO tumor bearing mice treated with extract a were stimulated with physiological saline or a prescribed amount of extract a. Ifnγ levels in the supernatants were determined by ELISA. (FIG. 14I) spleen cells were isolated from BCG-immunized WT tumor-bearing mice depleted of CD 4-positive or CD 8-positive cells using AUTOMACS and WT tumor-bearing mice treated with extract A, stimulated with physiological saline or the indicated amounts of extract A. Ifnγ levels in the supernatants were determined by ELISA. The data are plotted as bar graphs, with each point in the graph corresponding to an individual mouse. (FIG. 14K) the BCG vaccine resuspended in PBS was boiled at 95℃for 30 minutes to be dissolved, and the content of live attenuated Mycobacterium bovis of the BCG vaccine was released. The concentration of c-di-AMP in the extract A solution, PPD antigen solution, or BCG vaccine solution was measured by ELISA when boiling was present or not. Data are expressed as mean ± SE. * p <0.05, < p <0.01 (student t assay).
FIG. 15 is a graph showing that injection of tumor-unrelated proteins present in extract A inhibited tumor growth in BCG-immunized mice. (FIG. 15A) spleen cells obtained from BCG-immunized mice and mice treated with extract A were stimulated with physiological saline (S), extract A (Z), subtilisin-treated extract A (Sub), heat-inactivated subtilisin-treated extract A (HI-Sub), trypsin-treated extract A (Trp) or heat-inactivated trypsin-treated extract A (HI-Trp). Ifnγ production was determined by ELISA. Triangles represent the concentration of protease used in the experiment. The initial induced ifnγ production by extract a was set to 100% (% control), and the% value for each treatment was calculated based on the initial level of ifnγ expression induced by extract a. (FIG. 15B) spleen IFN gamma secretion was measured by ELISA in response to the antigen present in extract A (Table 1A) derived from WT or TLR4 KO mice immunized with extract A emulsified by IFA. (FIG. 15C) spleen IFN gamma secretion was determined by ELISA in response to overlapping peptides of LpqH or Y1269 from mice immunized with extract A emulsified by IFA. (FIG. 15D) response to the amount of spleen IFNγ secretion in mice immunized with extract A emulsified by IFA in response to extract A or LpqH. (FIG. 15E) on day 0, B16-BL6 cells were inoculated subcutaneously into the lower back of blank mice. From 8 days prior to tumor inoculation, lpqH (fig. 15E) or OVA (fig. 15H) was subcutaneously administered every other day, and tumor growth was measured using digital vernier calipers for 2 weeks. (FIG. 15F) on day 0, B16-BL6 cells were inoculated subcutaneously into the lower back of mice immunized with extract A emulsified by IFA. Mice were stimulated every other day by subcutaneous injection of LpqH (fig. 15F) or OVA (fig. 15I) starting 12 days before tumor inoculation (LpqH) or 8 days before OVA. Tumor growth was measured using a digital vernier caliper for 2 weeks. (FIG. 15G) on day 0, B16-BL6 cells were inoculated subcutaneously into the lower back of BCG-immunized mice. LpqH was administered subcutaneously every other day starting 12 days prior to tumor inoculation, and tumor growth was measured using digital vernier calipers for 2 weeks. B16-BL6 was inoculated 5 weeks after infection by nasal route administration of influenza (Flu) virus (PR 8 strain). Viral particle Flu vaccine was administered subcutaneously to either empty white mice (fig. 15J) or Flu-immunized mice (fig. 15K) 2 times 1 week from 8 days prior to tumor inoculation. Tumor growth was measured using a digital vernier caliper for 2 weeks. Data are expressed as mean ± SE. * p <0.05, < p <0.01 (student t assay).
FIG. 16 is a graph showing that extract A increases IFNγ -producing Th1 cells in tumor microenvironment. Extract a was administered to BCG immunized mice via the subcutaneous route every other day, starting 8 days prior to B16-BL6 tumor inoculation. After 14 days, tumor-bearing mice were euthanized and tumor tissue was harvested. TIL (abbreviation for tumor infiltrating lymphocytes (tumor infiltrating lymphocyte), tumor-reactive lymphocytes among lymphocytes infiltrating in tumors) isolated from tumor tissue was analyzed by intracellular staining and FACS. The number of TILs per 1mg of tumor tissue (CD 45 positive CD3 positive) (fig. 16A), the number of CD4 positive and CD8 positive TILs per 1mg of tumor tissue (fig. 16B), or the number of Tbet and Foxp3 positive or negative TILs per 1mg of tumor tissue (fig. 16C) were plotted. (FIG. 16D) is a representative FACS plot showing TIL rounds. (FIG. 16E) the correlation between tumor weight and the number of Tbet positive Foxp3 negative (left), tbet positive Foxp3 positive (center), tbet negative Foxp3 positive (right) TIL per 1mg of tumor tissue was plotted. (FIG. 16F) shows a representative FACS plot of the production of CD 4T cells from IFNγ in TIL obtained from mice treated with physiological saline or extract A. (FIG. 16G) IFN gamma producing CD 4T cells in control, TIL stimulated with extract A or LpqH were plotted. (FIG. 16H) the production of CD44 positive memory CD 4T cells by IFNγ in TILs expressing Tbet and/or Foxp3 after stimulation with extract A or LpqH was plotted. (FIG. 16I) the correlation between tumor weight and the number of IFNγ positive CD 4T cells per 1mg tumor after stimulation with extract A or LpqH was plotted. Data are expressed as mean ± SE. * p <0.05, < p <0.01 (student t assay).
FIG. 17 is a graph showing the response of human PBMC with memory T cells against PPD to extract A. Human PBMC were plated at 1X 10 in 96-well plates 6 Cell/well density was cultured and allowed to stand overnight in a CO2 incubator (incubator). Thereafter, extract A (100. Mu.g/ml), PPD (3. Mu.g/ml), CMV pp65 overlay peptide (3. Mu.g/ml), or recombinant Mtb protein (10. Mu.g/ml each) was added. The total of 1. Mu.g/ml of anti-CD 28 (CD 28.2), golgi Plug and Golgi Stop were added simultaneously with the stimulating substance, the cells were stimulated for 6 hours, and then PBMC were stained for intracellular molecules and analyzed by FACS. A graph showing the correlation of ifnγ, IL-2 or tnfα produced by TCM after stimulation with PPD (upper)/CMV (center)/MHSP 10 (lower) and TCM after stimulation with extract a is plotted.
FIG. 18 is a graph showing that a combination of extract A and SARS-CoV-2 antigen induces proliferation of an inherent T cell population in non-immunized PBMC. (FIG. 18A) shows the procedure for culturing human PBMC. (FIG. 18B) human PBMC from 3 healthy individuals were labeled with CTV, stimulated with extract A (30. Mu.g/ml), SARS-CoV-2 RBD (1. Mu.g/ml), or a combination thereof for 3 days, after which the medium was changed to fresh medium containing IL-2 and the cells were further cultured for 3 days. Cells were re-stimulated with SARS-CoV-2 RBD antigen for 18 hours on day 6, during which time protein transport inhibitors were added to the medium during the last 4 hours. Cell proliferation, intracellular cytokines and transcription factors were analyzed by FACS based on intracellular staining. After concentrating all samples from 3 individuals, a tSNE analysis was performed by FlowJo on surviving CD14/19/56 negative cells, and a representative tSNE plot from 1 individual was shown along with the tSNE plot for all the concentrated samples. (FIG. 18C) A thermal map shows the expression of surface markers and intracellular markers including cytokines and transcription factors in each specific population. The color scale indicates the level of each marker from low (dark blue) to high (red). Fig. 24 and 25 also refer to the above case.
FIG. 19 shows that extract A was not allowed to pass through the regulation of the balance of Treg/Th1Figure of enhanced anti-SARS-CoV-2 specific T cell responses in immunized PBMCs. (FIG. 19A) human PBMC from 21 healthy individuals were labeled with CTV, stimulated with extract A (30. Mu.g/ml), SARS-CoV-2 RBD (1. Mu.g/ml), or a combination thereof for 3 days, after which the medium was replaced with fresh medium containing IL-2 and the cells were further cultured for 3 days. Cells were re-stimulated with SARS-CoV-2 RBD antigen for 18 hours on day 6, during which time protein transport inhibitors were added to the medium during the last 4 hours. Ifnγ levels in the supernatant at day 6 after antigen re-stimulation were determined by ELISA, with data shown in box-line plots. SD (secure digital). * P is p<0.05，**p<0.01. (FIG. 19B) human PBMC from 3 healthy individuals were labeled with CTV, stimulated with extract A (30. Mu.g/ml), SARS-CoV-2 RBD (1. Mu.g/ml), or a combination thereof for 3 days, after which the medium was changed to fresh medium containing IL-2 and the cells were further cultured for 3 days. Cells were re-stimulated with SARS-CoV-2 RBD antigen for 18 hours on day 6, during which time protein transport inhibitors were added to the medium during the last 4 hours. Cell proliferation, intracellular cytokines and transcription factors were analyzed by FACS based on intracellular staining. After concentrating all samples from 3 individuals, the samples were concentrated by FlowJo against surviving CD14/19/56 negative cells TM tSNE analysis was performed showing tSNE plots for all concentrated samples. (FIG. 19C) the ratio of the C1 population resulting from tSNE analysis was plotted as a box plot using data from all 3 individuals. * P is p<0.05，**p<0.01，***p<0.001. (FIG. 19D) FACS plots show Tbet expression, IFNγ production from proliferating CD4 and CD8T cells (CTV low/negative circle). (FIG. 19E) the ratio of C2 populations resulting from tSNE analysis, and Foxp3MFI (CTV low/negative circle) in proliferating CD 4T cells were plotted as box plots using data from all 3 individuals. * P is p<0.05，**p<0.01. Fig. 24 and 25 also refer to the above case.
FIG. 20 is a graph showing that existing Mtb-specific T cell memory is necessary to promote the anti-SARS-CoV-2-specific T cell response mediated by extract A. (FIG. 20A) human PBMC obtained from healthy individuals with high/low PPD/CMV reactivity were labeled with CTV and with CMVpp65. PPD (1. Mu.g/ml), extract A (30. Mu.g/ml), SARS-CoV-2 RBD (1. Mu.g/ml), or a combination of RBD+extract A was stimulated for 3 days, after which the medium was changed to fresh medium containing IL-2 and the cells were further cultured for 3 days. Cells were re-stimulated with SARS-CoV-2 RBD antigen for 18 hours on day 6, during which time protein transport inhibitors were added to the medium during the last 4 hours. Ifnγ levels in supernatants were determined by ELISA, and cell proliferation, intracellular cytokines and transcription factors were analyzed by FACS based on intracellular staining. (FIG. 20A) the IFNγ production induced by RBD+PPD is plotted against the IFNγ production induced by PPD or CMV after 3 days and 6 days of restimulation. R is R 2 And p values are shown on the linear regression graph. * P is p<0.05，**p<0.01. (FIG. 20B) the Tbet/Foxp3 MFI ratio in RBD+ extract A proliferating EM CD 4T cells was plotted against the PPD ELISPOT count. R is R 2 And p values are shown on the linear regression graph. * P is p<0.05. See fig. 30 and tables 3A to 3B.
(FIG. 21A) experimental procedure for cell depletion in mice immunized with BCG and mice immunized with extract A. BCG was subcutaneously injected into mice 2 times prior to tumor inoculation, and B16-BL6 cells were inoculated into mice on day 0. Subcutaneous administration of extract a was performed every other day, starting 8 days prior to tumor injection. Depleted antibodies were injected on the days shown in the figures. The experiments (FIGS. 21B to 21H) were performed as described in FIG. 21A, and the experiments were performed using (FIGS. 21B to 21E) Batf3 KO mice, NK-1.1 depleted mice, fcgammaR KO mice, CD1d1 KO mice, (FIGS. 21G to 21H) γδ T cell KO mice, or NOD2 KO mice. (FIG. 21F) in the BCG immunized mice and extract A treated mice spleen cells, through ELISA to determine with physiological saline or extract A stimulation after IFN gamma production. Data are expressed as mean ± SE. * p <0.05, < p <0.01 (student t assay).
FIG. 22 is a graph showing cytokine secretion induced by extract A from spleen cells of BCG-immunized mice. (fig. 22A) experimental procedure: mice were immunized with BCG 4 weeks prior to euthanasia. Mice were subcutaneously injected every other day with saline or extract a starting 2 weeks prior to euthanasia. Spleen cells were prepared and stimulated with extract A (10. Mu.g/ml or 100. Mu.g/ml). (FIGS. 22B to 22E) the concentration of cytokines was quantified by ELISA. Data are expressed as mean ± SE. * p <0.05, < p <0.01 (student t assay).
Fig. 23 is a graph showing that extract a regulates Treg/Th1 balance in the intratumoral microenvironment, but not systemically. Extract a was administered via the subcutaneous route every other day, starting 8 days prior to B16-BL6 tumor inoculation, to BCG immunized mice. After 14 days, tumor-bearing mice were euthanized and tumor tissue was harvested. TIL isolated from tumor tissue was analyzed by intracellular staining and FACS. CD45 in TIL to express Tbet and Foxp3 + CD3 + CD4 + The proportion of cells is plotted.
FIG. 24 is a graph showing tSNE plots of naive T cell populations expanded proliferation donors 2 and 3 induced by a combination of extract A and SARS Cov-2 antigen. (FIG. 24A), day 7, round-robin strategy for intracellular staining of transcription factors and cytokines. Following cell cycle selection based on FSC and SSC, surviving CD14/19/56 is cycled from a single cell cycle - And (3) cells. From CD3 + CD4 and CD 8T cells are selected from the cells and then CD4 and CD 8T cells are selected based on CTV intensity (e.g., CTV diluted cells represent proliferating cells). Circle selection of Tbet from proliferated CD4 and CD 8T cells + IFN (interferon) gamma ray + And (3) cells. Foxp3 and IL-10 were selected from the expanded CD 4T cells. (FIG. 24B) human PBMC from 3 healthy individuals were labeled with CTV, stimulated with extract A (30. Mu.g/ml), SARS CoV-2 RBD (1. Mu.g/ml), or a combination thereof for 3 days, after which the medium was replaced with fresh medium containing IL-2 and the cells were further cultured for 3 days. Cells were incubated with SARS CoV-2 RBD antigen for 18 hours on day 6, during which time protein transport inhibitors were added to the culture over the last 4 hours. After intracellular staining, cell proliferation, intracellular cytokines and transcription factors were analyzed by FACS. After concentrating all samples from 3 individuals, surviving CD14/19/56 was subjected to FlowJo - Cells were subjected to tSNE analysis, representative tSNE plots derived from donors 2 and 3 were plotted against allThe tSNE plots of the concentrated samples are shown together. (FIG. 24C) Foxp3 in Foxp3 MFI and Total CD 4T cells using data obtained from all 3 individuals + Is plotted as a box plot. * P is p<0.05。
FIG. 25 is a graph showing that extract A enhances anti-SARS CoV-2 specific T cell responses by modulating Treg/Th1 balance in non-immunized PBMC. Human PBMC from 3 healthy individuals were labeled with CTV, stimulated with extract A (30. Mu.g/ml), SARS CoV-2 RBD (1. Mu.g/ml), or a combination thereof for 3 days, after which the medium was replaced with fresh medium containing IL-2 and the cells were further cultured for 3 days. Cells were re-stimulated with SARS CoV-2 RBD antigen for 18 hours on day 6, during which time protein transport inhibitors were added to the culture over the last 4 hours. After intracellular staining, cell proliferation, intracellular cytokines and transcription factors were analyzed by FACS. FACS plots show proliferation of CD4 and CD 8T cells and CD4 and CD 8T cells derived from proliferation (CTV) Low/negative Circle) Tbet expression and ifnγ production.
FIG. 26 is a graph showing proliferation induced by extract A of natural immune cells with inhibitory function capable of producing IL-10 at an earlier time point. (FIG. 26A) a round-robin strategy for intracellular staining of transcription factors and cytokines. After cell sorting based on FSC and SSC, viable CD14/19/56 is sorted out from a single cell circle - And (3) cells. From CD3 + CD4 and CD 8T cells are selected from the cells and then CD4 or CD 8T cells are selected based on CTV intensity (e.g., CTV diluted cells indicate proliferating cells). Circle selection of Tbet from proliferated CD4 and CD 8T cells + IFN (interferon) gamma ray + And (3) cells. Foxp3 and IL-10 were selected from the expanded CD 4T cells. Memory expression was determined based on CCR7 and CD45RA expression in proliferating CD 4T cells and CD 8T cells. (FIG. 26B) after 3 days of stimulation of human PBMC from 3 healthy individuals with CTV, with extract A (30. Mu.g/ml), SARS CoV-2 RBD (1. Mu.g/ml), or a combination thereof, the medium was replaced with fresh medium containing IL-2 and further cultured for 3 days. Restimulation of cells with SARS CoV-2 RBD antigen in the presence of protein transport inhibitor on day 3And 6 hours. Intracellular staining was performed and cell proliferation, intracellular cytokines, and transcription factors were analyzed by FACS. After all samples from 3 individuals were joined, they survived CD14/19/56 - In cells, tSNE analysis was performed by FlowJo, and a representative tSNE plot derived from 1 individual was shown along with tSNE plots for all the linked samples. (FIG. 26C) is a heat map showing the expression of surface and intracellular markers including cytokines and transcription factors in specific groups. The color scale indicates the expression level of each marker from low level (dark blue) to high level (red). (fig. 26D) shows: the presence ratios of the P1 group and the P2 group obtained by the tSNE analysis were plotted as a box-line graph by using data derived from all 3 individuals. * P is p <0.05，**p<0.01. (FIG. 26E) after stimulation of human PBMC derived from 21 healthy individuals with CTV for 3 days with extract A (30. Mu.g/ml), SARS CoV-2 RBD (1. Mu.g/ml), or a combination thereof, the medium was replaced with fresh medium containing IL-2 and further cultured for 3 days. Cells were re-stimulated with SARS CoV-2 RBD antigen for 18 hours on day 6, during which time protein transport inhibitors were added to the culture over the last 4 hours. IL-10 levels in supernatants at day 3 were determined by ELISA and data are shown as box-line plots. SD (secure digital). * P is p<0.05，**p<0.01。
FIG. 27 shows Bio-Plex analysis of PBMC stimulation over time. Human PBMC from 3 healthy individuals were labeled with CTV and stimulated with extract A (30. Mu.g/ml), SARS CoV-2 RBD (1. Mu.g/ml), or a combination thereof for 3 days, after which the medium was replaced with fresh medium containing IL-2 for a further 3 days. Cells were restimulated with SARS CoV-2 RBD antigen for 18 hours on day 6 (last 4 hours with protein transport inhibitor), the supernatant obtained before and after restimulation was recovered, and cytokine levels were determined by 48-Plex Bio-Plex analysis.
In FIG. 28-1, FIG. 28 is a graph showing that the enhancement of SARS CoV-2-specific T cells mediated by extract A is not solely due to adjuvant effects (by transcription factor analysis). (FIG. 28A) human PBMC from healthy individuals were labeled with extract A (30. Mu.g/ml) After 3 days of stimulation, SARS CoV-2 RBD (1 μg/ml), or a combination thereof, the medium was replaced with fresh medium containing IL-2 and the cells were further cultured for 3 days. Cells were re-stimulated with SARS CoV-2 RBD antigen for 18 hours on day 6. Transcription factors were analyzed by FACS after cell staining. Following cell-based selection by FSC and SSC, viable CD14/56 is selected from a single cell circle - And (3) cells. From surviving CD14/56 based on CD3 and CD19 expression - T cells and B cells are selected from the circle. From CD3 + CD4 and CD 8T cells are selected from the cells. Circle selection of Tbet from CD4 or CD 8T cells + 、IFNγ + Gata3 + And (3) cells. These cells were negative for the other 2 transcription factors (e.g., from Gata3 - Foxp3 - Tbet is selected by cell circle + Cells). And, memory expression was determined based on CCR7 and CD45RA expression in proliferating CD4 and CD 8T cells.
In FIG. 28-2, (FIG. 28B) all samples were ligated before surviving CD14/56 - In cells, tSNE analysis was performed by FlowJo, and a representative tSNE plot was shown along with tSNE plots for all the linked samples. (FIG. 28C) is a heat map showing the expression of the surface markers and transcription factors in each specific group. The color scale indicates the expression level of each marker from low level (dark blue) to high level (red). (FIG. 28D) the Foxp3/Tbet ratio in effector memory CD 4T cells is plotted as a bar graph.
In FIG. 29-1, FIG. 29 is a graph showing that the enhancement of SARS CoV-2-specific T cells mediated by extract A is not solely due to adjuvant effects. (FIG. 29A) after labelling of human PBMC derived from 2 healthy individuals and stimulation with extract A (30. Mu.g/ml), SARS CoV-2 RBD (1. Mu.g/ml), or a combination thereof for 3 days, the medium was replaced with fresh medium containing IL-2 and the cells were further cultured for 3 days. Cells were re-stimulated with SARS CoV-2 RBD antigen for 18 hours on day 6. Ifnγ levels in the supernatants were determined by ELISA. (FIG. 29B) cytokine production was analyzed by FACS after intracellular staining. After all samples from 2 individuals were joined, CD14/56 survived - In the cell, through FlowJo TM A tSNE analysis was performed and a representative tSNE plot derived from 1 individual was shown along with the tSNE plots for all the linked samples. (FIG. 29C) is a heat map showing the expression of the surface markers and transcription factors in each specific group. The color scale indicates the expression level of each marker from low level (dark blue) to high level (red). (FIG. 29D) the presence ratios of the P1 and P2 groups from tSNE analysis of representative healthy controls are plotted as bar graphs.
In FIG. 29-2, (FIG. 29E) shows dilution of CTV dye and proliferation of CD 4T Cells (CTV) Low/negative Circle) FACS plots of tnfα and ifnγ production resulting in proliferation of CD 4T cells. (FIG. 29F) shows the dilution of CTV dye and proliferation of CD 8T Cells (CTV) Low/negative Circle) FACS plots of tnfα and ifnγ production resulting in proliferation of CD 8T cells.
FIG. 30 is a graph showing the strategy of intracellular staining of cytokines shown in FIG. 20. After cell selection based on FSC and SSC, viable CD14/56 is selected by the selection - And (3) cells. From surviving CD14/56 based on CD3 and CD19 expression - T cells and B cells are selected from the circle. From CD3 + CD19 - The cells are circled to select for CD 4T cells and CD 8T cells, and then the expanded CD 4T cells and CD 8T cells are circled based on CTV intensity (e.g., CTV diluted cells indicate expanded cells). The IFNγ is selected from the proliferation of CD 4T cells or CD 8T cells + 、IL-10 + Or TNF alpha + And (3) cells. And, memory expression type was determined based on CCR7 and CD45RA expression in proliferated CD 4T cells and CD 8T cells.
Detailed Description
The present invention will be described below while showing some of the best modes. It should be understood that throughout this specification, singular forms also include plural concepts unless specifically mentioned. Thus, it should be understood that singular forms of articles (e.g., "a," "an," "the," etc. in english) also include plural forms of concepts unless specifically mentioned otherwise. In addition, it should be understood that the terms used in the present specification are used in the meanings commonly used in the art, unless specifically mentioned. Thus, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control.
(definition)
Hereinafter, terms used in the present specification will be described.
In the present specification, the "causative agent" of a disease or the like means a factor that becomes a cause of the disease, for example: in the case of an infectious disease, it means viruses, bacteria, protozoa, mycoplasma, etc. as pathogenic factors or infectious agents; in the case of autoimmune diseases such as allergies, examples thereof include substances (pathogenic substances) which become immunogens such as allergens; in the case of cancer, tumor and neoplasm, tumor cells, cancer genes, toxins and the like are exemplified.
In the present specification, "disease" is to be interpreted broadly as a state in which a human or animal is ill or ill with respect to the spirit or body, and refers to any state not specifically defined, called an "unhealthy state", such as a disease, disorder, and various symptoms.
In the present specification, the term "antigen component" refers to a component capable of controlling (e.g., initiating, enhancing, suppressing, disappearing, etc.) an antigen-antibody reaction in a certain subject, and is sometimes referred to as "antigen" in the present specification. The compound may be a single component (substance) or a complex. The antigen components may also be provided in a variety of different combinations, in which case they are referred to as "combinations of antigen components". In the present specification, the antigen component may be provided in the form of an isolated single component or a complex of these components, or an extract containing them.
In the present specification, the term "pathogenic antigen component" refers to an antigen component that causes a disease (for example, an infectious disease, an allergic reaction, or an autoimmune disease), and also refers to an antigen component that cross-reacts with a pathogenic agent (preferably, but not limited to, all or a part of a pathogenic agent). In the present specification, whether or not a certain component or substance is a "pathogenic antigen component" can be confirmed by, for example, comprehensively identifying and comparing proteins or mRNAs that cause diseases (for example, infection, allergy, or autoimmune disease). The identification is mainly performed by mass spectrometry, microarray, or a new-generation sequencer, and can be confirmed by examining sequence information. "antibody" refers to a protein having the function of recognizing and removing foreign substances. In this case, the foreign substance is referred to as an "antigen". The pathogenic antigen component may be, for example, a molecule having at least a part of the antigen component present on the membrane surface (for example, spike protein of virus such as coronavirus), or a molecule constituting virus particles (for example, envelope protein E, membrane protein M, nucleocapsid protein N, or capsid proteins VP1, VP2, VP3, and VP4 of rhinovirus). Alternatively, in the case where the pathogenic agent in the pathogenic agent antigen component is a conventionally unknown pathogenic agent such as a novel virus (e.g., SARS-CoV-2), the pathogenic agent may be a conventionally known (since it is known, it may also have an immunological memory) pathogenic agent such as a conventionally known coronavirus (e.g., HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV) or the like. The reason for this is that: because the pathogenic antigen component is sometimes strongly required as a therapeutic or prophylactic subject, it is expected to act as a molecule having a high possibility of eliciting an immune response.
In the present specification, the term "non-pathogenic antigen component" refers to an antigen component based on a factor which neither originates from or cross-reacts with a pathogenic agent responsible for a disease (for example, an infectious disease, an allergic reaction, an autoimmune disease, etc.). Basically, it can be said that the non-pathogenic antigen component is a factor different from the pathogenic antigen component. In the present specification, whether or not a certain component or substance is a "non-pathogenic antigen component" can be identified by the same method as that of the "pathogenic antigen component". Components such as proteins that are specific or excessively present for diseases (e.g., infections, allergies, autoimmune diseases) are sometimes also referred to as "disease antigens". Thus, a non-pathogenic antigen (component) is a component other than a disease antigen, and can be said to be any component that does not cross-react with the antigen. In this specification, the non-pathogenic antigenic component may have an immunopotentiating effect (or adjuvant activity). Examples of the non-pathogenic antigen component include a hot water extract of tubercle bacillus or a part thereof, and specific examples include a hot water extract of human tubercle bacillus Qingshan B strain or a part thereof.
In the present specification, "under the condition where (a certain component X) exists" means any condition where, when another component Y is administered to a subject, the component X exists in a form that acts in the subject, and examples thereof include: the combination of component Y and component X (the combination may be a mixture or a combination of separate agents) is administered simultaneously or not; or confirming the presence of component X in the subject (e.g., by an antigen test or, where appropriate, by a genetic test such as PCR), and administering component Y to the subject whose presence has been confirmed. To achieve one of the objects of the present invention, without being bound by theory, it is found that a non-pathogenic antigen component (neither originating from nor cross-reacting with a pathogenic agent of a disease) is allowed to act by administering to a subject in the presence of the pathogenic antigen component (originating from and/or cross-reacting with a pathogenic agent of a target disease) in the subject, such that the non-pathogenic antigen component (neither originating from nor cross-reacting with a pathogenic agent of the disease) is able to direct the somatic immunity that the subject may have to the pathogenic agent of the target disease, so as to provide one feature of the present invention.
In this specification, "pre-administration" refers to the act of: in the case where the subject does not have an immune response against the above-mentioned non-pathogenic agent, the non-pathogenic agent antigen component or the hot water extract of tubercle bacillus or a part thereof is administered to elicit an immune response. After the administration in advance, in the case where it is confirmed that the subject has an immune response, the composition of the present invention and the like may be administered to the subject.
In this specification, the term "specific" with respect to certain substances or components means that the substance or component has a property of controlling a particular response in a subject. As a representative example in the present specification, reference to "specific" in particular in the field of treatment, prophylaxis means that the subject has an immunological memory. The term may particularly mean having specificity for memory T cells of the subject.
In this specification, whether a subject "has immune memory" for a certain substance or component can be evaluated by, in the subject or a biological component (e.g., a cell or the like) derived from the subject, determining for the component or substance: whether (i) cytokine production is increased or proliferation promoting effect is provided on memory CD 4-positive T cells in an antigen-dependent manner, (ii) whether expression of surface antigens of memory regulatory T cells is changed, (iii) whether the ratio of Treg to Th1 is changed, (iv) whether IFN- γ production from T-bet-positive Th1 cells is induced, (v) whether IFN- γ production is changed, (vi) whether IL-2 production is changed, (vii) whether TNF- α production is changed, and (viii) whether antibodies specific to components or substances present in blood are present, and it is confirmed that at least one of these results is positive. These tests can also be used to confirm whether an immune response is present or has been present in the past. Therefore, whether or not the antibody is present in the immune memory, the present immune response, or the past immune response is present can be checked and confirmed, for example, typically by performing an antibody check or other immune response activity check for whether or not an antibody against an antigen to be tested (for example, an antigen against SARS-CoV-2, or any antigen derived from the virus) is present.
In this specification, a subject having an "immune response" to a certain component or substance means that the component or substance produces a certain immune response. The subject or a biological component (e.g., a cell) derived from the subject may be identified by observing changes in various immune cells or increases or decreases in immune-related substances (e.g., cytokines or the like), may be determined by objective indicators, or may be subjectively determined based on experience of a doctor or the like. The immune response may be confirmed by tuberculin response assays or assays based on gamma interferon release assays, or a health manual or equivalent thereof, medical records, or other medical information. In one embodiment, the objective confirmation of the immune response may be confirmed by a tuberculin response test or a test based on a gamma interferon release test, or objective information contained in a mother-son health manual or its equivalent, medical record, or other medical information, preferably may be performed in a tuberculin response test or a gamma interferon release test. In the present invention, objective confirmation may be preferable to subjective confirmation. The reason for this is that the immune effect of the present invention can be confirmed, but the theory is not intended to be limiting.
In the present specification, the term "substance for a subject" refers to any substance (e.g., protein, amino acid, peptide, nucleic acid molecule, polysaccharide, poison, etc.) that does not exist in the living body of the subject. In this specification, a "subject" is interchangeable and synonymous with a "subject" or "subject" and may be synonymous with a "patient" in the case of suffering from a disease. In the present specification, "subject" or "subject" includes a human or a mammal (for example, 1 or more of a mouse, a guinea pig, a hamster, a rat, a mouse, a rabbit, a pig, a sheep, a goat, a cow, a horse, a cat, a dog, a marmoset, a monkey, a chimpanzee, or the like) including a primate other than a human.
In the present specification, the "infection" may be any type of infection, and includes any type of infection such as viral infection (including any viral form such as single-or double-stranded DNA virus and RNA virus), bacterial infection, protozoal infection, and mycoplasma infection, and examples thereof include tuberculosis, coronavirus, malaria, yellow fever virus, smallpox, measles/rubella, poliomyelitis, MUMPS (adofosis)/MUMPS, rotavirus infection, varicella (chickenpox), yellow fever, ebola virus (Ebola), west nile fever, b-type influenza haemophilus infection, pneumococcal infection, pertussis, japanese encephalitis, meningococcal infection, salmonella infection, pathogenic escherichia coli, toxoplasmosis (Toxoplasma gondii), zika virus (Zika virus), herpes virus type 1, EBV (EPSTEIN BARR VIRUS)/epstein-barr virus (herpes 4), CMV/cytomegalovirus (virus type 5), influenza, s, and mar, and the like. In the present invention, the "non-pathogenic antigen component" and the "pathogenic antigen component" may be components derived from different infectious diseases. In one example, the infectious disease that becomes the source of the "pathogenic antigen component" is covd-19, and in the case where the pathogenic agent is SARS-CoV-2, the infectious disease that becomes the source of the "non-pathogenic antigen component" is tuberculosis, and the "non-pathogenic antigen component" is a component derived from tuberculosis. In this case, it is preferable to have the subject have a history of BCG vaccination, a history of tuberculosis infection, or an antigen responsiveness (having immune memory) against tubercle bacillus.
In the present invention, "virus" refers to an infectious structure that replicates itself by cells of other organisms. In terms of taxonomy, "virus" includes rhinoviridae, adenoviridae, coronaviridae, RS viridae, influenza viridae, parainfluenza viridae, enteroviridae, and the like.
In the present specification, "infection associated with coronavirus" refers to an infection caused by a virus belonging to the family coronaviridae. In terms of taxonomy, "coronaviridae" includes "coronaviridae of type a", "coronaviridae of type b", "coronaviridae of type d" and "coronaviridae of type c". As coronaviruses that infect humans, there are included, but not limited to, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV-2, and MARS-CoV.
In the present specification, "immune abnormality" refers to any disease, disorder or state that is generated or suspected to be generated at least partially due to an abnormality of the immune system. Refers to a state in which immunity is abnormal for some reason, and is susceptible to infection or allergy. Examples of immune abnormalities include allergies, autoimmune diseases, and the like, but are not limited thereto. In the case of autoantigens, it is generally known as autoimmune diseases, and in the case of external antigens, it is known as allergies. It can be said that when the immune response is strong, the autoimmune disease state is established for self antigens, the allergic reaction state is established for non-self antigens, and when the immune response is weak, the cancer state is established for self antigens, and the infectious disease is established for non-self antigens.
In the present specification, "autoimmune disease" means excessive immune reaction to a specific autoantigen. Autoimmune diseases can be said to be diseases caused by the breakdown of immune tolerance, that is, symptoms caused by an immune system having an effect of recognizing and removing foreign substances excessively reacting to and attacking normal cells or tissues of the self. As an example of autoimmune diseases, autoimmune uveitis may be cited.
In the present specification, "allergy" refers to a disease in which an immune response is excessively generated against a specific non-self antigen, and an immune response is generated against "allergen". "allergen" refers to an antigen capable of reacting with an antibody of a subject having an allergic disease, and examples thereof include: allergens derived from pollen of trees (acacia, alnus japonica, ash, beech, white birch, maple, huperzia serrata, red cedar, aspen, hinoki, elm, tree bark, white fir, rubber tree, eucalyptus, hackberry, hickory, basswood, maple, mesquite, papermulberry, oak, olive, pecan, pepper, pine, glossy privet, olea, phoenix tree, ailanthus, black walnut, black willow, etc.), allergens derived from pollen of grasses (cotton, bermuda, kentucky bluegrass, brome, corn, cow's tail grass, cogongrass, wild oat, duck grass, xifigwort, ryegrass, rice, yellow crotalaria, timothy, amaranth, quinoa, cocklebur, sheep hoof, goldenrod Kochia scoparia, white chenopodium, calendula, nettle, red amaranth, plantain longifolia, ragweed, euonymus alatus, salsola, artemisia, broom, rumex, etc.), insect-derived allergens (silkworm, mite, bee, wasp, ant, cockroach, etc.), bacteria-derived allergens (Alternaria, aspergillus, botulinum, candida, cephalosporium, curvularia, epicoccus, epidermidis, fusarium, desmodium, alternaria, mucor, penicillium, phoma, aureobasidium, rhizopus, etc.), animal body hair-derived allergens (dog, cat, bird, etc.), indoor dust-derived allergenic proteins, food-derived allergens (OVA, etc.), etc., however, the present invention is not limited to these. Representative diseases of "allergy" include atopic dermatitis, allergic rhinitis (pollinosis, etc.), allergic conjunctivitis, allergic gastroenteritis, bronchial asthma, pediatric asthma, food allergy, drug allergy, urticaria, etc.
In the present specification, an "inflammatory disease" refers to a disease or a state characterized by abnormal inflammation (e.g., an increase in the level of inflammation compared to a control of a healthy person or the like not suffering from the disease). As non-limiting examples of inflammatory diseases, there may be mentioned: atopic asthma, auto-inflammatory disease, allergy, pediatric allergic asthma, inflammatory bowel disease, celiac disease, crohn's disease, colitis, ulcerative colitis, collagenous colitis, lymphocytic colitis, diverticulitis, allergic enteritis syndrome, short bowel syndrome, dead loop syndrome (blind loop syndrome), chronic persistent diarrhea, refractory diarrhea in infancy, travelling diarrhea, immunoproliferative small intestine disease, chronic prostatitis, post enteritis syndrome, tropical stomatitis diarrhea, hupler's disease, wolman's disease, arthritis, rheumatoid arthritis, behcet's disease (Behcet's disease), uveitis, pyoderma gangrene, nodular erythema traumatic brain injury, psoriatic arthritis (psoriatic arthritis), juvenile idiopathic arthritis, multiple sclerosis, systemic Lupus Erythematosus (SLE), myasthenia gravis, juvenile diabetes, type 1 diabetes, guillain-Barre syndrome, hashimoto's encephalitis, hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, bullous pemphigoid, sarcoidosis, ichthyosis, graves 'eye disease, addison's disease, vitiligo, acne vulgaris, pelvic inflammatory disease, reperfusion injury, sarcoidosis, graft rejection, interstitial cystitis, atherosclerosis, and atopic dermatitis.
The term "prevention" in the present invention means the action of administering the active ingredient of the present invention to a person who is not suffering from a disease to be treated, for example, for the purpose of preventing the disease from suffering from the disease. Vaccines are said to be representative of drugs for prophylactic purposes. In the present invention, even when a disease causative agent is present in a subject, the disease is not usually determined as a disease state, and thus even in such a state, the prevention can be said to be a subject of treatment.
The term "treatment" in the present invention means an action of administering, for example, the active ingredient of the present invention to a person (subject, patient) diagnosed as having the onset of a disease by a doctor or a practitioner equivalent thereto, for example, the purpose of which is: alleviating the disease or symptom, reducing the number of pathogenic viruses or organisms of the infectious disease in the subject, or restoring the disease to a state prior to onset. In addition, even if the purpose of administration is to prevent deterioration of diseases or symptoms or reduce the number of pathogenic viruses or organisms of infectious diseases, the administration is therapeutic as long as the subject to be administered is a patient.
Prevention or treatment of immune abnormalities includes preventing, recovering from, or otherwise preventing immune abnormalities.
In the present specification, "memory T cells" or "memory T cells" refer to cells that function to maintain immunological memory by being present in a living body for a long period of time. In the body, effector T cells die 90% of cells after 1 to 2 weeks as long as the same antigen is not continuously exposed. Some of the remaining T cells are then substantially divided into two cell groups, and they function to maintain immunological memory by being present in the living body for a long period of time, and thus function as "memory cells". If the memory cells are roughly classified, they include central memory T cells (T CM ) And effector memory T cells (T EM ). By allowing these two memory T cells to survive for a long period of time, a rapid immune response can be initiated in the event of re-invasion by the same pathogen. Not only initially but alsoMemory T cells that are generated when encountering an antigen survive all the time, and a pool of new memory T cells is formed each time when encountering the same antigen again.
In the present specification, "effector T cell" or "Teff" refers to a T cell that positively controls an immune response, as an immune cell that directly attacks and destroys a subject factor or inhibits its proliferation. Examples of effector T cells include killer T cells, helper T cells, gamma delta T cells, NK cells, and NKT cells. In the present specification, CD 4-positive T cells and CD4 + Cells and CD 4T cells are used interchangeably and refer to T cells that are positive for CD 4. CD8 positive T cells, CD8 + Cells and CD 8T cells are used interchangeably and refer to T cells that are positive for CD 8. CD4 negative T cells and CD4 - T cells are used interchangeably and refer to T cells that are negative for CD 4. CD8 negative T cells and CD8 - T cells are used interchangeably and refer to T cells that are negative for CD 8.
T CM Cells approach the primary T cells in terms of cell surface markers, expressing CCR7 as one of the chemokine receptors and CD62L as one of the adhesion factors, etc., and are predominantly present in the T cell region of secondary lymphoid tissues. IL-2 production rapidly proliferates upon re-exposure to the same antigen, with a portion differentiated into T EM And (3) cells.
On the other hand T EM The reduction of expression of adhesion factors such as CCR7 and CD62L in cells occurs not only in secondary lymphoid tissues but also mainly in local parts of inflammation (e.g., lung, liver, intestinal tract, etc.), and by stimulation with the same antigen, cytokines such as IL-4, IFN- γ, IL-5, etc. are produced in large amounts.
In a preferred embodiment, the memory T cells to which the compositions of the invention are directed may also be memory regulatory T cells (IL-2 production). Regulatory T cells (tregs) are a type of T cells that block excessive immune responses. Treg cells are broadly divided into two types, endogenous Treg (nTreg) cells that are naturally produced in the thymus and induced Treg (iTreg) cells that are produced in peripheral tissues by stimulation with cytokines and the like. "memory regulatory T cells (IL-2 production)" refers to cells that have both the characteristics of "memory T cells" and "regulatory T cells".
In the present specification, "immune excessive reaction" means: the immune response in the living body acts more strongly than the normal response, and the target is a substance that does not adversely affect the living body. Examples of the "immune excess reaction" include symptoms such as allergic reaction, autoimmune disease, and cytokine storm. Allergies are diseases in which an immune system is excessively activated due to excessive production of IgE antibodies, igG antibodies, igM antibodies, and the like, which are produced when foreign substances such as allergens, bacteria, viruses, and the like invade the body. Autoimmune diseases are diseases in which the immune system does not function properly, and attacks the cells or tissues of itself. Cytokine storm is a disease in which inflammatory cytokines are excessively produced to induce an excessive immune response, and thus inflammation is produced in various cells and tissues. Organisms also have mechanisms for suppressing immune excess, for example, production of IL-10, which is an inhibitory cytokine, and the like. IL-10 is an inhibitory cytokine important for inducing and maintaining immune tolerance or controlling excessive immune response, and is considered to be involved in the elimination of pathogens or controlling excessive inflammatory response due to effector T cells in autoimmune response, or maintaining homeostasis (homeostasis) of the intestinal environment maintained by the symbiotic of intestinal bacteria and the intestinal immune system. It is considered that the immune response is quieted by acting on immune cells such as T cells and macrophages, directly inhibiting cell activation, or impairing the antigen presenting ability of macrophages.
In the present specification, "cellular immunity" refers to a cellular response to cells having characteristics that accompany the expression of antigen and/or presentation of antigen by class I or class II MHC. The cellular response is associated with cells called T cells or T lymphocytes that function as "helper" or "killer". Helper T cells (also known as CD4 + T cells) play a central role by modulating immune responses, killer cells (also known as cytonociceptive T cells, cytolytic T cells, CD 8) + T cells or CTLs) cause death of cells such as cells. As in the present inventionIt is clearly shown that the combination of the 2 components of the present invention can freely control humoral immunity or humoral immune memory, which is the first phenomenon discovered by the present invention, and can be called specific immune mechanism rather than natural immunity.
In the present specification, "antigen responsiveness" means that a subject controls an antigen-antibody reaction with a specific substance or the like, as is well known in the art. The antigen responsiveness can be typically checked and confirmed by performing an antibody test for checking the presence or absence of an antibody against a target antigen (for example, an antigen against SARS-CoV-2, or any antigen derived from the virus).
In the present specification, an "antigen responsiveness profile" refers to: when a certain subject is mentioned, the antigen responsiveness of the subject to various substances and the like is summarized to give a generic term (profile). The antigen responsiveness profile can be obtained by various methods, for example, by confirming the present or past physical state such as past medical history (for example, disease history of infection) and vaccination history, or by confirming the antigen responsiveness through a Panel (Panel) in which an antigen is actually used. They can be realized, for example, by a past medical history based on a consultation, a mother-son health manual or their equivalents, etc., a vaccination history, and combinations thereof. Further, confirmation of whether or not there is responsiveness can be performed by collecting body fluid (e.g., blood) from the subject, isolating peripheral blood cells, measuring whether or not the peripheral blood cells react with an antigen associated with the antigen profile to produce cytokines (IL-2, IFN-gamma, TNF-alpha, a combination of 2 or more thereof, etc.), and measuring other biomarkers.
In the present specification, the term "immune activation" refers to an action of non-specifically activating immune functions of an organism and enhancing a decreased defenses. Whether or not a substance has an "immune activation" can be confirmed by performing an assay for evaluating activation of immune cells using a reporter gene assay using a natural immune receptor, lymphocytes, or the like, using production of cytokines or the like as an index.
In the present specification, "activation" refers to a state in which functions of cells (e.g., T cells), proteins, polypeptides, genes, and the like are increased. "activation" includes a state in which a change or increase in cell function is confirmed, a state in which proliferation of cells is improved, a state in which expression of proteins, polypeptides, genes, etc. is increased, or a state in which expression patterns are changed, a state in which cells having inhibitory ability are inhibited, a state in which inhibited functions are released, and the like. In particular, in the present invention, activation of regulatory T cells (tregs) is meant. Activation of regulatory T cells (tregs) is sometimes referred to as the release or transformation (conversion) of the suppression of regulatory T cells (tregs), but both are synonymous. In the present specification, treg activation is sometimes referred to as a target, and in this case, treg exerts a prophylactic or therapeutic effect on a disease with activation of the target. As an example, activation of tregs involves transformation into effector T cells (Teff), or production of Teff, for a pathogenic agent or cells containing the pathogenic agent. Examples of the target include, but are not limited to, causative agents such as infection, allergy, and autoimmune disease.
Whether or not an immune cell is "activated" can be confirmed by an assay described in "immune activation" or the like. The "activation" of a gene may be quantified by a real-time PCR method, an RNA-Seq method, a Northern (Northern) hybridization method, a hybridization method using a DNA array, or the like, and the expression level of a polypeptide may be quantified by an antibody recognizing the polypeptide, a dye compound having binding property with the polypeptide, or the like. In addition to the above-listed quantitative methods, conventional methods used in the art may be used.
In the present specification, "adjuvant" refers to a substance that is used for enhancing the effect (immunogenicity) of an agent such as a vaccine (antigen) when administered together with the agent, and this term is derived from the word "adjuvant" (meaning "help"). Whether a substance functions as an "adjuvant" to another substance (e.g., an antigen) can be confirmed by performing a test described in the specification or by evaluating the production of an antigen-specific antibody by administering the substance to a mouse together with the antigen. In the case of being used for infectious diseases in the present invention, there is no antigen specificity, and the innate immunity is activated regardless of antigen, and has been proved to be effective for preventing infection in the present invention.
In the present specification, "action" of a component "in terms of" antigen-dependence "means that when a subject such as a T cell is referred to, the component acts on the subject, and as a result, an antigen-antibody reaction occurs, and it can be confirmed that the action disappears when the antigen-antibody reaction is blocked.
In the present specification, "memory CD 4-positive T cells" means cells positive for CD4 in memory T cells. In this specification, the CD4 positive is set to be positive by staining with an immunostaining method (using an antibody specific for CD4 labeled with a fluorescent dye or the like) or the like at a level higher than that of a nonspecific antibody used as a negative control.
In the present specification, "Foxp3 positive Treg cells" refers to cells positive for Foxp3 among Treg cells. Here, in this specification, positive for Foxp3 is set by performing staining by immunostaining (using an antibody labeled with a fluorescent dye or the like, which is specific for Foxp 3) or the like at a level higher than that of a nonspecific antibody used as a negative control.
In the present specification, "IFN-. Gamma.producing T cells" means cells having the ability to produce interferon-. Gamma.in T cells. Here, in the present specification, IFN- γ -producing T cells can be identified by staining at a higher level than in a nonspecific antibody used as a negative control by immunostaining (using an antibody specific for IFN- γ labeled with a fluorescent dye or the like) or the like.
In the present specification, "type 1 helper T cells" are also denoted as "Th1 cells", and are a subset of CD 4-positive T cells (so-called helper T cells) such as primary CD 4-positive T cells that mature in thymus, which are cells of a type that rapidly enter the blood stream and migrate to the site of infection, secrete cytokines such as IFN- γ or IL-2, and cause activation of macrophages or inflammatory responses. Th1 cells are responsible for the immune response, i.e., cellular immunity, in which CTLs or macrophages directly attack cells in the immune response that occurs locally. The subpopulation of CD4 positive T cells also includes helper T cells type 2 (Th 2 cells), and Th2 cells secrete cytokines such as IL-4 or IL-5 to activate primary B cells that recognize the same antigen in secondary lymphoid tissues. Th2 cells are responsible for the immune response, i.e., the humoral immunity, in which B cells and antibodies are central.
In the present specification, "T-bet positive Th1 cells" means cells that are positive for T-bet in Th1 cells. In this specification, regarding T-bet positivity, the positive is set by performing staining by an immunostaining method (using an antibody specific to T-bet labeled with a fluorescent dye or the like) or the like at a level higher than that of a nonspecific antibody used as a negative control. The transcription factor T-bet encoded as Tbx21 gene in Th1 cells directly forward feed-forwards controls gamma interferon production as a system-deterministic transcription factor. It is known that: gamma interferon, which is one of the families of interferons having anti-pathogenic and anti-infectious effects, is classified as type II interferon, which induces the expression of T-bet, which is a transcription factor of a predetermined Th1 cell, and maintains the production of gamma interferon by feedforward control.
In the present specification, the "hyperactivity" of IFN-. Gamma.production ability, IL-2 production ability, TNF-. Alpha.production ability and the like is determined as a marked increase in the production amount of IFN-. Gamma.and IL-2 and the number of cells produced by stimulation with an antigen or the like, as compared with a negative control, by an immunostaining method (using an antibody specific to IFN-. Gamma.or IL-2 or TNF-. Alpha.labeled with a label (substance or the like) such as a fluorescent dye) or the like. The amount of cytokine produced can be measured by ELISA and the number of cytokine producing cells can be measured by FACS.
In this specification, "biomarker" means: the presence, concentration or level of the substance or matter reflects the presence or progress of a specific physical state such as a disease, and the protein or matter is measured in a biological sample such as blood. It can thus be understood that: in the present specification, the term "biomarker" also includes matters such as whether or not it acts on memory CD 4-positive T cells in an antigen-dependent manner, whether or not memory regulatory T cells are altered, whether or not the ratio of Treg to Th1 is altered, whether or not IFN-gamma production from T-bet-positive Th1 cells is induced, whether or not IFN-gamma production capacity is altered, whether or not IL-2 production capacity is altered, and whether or not TNF-alpha production capacity is altered.
Whether or not an antigen-dependent effect on memory CD 4-positive T cells is achieved can be judged by a statistically significant increase in the number of positive cells of the antibody used in staining according to FACS analysis.
Whether or not memory regulatory T cells are altered can be judged by a statistically significant increase in the number of positive cells of the antibody used in staining according to FACS analysis.
Whether or not the ratio of Treg to Th1 is changed, whether or not IFN- γ production from T-bet positive Th1 cells is induced can be determined by measuring the intracellular cytokine staining and transcription factor staining by FACS, or measuring the produced cytokine by ELISA.
Whether or not IFN-. Gamma.production ability, IL-2 production ability and TNF-. Alpha.production ability are altered can be determined by measuring the intracellular cytokine staining and transcription factor staining followed by FACS or measuring the produced cytokine by ELISA.
In the present specification, "bias" of the "presence ratio" of cells means: the ratio of the cells to the ratio existing in the normal state is statistically significantly different from the ratio of the cells to the ratio existing in the normal state. Whether or not bias occurs can be determined by referring to the results of cell analysis obtained in any method of analyzing cells (e.g., FACS, etc.).
In the present specification, the "hot water extract of human tubercle bacillus" is typically a substance produced by human tubercle bacillus, and is a mixture containing polysaccharides including arabinose, mannose and glucose as main components. The anti-infective effect of hot water extracts based on tubercle bacillus has been studied for a long time, but the details of the mechanism of action are not necessarily clear and have not been used as preventive agents. In addition, the composition may contain trace components such as proteins, peptides, amino acids, nucleic acids, and lipids (glycolipids) as appropriate.
In the present specification, the "part of the hot water extract of human tubercle bacillus" may be any part (component, combination of components, part of components, or the like) of the hot water extract of human tubercle bacillus, and examples thereof include: polysaccharides such as arabinose, mannose, glucose, etc.; protein, amino acids, nucleic acids, lipids (glycolipids), and other minor components, such as mitochondrial heat shock protein 10 (mHSP 10; accession number P9WPE5, second accession number(s): L0TFJ, P09621), bacillus tuberculosis low molecular weight antigen (MTB 12; accession number P9WIN7, second accession number(s): L0T9F9, O05822, P0A5P 8), and/or lipoprotein LpqH (accession number P9WK61, second accession number(s): L0TGP1, P0A5J0, P11572). Any of these components or combinations thereof may be used as non-pathogenic antigenic components in the present invention. mHSP10, MTB12 and LpqH are antigen components contained in a hot water extract of human tubercle bacillus and are molecules having an activity of inducing ifnγ secretion.
In another embodiment, STING agonists derived from Mtb may be included alone or in combination with other ingredients as part of the hot water extract of mycobacterium tuberculosis.
"STING" (the (adaptor) stimulator of the IFN gene) identified as a membrane protein localized to the endoplasmic reticulumstimulator of interferon genes)) plays an important role in the organism's defense mechanism against infection with various RNA viruses and DNA viruses. In addition, STING has been reported to play an important role in inducing a natural immune response against viral and bacterial derived DNA components. Some of the inventors have clarified: STING is able to form complexes not only with viral-derived genomic DNA, but also with synthetic double-stranded DNA of 45 to 90 base pairs, known as ISD, and thus with self DNA components derived from apoptotic cells. Analysis of the DNA interaction region in vitro (in vitro) showed that the C-terminal region of STING was important. It was shown that various DNA components were isolated by STINGIdentification induces a change in dynamic localization of STING in the peripheral area of the nuclear membrane, and interferon production is induced by activation of TBK 1. And then prompt: STING is also likely to be involved in the control of chronic inflammatory responses by recognizing not only non-self DNA components derived from microorganisms, but also self DNA components.
In the present specification, "STING ligand" and "STING agonist" are used interchangeably as (adaptor) stimulators of the IFN genestimulator of interferon genes), induces type I IFN production and NF- κb mediated cytokine production. STING agonists are thought to be membrane proteins that localize to the endoplasmic reticulum. As STING agonists, in addition to cGAMP, cyclic dinucleotides, c-di-AMP and c-di-GMP, derived from bacteria are ligands for adaptor molecule Stimulators (STING) that induce type I IFN production and NF- κb-mediated cytokine production of IFN genes via TBK1-IRF3 axis signaling [ bursette et al, nature (2011) 478:515-8; mcwhister et al, j.exp.med. (2009) 206:1899-1911]. According to recent studies, these cyclic dinucleotides function as powerful vaccine adjuvants due to their ability to enhance antigen-specific T cells and humoral immune responses. According to some previous reports by the inventors et al, DMXAA as a STING agonist unexpectedly induces a type 2 immune response by producing STING-IRF3 mediated type 1 IFN [ Tang et al, PLoS one (2013) 8:1-6]. Because type 2 immune responses sometimes fail to induce a type 1 immune response, the clinical usefulness of STING agonists comprising cyclic dinucleotides is controversial. For example, the aluminum salts of the most common adjuvants (alum) induce insufficient ability to defend against cell-mediated immunity in the case of diseases or cancers derived from intracellular pathogens [ Hogenesch et al, front. Immunol (2013) 3:1-13 ]. To overcome this limitation, alum was combined with a composition comprising monophosphoryl lipid A [ Macleod et al, proc. Natl. Acad. Sci. U.S. A. (2011) 108:7914-7919]And CpG ODN [ Weeratna et al, vaccine (2000) 18:1755-1762]Is a combination of a plurality of different kinds of adjuvants. Regarding STING-related techniques, as with microbial DNA, host DNA may also become a dangerous signal, especially if host DNA is not present in the cytosol properlyThereby resulting in the production of interferon and inflammatory cytokines [ Desmet et al, nat. Rev. Immunol. (2012) 12:479-491; barber et al, immunol. Rev. (2011) 243:99-108]. One cytosolic DNA sensor recently identified is cyclic GMP-AMP synthetase (cGAS) which catalyzes the production of a non-standard cyclic dinucleotide cGAMP (2 '3' -cGAMP) containing non-standard 2',5' and 3',5' linkages to purine nucleotides [ Sun et al, science (2013) 339:786-91]. Standard cGAMP (3 ') is synthesized in bacteria with various linkages compared to mammalian 2'3' -cGAMP, GMP and AMP nucleotides are bound by bis- (3 ',5 ') linkages [ Wu et al, science (2013) 339:826-30; zhang et al, mol.cell. (2013) 51:226-35]。
Therefore, as STING agonists that can be used in the present invention, STING agonists derived from Mtb are preferable, and examples thereof include Cyclic Dinucleotides (CDN) such as 2'3' -cGAMP, c-di-AMP, 3' -cGAMP, 2'3' -cGAMP, and xanthone derivatives such as DMXAA. As shown in the present specification, examples of the substance derived from Mtb include c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP and/or dsDNA capable of mediating production of these substances by cGAS in human cytoplasm. For example, 3' -cGAMP can be used as an adjuvant for infectious diseases or as a therapeutic or prophylactic agent of the present invention, and has remarkable effects. In addition, STING agonists are as described in WO 2010/017248, the contents of which are incorporated herein by reference in their entirety.
A typical method for producing a hot water extract of Mycobacterium tuberculosis is as follows.
Culturing human type tubercle bacillus in a constant temperature bath of 37deg.C for 3-7 weeks, filtering to obtain membranous thallus formed on the culture medium, washing the culture medium with water, and removing to obtain wet thallus as extraction raw material. The bacterial cells are suspended in distilled water 15 to 40 times the wet weight, heated at 90 to 120 ℃ for 80 to 180 minutes, the bacterial cell residue is removed by a sterilizing filter, the extract is concentrated to 60% or less, acetone, trichloroacetic acid, ammonium sulfate, sulfosalicylic acid or the like is added thereto so as to be 0.5% (w/v) to 3% (w/v), the mixture is stirred and left standing, the precipitate thus separated is removed by centrifugation, and the supernatant is subjected to dialysis with running water. The dialysis inner liquid is concentrated under reduced pressure to 1/20 to 1/4 of the amount, sodium chloride is added to the concentrated liquid so as to be 0.5% (w/v) to 1% (w/v), ethanol with a capacity of 2 to 4 times is added, and after standing, the concentrated liquid is centrifuged to remove precipitate. Further adding 2-6 times of ethanol into the supernatant, standing, centrifuging, and collecting the precipitated polysaccharide to obtain hot water extract of human tubercle bacillus. Those skilled in the art will appreciate that: the same product can be obtained even if the above conditions are appropriately changed.
In the present specification, "kit" means: generally, the composition is divided into 2 or more blocks, and a unit for providing a portion (e.g., a composition, additional components, buffer, instructions, etc.) to be provided is provided. For stability and the like, it should not be provided in a mixed state, but preferably be mixed immediately before use or applied separately, and when such a composition is provided, the form of the kit is preferable. Such a kit is preferably provided with instructions or instructions for how to use or how to treat the provided parts (e.g. composition, additional ingredients) etc. In the present specification, when a kit is used, the kit generally includes instructions or the like for carrying methods of use or the like of the components, compositions or the like of the present invention.
In the present specification, the term "instruction" means a document which describes the use of the method of the present invention for the user. The instruction book is written with a language indicating the method of use of the present invention. The direction is produced in accordance with a pattern prescribed by a regulatory agency of a country in which the present invention is to be implemented (for example, in the united states of america, the Food and Drug Administration (FDA) in the province of thick birth, etc. in japan) if necessary, and a clear instruction is attached to indicate that approval by the regulatory agency is obtained. The directions may be provided in a paper medium, but are not limited thereto, and may be provided in the form of an electronic medium (e.g., a website provided by the internet, an email), or the like, for example.
(description of the preferred embodiment)
Preferred embodiments of the present invention will be described below. The following examples are provided for better understanding of the present invention, and are not to be construed as limiting the scope of the present invention. Accordingly, it will be apparent to those skilled in the art that the present invention can be appropriately modified within the scope of the present invention with reference to the description in the present specification. In addition, it is understood that the following embodiments of the present invention may be used alone or in combination.
< prevention and treatment of diseases based on combinations of pathogenic antigen component and non-pathogenic antigen component)
Part of the present invention is based on the following findings: if a pathogenic antigen component (which is derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject) and a non-pathogenic antigen component (which is neither derived from nor cross-reactive with a pathogenic agent of the disease) are combined, then cellular immunity useful for the prevention or treatment of the disease can be controlled, and the disease can be specifically prevented or treated. In one embodiment, it is found that: the subject has an immune memory against the non-pathogenic antigen component, whereby exposure to the subject by combination with a pathogenic antigen component other than the non-pathogenic antigen component can freely control the humoral immune memory against the pathogenic antigen component, and prevention or cure of the disease in the subject can be achieved by up-regulating (e.g., causing or enhancing) or down-regulating (e.g., inhibiting or eliminating) it as desired. While not wishing to be bound by theory, the inclusion of these responses in part allows for free control of immune responses in forms other than natural immunity. Such a combination may be achieved under any conditions in which the component X is present in an active form in a subject when another component Y is administered to the subject. Examples include: combining component Y with component X (the combination may be a mixture or a combination of separate agents) simultaneously or not; or confirming the presence of component X in the subject (e.g., by an antigen test or, where appropriate, by a genetic test such as PCR), and administering component Y to the subject whose presence has been confirmed. For example, according to the quartering method, the higher immune response-involved person is classified as "allergy" and "autoimmune disease", the lower immune response-involved person is classified as "infectious disease" and "cancer", and the higher immune response-involved person is classified as "autoimmune disease" and "cancer" and the lower immune response-involved person is classified as "allergic reaction" and "infectious disease" respectively, but the present invention proves that the present invention can cope with all these diseases, especially, can cope with infectious disease, allergic reaction and autoimmune disease, although not wishing to be bound by theory.
In the present invention, by using human Peripheral Blood Mononuclear Cells (PBMC) derived from uninfected/unexposed healthy donors, the inventors have found that with extract a, it is possible to promote a SARS CoV-2 specific T cell response, potentially derived from T cells specific for coronaviruses (associated with common colds and having cross-reactivity for SARS CoV-2), via modulating Treg/Th1 balance. Specifically, it is shown that: the promoting effect of T cells using extract a was dependent on existing Mtb memory, and the effect was hardly dependent on extract a-induced training immunity. Thus, by accelerating the xenogenic T cell response against SARS CoV-2 by both BCG and extract A, it is possible to provide therapeutic efficacy against COVID-19. In particular, although not limited thereto, in a preferred embodiment, it is shown that the extract of tubercle bacillus such as extract A is advantageous. In this respect, it has been shown that repeated administration of BCG causes excessive immune or inflammatory reaction, and repeated administration should be avoided, but that the tubercle bacillus extract such as extract a can be repeatedly administered, and has demonstrated safety, and that a significant increase in inhibitory cytokines suggests this, in addition to that repeated administration has been found to significantly improve effectiveness. Therefore, although not limited thereto, in a preferred embodiment, it can be said that the extract of tubercle bacillus such as extract a brings about particularly remarkable and unexpected effects even when compared with BCG. Such effects are, in particular, remarkable effects which have not been expected previously particularly in infections (e.g., bacterial infections, viral infections), which cannot be achieved by the previous drugs and the like. Therefore, it is expected to have a preventive and therapeutic effect not only on viral infections such as covd-19 but also on infections which may be newly developed and which are widely prevalent, and thus it is expected to be useful as a means for preventing epidemics.
In one embodiment, the non-pathogenic antigen component is a hot water extract of tubercule bacillus or a part thereof, preferably a hot water extract of human tubercule bacillus Qingshan B strain or a part thereof, and more preferably an extract a.
As part of the preferred embodiment, for example, the hot water extract of Bacillus tuberculosis or a part thereof may be a metabolite such as a STING agonist, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb-related antigen, STING agonist c-di-AMP derived from Bacillus tuberculosis, a component capable of synthesizing STING agonist in human cells, or a NOD2 agonist or a part other than it, and in the present invention, it has been found that the use of these sequences or a part thereof as an epitope may cause CD 4T cells. In a preferred embodiment, the hot water extract of tubercle bacillus or a part thereof may be a STING agonist derived from tubercle bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in the cytoplasm of a host cell such as a human cell mediated by cGAS.
Although not wishing to be bound by theory, as the active ingredient or non-pathogenic antigen ingredient or adjuvant used in the present invention, tuberculosis antigen-specific T cell epitopes (peptide sequences) derived from these hot water extracts of tubercle bacillus or a part thereof may be used. In addition, they have been found to act on CD 4T cells in the event that they are caused to react in an organism. To the best of the inventors' knowledge, the details of CD 4T cells are not known, and it has not been known heretofore that such phenomenon may be caused by a hot water extract of mycobacterium tuberculosis or a part or component thereof. In particular, in the components comprised in extract A, peptide sequences of nuclear antigen-specific T cell epitopes were unexpectedly found. Furthermore, the T cells are known as CD 4T cells. In addition, it is unexpected that a synthetic peptide having the same sequence as the protein contained in the extract A also causes activation of T cells, and thus not only a natural-derived substance can cause activation of T cells, but also a synthetic product or an artificial substance can cause activation of T cells. Based on the insight of MCH or its affinity to date, it can be said that this is an unexpected phenomenon.
In the past immunology, only antigen-specific reactions have been attracting attention, and it is considered that only antibodies having antigens are responsible for the immune reactions. However, in the present invention, it is found that T cells exhibiting antigen-specific responses also affect peripheral T cells or macrophages, and that immune responses caused by non-pathogenic antigens have been found to be effective against many diseases such as cancer and infectious diseases. Although BCG is described as persistent innate immunity rather than acquired immunity, in the present invention, acquired immunity is found to enhance innate immunity. Thus, it can be appreciated that the present invention has found a new aspect with respect to immunological memory.
In the present specification, lpqH is a 19kDa protein, which is a lipoprotein (Mycobacterium tuberculosis lipoprotein) of Bacillus tuberculosis (accession number: P0A5J 1). LpqH helps to activate TLR 2. Referring to Sanchez A, espinosa P, garcia T, mancilla R.the 19kDa Mycobacterium tuberculosis lipoprotein (LpqH) induces macrophage apoptosis through extrinsic and intrinsic pathways: a role for the mitochondrial apoptosis-reduction factor.Clin Dev immunol.2012;2012:950503.doi:10.1155/2012/950503.
In the present specification, Y1269 is a protein derived from Bacillus tuberculosis (accession number: P9WM 44). Reference is also made to https:// www.uniprot.org/uniprot/P9WM44.
In the present specification, PPD is an antigen purified from a culture filtrate of tubercle bacillus (PPD: purified Protein Derivative, purified protein derivative) and can be used for tuberculin reaction.
In the present specification, the CMV pp65 overlapping peptide is an antigen of cytomegalovirus, and is a structural protein detected at the early stage of CMV infection. Available from Miltenyi. Referring to Wills MR, carmichael AJ, mynard K, jin X, weekes MP, plachter B, sissons JG: the human cytotoxic T-lymphocyte (CTL) response to cytomegalovirus is dominated by structural protein pp: frequency, specificity, and T-cell receptor usage of pp-specific CTL.J virol.1996,70:7569-7579.
In the present specification, the "bacillus tuberculosis (Mtb) -related antigen" is also referred to as "Mtb antigen", and is any antigen related to tuberculosis. As a representative example, examples described in table 1B can be cited.
[ Table 1B ]
In the present specification, the NOD2 agonist is MDP (muramyl dipeptide) or a part of peptidoglycan having an MDP-like structure, and may be exemplified by a substance capable of binding to a NOD2 receptor to activate NOD2, and may be exemplified by MDP (muramyl dipeptide).
The term "MDP" as used in this specification is muramyl dipeptide that may be used in the present invention as an agonist to activate the NOD2 pathway to promote PGE2 secretion in mesenchymal stem cells.
In the present specification, c-di-AMP is adenylyl- (3 '. Fwdarw.5') -3 '-adenylate, cyclic nucleotide, disodium salt (adenlyl- (3' - >5 ') -3' -adenlylic acid, cyclic nucleotide, diodium salt). Available from Cayman et al.
In the present specification, c-di-GMP is guanyl- (3 '- > 5') -3'-guanylic acid, cyclic nucleotide, disodium salt (guanyl- (3' - >5 ') -3' -guanylic acid, cyclic nucleotide, disk salt). Available from Cayman et al.
In the present specification, 3' -cGAMP is adenylyl- (3 ' - >5 ') -3' -guanylic acid, cyclic nucleotide, disodium salt (adenyl- (3 ' - >5 ') -3' -guanylic acid, cyclic nucleotide, diodium salt), or otherwise named c-GMP-AMP sodium salt, cyclic AMP-GMP sodium salt. Represented by the following chemical formula 1. Available from Cayman et al.
[ chemical formula 1]
In the present specification, 2'3' -cGAMP is 2'3' -adenylyl- (3 '. Fwdarw.5') -3'-guanylic acid, cyclic nucleotide, disodium salt (adenyl- (3' - >5 ') -3' -guar acid, cyclic nucleotide, diodium salt), or otherwise named c [ G (2 ', 5') pA (3 ', 5') p ] sodium salt, cyclic [ G (2 ', 5') pA (3 ', 5') p ], 2',5' -3',5' -cGAMP, cGAMP (2 ', 5') experimental formula (Hill note). Available from Cayman et al.
[ chemical formula 2]
The trace amount of the tubercle bacillus (Mtb) antigen in extract a as a representative example has an effect on diseases in non-pathogenic agent (e.g., BCG) immunized mice by including a mechanism of strongly activating ifnγ to produce Th1 cells. Furthermore, extract a as a representative example contains STING agonists derived from Mtb (which are necessary for mediating the effect of extract a on diseases). Th1 cells that respond to non-pathogenic antigen components such as extract A are also found in human PBMC, and it is expected that the anti-tumor effect of extract A will be responded in humans. The non-pathogenic antigenic component of extract A accelerates the immunization against pathogenic agents (e.g., anti-SARS-CoV-2 immunization) by modulating the Treg/Th1 balance in PBMC insensitive to pathogenic agents and the like SARS-CoV-2.
Extract a, which is a representative example of the present invention, is a hot water extract of mycobacterium tuberculosis (Mtb). As shown in the examples, extract a, which is a representative of the non-pathogenic antigenic component, has anti-tumor and (especially against non-Mtb pathogens) antimicrobial capabilities. In the present invention, the mechanism associated with the antitumor and antimicrobial effects of extract a is elucidated. As shown in the present specification, it is shown that when animals such as mice are immunized with non-pathogenic antigen components such as extract a or non-pathogenic factors such as BCG, the non-pathogenic antigen components such as extract a exert a potent effect (e.g., antitumor effect) on the disease. As shown in the present specification, according to in vivo studies of BCG-immunized mice, ifnγ secretion of CD 4T cells and Mtb-derived STING agonists found in extract a are necessary in order to mediate the effects (e.g., antitumor effects) of non-pathogenic antigen components such as extract a on diseases. A trace amount of Mtb protein could be detected in the extract a solution, and even if 1 of such proteins was administered to BCG-immunized mice by injection, the effect on the disease could be exhibited. Furthermore, PPD-responsive Th1 cells in human PBMC are also responsive to non-pathogenic antigen components such as extract a, revealing that these cells may be responsible for diseases in humans. In addition, by using human PBMC derived from healthy donors insensitive to pathogenic factors such as SARS-CoV-2, the pathogenic factor-specific T cell response of SARS-CoV-2 can be promoted by modulating the Treg/Th1 balance from non-pathogenic antigen components such as extract A. Specifically, the T cell enhancement effect by the non-pathogenic antigen component such as extract A depends on the existing Mtb memory. Therefore, it was confirmed that non-pathogenic antigen components such as extract A are likely to have therapeutic effects on various diseases such as autoimmune diseases, allergies, cancers and infections (e.g., COVID-19) by enhancing heterogeneous Th1 cell responses or by training acquired immune cells in individuals with BCG immunity or a history of tuberculosis.
The inventors analyzed the potential mechanism of the antitumor and antiinfectious effects of non-pathogenic factor antigen components such as extract A. The discovery is as follows: the activity of the non-pathogenic antigen component such as extract A against diseases (e.g., antitumor activity, etc.) was observed only in mice having immunological memory against BCG, but not in blank mice. Further, as shown by mass spectrometry analysis of the extract a solution, the presence of Mtb-associated antigen has an effect on the disease as in the extract a. Furthermore, in vivo studies using mice deficient in various immune cells or molecules and using disease models (e.g., tumor-bearing mice) have been conducted, and according to the studies, ifnγ -producing Th 1-type CD 4T cells and STING pathways mediated by STING agonists derived from Mtb present in extract a were found to be effective for the effects of non-pathogenic antigen components such as extract a on diseases. Furthermore, it was found that there is a strong correlation between the T cell response induced by extract A and the T cell response mediated by the Mtb antigen in human PBMC obtained from healthy donors, suggesting that the anti-tumor effect of non-pathogenic antigen components such as extract A in the clinic is dependent on the T cell response, which may be non-pathogenic (e.g. Mtb) specific cross-reactivity.
In order to evaluate the antiviral effect of the non-pathogenic antigen component such as extract A, focusing on the Th1 cytokine IFNγ, it has been confirmed that the non-pathogenic antigen component such as extract A enhances the production of IFNγ mediated by the pathogenic factor such as SARS CoV-2 in PBMC obtained from healthy subjects insensitive to the pathogenic factor such as SARS CoV-2, which is detected at a high level in Th1 cells.
As a mechanism supporting the present invention, it can be understood that: the non-pathogenic antigenic components of extract a, etc., modulate Treg/Th1 balance by relying on pre-existing Mtb memory and not on the mechanisms of training immunity induced by adjuvants, thereby promoting T cell-derived ifnγ production specific for pathogenic antigenic components of SARS CoV-2, etc., without wishing to be bound by theory. The following is indicated: in the present invention, the non-pathogenic antigen component (e.g., extract A) can be an effective therapeutic tool against various diseases such as cancer and infectious diseases (including COVID-19).
In one embodiment, the pathogenic antigen component is a pathogenic agent of an infectious disease, and the non-pathogenic antigen component may function as an adjuvant when the pathogenic antigen component is used as a vaccine.
The inventors focused on the Th1 cytokine ifnγ, and shown that in non-infected healthy PBMCs, non-pathogenic antigen components (e.g., extract a) can be mediated by pathogenic agents (e.g., SARS CoV-2) to promote production of ifnγ derived from CD 4T cells and CD 8T cells. Non-pathogenic antigenic components (e.g., extract a) modulate Treg/Th1 balance by a mechanism that relies on pre-existing Mtb memory rather than on adjuvant-induced training immunity, whereby pathogenic agents (e.g., SARS CoV-2) specifically promote ifnγ production from T cells, but are not intended to be bound by theory. Thus, the experimental data provided in the present invention demonstrate that: the non-pathogenic antigenic component (e.g., extract a) can be a means of effective immunotherapy against viral infections (e.g., covd-19).
In one embodiment of the present invention, it was confirmed that extract A, which is a representative example of a non-pathogenic antigen component, can induce antitumor immunity only in mice having an existing immunity induced by BCG immunization. As a mechanism in this embodiment of the invention, the presence of multiple Mtb-derived proteins in extract a was found to be critical for eliciting and activating Th 1-type memory T cell responses induced by BCG immunity in the tumor microenvironment, but is not intended to be bound by theory. Furthermore, in the tumor microenvironment of BCG immunized mice, tbet derived from extract a was induced + Ifnγ production by CD 4T cells, and activation of STING pathways mediated by STING agonists derived from Mtb found in extract a, are essential for mediating the antitumor effects of extract a. It is important to find that extract a-reactive cells are associated with Mtb-derived protein antigen comprising protein antigen (e.g. MHSP 10) detected in extract a, which means that the mechanism of mediating the anti-tumor effect of extract a in a person immunized by BCG vaccination, or a person with a history of tuberculosis, may be the same as that observed in BCG immunized mice. Furthermore, the present invention has found that: in SARS CoV-2 insensitive hBMC, extract A derived from Mtb converts Treg/Th1 balance into Th1 type effector T cell expression by a mechanism that depends on the memory of existing Mtb-specific T cells, thereby enhancing SARS CoV-2-specific Th1 type T cell response. The present invention focused on the immune response obtained mediated by SARS CoV-2 and not on the general natural immune response, and the results of the present invention considered that the phenomenon observed in the present invention was not dependent solely on the training immunity induced by extract A, as it was dependent on the existing Mtb memory. Taken together, the data relating to anti-tumor effects obtained under in vivo conditions and the data relating to antiviral effects of extract a obtained under in vitro conditions indicate that the protective effect mediated by extract a against pathogens or tumors containing Mtb non-associated antigens is likely to be induced by 2 mechanisms. A first part On the one hand, it includes Mtb/coronavirus specific T cell responses that are cross-reactive against SARS CoV-2/tumors, and on the other hand, it includes induction of an acquired immune response against non-Mtb pathogens or after tumor training due to the expanded proliferation of Mtb specific Th1 cells produced by ifnγ, and recruitment to tumor/infection sites.
In one embodiment, as the non-pathogenic antigen component, a hot water extract of tubercle bacillus or a part thereof may be mentioned: STING agonists derived from tubercle bacillus, lpqH, Y1269, PPD, CMV pp65 overlapping peptides, mtb related antigens, components capable of biosynthesis of STING agonists in human cells, or NOD2 agonists (e.g. MDP or a part of peptidoglycans having MDP-like structures), etc.
In one example, the invention can provide specific and effective therapeutic and prophylactic effects on target diseases (e.g., infections, allergies, or autoimmune diseases) by using non-pathogenic antigen components of a subject having an immune memory in the presence of pathogenic antigen components (pathogenic agents derived from and/or cross-reactive with the target disease).
In one aspect, the invention provides a composition for preventing or treating a disease comprising a non-pathogenic antigen component that is neither derived from nor cross-reactive with a pathogenic agent of the disease, the composition being administered in the presence of a pathogenic antigen component that is derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject.
In another aspect, the invention provides a medicament for preventing or treating a disease comprising a combination of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject and a non-pathogenic antigen component neither derived from nor cross-reactive with a pathogenic agent of the disease.
In still another aspect, the invention provides a kit for preventing or treating a disease comprising a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject, and a non-pathogenic antigen component that is neither derived from nor cross-reactive with a pathogenic agent of the disease.
By providing such a composition, a drug, a kit, or the like, and exposing it to a subject in combination with a pathogenic antigen component other than a non-pathogenic antigen component, the humoral immune memory against the pathogenic antigen component can be controlled, enabling prevention or cure of a disease in the subject.
In one embodiment, the pathogenic agent comprises a foreign substance to the subject. Alternatively, in another embodiment, the causative agent comprises an immunocompromised causative agent of an infectious disease, an allergic reaction, an autoimmune disease, or a poison.
In a preferred embodiment, the target disease of the invention is an infection. The target disease of the present invention may be, for example, bacterial infection, microbial infection, viral infection, mycoplasma infection, etc., preferably viral infection. The viral infection may be a disease caused by a virus belonging to the family coronaviridae, or may be a disease caused by a virus belonging to the family selected from the group consisting of rhinoviruses, adenoviruses, coronaviruses, RS viruses, influenza viruses, parainfluenza viruses and enteroviruses. Alternatively, the causative agent may be a virus belonging to the genus coronavirus B, specifically, a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2, and as one of specific embodiments, the causative agent may be SARS-CoV-2 virus. The SARS-CoV-2 virus is understood to include any variant.
In a preferred embodiment, the subject has an immunological memory for the non-pathogenic antigenic component. While not wishing to be bound by theory, by administering the combination of components of the present invention to a subject having immunological memory to a non-pathogenic antigen component (e.g., tuberculosis extract, etc.), such as a subject having past history of tuberculosis or vaccination history, humoral immunity controlled by the non-pathogenic antigen component becomes directed against the pathogenic antigen component, whereby the humoral immunity acts on the target pathogenic. In this preferred embodiment, it is considered that the effect is exerted by inducing or enhancing the body fluid immunity.
In one embodiment, the composition, medicament or kit of the invention may also comprise a pathogenic antigen component. By including a pathogenic antigen component in a composition in addition to a pathogenic antigen component, a non-pathogenic antigen component may be administered whenever in the presence of a pathogenic antigen component, and is therefore preferred. Alternatively, by including a pathogenic antigen component in a composition in addition to a pathogenic antigen component, although it is the case that a pathogenic antigen component is already included in a subject, the effect can be enhanced by administering the composition without sufficiently controlling the body fluid immunity.
In one embodiment, the composition, medicament or kit of the invention is used for preventing the above-mentioned diseases. In another embodiment, the compositions, medicaments or kits of the invention are used for the treatment of the above-mentioned diseases. In the case where the composition, the drug, the kit or the like of the present invention is directed to prevention, the composition, the drug, the kit or the like of the present invention may preferably contain a pathogenic antigen component. The reason for this is considered to be: the subject to be prevented often does not contain a pathogenic antigen component, and often does not contain a pathogenic antigen component but does not exert sufficient effect.
In one embodiment, the compositions, medicaments or kits of the invention, etc., prevent or treat the above-described diseases in a form that does not accompany or reduce an immune overreaction. While not wishing to be bound by theory, it is often observed that agents that affect the immune system are associated with an immune overreaction, which sometimes occurs as a cytokine storm, for example, severe patients in covd-19 experience severe exacerbation and death due to the immune overreaction. While not wishing to be bound by theory, the techniques of the present invention may achieve treatment or prevention by combining pathogenic antigen components with non-pathogenic antigen components, without or with reduced immune overreaction, by controlling humoral immunity and eliciting an immune response against the pathogenic agent that is the desired target. Those skilled in the art can also check whether an immune excessive reaction is generated or not, and adjust the pathogenic and non-pathogenic antigen components to appropriate amounts as needed based on the inventive content of the present specification. In a preferred embodiment of the present invention, the extract of tubercle bacillus such as extract A is capable of preventing or treating a disease in a form not accompanied by or reduced in immune excess, which is particularly advantageous in fields where repeated administration is expected such as a broad prevalence, as compared with the case where the previous immune excess is accompanied by repeated administration of a part.
In one embodiment, the compositions, medicaments, kits, etc. of the present invention are administered in a form effective to control (e.g., elicit, enhance, inhibit, disappear, etc.) the cellular immunity against the causative agent of the disease. Such administration forms may be administered at different periods of time in addition to the single-use administration, and may be the following administration forms: alternating administration of a non-pathogenic agent antigen component and a pathogenic agent antigen component; or the first administration of the non-pathogenic antigen component and the pathogenic antigen component simultaneously, the 2 nd and later administration of the non-pathogenic antigen component alone, etc. Here, the pathogenic antigen component may be administered intentionally (in the form of a vaccine or the like for the disease) or may be naturally occurring (including the case of subjective symptoms, and also including the case of no subjective symptoms, in the case of an infectious disease, and also including the stage of infection before onset, and the like). In the case of natural suffering, it may also be assumed that there is a history of the disease or that the disease is currently suffering.
In one embodiment, it is characterized in that it is determined whether a pathogenic antigen component is present in said subject and, in the absence, the pathogenic antigen component is administered together with said non-pathogenic antigen component, said pathogenic antigen component being derived from and/or cross-reactive with a pathogenic agent of the target disease. The presence of the pathogenic antigen component can be carried out by performing any antigen test or the like known in the art.
In one embodiment, the disease to be treated is an infection, allergy or autoimmune disease.
In one embodiment, the disease is a viral infection or bacterial infection, and in particular embodiments, the disease is a viral infection, such as may be associated with coronavirus.
The pathogenic antigen component is a molecule that is at least partially present on the surface of the pathogenic agent of the target disease. Thus, the molecule constituting the virus particle may be a molecule in the case where the target disease is a viral infection, or a molecule existing in a cell membrane or a cell wall in the case where the target disease is a bacterial infection.
In another aspect, the invention provides a combination of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject, and a non-pathogenic antigen component derived from or cross-reactive with neither the pathogenic agent of the disease. To the inventors' knowledge, this combination has not previously been provided as a combination of substances.
In one embodiment, the pathogenic antigen component comprises an immunocompromised pathogenic agent of an infectious disease, an allergic reaction, an autoimmune disease, or a poison. In particular embodiments, the pathogenic antigen component is a bacterium, microorganism, virus, protozoan, or a portion thereof. Here, "a part" may include a part (fragment) of each organelle or unit of a living body, such as a protein. May be the smallest unit capable of controlling the antigen-antibody reaction. In one embodiment, the pathogenic antigen component is a virus or a portion thereof. As a specific example, for example, the pathogenic antigen component is a virus belonging to the family Coronaviridae, or a portion thereof, and in another embodiment, the pathogenic agent is a virus belonging to the family selected from the group consisting of rhinoviruses, adenoviruses, coronaviruses, RS viruses, influenza viruses, parainfluenza viruses and enteroviruses, and the pathogenic agent is preferably a virus belonging to the genus Corona, for example, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, SARS-CoV-2 and the like. In a particular embodiment, the pathogenic agent is SARS-CoV-2 virus.
In another embodiment, the non-pathogenic antigenic component of the present invention is a hot water extract of Bacillus tuberculosis or a part thereof, for example, it may be a hot water extract of the human Mycobacterium tuberculosis Qingshan B strain or a part thereof.
In one embodiment, the kits of the invention comprise instructions for how the components contained in the kits of the invention should be used. In the case where the component included is a drug or a composition, there is a description of how to administer the composition, and in the case where the kit includes a drug for antigen detection, there may be a description of a method for antigen detection.
In another aspect, the present invention provides a method for preventing or treating a disease in a subject, comprising the steps of: administering to the subject an effective amount of a non-pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of the disease in the subject under conditions of a pathogenic agent antigen component that is neither derived from nor cross-reactive with a pathogenic agent of the disease. In this method, any of the embodiments described in the above-mentioned < prevention and treatment of diseases based on a combination of a pathogenic antigen component and a non-pathogenic antigen component > or elsewhere may be used.
In another aspect, the present invention provides a method for preventing or treating a disease in a subject, comprising the steps of: administering to the subject an effective amount of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of the disease; and administering to the subject an effective amount of a non-pathogenic antigen component that is neither derived from nor cross-reactive with a pathogenic agent of the disease. In this method, any of the embodiments described in the above-mentioned < prevention and treatment of diseases based on a combination of a pathogenic antigen component and a non-pathogenic antigen component > or elsewhere may be used.
In another aspect, the present invention provides a method for preventing or treating a disease in a subject, comprising the steps of: testing for the presence of a pathogenic antigen component in the subject, said pathogenic antigen component being derived from and/or cross-reactive with a pathogenic agent of the disease; and administering to the subject an effective amount of a non-pathogenic antigen component that is neither derived from nor cross-reactive with the pathogenic agent of the disease in the event that an effective amount of the pathogenic antigen component is present in the subject as a result of the test, and administering to the subject an effective amount of the pathogenic antigen component and an effective amount of a non-pathogenic antigen component that is neither derived from nor cross-reactive with the pathogenic agent of the disease in the event that an effective amount of the pathogenic antigen component is not present in the subject. In this method, any of the embodiments described in the above-mentioned < prevention and treatment of diseases based on a combination of a pathogenic antigen component and a non-pathogenic antigen component > or elsewhere may be used.
< prevention and treatment of diseases based on the immune memory mechanism >
The present invention generally provides compositions or therapeutic or prophylactic methods using the same for preventing or treating diseases (e.g., infections, allergies, and autoimmune diseases) in a subject based on an immune memory mechanism. While not wishing to be bound by theory, the present invention provides compositions, medicaments, kits, or the like that achieve these based on the principle of controlling an immune response against a target disease by combining a pathogenic antigen component (which is derived from and/or cross-reacts with a pathogenic agent of the target disease) with a non-pathogenic antigen component of a subject having immune memory.
In one embodiment, a composition, medicament, kit or the like of the invention comprising a non-pathogenic antigen component is characterized in that the non-pathogenic antigen component is administered under conditions of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject. That is, the compositions, medicaments, kits, etc. of the present invention may be administered alone with non-pathogenic antigen components to subjects already having a pathogenic agent of a target disease (e.g., an infection, allergy, or autoimmune disease). On the other hand, for subjects without a causative agent of a target disease (e.g., an infection, allergy, or autoimmune disease), the compositions, medicaments, kits, or the like of the present invention may be administered in combination with a non-causative agent antigen component of the target disease.
In one embodiment, the causative agent of the target disease in the subject comprises a foreign body to the subject. In a more specific embodiment, the pathogenic agent includes an immune-abnormal pathogenic agent such as an infectious agent, an allergic reaction, an autoimmune disease, or a poison.
In one embodiment, the compositions, medicaments, kits, etc. of the present invention prevent or treat the above-described diseases in a form that does not accompany or reduce an immune overreaction in a subject. While not wishing to be bound by theory, it is believed that the compositions, medicaments, kits, etc. of the present invention, in addition to activating an immune response against a target disease in a subject, enhance the production of IL-10 that acts to suppress the immune response, and thus do not cause hyperimmunization in the subject.
In one embodiment, the compositions, medicaments, kits, or the like of the invention are administered in a form effective to control (including up-or down-regulate, etc.) cellular immunity against a disease (e.g., an infection, allergy, or autoimmune disease) in a subject.
In one embodiment, the composition, medicament or kit of the present invention is used in the treatment of an infectious disease, an allergic reaction or an autoimmune disease. In a specific embodiment, the disease is a viral infection, a bacterial infection (e.g., bacterial conjunctivitis), or a parasitic infection (e.g., acanthamoeba keratitis). In a more specific embodiment, the disease is a viral infection. In a more specific embodiment, the disease is an infection associated with a coronavirus.
In yet another embodiment, the invention provides a composition for activating (or deactivating, switching or inhibiting the transformation of) regulatory T cells (tregs) against a target, wherein said regulatory T cells (tregs) inhibit the activity of a pathogenic agent against or against cells infected with or comprising the infectious agent, allergy and/or autoimmune disease in the subject, said composition comprising a non-pathogenic antigen component that neither originates from nor cross-reacts with the infectious, allergy and/or autoimmune disease that is the target, said subject having an immunological memory against the antigen component. Alternatively, the invention provides a method for activating (or releasing, switching or transforming inhibiting) regulatory T cells (tregs) against a target, comprising the steps of: administering to the subject an effective amount of a non-pathogenic antigen component to which the regulatory T cells (tregs) have an immune memory in the presence of a pathogenic agent of the target infection.
In this embodiment, the Treg is preferably transformed into effector T cells (Teff) derived from and/or cross-reactive with a causative agent of a target disease by allowing a causative agent antigen component to be present in the subject, the effector T cells (Teff) being directed against or comprising a causative agent of the disease (an infectious disease, an allergic reaction or an autoimmune disease). In a further preferred embodiment, the subject has an immunological memory for the aforementioned pathogenic agent and/or a factor that cross-reacts with the pathogenic agent.
In the present invention, it was found that the contained component (non-pathogenic component) exerts an excellent anti-pathogenic immune effect in the presence of a target (pathogenic factor) unlike the non-specific immune effect, and that this effect is confirmed also among other components, whereby the non-pathogenic antigen component having specificity to a subject (or having immunological memory of a subject) can be widely used for treatment or prevention of a target (for example, an infectious disease, an allergic reaction, or an autoimmune disease). For example, it was demonstrated that in BCG-infected cells used as a model (i.e., cells that can be evaluated as having immunological memory to a tubercle bacillus component as an antigen), a hot water extract of human tubercle bacillus containing the antigen shows a prophylactic effect and a therapeutic effect against the onset of a disease other than tuberculosis (for example, an infectious disease, an allergic reaction or an autoimmune disease) in the presence of a causative agent of the disease. In addition, new findings: the therapeutic and/or prophylactic effects of a specific component (e.g., a hot water extract of human tubercle bacillus in the case of BCG) in a subject having immunological memory against the specific component such as BCG-infected cells are also important, and the antigen responsiveness of the specific component (e.g., a hot water extract of tubercle bacillus) is also important, as a mechanism thereof, to evoke an antigen response based on immunological memory (which is an immunological memory generated by a vaccine (antigen) or the like inoculated in the past), and the antigen response based on antigens other than the target promotes the immunization against the target. In addition, while not wishing to be bound by theory, it can be said that tregs can be transformed into effector T cells (Teff) derived from and/or cross-reactive with the causative agent of the target disease by the presence in the subject of a causative agent antigen component that is directed against or comprises the causative agent of the disease (an infectious disease, an allergic reaction or an autoimmune disease).
In one embodiment, the invention provides a composition for activating regulatory T cells (tregs), wherein the regulatory T cells (tregs) inhibit the activity of a causative agent of the infection or of a cell infected with the causative agent of the infection, the composition comprising an antigen component other than the causative agent of the target infection, the subject having an immune memory against the antigen component. Alternatively, the invention provides a method for activating suppressed regulatory T cells (tregs) in the subject, comprising administering to the subject an effective amount of a non-pathogenic antigen component to which the regulatory T cells (tregs) have an immune memory. In the present invention, activation of tregs can provide an infectious cell with killing ability or an immune activation effect on a causative agent of infectious diseases. In particular, it is preferred that such tregs are transformed into effector T cells (Teff) against a disease (an infectious disease, an allergic reaction or an autoimmune disease) or cells comprising a causative agent of the infectious disease (e.g., in the case that the causative agent is an infectious disease, cells infected with the causative agent of the infectious disease) by allowing the antigen component of the causative agent (which is derived from and/or cross-reacts with the causative agent) to be present in the subject.
In one embodiment, the tregs are positive for memory T cells, and/or CD 4. While not wishing to be bound by theory, the reason for this is that: there was also found to be a relationship with immune memory and activity via CD4 positive cells.
In another embodiment, the antigen component comprises a protein, a portion thereof, or a peptide.
In one embodiment, the non-pathogenic antigen component comprises an antigen selected from the group consisting of a pathogen or a portion thereof that is an infectious disease of a non-subject, an antigen associated with a prior medical history, and an antigen associated with a vaccination history. In one embodiment, the non-pathogenic antigenic component comprises a hot water extract of tubercle bacillus.
It is to be understood that, in the technique of the present invention, various embodiments of the same constituent elements described in the present specification can be employed as the constituent elements, and combinations thereof are also within the scope of the present invention.
In one aspect, the invention provides a method of making or otherwise providing a composition for preventing or treating an infectious disease, allergy or autoimmune disease in a subject, comprising the steps of: step a) identifying an antigenic component specific to the subject, said antigenic component being neither derived from nor cross-reactive with a causative agent of the infection, allergy or autoimmune disease; step B), determining whether the antigen component has an immunological memory in the subject, and selecting the antigen component having the immunological memory; and step C) of manufacturing or otherwise providing the selected antigen component.
As described above, the present invention prevents or treats a disease by specifying responsiveness of a subject to a component effective as a vaccine for the disease, based on past physical states of the subject, and administering the component responsive to the physical states to the subject.
Accordingly, in another aspect, the present invention provides a method for preventing or treating the disease, comprising the steps of: step a) obtaining a past physical state of the subject; step b) specifying the responsiveness of the subject to a component effective as a vaccine for the subject disease based on the physical state; and step c) administering to the subject the component that exhibits responsiveness to the physical state.
In one embodiment, the active ingredient such as the non-pathogenic antigen component in the present invention is preferably a component specific to the memory T cells of the subject. Specific for memory T cells means that the subject has immunological memory for a particular antigen.
In one embodiment, specific examples of the agent for treating infectious diseases found in the present invention include those in which a hot water extract of tubercle bacillus in the presence of a causative agent of the infectious disease is found to exert an anti-infectious effect in the present invention, and this is a concern. Although there has been a nonspecific immunotherapy and an immune activation action as a main action mechanism in the hot water extract of human tubercle bacillus, the present inventors have conducted intensive studies, and as a result, have found that, unlike a nonspecific immunization action in the presence of a causative agent of an infectious disease, a component contained therein exerts an anti-infectious immune action similar to or superior to an antigen causative of an infectious disease, and that this action is confirmed in other components, whereby a non-causative antigen component specific to a subject (or having an immunological memory in a subject) can be widely used for the treatment or prevention of an infectious disease. For example, it was demonstrated that, in BCG-infected cells used as a model (i.e., cells that can be evaluated as having an immunological memory for a tubercle bacillus component as a non-pathogenic antigen), a hot water extract of human tubercle bacillus containing the non-pathogenic antigen shows a prophylactic effect and a therapeutic effect for the onset of an infectious disease in the presence of a pathogenic agent of the infectious disease. In addition, new findings: the therapeutic and/or prophylactic effects of a specific component (in the case of BCG, a hot water extract of human tubercle bacillus) in a subject having an immunological memory against the specific component such as BCG-infected cells are also important, and the antigen responsiveness of the specific component (for example, a hot water extract of tubercle bacillus) is also important, as a mechanism thereof, to evoke an antigen response based on an immunological memory, which is an immunological memory generated by a vaccine (antigen) or the like inoculated in the past, and the antigen response based on the antigen of the non-pathogenic factor promotes an anti-infectious immunity.
In one embodiment, the memory T cells of the present invention that are targets for immunological memory are memory-related regulatory T cells, for example, IL-2 production can be observed as an indicator. Examples of the index include IFN-. Gamma.production, TNF-. Alpha.production, and combinations of 2 or 3 of these, in addition to IL-2 production. That is, when it is determined that there is an immunological memory, the subject antigen is added to a test system including T cells, and thereafter, in addition to the increase in IL-2 production, the increase in IFN- γ production, TNF- α production, or a combination of 2 or 3 thereof is observed, whereby it can be determined that there is an immunological memory for the antigen.
In one embodiment, specific components such as the non-pathogenic antigenic components of the present invention have an immunopotentiating effect (e.g., adjuvant activity). Immune activation can be confirmed by any method known in the art. For example, the effect on a natural immune receptor, the evaluation of the ability to induce the production of a specific antibody, and the like can be used.
In one embodiment, the specific component such as the non-pathogenic antigen component of the present invention is a component that acts on memory CD4 positive T cells in an antigen-dependent manner. Whether or not an antigen-dependently acts on memory CD 4-positive T cells can be confirmed by any method known in the art. For example, flow cytometry analysis using MHC II tetramers and specific antigen peptides, or analysis of IFN-gamma producing cells after stimulation with specific antigen can be used.
In one embodiment, specific components such as the non-pathogenic antigenic components of the present invention have activity that biases the ratio of Foxp3 positive Treg cells to IFN- γ producing T cells present. The bias in the presence ratio of Foxp 3-positive Treg cells and IFN- γ -producing T cells can be confirmed by any technique (e.g., FACS) for analyzing the cells, and typically, for example, a method of measuring the presence ratio by FACS after intracellular cytokine staining and transcription factor staining can be used. As a criterion in this case, for example, the presence ratio of Foxp 3-positive Treg cells to IFN- γ -producing T cells is biased to increase IFN- γ -producing T cells as compared to Foxp 3-positive Treg cells, but the present invention is not limited thereto. IFN-gamma producing T cells may comprise type 1 helper T cells. Alternatively, in another embodiment, specific components such as the non-pathogenic antigenic components of the present invention have activity that biases the ratio of Foxp3 positive Treg cells to type 1 helper T cells present.
While not wishing to be bound by theory, as an important aspect of biasing the presence ratio of Foxp3 positive Treg cells and IFN- γ producing T cells, the present inventors have found that, as their mechanism of action, the mechanism of action can be considered: specific components (components for controlling immune memory) such as hot water extract of human tubercle bacillus act on memory CD4 positive T cells in an antigen-dependent manner, and the existence ratio of IFN-gamma producing T cells such as Foxp3 positive Treg cells and type 1 helper T cells (Th 1 cells) is biased, so that the cells are changed into immunity against infectious diseases. That is, the present invention can be expected to express more strongly an infectious antigen-dependent anti-infectious immunity in a living body by activating T cells in dormancy and changing the balance between inhibitory T cells and the anti-infectious immunity by a non-pathogenic antigen component contained in a main agent or the like. In one embodiment, the antigenic component of the invention comprises an antigenic component capable of controlling an immune response mediated by CD4 positive T cells. In one embodiment, the invention is characterized in that: confirming whether the subject is capable of controlling an anti-infective immune response mediated by CD4 positive T cells, and administering the composition in a condition in which the subject is capable of controlling an anti-infective immune response mediated by CD4 positive T cells. In yet another embodiment, the immune response described above is an immune response that is not mediated by CD8 positive T cells.
In one embodiment, IFN-gamma producing T cells targeted in the present invention may comprise type 1 helper T cells. While not wishing to be bound by theory, the reason for this is that: the anti-infective effect can be enhanced by acting on memory CD4 positive T cells in an antigen-dependent manner to change them into an anti-infective immune state such as type 1 helper T cells (Th 1 cells) and increasing IFN- γ producing T cells in a subject having an infectious disease.
In another embodiment, the IFN-. Gamma.producing T cells of the invention are T-bet positive Th1 cells. While not wishing to be bound by theory, the reason for this is that: gamma interferon is known to induce the expression of T-bet (which is a transcription factor specifying Th1 cells) in host defenses, and to maintain the production of gamma interferon by feedforward control. In the identification of Th1 cell-derived interferons, new actions exerted by T-bet have also been studied, and gamma interferon in the absence of T-bet causes an abnormal type I interferon response. T-bet preferentially inhibits the gene and pathway activated by the autocrine of type I interferon, inhibiting abnormal amplification of the type I interferon signaling system. Thus, it can be said that T-bet not only actively induces differentiation into Th1 cells, but also plays a role in inhibiting abnormal autocrine of type I interferon in Th1 cells and a downstream signal transmission system thereof (see Harms Pratcboard, G., hall, A.O., christian, D.A.et al.: diverse roles for T-bet in the effector responses required for resistance to in. J.immunol.,194,1131-1140 (2015), etc.).
In one embodiment, the specific (or the subject having immunological memory) non-pathogenic antigen component in the present invention preferably has an ability to potentiate at least one selected from the group consisting of IFN-gamma producing ability and IL-2 producing ability and TNF-alpha producing ability in a sample derived from the above-mentioned subject. While not wishing to be bound by theory, the reason for this is that: IFN-gamma producing ability and IL-2 producing ability and TNF-alpha producing ability are advantageous in anti-infective effects.
BCG infection models usable in the present specification are infection models similar to vaccination history or past medical history, and therefore, as facts that can be deduced based on the data confirmed by this, it is considered that: memory T cells established and dormant by past vaccination are reactivated by stimulation with specific antigens that promote an anti-infective immune response in the presence of disease causative agent antigens. Moreover, this hypothesis can be confirmed by experiments performed in other immunological memory models. It is thus understood that the treatment of diseases based on the immunological memory model of the present invention is not limited to the examples, but can be applied to any diseases. In addition, even at the clinical test level, the same effect was observed.
Further, although not wishing to be bound by theory, as the mechanism of action of the present invention, it is considered that: in addition to the importance of bias in the ratio of Th1 cells to Foxp3 positive Treg cells and production of IFN- γ in animal models, the initial response of the specific components of the present invention in cells derived from peripheral blood (of humans, etc.) is based on memory regulatory T cells (IL-2 production) of vaccination history or past history, the specific components of the present invention control IFN- γ production, the ratio of Foxp3 positive regulatory T cells (Treg) to T-bet positive Th1 cells is changed through experiments over the course of the day, or IFN- γ production derived from T-bet positive Th1 cells is induced, which also plays an important role as a functional mechanism. The findings concerning IFN-. Gamma.production, IL-2 production and TNF-. Alpha.production derived from memory-type regulatory T cells based on the immunological memory of a subject with a history of vaccination or a past history or the like are obtained as a result of intensive studies by the present inventors, which have not been known heretofore. Thus, it can be said that IFN-gamma production, IL-2 production and TNF-alpha production using cells derived from peripheral blood of a human or the like can be confirmed by the present invention as biomarkers for selecting responders. In addition, it is worth mentioning that tregs can be transformed into effector T cells (Teff) derived from and/or cross-reactive with the causative agent of the target disease by the presence in the subject of a causative agent antigen component directed against or comprising cells of the causative agent of the disease (infectious disease, allergic reaction or autoimmune disease).
That is, it was revealed that IFN-. Gamma.production ability, IL-2 production ability and TNF-. Alpha.production ability of the main agent could be confirmed in advance by using human peripheral blood-derived cells for each subject, and that the possibility of diagnosis was revealed as a concomitant type. In addition, the present biomarker is not responsive to a disease-causing antigen, and therefore can be used for healthy subjects who do not have the disease-causing antigen, and thus can be treated prophylactically.
As described above, it can be said that a new knowledge based on scientific basis was obtained for the anti-infectious immune action against the confirmed safe hot water extract of human tubercle bacillus, and the invention of a novel anti-infectious immunotherapy and prevention method by which an appropriate subject can be selected for treatment was completed. Furthermore, the mechanism is not only applicable to tubercle bacillus, but also expected to improve the anti-infective effect even in the corresponding antigen treatment based on the history of infection and the past history of vaccine against other infections, and to provide the best treatment for individual persons.
< vaccine adjuvant >
In another aspect, the invention provides an adjuvant or adjuvant composition comprising a hot water extract of tubercle bacillus or a part thereof, a vaccine against an infectious disease, or a use of an adjuvant or a method of treatment or prophylaxis with an adjuvant.
In another aspect, the invention provides an adjuvant or adjuvant composition comprising a STING agonist, a vaccine against an infectious disease, or a use of an adjuvant or a method of treatment or prophylaxis with an adjuvant.
In another aspect, the invention provides an adjuvant or adjuvant composition comprising a STING agonist for a vaccine against a viral infection, or a use of the adjuvant or a method of treatment or prophylaxis with the adjuvant.
In one embodiment, the hot water extract of tubercle bacillus or a part thereof is a hot water extract of the strain B of human tubercle bacillus, and in a preferred embodiment, the hot water extract of tubercle bacillus or a part thereof is extract a.
In one embodiment, the hot water extract of tubercle bacillus or a portion thereof comprises a STING agonist derived from tubercle bacillus, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb related antigen, a component capable of biosynthesis of STING agonists in human cells, or NOD2 agonist, etc., the hot water extract of tubercle bacillus or a portion thereof comprises a STING agonist derived from tubercle bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing said STING agonist in human cytoplasm mediated by cGAS.
In one embodiment, the causative agent of the infection is a bacterium, a virus, or a protozoan, and the causative agent of the infection is preferably a virus. In a preferred embodiment, the causative agent of the infection is a virus belonging to the family coronaviridae, the causative agent of the infection is a virus belonging to the family selected from the group consisting of rhinoviruses, adenoviruses, coronaviruses, RS viruses, influenza viruses, parainfluenza viruses and enteroviruses, in a particular embodiment the causative agent of the infection is a virus belonging to the genus coronavirus b, in a particular embodiment the causative agent of the infection is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2, in a particular embodiment the causative agent of the infection is SARS-CoV-2 virus. In one aspect of an embodiment of the invention, the invention may enhance immunity and suppress excessive reactions (improve, maintain self-defense functions inherent to organisms).
(concomitant diagnosis and treatment)
In another aspect, the invention provides a treatment based on concomitant diagnosis involving infection, allergy, autoimmune disease. In this aspect, the invention provides a composition for preventing or treating the infection, allergy and/or autoimmune disease comprising a non-pathogenic antigenic component derived from or cross-reactive with a pathogenic agent of the infection, allergy and/or autoimmune disease in a subject, the composition having the following characteristics: 1) Confirming that the subject has an immune response against the non-pathogenic agent; 2) In the event that the subject has the immune response, the composition is administered to the subject.
In another aspect, the present invention provides a method for preventing or treating an infection, allergy and/or autoimmune disease in a subject, comprising the steps of: confirming that the subject has an immune response against the non-pathogenic agent; and administering to a subject in need thereof an effective amount of a non-pathogenic antigen component that is neither derived from nor cross-reactive with a pathogenic agent of an infectious, allergic, and/or autoimmune disease in the subject, in the event that the subject has the immune response.
In another aspect, the present invention also provides a non-pathogenic antigenic component for use in the prevention or treatment of an infectious, allergic and/or autoimmune disease, which component is neither derived from nor cross-reactive with a pathogenic agent of an infectious, allergic and/or autoimmune disease in a subject, the component having the following characteristics: 1) Confirming that the subject has an immune response against the non-pathogenic agent; 2) In the event that the subject has the immune response, the composition is administered to the subject.
In another aspect, the present invention provides a use for the manufacture of a medicament for the prevention or treatment of an infection, allergy and/or autoimmune disease, wherein the medicament comprises a non-pathogenic antigen component which is neither derived from nor cross-reactive with a pathogenic agent of an infection, allergy and/or autoimmune disease in a subject, the medicament having the following characteristics: 1) Confirming that the subject has an immune response against the non-pathogenic agent; 2) In the event that the subject has the immune response, the composition is administered to the subject.
In one embodiment, the infection, allergy and/or autoimmune disease is an infection. While not wishing to be bound by theory, for infections, it has been confirmed that the compositions of the present invention pass: 1) Confirming that the subject has an immune response against the non-pathogenic agent; 2) In the case of the subject having such an immune response, the composition is administered to the subject, thereby utilizing the immunological memory to convert the natural immunity to an acquired immunity, advantageously producing a vaccine effect, providing a previously unexpected use. The subject has an immunological memory of the non-pathogenic antigenic components, thereby finding: by further exposing non-pathogenic antigen components (e.g., components derived from tuberculosis) to a subject, humoral immunity against pathogenic antigen components (infectious agents other than tuberculosis, etc.) can be controlled, thereby achieving prevention or cure of a disease in the subject.
In one embodiment, the present invention provides a composition, method, use or non-pathogenic antigen component for preventing or treating an infection of non-tuberculosis in a subject, the composition or non-pathogenic antigen component comprising a hot water extract of bacillus tuberculosis or a portion thereof, the composition or non-pathogenic antigen component having the following characteristics: 1) Confirming that the subject has an immune response against mycobacterium tuberculosis; 2) In the event that the subject has the immune response, the composition is administered to the subject.
In one embodiment, the hot water extract of tubercle bacillus or a part thereof is a hot water extract of the strain B of human tubercle bacillus, and in a preferred embodiment, the hot water extract of tubercle bacillus or a part thereof is extract a.
In one embodiment, the compositions or ingredients of the invention are administered in an amount effective to produce IL-10.
In another embodiment, the infection in the present invention is a viral infection, and in a specific embodiment, the infection is a coronavirus-related viral infection.
In one embodiment, the immune response may be confirmed subjectively or objectively, preferably objectively. In particular embodiments, objective confirmation of an immune response may be performed by a tuberculin response test or a test based on a gamma interferon release test, or objective information contained in a health manual or its equivalent, medical records, or other medical information. The immune response is preferably checked by tuberculin response check or gamma interferon release test.
In one embodiment, the non-pathogenic antigen component or the hot water extract of tubercule bacillus or a portion thereof is administered to the subject in advance in the event that the subject does not have an immune response, and then the composition or the non-pathogenic antigen component or the hot water extract of tubercule bacillus or a portion thereof is administered to the subject in the event that the subject is confirmed to have the immune response. Thus, even in a subject having no immunological memory or no immunological memory, an immune response can be generated, and the therapeutic or prophylactic effect expected in the present invention can be achieved. The administration may be repeated as necessary until the subject has the above-described immune response.
In one embodiment, the prior administration is administration before or after the onset of the infection described above.
In another embodiment, the prior administration is after the onset of the infection described above.
In one embodiment, administration is performed in the presence of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent.
< manufacturing method, other forms of providing method >
In another aspect, the invention provides a method of making or otherwise providing a composition for preventing or treating a disease or disorder in a subject. The method comprises the following steps: step a) of specifying an antigen component specific to the subject that is different from a causative agent of the infection; step B), determining whether the antigen component has an immunological memory in the subject, and selecting the antigen component having the immunological memory; and step C) of manufacturing or otherwise providing the selected antigen component. As used in this specification, "or otherwise provided" refers to any method of providing other than newly manufacturing an object, for example, a method that can be separated, purified, or obtained from an appropriate supply source of the object, or the like. In step C), the non-pathogenic antigen may be newly produced, or may be provided by separation from other sources, or the like.
< methods of treatment and prevention, concomitant diagnosis and treatment, and drugs >
In one aspect, the present invention provides a method for preventing or treating diseases such as infection, allergy or autoimmune disease, comprising the steps of: step a) obtaining an antigen responsiveness profile of the subject; step b) is a step of specifying an antigen component or a combination of antigen components according to the antigen responsiveness profile, wherein the antigen component or the combination of antigen components is specified based on whether the subject is present with an immune responsiveness or has been present with an immune responsiveness in the past; and step c) administering the antigen component or combination of antigen components identified in step b) to the subject in an amount sufficient to control an immune response in the subject.
In a particular embodiment, the acquisition of the antigen responsiveness profile in the present invention may also be confirmed by a method comprising the steps of confirming a past physical state of the subject; confirming whether 1 or more antigen candidates are responsive in a sample derived from the subject; or both. For example, in the case of confirming the immune response against tubercle bacillus, the immune response can be confirmed by examination such as tuberculin response examination and gamma interferon release test, based on objective index.
In another embodiment, the acquisition of an antigen-responsive profile in the present invention, i.e., the acquisition of an antigen-responsive profile as described above, comprises specifying an antigen component or combination of antigen components that controls an immune response mediated by CD4 positive T cells.
In particular embodiments, the past physical states available include a past medical history and a vaccination history. The past medical history or vaccination history may be obtained, for example, by referring to a mother-child health manual or its equivalent or medical record, other medical information (including information recorded electronically by the subject stored in the cloud, an electronic chip, or the like), and the like. A mother-child health manual (MCH Handbook) is a manual (book) maintained by a family that contains the necessary information for promoting and maintaining the health of the mother and child (2009 International Committee on MCH Handbook:ICMCHH).
In particular embodiments, the physical state available comprises a history of an infection, and the non-pathogenic antigen available comprises an antigen against the infection. The types of infections that can be used may be any type of infections, and examples thereof include: tuberculosis, malaria, yellow fever virus, smallpox virus, seed pox, measles/rubella, polio, MUMPS (adofosis)/MUMPS, rotavirus infection, varicella (chicken pox), yellow fever, ebola virus (Ebola), west nile fever, haemophilus influenzae type b infection, pneumococcal infection, pertussis, japanese encephalitis, meningococcal infection, salmonella infection, pathogenic escherichia coli, toxoplasmosis, zika virus (Zika virus), herpes virus type 1, EBV/epstein-barr virus (herpes virus type 4), CMV/cytomegalovirus (herpes virus type 5), influenza, MARS, rabies, diphtheria, and the like.
The disease such as an infectious disease, an allergic reaction, or an autoimmune disease derived from a non-pathogenic agent used in the present invention may be any of the diseases described in the present specification. Therefore, in the context of the physical state described in the present specification, when the physical state is described as "history of BCG vaccination", "history of tuberculosis infection", or "antigen responsiveness to tubercle bacillus", the physical state may be replaced with any of the infections described in the present specification.
In a preferred embodiment, the disease such as an infection, allergy or autoimmune disease that is used as a non-pathogenic agent is tuberculosis. In this case, the physical state comprises a history of BCG vaccination, a history of tuberculosis infection or an antigen responsiveness against tubercule bacillus. In a preferred embodiment, in the case where the infection is tuberculosis, it can be said that it is advantageous to include a hot water extract of human type tubercle bacillus as a non-pathogenic factor antigen component. The invention can be used for therapy and also for prophylaxis.
The non-pathogenic antigens of the present invention may be provided in the form of a pharmaceutical composition. In particular embodiments, a pharmaceutical composition, medicament, kit, or the like may comprise 1 or more compounds and at least 1 pharmaceutically acceptable carrier, where the 1 or more compounds are convertible in a subject to at least 1 compound (i.e., prodrug) such as extract a (reference example). In particular embodiments, a pharmaceutical composition, medicament, kit, or the like may comprise 1 or more compounds and at least 1 pharmaceutically acceptable carrier, where the 1 or more compounds are convertible into at least 1 (non-infectious) antigen component (i.e., prodrug) in a subject. In the case of containing a plurality of agents, they may be contained in a single composition (mixture) or may be contained in different compositions. In the case of preparing a preparation in the form of a single composition, a preparation in a form known in the art including the modes exemplified in the present specification can be used as the preparation.
The term "carrier" as used in this specification refers to a pharmaceutically acceptable substance, composition or excipient, such as a liquid or solid extender, diluent, additive, solvent or encapsulating agent, or the like, in relation to, for example, the transport or delivery of a subject pharmaceutical compound from one organ or portion of the body to another organ or portion of the body, or making it possible. By "pharmaceutically acceptable" is meant having compatibility with other materials in the formulation and being not harmful to the patient. Non-limiting examples of pharmaceutically acceptable carriers, carriers and/or diluents include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate, and derivatives thereof; excipients such as powdered tragacanth, malt, gelatin, talc, cocoa butter and suppository waxes (suppositoriy wax); oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; diols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; buffers such as agar, magnesium hydroxide, and aluminum hydroxide; alginic acid; water without heating substances; isotonic physiological saline; ringer's solution; ethanol; phosphate buffer; and other non-toxic compatible substances used in pharmaceutical formulations. The composition may contain a wetting agent, an emulsifying agent, a lubricant such as sodium lauryl sulfate, magnesium stearate and a polyethylene oxide-polypropylene oxide copolymer, and may contain a coloring agent, a releasing agent, a coating agent, a sweetener, a flavoring agent, a perfume, a preservative and an antioxidant.
In the present specification, "parenteral administration" means an administration form not intended to be any route of oral administration, and any form and level of administration effective for the treatment or prevention of a target disease such as an infectious disease treatment or prevention can be used, and examples of the means for parenteral administration include administration by percutaneous absorption or transmucosal absorption, including injection or infusion, and a combination of both. For example, as administration based on percutaneous absorption or transmucosal absorption, a percutaneous absorption preparation such as a coating agent, an adhesive agent, a spray, or the like is brought into contact with skin or mucosa, and a drug in the preparation is transferred into the body through the skin or mucosa, thereby exerting an effect. Examples of administration by injection or infusion include intravenous, intradermal, subcutaneous, intramuscular, enteral (enema) administration, bolus (bolus) administration and/or continuous infusion. They may also be used as suspensions, solutions, emulsions, implants in oily or aqueous media containing other formulation substances such as suspending, stabilizing and/or dispersing agents. As intradermal administration, a less invasive administration form can be produced in combination with a device such as a microneedle. As for enteral (enema) administration, a tube and a portable infusion pump can be used for continuous delivery to the proximal small intestine by a percutaneous endoscopic gastrostomy. It may further be preferred to administer subcutaneously or intradermally or intramuscularly. Parenteral administration (e.g., transdermal administration) may also be performed by tape/patch or powder, spray, ointment, paste, cream (stream), lotion, gel, solution, and the like. Compositions, medicaments or kits suitable for parenteral administration may comprise at least 1 sterile isotonic aqueous or non-aqueous solution, dispersion, suspension, emulsion (emulgent), implant, or sterile powder which may be reconstituted into a sterile injectable solution or dispersion immediately prior to use as a pharmaceutical.
Compositions, medicaments or kits and the like disclosed in this specification suitable for oral administration may be in the form of capsules, cachets, pills, tablets, diamond shaped tablets (typically using a flavored base which is sucrose and acacia or tragacanth), powders, granules, aqueous or non-aqueous liquid solutions, aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, water-in-oil emulsions, elixirs, syrups, lozenges (using inactive bases such as gelatin, glycerol, sucrose and/or acacia) and/or mouthwashes (mouthwash), each containing a specified amount of at least 1 compound of the present invention.
The compositions, medicaments, kits, etc. disclosed in the present specification may be administered in the form of pellets (bolus), dragees (electuary), or pastes.
The pathogenic and nonpathogenic antigens of the present invention may be administered in any administration form, and may be administered orally or parenterally, and any administration form may be used as long as the effect is exhibited. Preferably non-oral administration.
In the case of administering the pathogenic antigen and the non-pathogenic antigen of the present invention as a drug, various Delivery systems are known, and the therapeutic agent of the present invention can also be administered to an appropriate site using such systems, for example, film coatings in liposomes, lipid particles, microparticles, and microcapsules; in the case where the therapeutic agent is a polypeptide, using recombinant cells capable of expressing it, receptor-mediated endocytosis is used; construction of a therapeutic nucleic acid that is part of a retroviral vector or other vector, and the like. The method of introduction is not limited and includes intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural and oral routes. The medicament can also be administered by any suitable route, for example by injection, by bolus injection, by absorption through epithelial or skin mucosal substrates (e.g. oral, rectal and intestinal mucosa, etc.), by nebulizing agents and using inhalers or nebulizers, as required, and can also be administered together with other biologically active agents. Administration may be systemic or local. Further, in the case where a lesion is present, the administration may be performed by any suitable route such as direct injection into the lesion.
Solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.) can be mixed with any of the following: more than 1 pharmaceutically acceptable carrier such as sodium citrate or dicalcium phosphate, and/or starches, lactose, sucrose, glucose, mannitol, and/or fillers or extenders such as silicic acid; binding agents such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and/or acacia; humectants such as glycerin; disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, specific silicate, sodium carbonate, sodium starch glycolate, etc.; dissolution retarders such as paraffin; absorption accelerators such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glyceryl monostearate, and polyethylene oxide-polypropylene oxide copolymers; absorbents such as kaolin and bentonite (bentonite clay); lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; a colorant. In the case of capsules, tablets and pills, pharmaceutical compositions, medicaments or kits and the like may also comprise buffers. The same type of solid composition, drug, kit, etc. can also be used with lactose or lactose, as well as additives such as high molecular weight polyethylene glycols and the like as fillers in soft and hard filled gelatin capsules.
Liquid dosage forms for oral administration may comprise pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid administration form may contain inert diluents used in the prior art, such as water or other solvents, solubilizing agents and emulsifiers, and examples thereof include ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, and mixtures thereof. Furthermore, a cyclodextrin such as hydroxypropyl- β -cyclodextrin can be used to dissolve the compound.
The ingredients of the present invention may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, coloring agents, flavoring agents, preserving agents, and the like. The suspension may contain a suspending agent in addition to 1 or more compounds according to the present invention, and examples thereof include: ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum metahydroxide (aluminum metahydroxide), bentonite, agar-agar, tragacanth, mixtures thereof, and the like.
The compositions, medicaments, kits, etc. disclosed in the present specification may be formulated as suppositories for rectal or vaginal administration, and 1 or more compounds according to the present invention may be mixed with 1 or more suitable non-irritating additives or carriers comprising cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, etc. to prepare suppositories, which are solid at room temperature but liquid at body temperature and thus melt in the rectum or vaginal cavity to release the compounds of the present invention. Pharmaceutical compositions, medicaments or kits suitable for vaginal administration, etc. may also include pessaries (pessary), tampons (tampon), creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
The dosage forms of the compositions of the present invention for topical or transdermal administration may include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The pharmaceutical composition or pharmaceutical tablet may be mixed under sterile conditions with a pharmaceutically acceptable carrier, preservative, buffer or high pressure gas as required.
Ointments, pastes, creams and gels may contain, in addition to the compositions of the invention, additives such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, zinc oxide, or mixtures thereof.
The powder and spray may contain additives such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or a mixture of these substances, in addition to the pharmaceutical composition or pharmaceutical tablet of the present invention. The spray may contain a normal high-pressure gas such as chlorofluorocarbon, and volatile unsubstituted hydrocarbon such as butane and propane.
Ophthalmic preparations, ophthalmic ointments, powders, solutions, etc. are also intended to be within the scope of this invention.
Compositions, medicaments or kits suitable for parenteral administration may comprise at least 1 sterile isotonic aqueous or non-aqueous solution, dispersion, suspension, emulsion acceptable for use as a pharmaceutical, or sterile powder which may be reconstituted into a sterile injectable solution or dispersion immediately prior to use.
Typically, the composition for injection administration is a solution in a sterile isotonic aqueous buffer. If desired, the composition may further comprise a solubilizing agent and a local anesthetic such as lidocaine which can alleviate pain at the site of injection. The components are usually supplied separately or mixed together in unit dosage form, and may be supplied, for example, in a sealed container such as an ampoule or sachet showing the active amount, in the form of a lyophilized powder or a concentrate free of water. Where it is desired to administer the composition by infusion, an infusion bottle containing sterile pharmaceutical grade water or saline may also be used for dispensing. Where it is desired to administer the composition by injection, an ampoule of sterile water for injection or physiological saline may also be provided to enable the ingredients to be mixed prior to administration.
The components of the present invention may also be formulated in neutral or salt form or other prodrug (e.g., ester, etc.) form, as applicable as desired. Pharmaceutically acceptable salts include: salts formed with free carboxyl groups derived from hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, tartaric acid, and the like; salts formed with free amine groups such as amine groups derived from isopropylamine, triethylamine, 2-ethylaminoethanol, histidine, procaine, etc.; and salts derived from sodium, potassium, ammonium, calcium, iron hydroxide, and the like.
The term "salt" as used in this specification includes acid and/or base salts formed from inorganic and/or organic acids and bases. As used in this specification, the term "pharmaceutically acceptable salt" refers to: the salt is suitable for use in contact with the tissue of a subject without undue toxicity, irritation, allergic response, and/or the like, and is well balanced in terms of a reasonable effect/risk ratio, within the scope of the definite medical judgment. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts are described in detail, for example, in Berge et al, J.pharmaceutical Sciences (1977) 66:1-19.
Pharmaceutically acceptable salts may be formed with inorganic or organic acids. Non-limiting examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid. Non-limiting examples of suitable organic acids include acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid. Other non-limiting examples of suitable pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, borate, butyrate, camphoric acid, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodite, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate (pamoic acid salt), pectate, persulfate, 3-phenylpropionate, phosphate, bittering, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate. In some embodiments, the organic acid that can form a salt includes, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.
Salts can be prepared in situ upon isolation and purification of the disclosed compounds, or can be prepared by additionally reacting the compounds with an appropriate base or acid, respectively, and the like. Non-limiting examples of salts derived from bases that are acceptable as pharmaceutical products include alkali metals, alkaline earth metals, ammonium and N+ (C) 1～4 Alkyl) tetrasalts. Non-limiting examples of suitable alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Further, non-limiting examples of suitable pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counter ions such as halide ions, hydroxide ions, carboxylate ions, sulfate ions, phosphate ions, nitrate ions, lower alkyl sulfonate ions, and aryl sulfonate ions, as desired. Non-limiting examples of suitable organic bases from which salts can be formed include basic ion exchange resins such as primary, secondary, tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and isopropyl, trimethyl, diethyl, triethyl, tripropyl, and ethanolamine. In particular embodiments, the base addition salt that is acceptable as a pharmaceutical product may be selected from the group consisting of ammonium, potassium, sodium, calcium, and magnesium salts.
In embodiments of the invention, the subject may be a patient prior to onset of a disease (e.g., an infection, allergy, or autoimmune disease), after treatment of the disease, or at an initial stage of the disease. Alternatively, the subject may be a healthy person. In the case where the healthy subject is a subject, the method is performed as a preventive method.
In the present invention, a step of specifying an antigen or a combination of antigens that are responsive to the subject based on the antigen responsiveness profile is performed. Here, the responsiveness to a subject may be any responsiveness as long as it is a responsiveness related to treatment or prevention of a disease, and in particular, it is sufficient to reveal a responsiveness related to immunological memory, and thus, for example, the responsiveness may include responsiveness to any one of IFN- γ production, IL-2 production, TNF- α production, or responsiveness of any two or three thereof.
In another aspect, the present invention provides concomitant diagnostic agents or diagnostic methods for the prevention or treatment of diseases (e.g., infections, allergies, or autoimmune diseases) and therapeutic or prophylactic methods or agents based thereon.
In a specific embodiment, the confirmation of the responsiveness is characterized in that the syndrome diagnosis is performed in advance based on a past medical history, a vaccination history, and an examination of immune responsiveness to Peripheral Blood Mononuclear Cells (PBMCs) isolated from a subject, and it has been confirmed that such syndrome diagnosis can be performed in the examples of the present specification. It should be understood to those skilled in the art that: based on the examples and other specific descriptions, syndrome diagnosis can be performed in advance similarly in other diseases and disorders.
In the present specification, "concomitant diagnosis is performed in advance based on past medical history, vaccination history, and examination of immune response to Peripheral Blood Mononuclear Cells (PBMCs) isolated from a subject" is preferably confirmed based on objective indicators, and if objectivity can be ensured, confirmation may be performed based on subjective indicators. In the case of confirmation based on the objective index, it can be implemented as follows, for example.
Peripheral Blood Mononuclear Cells (PBMCs) are isolated from human subjects (which may include subjects having developed viral infections, not having developed viral infections (viral antigens are confirmed but asymptomatic or the viral infections have cured), and normal subjects) for which a vaccine effect or treatment based on the present invention is expected.
The immunological memory (immune response) of the subject is objectively confirmed by examination of tuberculosis infection by examination of tuberculin reaction, gamma interferon release test, or the like.
In the case where the above-described examination is not used, it may alternatively be implemented as follows, on the basis of ensuring objectivity.
The antigen response profile is obtained by non-invasive methods, interrogation, past medical history or vaccination history from a mother and child health manual or its equivalent, medical history, or other medical information (information that may be recorded electronically by the subject as stored in the cloud, electronic chip, etc.), etc.
Here, the history of vaccination and infection may include tuberculosis, malaria, yellow fever virus, smallpox virus, seed pox, measles/rubella, polio, MUMPS (adofu disease)/MUMPS, rotavirus infection, varicella (chicken pox), yellow fever, ebola virus (Ebola), west Nile fever, haemophilus influenzae type b infection, pneumococcal infection, pertussis, japanese encephalitis, meningococcal infection, salmonella infection, pathogenic E.coli, toxoplasmosis, zika virus (Zika virus), herpes virus type 1, EBV/Epstein-Barr virus (herpes virus type 4), CMV/cytomegalovirus (herpes virus type 5), influenza (virus), MARS, rabies, diphtheria, etc., but is not limited thereto.
In the case where the syndrome diagnosis is objectively performed in advance based on the past history, the vaccination history, and the examination of the immune response of Peripheral Blood Mononuclear Cells (PBMCs) isolated from the subject, the following can be specifically confirmed.
PBMC isolated from a human subject expected to be treated or vaccine efficacy based on the present invention (e.g., 1.0X10) are treated with extract A (0.01. Mu.g/mL to 1 mg/mL) or an extract comprising extract A (0.01. Mu.g/mL to 1 mg/mL) 4 Cell to 1.0X10 6 Cells) are stimulated for about 6 to 24 hours, followed byCytokine production (e.g., IFN-. Gamma., IL-2, and/or TNF-. Alpha., etc.) is determined by detection methods (e.g., ELISA, qPCR, and/or FACS, etc.) that are conventional in the art. A human subject whose cytokine production after stimulation is equal to or greater than a standard threshold (e.g., 1.1-fold or greater, 1.2-fold or greater, 1.3-fold or greater, 1.4-fold or greater, 1.5-fold or greater, 1.6-fold or greater, 1.7-fold or greater, 1.8-fold or greater, 1.9-fold or greater, 2-fold or greater, 3-fold or greater, 4-fold or greater, 5-fold or greater, 6-fold or greater, 7-fold or greater, 8-fold or greater, 9-fold or greater, or 10-fold or greater, preferably 2-fold or greater) of the cytokine production before stimulation is selected as an inoculation target.
Examples of such concomitant diagnostics and treatments include: identifying whether the subject has an antigen directed against a causative agent of the disease; and determining whether the history of tuberculosis infection can be used as the past physical state and using the hot water extract of human type tubercle bacillus as an antigen component. Although not wishing to be bound by theory, as an example, by judging using the history of tuberculosis infection as a past physical state, it is possible to specify a subject who can use a hot water extract of human type tubercle bacillus to prevent a disease (for example, an infectious disease, an allergic reaction, or an autoimmune disease), and thus prevention of the disease can be achieved. Alternatively, as an example, by judging a tuberculosis infection history as a past physical state, a subject who can use a hot water extract of human tuberculosis bacteria to prevent a disease (for example, an infectious disease, an allergic reaction, or an autoimmune disease) can be specified, and thus treatment of the disease can be achieved. Further, in order to identify whether or not the subject has an antigen against a causative agent of a disease, for example, an antigen test can be confirmed by a method such as an antigen test in the blood of the subject.
The above-mentioned past physical state may be 1 or more selected from tuberculosis, malaria, yellow fever virus, smallpox virus, seed pox, measles/rubella, poliomyelitis, MUMPS (adofosis)/MUMPS, rotavirus infection, varicella (chicken pox), yellow fever, ebola virus (Ebola), west nile fever, haemophilus influenzae type b infection, pneumococcal infection, pertussis, japanese encephalitis, meningococcal infection, salmonella infection, pathogenic escherichia coli, toxoplasmosis, zika virus (Zika virus), herpes virus type 1, EBV/epstein-barr virus (herpes virus type 4), CMV/cytomegalovirus (herpes virus type 5), influenza virus, MARS, rabies, diphtheria.
In one embodiment, the subject of the invention is a patient having a history of BCG vaccination or a history of tuberculosis infection or a healthy person who is able to confirm antigen responsiveness, and the method of the invention is an individualized therapy. Here, the subject may be a person with a history of vaccination, a history of infection, a person with a history of tubercle bacillus infection, or a person with a history of BCG vaccination.
In addition, the extract of tubercle bacillus usable in the present invention is administered prophylactically before onset, prophylactically against recurrence after treatment, or at the beginning of onset of a disease (for example, an infectious disease, an allergic reaction, or an autoimmune disease), and in the beginning of onset of the disease, in addition to the extract produced by the method exemplified in the present specification, the extract derived from tubercle bacillus obtained by the method of improvement thereof is also administered subcutaneously, intradermally, or intramuscularly.
In a particular embodiment, the invention provides a method of preventing or treating a disease (e.g., an infection, allergy, or autoimmune disease) in a subject based on a non-pathogenic agent component. A method is provided based on a non-pathogenic agent, wherein the agent as used herein is an antigen or extract identified by interrogation and/or by reference to the past medical history and vaccination history of the subject who has been identified as having a history of infection or who has a history of vaccination based on the past medical history and vaccination history, is administered prophylactically to the subject after treatment, prior to onset, or at the beginning of the disease onset, and is administered as desired at the beginning of the disease onset. The present invention also provides a non-pathogenic antigen component for use in a method of preventing or treating a disease (e.g., an infection, allergy or autoimmune disease) in a subject, the component being an antigen or extract identified by interrogation and/or identified with reference to the past history and vaccination history of the subject, the subject being a person having a history of infection or a person having a vaccination history as described in the present invention, the component being administered prophylactically to the subject for a relapse after treatment, prophylactically to the subject before onset or at the beginning of an infection onset, and the component being administered at the beginning of an infection onset as desired.
In one aspect, the invention provides a vaccine formulation comprising any of the antigens of the invention and an adjuvant base. In one embodiment, the vaccine formulation is used for personalized medicine. In this individualization treatment, a vaccine can be appropriately provided to each patient or subject based on the concomitant treatment provided in the present invention. In a specific embodiment of the present invention, the disease to be treated according to the present invention may be an infection, an allergy, an autoimmune disease, or the like.
In one embodiment, in the treatment or prevention of the present invention, the identification of the responsiveness of the subject may be performed using any one of a past history of infection, a history of vaccination, and responsiveness to IFN-gamma production, IL-2 production, TNF-alpha production, or any two or three using peripheral blood. The "response to IFN-gamma production, IL-2 production, TNF-alpha production, or any two or three using peripheral blood" may be performed as follows.
Isolating peripheral blood mononuclear cells from the blood of the subject.
Peripheral blood mononuclear cells are cultured in the presence of the substance or a protein transport inhibitor such as PPD (purified protein derivative), a stimulating substance such as tuberculin, tuberculosis antigen, etc., brefeldin (Brefeldin) A, monensin (monensin), etc.
Peripheral blood mononuclear cells were collected after culturing for a predetermined period of time, stained with a cell surface marker and a fluorescent-labeled antibody specific for intracellular cytokines, and analysis of the stained cells was performed using a flow cytometer.
In memory CD 4T cells (CD 3 positive CD4 positive CD45RA negative), the increase of various cytokine-producing cells due to stimulation with extract A or tuberculosis antigen was judged as an index. The extract A will be exemplified and described in detail in example 1 and the like.
In a specific embodiment, the extract of Bacillus tuberculosis used in the present invention is a hot water extract of human type Bacillus tuberculosis or an extract derived from other Bacillus tuberculosis (extract with high safety). Compositions used for tuberculin and the like are also preferable.
In one aspect, the invention provides a vaccine formulation comprising an antigen provided by the invention and an adjuvant-based agent (e.g., a substance that promotes a Th 1-type immune response). In a particular embodiment, the vaccine formulation is used for individualization therapy. In this individualization medicine, a vaccine suitable for each patient or each subject is prepared based on the concomitant medical treatment provided in the present invention. In one embodiment, the medicament or antigen component provided by the invention comprises an adjuvant base and a hot water extract of human tubercle bacillus or an extract (high-safety extract) or an extract component derived from other tubercle bacillus, or an antigen, and can be provided in the form of a vaccine preparation. The method for producing such a vaccine preparation can be produced by mixing the respective material substances at an arbitrary concentration, and the results are illustrated in example 4. In certain embodiments, the vaccine formulation is for use in a method of individualizing medicine.
As adjuvant bases that can be used as vaccine preparations, the following can be mentioned.
Adjuvant base of natural immune receptor-activating forms (e.g. bacterial membrane-derived substances as TLR agonists, DNA, RNA, dinucleotides, NOD1, NOD2 agonists)
Aluminum-containing adjuvant base such as aluminum hydroxide
Adjuvant-based agents that can be formulated into emulsions such as ISA51 and ISA 720.
An adjuvant base comprising cytokines (IL-2, IL-12, IFN- α, GM-CSF). The adjuvant base preferably comprises a substance that promotes a Th1 type immune response (e.g., a nucleic acid-based matrix such as CpG).
In one aspect, the invention provides a composition, medicament or kit for use in the treatment or prophylaxis of a disease, disorder or condition in a subject, wherein the composition, medicament or kit or the like comprises pathogenic and non-pathogenic antigen components of the disease, disorder or condition (the antigen components may be isolated or may be an extract or other form comprising the antigen components) and is administered in appropriate amounts, e.g., 1 day (week 1), and about 1 week (week 2 and beyond), subcutaneously or intradermally or intramuscularly. The invention also provides a method of prophylaxis and a method of treatment associated with the composition. In one embodiment, the antigen component is present in an amount of about 0.001 μg or more per unit of preparation. The amount to be administered, the interval between administrations, and the administration method may also be appropriately selected according to the age, weight, symptoms, organs of the subject, etc. of the patient. In addition, the therapeutic agent preferably contains a therapeutically effective amount, or an effective amount of an active ingredient that exerts a desired effect. The effective amount can be estimated from the amount-response curve obtained from in vitro or animal model test systems.
In a preferred embodiment, the pathogenic agent antigen, as well as the non-pathogenic agent antigen, may be administered multiple times (e.g., any integer value greater than 2 times, greater than 3 times, etc.). With respect to multiple administrations, the frequency may be suitably changed, and may be increased or decreased. In one embodiment, the pathogenic antigen, and the non-pathogenic antigen may be administered 1 day 1, 1 week 3 times, 1 week 2 times, 1 week 1 times, 2 weeks 1 times, 3 weeks 1 times, 4 weeks 1 times, 5 weeks 1 times, 6 weeks 1 times, 7 weeks 1 times, 8 weeks 1 times, 9 weeks 1 times, 1 month 1 times, 2 months 1 times, 3 months 1 times, 4 months 1 times, 5 months 1 times, 6 months 1 times, 7 months 1 times, 8 months 1 times, 9 months 1 times, 10 months 1 times, 11 months 1 times, 1 year 1 times, 2 years 1 times, 3 years 1 times, 4 years 1 times, 5 years 1 times, 6 years 1 times, 7 years 1 times, 8 years 1 times, 9 years 1 times, or 10 years 1 times, or may be administered 1 time over 10 years. The first time is 1 day 1, and the 2 nd time and later can be increased or decreased appropriately, for example, 1 week 1, etc.
By administering the non-pathogenic antigen a plurality of times, the immune response of the subject can be moderately maintained over a long period of time, assuming that a state of high resistance to the disease, disorder or symptom of the subject can be maintained.
In one aspect, the compositions, medicaments or kits of the invention for treating or preventing a disease, disorder or symptom in a subject can also be administered to a subject having no history of BCG vaccination or tuberculosis infection, no confirmed antigen responsiveness. In this case, the non-pathogenic antigen component described in the present specification or the hot water extract of tubercle bacillus or a part thereof is administered to a subject in advance, and then, in the case where it is confirmed that the subject has an immune response, the composition, the drug or the kit of the present invention is administered to the subject, whereby the treatment or prevention of a disease, a disorder or a symptom can be achieved. While not wishing to be bound by theory, it is believed that the reason for this is: by previously administering the non-pathogenic antigen component described in the present specification or the hot water extract of tubercule bacillus or a part thereof to a subject, an immune memory against tuberculosis is formed in the subject, whereby immune responsiveness against tuberculosis is obtained in the same manner as in a subject having a history of BCG vaccination or a history of tuberculosis infection. Therefore, the administration of the non-pathogenic antigen component or the hot water extract of tubercle bacillus or a part thereof described in the present specification to the subject may be performed 1 time or may be repeated a plurality of times until the subject obtains immune responsiveness. In addition, the prior administration may be performed before or after the subject has suffered a disease, disorder, or symptom (e.g., infection). Furthermore, the compositions of the present invention may be administered in the presence of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a disease, disorder or condition (e.g., an infection).
The amount of the composition of the present invention to be administered may vary depending on the nature of the disease, disorder or condition, and may be determined by one skilled in the art based on the description herein and according to standard clinical techniques. In vitro assays may also be used to aid in identifying the optimal dosage range as appropriate. The exact amount of the complex desired to be used may also vary depending on the route of administration and the severity of the disease or disorder, and should be determined according to the judgment of the attending physician and the condition of the individual patient. In another embodiment, the pathogenic and non-pathogenic antigens of the present invention are administered in an amount of about 0.1pg/1 dose to about 1mg/1 dose.
In particular embodiments, the pharmaceutical compositions comprising the ingredients of the present invention may be administered in the form of liposomes, lipid particles, microparticles, or microcapsules. In various aspects of the invention, it may be useful to use such compositions to achieve sustained release of the ingredients of the invention.
The preparation step of the drug and the like of the present invention is a well-known step in the art, and is described in, for example, japanese pharmacopoeia, united states pharmacopoeia, pharmacopoeia of other countries, and the like. Accordingly, one skilled in the art can determine the embodiments such as the amount to be used based on the description herein without undue experimentation.
In this specification, "or" is used when "at least one item" of the items listed in the article can be adopted. "or" is also the same. In the case where "within a range of two values" is explicitly described in the present specification, the range also includes the two values themselves.
References such as scientific literature, patents, patent applications, and the like cited in this specification are incorporated by reference in their entirety into this specification to the same extent as if each was specifically recited.
The preferred embodiments are shown above to illustrate the present invention for ease of understanding. The present invention will be described below based on examples, but the above description and examples below are provided for illustrative purposes only and are not intended to limit the present invention. Accordingly, the scope of the present invention is not limited to the embodiments and examples specifically described in the present specification, but is limited only by the claims.
Examples
The examples are described below. Where necessary, the treatment of animals used in the examples below was conducted in compliance with the university of tokyo animal experiment practice rules and other relevant ethical guidelines or guidelines, as necessary, and based on the declaration of helsinki (Declaration of Helsinki). The reagents were specifically those described in the examples, but may be replaced by those of other manufacturers (Sigma-Aldrich, wako pure chemical industries, nacalai, R & DSsystems, USCN Life Science INC, etc.).
(production example)
The extract a used in this example was produced as follows.
Freeze-drying the strain B of Mycobacterium tuberculosis Qingshan (Mycobacterium tuberculosis strain Aoyama B) in the culture medium (Sauton potato medium) (1) Culturing the strain at 37+ -1deg.C. Transplanting the strain culture to a culture medium for production (2) The cells were cultured at 37.+ -. 1 ℃ for 5 to 7 weeks (main culture), washed with water for injection, and then added with water for injection in an amount 20 times the weight of the wet cells, and heated at 100 ℃ for 120 minutes to obtain an extract. The extract was filtered through a 0.45 μm membrane filter, and then concentrated under reduced pressure to give a sugar content (in terms of D-arabinose by phenol-sulfuric acid method) of 4.0mg/mL to 6.0mg/mL, to give a concentrate. Next, 1W/V% sulfosalicylic acid was added to the concentrate for the purpose of removing proteins, and after leaving the concentrate at 10℃for 15 to 20 minutes, the precipitate was removed by centrifugation (10℃or less, 1150 XG, 10 minutes), and the supernatant was recovered. The protein concentration of the supernatant was 0.30mg/mL or less (Lowry method, tyrosine conversion). Further, sulfosalicylic acid was removed from the supernatant until the detection limit was reached or lower (10 ppm or lower, ferric chloride solution method). The solution was concentrated under reduced pressure so that the sugar content was 1.8mg/mL to 2.2mg/mL, sodium chloride (0.9W/V%) and cold ethanol having the same capacity as the concentrate were added thereto, and after standing at 10℃or lower for 40 hours or more, the precipitate (polysaccharide in the polymer region) was removed by centrifugation (10℃or lower, 2040 XG, 10 minutes). Then, 4 times of cold ethanol was added to the supernatant, and the mixture was left at 10℃or lower for 40 hours or longer, and then the precipitate was recovered by centrifugation (2040 XG or lower at 10℃or lower for 10 minutes). The precipitate was dissolved in water for injection, the sugar content was adjusted to 1.8mg/mL to 2.2mg/mL, and then, the solution was filtered through a 0.45 μm membrane filter, and subjected to high-pressure steam sterilization (121 ℃ C., 20 minutes) to prepare an extract A.
(1): sutong potato culture medium
The washed potato slices were immersed in a culture medium for stoneware and sterilized at 115 ℃ for 15 minutes, and used as a culture medium for stoneware potatoes.
Sutong culture medium
The above components were dissolved in water to make 1000mL. The pH was adjusted to 7.0 to 7.3 with sodium hydroxide solution.
(2): culture medium for production
The above components were dissolved in water to 1000mL, and autoclaved (121 ℃ C., 20 minutes). The pH was adjusted to 7.0 to 7.3 with sodium hydroxide solution.
The physicochemical properties of the obtained extract A are as follows.
(1) Appearance of
Pale yellow clear liquid
(2) pH value of
4.50 to 5.30
(3) Protein content
3.5% by weight (in terms of amino acids) in the lyophilized product
(4) Nucleic acid content
0.1 wt% in the freeze-dried product
(5) Polysaccharide body mainly comprises monosaccharide
43.4% by weight of mannose, 18.2% by weight of arabinose and 10.4% by weight of glucose. (after hydrolysis with 2N trifluoroacetic acid at 100℃for 2 hours, by liquid chromatography using fluorescent derivatives of 2-cyanoacetamide (S.Honda, et al, anal. Chem.,52,1079 (1980))
The extract a prepared by the method described in the above production example may be used by appropriately diluting it before use. In the following examples, the compositions were diluted 1 to 50,000 times and used in appropriate concentrations.
(usual experimental methods)
Unless otherwise indicated, the examples of the present invention were carried out using the following experimental methods, reagents, and the like.
(human PBMC)
PBMC were isolated from blood donors of healthy volunteers by gradient separation using Ficoll-Paque Plus (GE Healthcare). Also, frozen PBMC with different reactivity to PPD and CMV antigens (obtained before the prevalence of COVID-19 infection) were purchased from Cellular Technology Limited (CTL). Fresh isolated PBMC were incubated in RPMI containing 1% penicillin/streptomycin (P/S), 10% FCS and 5% autologous plasma. Frozen PBMCs were thawed according to the protocol provided by CTLs. Briefly, cells were thawed in a 37 ℃ water bath, washed with CTL anticoagulation wash medium, and then cultured in CTL test medium containing 1% penicillin/streptomycin (P/S), 10% fcs, and 5% autologous plasma supplemented with 1% L-glutamine.
(human PBMC markers and stimulation)
After counting the cells, PBMCs were labeled with 2.5 μm CTV (Thermo Fischer Scientific) in a 37 ℃ water bath for 20 min while gently shaking in RPMI. After labelling, cells were washed with PBS containing 5% fbs and cultured in RPMI or CTL assay medium containing 1% penicillin/streptomycin (P/S), 10% fcs and 5% autologous plasma in 96 well round bottom plates. To evaluate CTV staining efficiency, samples on day 0 were analyzed by FACS. Initially, cells were cultured in SARS CoV-2 RBD antigen (GenScript), PPD (JAPAN BCG LABORATORY), CMV pp65 (Miltenyi Biotec) for 3 days in the presence and absence of extract a (ZERIA Pharmaceutical co., ltd). Then, the cell culture medium was replaced with a medium containing IL-2 and autologous plasma, and the cells were stimulated for 3 days to expand antigen-specific T cells. After this expansion step, cells were re-stimulated with SARS CoV-2 RBD, PPD, CMV antigen only for 18 hours (protein transport inhibitor was added during the last 4 hours), and T cell responses were analyzed by intracellular staining and FACS.
(cytokine measurement)
IL-13 and IFN gamma DuoSet ELISA kit (R & D Systems) was used to determine IL-10 and IFN gamma levels in culture supernatants from day 3 and day 6 after restimulation, as indicated by the kit. Culture supernatant cytokines derived from PBMC at day 6 after the start of stimulation were assayed by Bio-Plex Pro human cytokine screening 48-Plex panel (Bio-Rad).
(FACS analysis)
After stimulation, cells were recovered, incubated in human trustin FcX Fc receptor blocking solution (Biolegend) for 10 min, stained with LIVE/DEAD fixable near infrared stain (Thermo Fischer Scientific) using the following cell surface molecule staining antibodies.
CD19-APC/Cy-7 (clone: HIB19, bioleged)
CD14 APC/Cy-7 (clone: M5E2, biolegend)
CD56 APC/Cy-7 (clone: HCD56, biolegend)
CD3-AF700 (clone SK7, biolegend)
CCR7-BV605 (clone G043H7, bioleged)
CD45RA-AF488 (clone: HI100, bioleged)
CD4-PerCpCy5.5 (clone: OKT4, biolegend)
CD8-BV785 (clone: RPA-T8, biolegend) antibody in Brilliant Stain Buffer (BD Biosciences)
After staining and washing, cells were fixed and permeabilized for at least 30 minutes using the fixing and permeabilizing reagent of the eBioscience Foxp 3/transcription factor staining buffer set (Thermo Fischer Scientific). Then, the cells were washed with a permeation/washing buffer, and stained with the following intracellular staining antibodies.
T-bet-PE dazle 594 (clone 4B10, bioleged)
Foxp3-PE (clone 206D, biolegend)
IFNγ -PE/Cy-7 (clone: 4S. B3, biolegend)
IL-10-APC (clone JES3-19F1, biolegend)
Thereafter, the cells were washed and analyzed by LSR Fortessa (BD Biosciences). The strategy of the FACS circling in this example is shown in fig. 2.
(tSNE analysis)
Removal of dead cells and CD14/19/56 from analysis - At the time of cells, the maximum event number was set to 20,000, whereby all samples from healthy PBMC donors in each experiment were joined, and t-distribution random neighborhood embedding (t-SNE) analysis was performed in FlowJo software under the following default settings.
iterations：1000，perplexity：30，KNN algorithm，Exact(vantage point tree)，gradient algorithm：Barnes-Hut.
A heat map tSNE plot is generated from the joined samples.
(statistical analysis)
Statistical analysis was performed by GraphPad Prism Software version (GraphPad). Unless specifically noted, student's t-test was used to determine significant differences (< p <0.05; < p < 0.01;).
( Example 1: verification of the correlation of tubercle bacillus infection with memory T cells )
In this example, the effectiveness of the individualization treatment was verified by performing antigen-based stimulation on patients having a history of BCG vaccination or tuberculosis infection or healthy subjects who have confirmed antigen responsiveness, and analyzing the responses of memory T cells.
(method)
To investigate the heterogeneous T cell responses against SARS CoV-2 mediated by extract a, human PBMCs derived from healthy and uninfected individuals were labeled with Cell Trace Violet (CTV), initially cultured for 3 days with SARS CoV-2 Receptor Binding Domain (RBD) antigen (1 μg/ml) in the presence and absence of extract a (30 μg/ml), after which the cell culture medium was replaced with one comprising IL-2 and autologous serum for a further 3 days to expand antigen-specific T cells. At the position ofAfter 6 days of this step of expanding proliferation, the cells were re-stimulated with SARS CoV-2 RBD antigen only for 18 hours, during which time the protein transport inhibitor was added to the medium for the last 4 hours. Then, intracellular staining was performed, and cell proliferation, intracellular cytokines, and transcription factors were analyzed by FACS (fig. 1A). To identify the unique T cell population induced by the combination of extract A and SARS CoV-2 RBD antigen, dead cells and CD14/19/56 were excluded from the assay - After cells, all samples from 3 healthy PBMC donors were pooled and t-distribution random neighborhood embedding (t-SNE) analysis was performed (fig. 1B and 1C).
(results and discussion)
From the tSNE plot, the circled population elicited different induction by each stimulus (fig. 1B). From the tSNE plot compared to the control stimulation in representative individuals, extract a showed that although stimulating the C5 population (proliferated Tbet + Expansion of Effector Memory (EM) CD 8T cells resulted in a decrease in the rate of presence of C4 populations (EM (TEMRA) CD 8T cells differentiated to the end stage) (fig. 1B and 1C). Further, RBD stimulation causes C1 (IFNg + Tbet + Proliferation of EM CD 4T cells) and C2 (proliferation of Foxp3 + EM CD 4T cells) are increased, but C3 (proliferation of CD3 - CD4 + Foxp3 + Tbet + IL-2 + Cell) population reduction (fig. 1B and 1C). In contrast, rbd+ extract a stimulation reduced the C2 population while significantly increased the C1 population (fig. 1B and 1C). This indicates that extract A can control the Treg/Th1 balance. The same results were also observed in the additional 2 healthy donors (fig. 3).
( Example 2: verification of anti-SARS-CoV-2 specific T cell response in uninfected PBMC mediated by modulation of Treg/Th1 balance by extract A )
In this example, a SARS CoV-2-specific Th 1-type immune response mediated by extract A in human PBMC derived from non-infected individuals was validated.
(method)
Human PBMC from 3 healthy individuals were labeled with CTV and stimulated with extract A (30. Mu.g/ml), SARS CoV-2 RBD (1. Mu.g/ml), or a combination thereofAfter 3 days, the medium was replaced with fresh medium containing IL-2 and further cultured for 3 days. Cells were re-stimulated with SARS CoV-2 RBD antigen for 18 hours on day 6, during which time protein transport inhibitors were added to the medium during the last 4 hours. Ifnγ levels in the supernatant after 6 days of antigen re-stimulation were determined by ELISA (fig. 4A). Next, intracellular staining was performed, and cell proliferation, intracellular cytokines and transcription factors were analyzed by FACS, and all samples derived from 3 individuals were linked and then survived to CD14/19/56 - In cells, tSNE analysis was performed by FlowJo (FIG. 4B). The presence ratio of the C1 group resulting from the tSNE analysis was plotted as a box plot using data from all 3 individuals (fig. 4C). In proliferating CD4 and CD 8T cells (CTV Low/negative Circle), tbet expression and ifnγ production were analyzed by FACS (fig. 4D). By using data from all 3 individuals, the presence ratio of the C2 population obtained by tSNE analysis, and the proliferated CD 4T cells (CTV Low/negative Circle) is plotted as a box plot (fig. 4E).
(results and discussion)
SARS CoV-2 antigen was found to cumulatively induce IFNγ production from human PBMC with extract A (FIG. 4A). In relation to the ifnγ data in the supernatant, tSNE and FACS analysis showed that ifnγ production Tbet could be induced cumulatively by combined stimulation + CD 4T cell proliferation (C1 population) (fig. 4B and C). This situation reveals that extract A enhances SARS CoV-2 specific Th1 type T cell response. Furthermore, it was found that extract A caused SARS CoV-2 antigen specific IFN gamma in non-infected human PBMC + Tbet + CD 8T cell proliferation was also enhanced (FIGS. 4D and 5).
( Example 3: verification of the proliferation of suppressive natural immune cells induced by extract A at an earlier time point capable of producing IL-10 )
In this example, tSNE analysis was performed on immune cell populations at an earlier time point 3 days after stimulation with SARS CoV-2 antigen in the presence or absence of extract A.
(method)
Human PBMCs derived from 3 healthy individuals were labeled with CTV,after 3 days of stimulation with extract A (30. Mu.g/ml), SARS CoV-2 RBD (1. Mu.g/ml), or a combination thereof, the medium was replaced with fresh medium containing IL-2 and further cultured for 3 days. Cells were restimulated with SARS CoV-2 RBD antigen in the presence of protein transport inhibitor for 6 hours on day 3. Intracellular staining was performed and cell proliferation, intracellular cytokines, and transcription factors were analyzed by FACS. After all samples from 3 individuals were joined, they survived CD14/19/56 - tSNE analysis was performed by FlowJo in cells (FIG. 6A). A heat map was generated for expression of surface and intracellular markers including cytokines and transcription factors in specific groups (fig. 6B). The presence ratios of the P1 group and the P2 group obtained by the tSNE analysis were plotted as a box plot by using data derived from all 3 individuals (fig. 6C). The IL-10 level in the supernatant on day 3 was determined by ELISA (FIG. 6D).
(results and discussion)
Because of the short incubation time, no significant T cell proliferation was observed due to CTV pigment dilution, but some innate immune cell proliferation (P1 and P2) was observed due to extract a stimulation (fig. 6). When these groups were analyzed in more detail, it was found that extract A induced CD3 - CD4 + Tbet + Foxp3 + IL-2 + CD3 - CD4 + Tbet + IL-2 + Proliferation of the natural immune population. CD3 - CD4 + Tbet + Foxp3 + IL-2 + The extract A significantly increased IL-10 production mediated by SARS CoV-2, with potential inhibitory activity (FIGS. 6C and 6D). However, due to the IL-10 levels induced by extract A and CD3 - CD4 + Tbet + Foxp3 + IL-2 + Since there is no correlation in increasing the presence ratio of the population, it is considered that there is a possibility that there is an additional IL-10 supply source containing other natural immune cells (for example, immune cells may be obtained by DC or non-expanded Treg since no Treg expansion is observed on day 3 of CTV dilution) (FIGS. 6C and 6D). Furthermore, the Bio-Plex analysis of the supernatant derived from PBMC cultures showed that: the RBD and extract A are stimulated againIL-12p40 and IL-1α were potentially induced 3 days after restimulation and 6 days after restimulation, IL-2, GM-CSF and TNF α were potentially induced and IL-17A was induced 6 days after restimulation. This situation is associated with the modulation of Th1/Treg balance by extract a, suggesting that Th 1-driven cytokines have a potential contribution (fig. 8).
Further, since extract a contains Mtb-related antigen and an adjuvant (e.g., NOD 2) capable of activating a natural immune receptor, extract a was compared with other adjuvants (including cGAMP which induces a balanced Th1/Th2 immune response in addition to K3CpG and LPS as adjuvants for inducing Th 1). For intracellular staining of transcription factors after 7 days of stimulation with SARS CoV-2 antigen in human PBMC derived from healthy donors in the presence or absence of extract A or K3CpG, extract A resulted in the expression of the EM-bearing Treg (Foxp 3 + CCR7 - CD45RA - CD 4T cells) and reduced Foxp3/Treg ratios in EM CD 4T cells, the same effect was not confirmed in K3 CpG. This situation suggests that Th1/Treg modulation based on extract a did not result solely from the adjuvant effect (fig. 9A). Furthermore, RBD-induced ifnγ production from human PBMCs was induced only by extract a, unlike the adjuvants of the other experiments (including K3CpG, LPS and cGAMP) (fig. 8). Specifically, ifnγ mediated by RBD + TNFα + Proliferation of CD 4T cells and CD 8T cells was enhanced by the addition of extract a, but not with other adjuvants (fig. 9B-9F). This situation suggests that the enhancement of the SARS CoV-2 specific T cell response mediated by extract a did not result from induction of training immunity based on the adjuvant contained in extract a.
( Example 4: the demonstration that existing Mtb-specific T cell memory is necessary to promote the anti-SARS CoV-2-specific T cell response mediated by extract A )
In this example, it was investigated whether existing Mtb memory was necessary for the enhancement of T cell response of extract a against SARS CoV-2 antigen observed in non-infected human PBMC.
(method)
The effect of extract a on SARS CoV-2 specific T cell responses was analyzed in PBMCs with different reactivity to Mtb antigen PPD or Cytomegalovirus (CMV) antigen (using Mtb non-related antigen as negative control). Human PBMC derived from healthy individuals with high/low PPD/CMV reactivity were labeled with CTV and after 3 days of stimulation with CMVpp65, PPD (1. Mu.g/ml), extract A (30. Mu.g/ml), SARS CoV-2 RBD (1. Mu.g/ml), or a combination thereof, the medium was replaced with fresh medium containing IL-2 for a further 3 days of culture. Cells were re-stimulated with SARS CoV-2 RBD antigen for 18 hours on day 6, during which time protein transport inhibitors were added to the medium during the last 4 hours. Ifnγ levels in supernatants were measured by ELISA, intracellular staining was performed, and cell proliferation, intracellular cytokines, and transcription factors were analyzed by FACS. The percentage of ifnγ -producing RBD/CMV proliferating CD 4T cells was plotted against the percentage of ifnγ -producing rbd+ extract a proliferating CD 4T cells, or the Foxp3: tbet ratio in rbd+ extract a proliferating CD 4T cells (fig. 11A). The number of PPD/CMV points was plotted against the percentage of ifnγ -producing rbd+ extract a proliferating CD 4T cells or CD 8T cells (fig. 11B).
(results and discussion)
Not only IFNγ induced by PPD + A strong positive correlation occurred between proliferating CD 4T cells and RBD+ extract A, and a strong positive correlation also occurred between proliferation of CD 4T cells induced by RBD+ extract A and PPD number or proliferation of CD 4T cells induced by PPD. Nevertheless, ifnγ induced by PPD + There was a tendency for the Foxp3/Tbet ratio in proliferating CD 4T cells to be inversely correlated with CD 4T cells induced by rbd+ extract a (p=0.075). The results revealed that existing Mtb memory was necessary to promote the SARS CoV-2 specific T cell response mediated by extract a by modulating the Treg/Th1 ratio (fig. 11). On the other hand, no strong correlation was confirmed between the T cell response induced by CMV and the T cell response induced by rbd+ extract a. This result enhanced the anti-SARS CoV-2 specific T cell potentiation based on extract A requiring Mtb memory, but not CMV memory.
TABLE 1
Table 1. (A) PPD response information for commercially available frozen PBMC provided by CTLs.
(B) CMV response information for commercial frozen PBMCs provided by CTLs.
The above results show the anti-SARS CoV-2 specific T cell enhancement based on extract A, from which it can be deduced that the administration of extract A has therapeutic effects on SARS CoV-2 and other viral infections.
Example 5 Effect in other diseases
In this example, in vivo confirmation experiments were performed for treatments with non-pathogenic antigen components (which are neither derived from nor cross-reactive with the pathogenic agent of the disease) characterized by administration in the presence of pathogenic antigen components (which are derived from and/or cross-reactive with the pathogenic agent).
(materials and methods)
A mouse
All animal experiments were conducted based on the guidelines concerning management and use for use of animals (approval numbers: DS27-25R1 and PM-21-81, respectively) approved by the national institute of research and development, human pharmaceutical foundation, health, and nutrition, and the university of Tokyo, medical science Institute (IMSUT). Female C57BL/6J mice were purchased from CLEA Japan, inc. CD4, MHC class II, batf3, IL12p40, CD1d1, NOD2 or γδ T cell deficient mice were purchased from Jackson Laboratory. Embryonic stem cells of STING (Tmem 173) deficient mice (Tmem 173tm1Camb (KOMP) Mbp ES cell line (jm8a3.n1) were purchased from Knockout Mouse Project (KOMP) repostor, and STING deficient mice were born in the animal facility of the national institute of research and development of human medicine, health, and nutrition, almost all experiments for evaluating antitumor effects were performed with female mice.
Cell strain
B16-BL6 melanoma cells were obtained from university of northeast. B16-F10 cells were purchased from BRC. These cell lines were maintained in R10 medium (including RPMI medium 1640 (Nacalai Tesque Co., ltd.) supplemented with 10% fetal bovine serum (Nichirei Bioscience), 100U/ml penicillin (Meiji Seika Pharma Co., ltd.), and 100. Mu.g/ml streptomycin (Meiji Seika Pharma Co., ltd.).
Freeze-dried glutamic acid BCG vaccine and Purified Protein Derivative (PPD) were obtained from Japanese BCG research. Freund's Incomplete Adjuvant (FIA) was purchased from Sigma Aldrich. Extract a solution was purchased from ZERIA Pharmaceutical co. Sodium chloride was added to the extract A solution to give an isotonic extract A solution (stock solution concentration: 2 mg/ml). For in vivo experiments, isotonic extract a solution was diluted 10-fold using physiological saline. anti-CD 4 (GK 1.5), anti-CD 8 (53-6.7), IFN gamma (XMG 1.2) and anti-NK 1.1 (PK 136) antibodies, and corresponding isotype control antibodies were purchased from Biolegend. Recombinant Mtb LpqH and MtbHsp10 were obtained from LIONEX GmbH. Human Hsp10 protein was obtained from ATGen. Oligodeoxynucleotide K3 (5-ATC GAC TCT CGA GCG TTC TC-3) was synthesized by Geen design, inc.
Animal experiment
The lyophilized glutamic acid BCG vaccine was resuspended in physiological saline (1 mg/ml). Mice were subcutaneously injected 2 times (5 days before and 2 weeks before tumor inoculation) with a total of 100 μl of BCG solution. In the case of immunization of extract A and IFA, the extract A was emulsified in equal amounts of IFA using a GP syringe coupler (Green Peptide Co., ltd.) and Norm-select (HENKE SASS WOLF). The tail root of the mice was injected intradermally with a total of 100 μl of the extract a emulsion 4 weeks and 2 weeks before tumor inoculation. Next, mice were injected with lpqH, extract a or normal saline every other day, starting 8 days prior to tumor inoculation, until euthanasia. B16-BL6 cells were inoculated subcutaneously into blank mice, BCG-immunized mice and mice immunized with the extract A emulsion (3.0X10 4 Cell/mouse) and B16-F10 cells (3.0X10) 4 Cell/mouse), tumor size was measured using a digital vernier caliper (MITUTOYO corporation) and length (L), width (W) and height (H) were evaluated. Tumor volume (V) was calculated as v=l×w×h.
In vivo depletion experiment
To deplete cd4+ cells, a total of 200 μg of anti-CD 4 antibody was intraperitoneally injected 1 day before, 3 days after, 7 days after, and 11 days after tumor inoculation. In the case of CD8 depletion, 200 μg of antibody was intraperitoneally injected 3 days before, 2 days before and 1 day before and 2 days after, 5 days after, 8 days after and 11 days after tumor inoculation. In the case of ifnγ, 200 μg of antibody was injected intraperitoneally immediately before and 3 days after, 6 days after, 9 days after, and 12 days after tumor inoculation.
Cytokine and c-di-AMP ELISA
After harvesting cells from the spleens of previously immunized mice, spleen cells were resuspended in R10 medium and the number of cells was determined using a Z1 particle counter (Beckman coulter, inc, CA, USA). Next, the cell number was adjusted to 2X 10 in R10 medium 7 Cells/ml. Mu.l total of the cell suspension was dispensed into 96-well flat bottom microplates (AGC Techno Glass) and cells were stimulated with 100. Mu.l of R10 medium containing extract A. After 48 hours, the microplates were centrifuged and the supernatant of the cell culture was recovered. An enzyme-linked immunosorbent assay (ELISA) kit (R&D systems) was used to quantify the concentration of cytokines.
IL-10 and IFNγ levels in hBMC culture supernatants at day 3 and day 6 of culture (after restimulation) were measured using human IL-13 and IFNγ DuoSet ELISA kit (R & Dsystems) according to manufacturer's instructions.
Cytokine in culture supernatants from 6 day stimulated PBMC were analyzed using Bio-Plex Pro human cytokine screening 48-Plex panel (Bio-rad).
The level of c-di-AMP in the BCG vaccine, extract A solution or PPD with or without boiling was determined using the c-di-AMP ELISA kit (Cayman Chemical Company) according to manufacturer's instructions. The step of boiling the BCG vaccine solution and extracting the recent intracellular contents of live attenuated mycobacterium bovis is performed as follows: the lyophilized BCG vaccine was resuspended in PBS to a final concentration of 1mg/ml and a portion of the BCG solution was boiled at 95℃for 30 minutes. The boiled BCG vaccine solution was cooled and used in ELISA to determine the c-di-AMP level.
Protease treatment of extract A
EDTA-0.5% trypsin solution was purchased from Nacalai Tesque Co. Subtilisin (P5380) was purchased from Sigma Aldrich. Heat Inactivation (HI) was performed by incubating these proteases at 96 ℃ for 15 min. The whole or HI protease was mixed with extract A and incubated for 16 hours. These solutions were then incubated at 96℃for 15 minutes to inactivate the intact enzymes.
In vitro exhaustion (MACS)
Experiments were performed using AUTOMACS according to manufacturer's instructions.
Isolation of Tumor Infiltrating Leukocytes (TILs)
After 14 days of tumor inoculation, tumor tissue was harvested from mice and cut into small pieces using scissors. The tumor pieces were further digested using a tumor isolation kit (Miltenyi Biotec) and a genetlemacs separator (Miltenyi Biotec). After digestion, the cell suspension was filtered using a 70 μm size screen. Density gradient centrifugation was performed using Lymholyte-M (Cedarlane) to isolate TIL from tumor cells, residual erythrocytes and other cells including dead cells. After centrifugation, the intermediate layer containing TIL was recovered and cells were stimulated with extract A (100. Mu.g/ml) or LpqH (10. Mu.g/ml). Golgi Plug and Golgi Stop are added simultaneously with the stimulating substance. After 10 hours of stimulation, cells were recovered and washed with PBS. Blue Dead cell stain kit (fixable blue Dead cell stain kit) (Thermo Fisher Scientific) was used to stain cells, and after blocking with anti-mouse CD16/32 antibody, cells were fixed, and the cells were stained with the following fluorochrome-binding antibodies by permeation using BD Cytofix/Cytoperm (BD) according to the manufacturer's instructions: anti-CD 3 (17A 2), anti-CD 4 (GK 1.5), anti-CD 8 (53-6.7), anti-CD 44 (IM 7), anti-CD 45 (30-F11), anti-T-bet (4B 10), anti-Foxp 3 (150D), and anti-IFN-y (XMG 1.2). Fluorescent pigment binding antibodies were purchased from BioLegend. Stained cells were analyzed using FACS LSRII (BD) and data were analyzed using FlowJo software (FlowJo).
Flow cytometer analysis of spleen cells
Spleen cells were stimulated with Golgi Stop and Golgi Plug (BD biosciences) along with extract A (20. Mu.g/ml) for 6 hours. Following stimulation, cells were stained with Live/Dead fixable blue Dead cell stain kit (Thermo Fisher Scientific) for 5 minutes followed by anti-CD 4 (RM 4-5, BD), anti-CD 8 alpha (53-6.7, biolegend) and anti-CD 44 (IM 7, biolegend) antibodies. After fixation and permeation with BD Cytofix/Cytoperm solution (BD), intracellular cytokines were stained with anti-CD 3 (17A 2, biolegend), anti-IFNγ (XMG 1.2, biolegend), anti-IL-13 (ebio 13A, eBioscience), and anti-IL-17 (TC 11-18H10.1, biolegend) antibodies.
Human PBMC stimulation and Intracellular Cytokine Staining (ICS)
All experiments performed using human PBMC were approved by the ethical review Committee of the national institute of research and development, pharmaceutical Foundation, health, and nutrition (approval No. 146-05) of Japan and the ethical review Committee of the university of Tokyo, medical science research Institute (IMSUT) (approval No. 2019-25-0919). To study fresh PBMCs, PBMCs were isolated from healthy volunteer blood donors by gradient separation with Ficoll-Paque Plus (GE Healthcare). Lyophilized human PBMC were purchased from CTL Europe GmbH. Frozen PBMCs were thawed in a water bath at 37 ℃, washed using CTL anticoagulation washing (CTLEurope GmbH), and thereafter resuspended in RPMI1640 medium containing 10% FBS. The cells were mixed at 1X 10 6 Cell/well density was cultured in 96-well plates and allowed to stand overnight in a CO2 incubator. Next, extract A (100. Mu.g/ml), PPD (3. Mu.g/ml), cytomegalovirus (CMV) pp65 overlapping peptide (3. Mu.g/ml) or recombinant Mtb protein (10. Mu.g/ml each) was added. The cells were re-stimulated with a total of 1. Mu.g/ml of anti-CD 28 (CD 28.2), golgi Plug and Golgi Stop added simultaneously with the stimulating substance for 6 hours. Following stimulation, PBMCs were collected and washed with PBS. Blue Dead cell stain kit (Thermo Fisher Scientific) was used to fix blue cells and after blocking with human TruStain FcX (bioleged), surface staining was performed with the following fluorochrome binding antibodies: anti-CD 4 (OKT 4), anti-CD 8 (RPA-T8), anti-CD 45RA (HI 100) and anti-CCR 7 (G043H). After fixation and permeation of cells using BD Cytofix/Cytoperm solution (BD), cells were stained with fluorochrome-conjugated anti-CD 3 (SK 7), anti-CD 154 (24-31), anti-IL-2 (MQ 1-17H 12), anti-TNFα (MAb 11), and anti-IFNγ (4 SB 3) antibodies. All of the foregoing antibodies were purchased from BioLegend. Stained cells were analyzed using FACS LSRII (BD) and data was analyzed using FlowJo software.
CTV markers and manipulations for long-term cultured human PBMC
Following cell counting, PBMCs were labeled by gently shaking in RPMI with 2.5 μm CTV (Thermo Fisher Scientific) at 37 ℃ for 20 minutes while incubating. After labelling, cells were washed with PBS containing FBS (5%) and incubated in 96-well round bottom plates in CTL assay medium containing RPMI, or 1% penicillin/streptomycin (P/S), 10% fcs and 5% autologous plasma. The samples recovered on day 0 were analyzed by FACS to evaluate CTV staining efficiency. Cells were first stimulated with SARS CoV-2 RBD antigen (GenScript), PPD (Japanese BCG manufacturing Co., ltd.), and CMV pp65 (Miltenyi Biotec) in the presence or absence of extract A (ZERIA Pharmaceutical Co., ltd) for 3 days, and then the cell culture medium was changed to a medium containing IL-2 and autologous plasma, followed by additional stimulation for 3 days to expand antigen-specific T cells. After the expansion step, cells were re-stimulated with SARS-CoV-2 RBD, PPD and CMV antigens for 18 hours (protein transport inhibitors added during the last 4 hours) and T cell responses were analyzed by intracellular staining and FACS.
Cells were harvested after stimulation, incubated with human TruStain FcX Fc receptor blocking solution (Biolegend) for 10 min, and stained with LIVE/DEAD Fixable Near infrared stain (Fixable Near-IR stain) (Thermo Fisher Scientific) using cell surface molecules (including CD19-APC/Cy-7 (clone: HIB19, biolegend), CD14APC/Cy-7 (clone: M5E2, biolegend), CD56 APC/Cy-7 (clone: HCD56, biolegend), CD3-AF700 (clone: SK7, biolegend), CCR7-BV605 (clone: G043H7, biolegend), CD45RA-AF488 (clone: HI100, biolegend), CD 4-CpCy5.5 (clone: OKT4, biolegend), CD8-BV785 (clone: RPA-T8, biolegend) antibodies). After staining and washing, cells were fixed and permeabilized for at least 30 minutes using the fixing and permeabilizing reagent of the eBioscience Foxp 3/transcription factor staining buffer set (Thermo Fischer Scientific). Next, the cells were washed with perm/wash reagent and stained with intracellular staining antibodies (including T-bet-PE dazle 594 (clone: 4B10, bioleged), foxp3-PE (clone: 206D, bioleged), IFN-. Gamma. -PE/Cy-7 (clone: 4S. B3, bioleged) and IL-10-APC (clone: JES3-19F1, bioleged) antibodies). Thereafter, the cells were washed and analyzed by LSR Fortessa (BD Biosciences).
tSNE analysis
In the verification, the maximum number of events was set to 30,000 at the time of exclusion of dead cells and CD14/19/56 negative cells from the analysis, whereby all samples from healthy PBMC donors were concentrated and t-distribution random neighborhood embedding (t-SNE) analysis was performed using FlowJo software by the following default settings: the events: 1000, superplexity: 30, knn algorithm, accurate (vantage point tree), gradient algorithm: barnes-Hut. A heat map tSNE plot is generated from the concentrated sample.
Statistical analysis
Data are expressed as mean ± standard error (s.e.), and are analyzed by using Graphpad Prism (Graphpad Prism). As long as there is no difference in the description of the figures, a non-corresponding student t-test is used to determine statistical reliability. * p <0.05, < p <0.01, < p <0.001.
(extract A exerts antitumor effect only in mice immunized in advance.)
Extract A is a hot water extract of Bacillus tuberculosis, contains molecules such as NOD2 agonist, and can stimulate natural immunity (Katsun ma et al, 2015). Therefore, the inventors first investigated whether or not the innate immunity mediates the antitumor effect of extract a. Mice were injected intratumorally every other day, starting 2 days after tumor inoculation, with either extract a or K3 CpG as TLR9 agonist that induces anti-tumor type 1 immunity (kliman, 2004). Intratumoral administration of extract a or physiological saline was shown to fail to inhibit tumor growth (fig. 13A and 13B), but on the other hand, K3 CpG almost completely inhibited B16-BL6 melanoma in wild-type blank mice (fig. 13C). Furthermore, even when the treatment with extract A was started 8 days before tumor inoculation, no antitumor effect of extract A was observed in either B16-BL6 or B16-F10 tumor-bearing mice (FIGS. 13D and 13G).
Regarding the expected results of the proven extract a in clinical trials, one of the main differences between mice and humans is: mice were raised in an environment free of Specific Pathogens (SPF), whereas humans were exposed to multiple pathogens and received a BCG-containing vaccination (Sugiyama et al, 2014). In particular, almost all Japanese subjects who participated in the clinical trial had a history of tuberculosis or were vaccinated with BCG (Yamamoto and Yamamoto, 2007). Accordingly, the inventors have then investigated the anti-tumor effect of extract a in BCG-immunized animals. In BCG immunized mice, extract a exerted an anti-tumor effect in a model in which tumors were transplanted by subcutaneous injections of B16-BL6 melanoma (fig. 13E), B16-F10 melanoma (fig. 13H), and Lewis Lung Cancer (LLC) cells (fig. 13J). These data indicate that the immune response induced by BCG plays an important role in mediating the anti-tumor effect of extract a. In yet another study, when mice were immunized with extract A emulsified in IFA, it was confirmed that extract A exerted potent antitumor effects in animal models of B16-BL6 melanoma (FIG. 13F) and B16-F10 melanoma (FIG. 13I). It was further found that the antitumor effect of extract A varied depending on the kind of adjuvant used at the beginning of immunization. The anti-tumor effect of extract a was demonstrated in the case where k3 cpg+cgamp, which induced a potent Th1 response (Temizoz et al, 2015), was used for the onset of immunization (fig. 13K). As a control, extract a showed no antitumor effect with Th2 aluminum adjuvant (Brewer et al 1999) (fig. 13L).
(CD 4T cells are necessary and CD8 positive T cells are not necessary for the antitumor effect of extract A in BCG-immunized tumor-bearing mice.)
The foregoing results indicate that the antitumor effect of extract a requires immunization in connection with obtaining immunity (fig. 13). To confirm this, the antitumor effect of extract a was verified in Rag 2-deficient mice (CD 4T cells, CD8 positive T cells, B cells, γδ T cells, and NKT cells were deficient due to lack of Rag2 recombination activity required for V (D) J reconstitution) (Shinkai et al, 1992 and Tatsumi et al, 1993). Extract a did not exert an antitumor effect in tumor-bearing BCG immunized RAG 2-deficient mice (fig. 14A). The results strongly reveal that the antitumor effect of extract a is dependent on the acquired immunity. Therefore, the participation of CD 4T cells and CD8 positive T cells was further studied by depleting CD4 expressing cells and CD8 expressing cells using specific antibodies. The results prove that: the antitumor effect of extract a was lost in mice depleted of CD4 positive cells (fig. 14B), whereas the antitumor effect was observed in mice depleted of CD8 positive cells (fig. 14C). Further, it was confirmed by additional experiments using CD 4-deficient mice (FIG. 14D) and MHC class II-deficient mice (FIG. 14E) that CD 4T cells were also necessary for the antitumor activity of extract A. As a control, the effect of extract a was also confirmed in Batf 3-deficient mice (deficient CD8 a positive DCs), indicating that CD8 positive cells comprising CD8 positive T cells were not necessary for the antitumor effect of extract a (fig. 21B).
By using FcgammaR deficient mice and NK1.1 + Cell depleted mice, the involvement of antibody-dependent cell-mediated cell killing (ADCC) in the potential mechanism of the antitumor effect of extract a was also investigated. Extract A in FcgammaR deficient mice and NK1.1 + The antitumor effect was maintained in both cell-depleted mice (fig. 21C and 21D). Furthermore, extract a showed antitumor effect even in CD1d 1-deficient mice (Skold and Behar, 2003) deficient in CD1 d-restricted NKT cells, and mice deficient in γδ T cells (fig. 21E and 21G). Taken together these results show that the anti-tumor effect of extract a in BCG immunized mice is dependent on CD 4T cells, but not CD8 positive T cells, NKT cells, γδ T cells, or ADCC.
(Th 1 response and STING are essential for mediating the antitumor effect of extract A.)
Since CD 4T cells are essential for the anti-tumor effect of extract a in BCG immunized mice, the variety of these T cell responses was studied next. After BCG infection, spleen cells of mice were recovered after multiple subcutaneous administrations of extract a by the same method as in the main study, and the type of T cell response induced by the treatment of extract a was evaluated by stimulation with extract a (fig. 22A). As a result, extract a strongly induced secretion of Th1 cytokine ifnγ derived from spleen cells of immunized mice (fig. 22B). Induction of IL-13 and IL-10 by extract a administration was also observed in the blank mice (fig. 22C and 22D). Also, small amounts of IL-17 secretion were detected in BCG-immunized mice not administered extract a (fig. 22). Furthermore, from the intracellular staining and FACS analysis of spleen cells obtained from mice, it was confirmed that the number of ifnγ -producing memory CD 4T cells was significantly increased by administration of extract a in BCG-immunized mice. Nevertheless, the production of IL-17 or IL-13 upon administration of extract A was not confirmed in both BCG-immunized and non-immunized mice (FIG. 14F).
The above results reveal that ifnγ plays an important role in mediating the antitumor effect of extract a. To confirm this, the antitumor effect of extract a was studied in mice treated with ifnγ neutralizing antibodies. The antitumor effect of extract a disappeared in mice treated with ifnγ neutralizing antibodies, from this result, it was shown that ifnγ plays an important role in mediating the antitumor effect of extract a (fig. 14G). Furthermore, secretion of ifnγ induced by extract a from spleen cells of BCG-immunized mice was not confirmed in both CD 4-deficient mice and MHC class II-deficient mice (fig. 14H). Furthermore, ifnγ secretion from spleen cells responding to extract a was reduced after depletion of CD4 positive cells, but not after depletion of CD8 positive cells (fig. 14I). Based on these results, extract a elicits potent Th 1-type CD 4T cell responses that can produce ifnγ, which is essential for mediating the anti-tumor effects of extract a in BCG immunized mice.
Intracellular nucleic acids that sense the cGAS-STING pathway are one of the pathways important for mediating anti-tumor immunity, and hot water extracts of Mtb may contain bacterial STING agonists such as cyclic dinucleotides c-di-AMP, c-di-GMP, or 3' cgamp (Temizoz et al, 2016; dey et al, 2015 and Bai et al, 2012). Thus, the antitumor effect of extract a in STING-deficient mice was evaluated. As a result, in STING-deficient mice (STING-deficient host cells alone and tumor cells not deleted), the antitumor effect of extract a, which was clearly confirmed in STING-type nugget mice, was not confirmed (fig. 14J). These results reveal that STING ligands obtained from tumor cells, or found in extract a, may be the cause of mediating the anti-tumor effects of extract a. To analyze the supply of STING ligand, the concentration of cyclic dinucleotide c-di-AMP in the extract a solution was then determined, c-di-AMP (which can be produced by Mtb (Bai et al 2012)) was confirmed in the extract a solution, and its level was found to be elevated by boiling the BCG vaccine. This situation reveals that: the tubercle bacillus of BCG vaccine may produce c-di-AMP that may be released by killing bacteria by boiling (fig. 14K). Taken together, extract a was shown to induce anti-tumor immunity mediated by activation of STING pathway (which is induced by ifnγ secreting CD 4T cells and STING derived from Mtb) in BCG immunized tumor-bearing mice.
(injection of tumor-associated protein contained in extract A inhibits tumor growth in BCG-immunized mice.)
To evaluate whether the protein antigen contained in extract a would be responsible for inducing ifnγ derived from Th 1-type CD 4T cells, extract a was treated with protease. Unlike heat-inactivated (HI) enzyme, protease treatment confirmed a tendency to decrease extract a activity, which is the cause of induction of ifnγ expression (fig. 15A). And, it was shown by mass spectrometry that at least 20 proteins were present in the extract a solution (table 1A).
[ Table 1A ]
TABLE 1 Mass Spectrometry analysis of extract A
These candidate proteins were screened in spleen cells of mice injected with the extract a emulsion, and it was found that protein No. 1 (LpqH) and protein No. 18 manage induction of ifnγ derived from spleen cells of mice injected with the extract a emulsion (fig. 15B). Next, peptide libraries of these proteins were synthesized, and spleen cells of mice injected with extract a were screened for activity related to induction of ifnγ. The results showed that 2 peptides derived from the LpqH peptide pool induced expression of ifnγ (fig. 15C). Furthermore, stimulation of spleen cells obtained from BCG immunized mice with LpqH induced ifnγ secretion (fig. 15D). Furthermore, injection of recombinant LpqH protein showed anti-tumor activity in mice immunized with the extract a emulsion and in BCG immunized mice, but not in blank mice, as in the anti-tumor effect of extract a (fig. 15E to 15G). The above results reveal that: administration of extract a-driven antigen to BCG immunized mice can inhibit tumor growth, and one of the active ingredients of extract a is a protein antigen.
(administration of antigen to tumor-non-associated antigen can inhibit tumor growth by specific Th1 cells.)
In order to clarify the relationship between tumor-non-associated antigen-specific T cell responses and anti-tumor effects, immunization was performed with bovine albumin (OVA) as a model antigen. As a result, in mice immunized with the extract a emulsified in IFA adjuvant (water-in-oil emulsion adjuvant) in addition to OVA, the growth of B16-BL6 tumor was inhibited (fig. 15H and 15I). In addition, similar to the results of extract a, administration of Flu antigen mediated tumor suppression in Flu (PR 8 strain) -infected mice, but was not confirmed in blank mice. This revealed that BCG immunization was required for the antitumor effect (fig. 15J and 15K).
(extract A increases the number of Th1 cells in tumor microenvironment.)
Next, analysis of the tumor microenvironment was performed, and it was clear how the extract a exerted an anti-tumor effect. As a result, when extract a was administered to BCG-immunized mice, the number of CD 3-positive CD 45-positive cells in the tumor microenvironment was significantly increased, but not when administered to blank mice (fig. 16A). Further examination showed that these TILs consisted mostly of CD 4T cells compared to CD 8T cells in BCG immunized mice and extract a treated mice (fig. 16B). Expression analysis of CD 4-positive T cells was performed by evaluating the expression of transcription factors T-bet (Th 1) and Foxp3 (Treg), and from this analysis, it was shown that the number of T-bet-positive Th 1-type CD 4T cells was significantly increased (FIGS. 16C and 16D). It was also confirmed that the number of T-bet negative Foxp3 positive cells was significantly increased mediated by extract a, but the difference was relatively lower than that confirmed in T-bet positive cells (fig. 16C). Furthermore, in addition to an increase in the proportion of T-bet positive Foxp3 negative and T-bet positive Foxp3 positive CD 4T cells in the tumor microenvironment of BCG immunized mice and extract a-treated mice, a significant negative correlation was also confirmed between tumor weight and the number of T-bet positive CD 4T cells infiltrating the tumor (fig. 16E). As a control, no correlation was confirmed between tumor weight and T-bet negative Foxp3 positive CD 4T cells in TIL (FIG. 16E). These changes were confirmed only in the tumor microenvironment, but not in the inflow regional lymph nodes or spleen (fig. 23). Thus, it was shown that the increase in the number of T-bet positive T cells in the tumor microenvironment mediated by extract a is a tumor specific phenomenon, not a systemic change.
Next, in order to investigate whether TIL is produced by ifnγ, the intracellular level of ifnγ derived from TIL was measured in the presence or absence of stimulation by extract a (fig. 16F and 16G). Ifnγ -producing memory CD4T cells were detected in the presence and absence of stimulation. This situation revealed that T cell independent antigen derived from extract a was activated (fig. 16G). Under these experimental conditions, it is considered that tumor-derived cells and inclusions exist in the medium, and thus it is possible to detect a T cell response to a tumor antigen. Furthermore, CD4T cells in TIL producing ifnγ responded to extracts a and LpqH in the tumor microenvironment of BCG-immunized mice and extract a-treated mice (fig. 16G). In fact, ifnγ was initially produced by T-bet positive Foxp3 negative CD44 positive memory T cells and a fraction of T-bet positive Foxp3 positive CD44 positive memory T cells in the tumor microenvironment (fig. 16H). Nevertheless, in BCG immunized or extract a treated mice, the number of ifnγ positive CD4T cells showed a negative correlation with tumor weight after stimulation with extract a or LpqH. This situation reveals that: extract a exerts an anti-tumor effect by recruiting extract a-responsive Th1 cells into the tumor microenvironment, thereby accumulating ifnγ -mediated tumor regression (fig. 16I).
(extract A-induced, human PBMC-derived IFN gamma and IL-2 secretion associated with Mtb antigen reactivity.)
To determine whether extract a stimulated the same Th1 type T cell response in humans, extract a-induced ifnγ secretion from human PBMCs was evaluated. Human PBMCs were stimulated with extract A, PPD, CMV peptide or a portion of the recombinant proteins present in extract a (MHSP 10, HSP60.1, lpqH, rv 2376) followed by intracellular staining and FACS analysis for cytokine secretion. The results demonstrate that extract A induces secretion of IFNγ, IL-2 and TNF α from CD154 positive activation delegated CD4 positive CD45RA negative CCR7 positive cells (central memory T cells; TCM) in PBMC derived from multiple human donors. Ifnγ secretion was also induced in multiple donors when stimulated with CMV pp65 peptide (used as Mtb non-relevant negative control) or Mtb antigen, such as PPD and MHSP 10. More importantly, a strong positive correlation was confirmed between the response of human PBMC to extract a and the response to Mtb antigen PPD and MHSP10 (also detected in extract a), but on the other hand no correlation was confirmed between the response of hPBMC to extract a and the response to CMV pp65 overlapping peptide (fig. 17). In addition, a significant correlation was also confirmed between IL-2 induced by extract A and IL-2 induced not only by PPD but also by proteins present in extract A (MHSP 10, HSP60.1, lpqH, rv 2376) (Table 2). Thus, these results reveal that extract a-reactive central memory T cells (which are found in PBMCs obtained from individuals with a history of tuberculosis infection or BCG vaccination) may contribute to the anti-tumor effect of extract a in humans.
TABLE 2
TABLE 2 correlation between extract A and antigen
Relative to TCM extract A
Example 6 demonstration of viral infection
In this example, the effect of the technique of the present invention in viral infections was demonstrated. Unless otherwise mentioned, the experimental procedure is based on the procedure described in example 5.
(combination of extract A and SARS-CoV-2 antigen induces proliferation of an inherent T cell population in SARS-CoV-2 insensitive PBMC.)
Next, investigation was made as to whether the cross-defensive T cell response induced by extract a could mediate the defensive effect on covd-19. Previous studies have shown that common coronavirus-non-specific T cells in SARS-CoV-2 insensitive or non-immune/non-exposed individuals can provide cross-defenses against SARS-CoV-2 (Mateus et al 2020). As a control, BCG vaccination can induce cross-defensive immune responses to a variety of non-Mtb pathogens by mechanisms that involve the induction of training immunity and heterologous T cell responses. Thus, to analyze the enhancement of the heterogeneous T cell response to SARS-CoV-2 mediated by extract A (comprising the tubercule antigen), human PBMC obtained from healthy and SARS-CoV-2 insensitive individuals, labeled with CTV, were first incubated with the SARS-CoV-2 Receptor Binding Domain (RBD) antigen for 3 days in the presence and absence of extract A. Then, the cell culture medium was replaced with a medium containing IL-2, and the cells were stimulated for 3 days to expand antigen-specific T cells. After this expansion step, cells were re-stimulated with only SARS-CoV-2 RBD antigen and T cell responses were analyzed by intracellular staining and FACS (FIG. 18A). To identify the subset of resident T cells activated by the combination of extract A and SARS-CoV-2 RBD antigen, dead cells and CD14/19/56 negative cells were removed from the assay, whereby all samples from 3 healthy PBMC donors were concentrated and subjected to a T-distribution random neighborhood embedding (T-SNE) assay. the circled population in the tSNE plot was induced differently by various stimuli (fig. 18B). The tSNE plot compared to subject stimulation in a representative individual shows that: extract a stimulated the expansion of the C5 population (expanded Tbet positive Effect Memory (EM) CD 8T cells), but on the other hand induced a decrease in the rate of C4 population (hyperdifferentiated EM (TEMRA) CD 8T cells) (fig. 18B and 18C). Further, RBD stimulation mediated an increase in the population of C1 (IFN-g positive Tbet positive proliferating EM CD 4T cells) and C2 (proliferating Foxp3 positive EM CD 4T cells), but a decrease in the population of C3 (proliferating CD3 negative CD4 positive Foxp3 positive Tbet positive IL-2 positive cells) (fig. 18B and 18C). As a control, stimulation with rbd+ extract a mediated a dramatic increase in C1 population, but on the other hand, decreased C2 population (fig. 18B and 18C). This situation brings the hypothesis that extract a can modulate Treg/Th1 balance. The same phenomenon was also confirmed in 2 additional healthy donors (fig. 24).
Example 7 enhancement Effect in viral infection
In this example, it was confirmed that the composition and the like of the present invention have an enhancing effect in viral infections. Unless otherwise mentioned, the experimental procedure is based on the procedure described in example 5.
(enhancing anti-SARS-CoV-2 specific T cell response in SARS-CoV-2 insensitive PBMC by modulating Treg/Th1 balance.)
Recent studies by the present inventors have demonstrated that production of CD 4T cells from IFNγ mediates the anti-tumor effect of extract A in a mouse tumor model (Oka et al, 1999; oka et al, 2003; oka et al, 2004). Thus, the induction of a SARS-CoV-2 specific Th1 type immune response mediated by extract A in human PBMC obtained from SARS-CoV-2 insensitive individuals was analyzed. As a result, it was found that the combination of SARS-CoV-2 antigen with extract a significantly enhanced ifnγ production in human PBMC compared to the results observed with RBD or extract a alone in human PBMC (fig. 19A). Concerning ifnγ data of the supernatant, tSNE analysis and FACS analysis also showed: proliferation of ifnγ -producing Tbet-positive CD 4T cells (C1 population) was cumulatively induced by combined stimulation. This situation reveals that extract A enhances SARS-CoV-2 specific Th1 type T cell responses (FIGS. 19B and C). Furthermore, extract A also enhanced SARS-CoV-2 specific IFN gamma positive Tbet positive CD 8T cell proliferation in SARS-CoV-2 insensitive human PBMC (FIGS. 19D and 25).
Although tregs have been reported to have beneficial effects on viral infections comprising SARS-CoV-2, inhibition of the antimicrobial T cell response mediated by tregs may interfere with the expression of a potent antiviral T cell response (Meckiff et al 2020, bhela et al 2017,Anghelina et al, 2009, peng et al 2008). Thus, analysis of the modulation of tregs mediated by extract a, it was found that extract a inhibited activation of tregs induced by SARS-CoV-2 RBD. This situation reveals that extract A can induce potent anti-SARS-CoV-2T cell responses that are likely to control viral replication by modulating the Treg/Th1 balance (FIG. 19E). Furthermore, foxp3 positive central fluorescence intensity (MFI) in total CD 4T cells was enhanced upon stimulation with SARS-CoV-2 antigen and significantly reduced to the same level as that observed by stimulation with extract a. This case confirms: inhibition of regulatory T cells activated by SARS-CoV-2 antigen by extract A potentiates SARS-CoV-2 specific T cell response (FIG. 24C).
To further analyze the anti-SARS-CoV-2 specific T cell response mediated by extract A, a study of immune cell populations at an earlier time point (3 days after stimulation with SARS-CoV-2 antigen in the presence or absence of extract A) was performed by tSNE analysis. Since the culture period was short, the T cell population diluted with CTV pigment was not significantly observed, but a part of the proliferated innate immune cell population was confirmed to be (P1 and P2) when stimulated with extract a (fig. 26). Analysis of these cell populations in more detail showed that extract a stimulated proliferation of CD3 negative CD4 positive Tbet positive Foxp3 positive IL-2 positive and CD3 negative CD4 positive Tbet positive IL-2 positive naive immune subsets. A subset of the former observed high levels of IL-10 production upon stimulation with a combination of RBD and extract a and thus were likely to have inhibitory activity (fig. 26B-26E). However, the induction of IL-10 expression mediated by extract a was not correlated with an increase in the ratio of CD3 negative CD4 positive Tbet positive Foxp3 positive IL-2 positive subset, so there was a possibility of the presence of a further supply of IL-10 comprising other innate immune cells (which may be DC, or non-proliferating tregs (since no proliferation of tregs was observed on day 3 of Ctv dilution) etc. (fig. 26D and 26E). Further, the Bio-Plex analysis of the supernatant from the PBMC cultures showed that: RBD and extract A strongly induced IL-12p40 and IL-1 alpha production on day 3 after restimulation, and IL-17A production on days 6 in addition to IL-2, GM-CSF and TNF α production on days 3 and 6. This situation revealed that cytokines driven by these Th1 s are likely to contribute to the regulation of Th1/Treg balance mediated by extract a (fig. 27).
Adjuvants have the ability to disintegrate immune tolerance, stimulating a specific T cell response (e.g. Th 1/2/17) depending on the downstream pathway activated by the specific adjuvant (Temizoz et al, 2018). Since extract a contains both Mtb-related antigen and an adjuvant such as NOD2 that activates the innate immune receptor, the effect of extract a was compared with the effect of other adjuvants including K3CpG and LPS as Th-inducing adjuvants, and cGAMP (which can induce modulated Th1/2 type immune receptors) (Temizoz et al, 2016). For analysis of transcription factors 7 days after stimulation with SARS-CoV-2 antigen in the presence or absence of extract A or K3, human PBMC from healthy donors were subjected to intracellular staining, as demonstrated by this intracellular staining: extract a mediated a decrease in the ratio of Foxp3/Treg in EM CD 4T cells in addition to a decrease in the ratio of Treg with EM expression pattern (Foxp 3 positive CCR7 negative CD45RA negative CD 4T cells), but no such phenomenon was confirmed in K3 CpG. This case reveals that the modulating effect of extract a in Treg/Th1 is not solely caused by the adjuvant effect (fig. 28). Furthermore, RBD-induced ifnγ production from human PBMCs was only enhanced by extract a, unlike other adjuvants tested containing K3CpG, LPS and cGAMP (fig. 29). Specifically, RBD-induced proliferation of ifnγ -positive tnfα -positive CD4 and CD 8T cells was enhanced by addition of extract a, but not by addition of other adjuvants. These results indicate that: enhancement of the SARS-CoV-2 specific T cell response mediated by extract A is not solely dependent on the induction of training immunity mediated by the adjuvant contained in extract A (FIGS. 29B-29F).
Example 8 action of immunological memory in viral infection
In this example, in the verification of the technique of the present invention, it was confirmed that the immunological memory plays a role. Unless otherwise mentioned, the experimental procedure is based on the procedure described in example 5.
(the memory of existing Mtb-specific T cells is critical for promoting the anti-SARS-CoV-2-specific T cell response mediated by extract A.)
The above results concerning extract A were studied, and revealed that the antitumor effect of extract A required the existing Mtb memory, and that the data showing the anti-SARS-CoV-2 specific T cell response enhancement effect of extract A was not based solely on its adjuvant effect. Next, studies were made on whether the T cell response enhancing effect of extract a on SARS-CoV-2 antigen observed in SARS-CoV-2 insensitive human PBMC required pre-existing Mtb memory. Also, the effect of extract A on SARS-CoV-2 specific T cell responses in PBMC with different reactivity to either the Mtb antigen PPD or CMV antigen (Mtb non-associated antigen used as negative control) was analyzed. The result shows that: IFNγ induced by PPD and RBD+ extract A was strongly correlated not only between day 3 and day 6, but also between Tbet/Foxp3 MFI ratio and PPD number in EM CD 4T cells proliferated by RBD+ extract A (FIG. 20). Taken together, these results reveal: the existing Mtb memory was necessary to promote SARS-CoV-2 specific T cell responses mediated by extract a by modulating Th1/Treg ratios (figure 20). As a control, no strong correlation was confirmed between the T cell response induced by CMV and the T cell response induced by rbd+ extract a. This case confirms that the enhancement of anti-SARS-CoV-2 specific T cell response based on extract A specifically requires Mtb memory (FIG. 20). See table 3 and fig. 30 for information on the reactivity of PPD and CMV of commercially available frozen PBMCs provided by CTLs.
TABLE 3
TABLE 3 PPD and CMV response information of commercial frozen PBMC provided by CTL
While not wishing to be bound by theory, it is speculated that according to the above embodiments, the following is possible.
Since in vivo studies in the present invention were performed using depleted antibodies, and a variety of KO mice (e.g., RAG 2-deficient mice lacking immune cells comprising T cells, none), it was revealed that the antitumor effect of non-pathogenic antigen components (e.g., extract a) was entirely dependent on induction of xenogenic CD 4T cell responses, not on training immunity, and hardly on natural immune cells (see fig. 14 and 21). BCG and β -glucan were considered as agonists for training immunity according to Lardone et al and Kalafati et al, indicating that β -glucan induces an anti-tumor immune response by epigenetic regulation of granulocyte formation and neutrophil function in mice, while BCG trains tumor infiltrating M2 macrophages to enhance production of ifnγ derived from CD 4T cells in patients with melanoma (Lardone et al 2017;Kalafati et al, 2020). In the present invention, since the effect of extract a on the disease was not confirmed in RAG 2-deficient mice having neutrophils and macrophages, it is considered that such a training immune-related mechanism plays no important role in mediating the antitumor effect of extract a in the study model of the present invention. Furthermore, in the present invention, extract a was subcutaneously administered to the vicinity of a tumor, but based on various studies (Biot et al 2012) that confirmed the anti-tumor effect by BCG intratumoral injection on solid tumors (including bladder cancer), a more potent anti-tumor effect might be observed due to intratumoral administration. In the studies carried out according to Biot et al, protein antigens have still been found to be critical as active ingredients of extract a, as the reactivity to these protein antigens can be used as predictive markers of responsiveness of various disease patients to extract a immunotherapy. The discovery that the Mtb-derived antigen of the present invention can exert an effect against a disease is contrary to the above-described discovery, but a combination of a pathogenic antigen and a Th 1-stimulated pathogenic tumor-unrelated antigen may exert an effect against a disease more effectively than the conventional antigen-based immunotherapy.
Attenuated live vaccines and infections (smallpox, etc.) are well known to be mediated by long-lasting activation of memory B-cells or T-cells, while eliciting a firm immune response that lasts for years, even providing lifelong immunity (e.g., hammarlund et al, 2003). As shown in the present invention, mtb-reactive T cells caused by BCG vaccination in childhood or tubercle bacillus infection also persisted in adults (see fig. 17). Furthermore, the present invention demonstrates that: by utilizing an immune response generated by vaccination with a non-pathogenic antigen component such as an attenuated live vaccine, immunity against pathogenic agents can be induced. In the present invention, it is assumed that the immunological memory obtained from other infectious diseases is applied to therapeutic use. In the present invention, tumor regression was observed after Flu vaccine administration following influenza vaccine infection. Thus, such a heterogeneous immune memory response can also be applied to a variety of other infectious diseases including covd-19. In this specification, the main experiment was performed by immunizing animals with BCG, but other live vaccines (yellow fever or vaccinia, etc.) may also be used.
As one embodiment, the data obtained from CD4 and MHC class II deficient mice clearly indicate that CD 4T cells are required for the effect of extract A on disease, but that CD4 is even in the absence of extract A treatment + Depletion of cells also effectively promoted cure of the disease (fig. 14B, 14D and 14E). CD4 + The delay in tumor growth (compared to other WT mice) in cell depleted mice arises from inhibitory tregs mediated by anti-CD 4 antibodies (which are also CD4 + )。
As shown in the present invention, the expression of Tbet in mice is in Foxp3 + Cells are induced upon exposure to ifnγ (e.g., see lightani et al, 2001). Nonetheless, it is reported by Overacre-Delgoffe et al that Foxp3 in a tumor microenvironment was designated as fragile Treg + The population of tregs can produce ifnγ, inducing anti-tumor immunity by driving the onset of more ifnγ producing fragile tregs (Overacre-Delgoffe et al, 2017). According to the invention, tbet + Foxp3 + Immunosuppressive activity of cells is lower than that of Tbet-Foxp3 + Immunosuppressive activity of cells. In one embodiment of the invention, the total Foxp3 + The cell population increased in the population subjected to extract a treatment. Specifically, tbet-Foxp3 + The population of cells (with potent high immunosuppressive activity) increased slightly in the population treated with extract a, tbet + Foxp3 + The number of cells increases significantly. This indicates that the antitumor effect of extract a is not dependent on an increase in the number of Treg cells. As a control, levine et al will Tbet + Foxp3 + T cells are defined as stable T cells that specifically inhibit Th1 responses but do not inhibit Th2/17 responses (Levine et al, 2017). On the other hand, foxp3, which has reduced inhibitory activity and is therefore expressed friable + Tbet + IFNγ + Treg populations have been identified in patients with autoimmune diseases such as Multiple Sclerosis (MS) and type I diabetes (McClymont et al, 2011, domiiguez-Villar et al, 2011). Thus, in the case of fragile tregs activated systemically, there is a risk of autoimmune disease onset. Thus, in the case of application to cancer immunotherapy, it is desirable to specifically activate fragile tregs within the tumor microenvironment. Since extract A does not induce Tbet + Foxp3 + The proportion of T cells in the whole body varies considerably, so extract a is considered safe in terms of the risk of inducing autoimmune dependence on fragile tregs systemically (fig. 23).
In the present invention, when the protein derived from extract a is administered to BCG-immunized mice, an effect against the disease is successfully obtained, but the amount used is at least hundreds times that present in extract a. Although protein antigens are present at low concentrations, potent anti-tumor effects are mediated by extract A, which suggests that other components of extract A (various other Mtb-related antigens, metabolites such as STING agonists c-di-AMP, or a portion of natural immunostimulatory substances such as NOD2 agonists) accumulate with each other, and that an extract A-specific Th1 response that is effective in eradicating tumors may be enhanced. Indeed, experimental data obtained in this specification using NOD 2-deficient mice showed that extract a had a significant anti-tumor effect, which revealed that the NOD2 agonist present in extract a or BCG was required to mediate the anti-tumor effect of extract a (fig. 21H)). However, it is important that tumor growth in NOD 2-deficient mice is retarded compared to WT or other KO mice, which reveals that NOD2 itself contributes to tumor growth. Consistent with this hypothesis, biswas et al demonstrate that NOD2 can inhibit inflammation in the ileum driven by Th1 (Biswas et al, 2010). Since Th1 response is critical for tumor eradication, an increase in Th1 response in NOD 2-deficient mice is likely to prevent tumorigenesis. As a control, experimental data in this specification clearly show that: extract a contained STING agonist c-di-AMP derived from Mtb, which was critical for mediating the anti-tumor effect of extract a in BCG immunized mice (fig. 14J and 14K). Although c-di-AMP is produced by Mtb, no report has shown that extract a, which is a hot water extract of Mtb, contains c-di-AMP (Bai et al 2012). In the experimental data described in the present specification, it is expected that the hot water extract of Mtb contains c-di-AMP released by killing bacteria by heating in order to extract water-soluble substances by boiling BCG to release intracellular c-di-AMP-containing substances of live mycobacterium bovis (fig. 2K). Although the c-di-AMP found in the extract a solution injected at the concentrations used in the in vivo experiments of the present specification was low concentration (about 0.4 ng/injection), repeated injections of low amounts of STING agonist could produce synergistic effects with low amounts of other pathogen-associated molecular patterns (PAMPs) or lesion-associated molecular patterns (DAMPs), including microbial or tumor-derived nucleic acids, for inducing a robust anti-tumor immune response.
The PBMC culture protocol referred to in the present invention for evaluating the effect of extract a (including the enhancement of anti-SARS CoV-2T cell response observed in the examples of the present invention) included: to expand the population of SARS CoV-2 cross-reactive T cells (including normal coronavirus-specific T cells), stimulation with antigen was performed for 3 days. The number of these cells was low in healthy individuals without any stimulus (Grifoni et al 2020;Weiskopf et al, 2020;Le Bert et al, 2020;Mateus et al, 2020). Nevertheless, in the present invention, IL-2 was added to PBMC cultures 3 days after antigen stimulation, mediated by co-stimulation that did not induce high background proliferation, while maintaining the state of antigen-specific proliferating T cells surviving. This is consistent with the reports of Kennell et al, which show that the late addition of IL-2 increases the sensitivity of proliferation assays, while the background decreases (Kennell et al, 2014).
Although not limited thereto, in one embodiment, extract A reduces the number of EM tregs induced by SARS CoV-2, and increases the proliferation of IFNγ -producing Tbet+CD4T cells, based on these data, it is hypothesized that Mtb/ordinary coronavirus-specific tregs that are cross-reactive to SARS CoV-2 can be transformed into Th1 type T cells that produce IFNγ in response to SARS CoV-2. Although there is no direct evidence for this hypothesis, the IL-12 and IL-16 mediated transformation of CD25lowTreg (considered Foxp3 unstable) into Th1 cells was reported in a mouse model of herpes simplex virus-1 (HSV-1) infection, compared to CD25highTreg, which is resistant to Th1 transformation (Bhela et al, 2017). Nonetheless, these Foxp 3-unstable tregs are pathogenic to chronic HSV-1 infection. These data, as well as the beneficial effects of Treg in SARS CoV-2 infection (Meckiff et al 2020, bhela et al 2017) were studied and extract a was thought to exacerbate SARS CoV-2 disease. However, since extract a reduced the rate of proliferated strong antigen-specific tregs rather than completely depleting tregs, it is thought that treatment of mice with extract a did not reduce the number of whole-body tregs (figures S3 and S4C), and the likelihood of toxicity was low. As a control, su et al demonstrate that a decrease in Lymphocytic Choriomeningitis (LCMV) specific Treg was also confirmed as a negative correlation between the ratio of Treg and antigen specific memory T cells in hPBMC, in addition to the viral clearance in mice (Su et al 2016). However, inhibition of activation of tregs mediated by SARS CoV-2 is believed to be useful in supporting the induction of a powerful anti-SARS CoV-2T cell response (which may assist in efficient virus removal). Moreover, the inventors' hypothesis was supported by the following epidemiological observations and clinical trials: BCG vaccination is safer, can mediate protective effects against respirator infections caused by non-Mtb pathogens, and by reducing the severity and incidence of symptoms, it is possible to improve the prognosis of covd-19 (Hensel et al 2020;Moorlag et al, 2020; giamarellos-Bourboulis et al 2020). Additional or alternative other assumptions to the above-described transformation assumption from Treg to Th1 refer to: mtb/common coronavirus-specific memory T cells that are cross-reactive with SARS CoV-2 are due to Th 1-induced adjuvants (MDP, etc.) contained in extract a, whereas more tregs are mediated by SARS CoV-2 antigen than tregs (Girvan et al, 2011;Caruso et al, 2014;Prescott et al, 2020).
In one example of the invention, stimulation of hBMC with extract A for 3 days induces CD3 - CD4 + Tbet + Foxp3 + IL-2 + (P1) and CD3 - CD4 + Tbet + IL-2 + (P2) proliferation of a subset of innate immunity. The inventors consider that: the combination of SARS CoV-2 antigen in the supernatant of human PBMC with extract A stimulation resulted in elevated levels of Foxp3 expression and IL-10, thus allowing P1 cells to exhibit inhibitory capacity (FIG. 26). No significant production of IL-10 was observed by ELISA or FACS with stimulation with extract a alone, relative to the significant increase in proliferation of P1 population mediated by extract a on day 3. This indicates that there is an additional IL-10 supply activated by extract A, unknown, possibly containing other immune cells (even those that could be derived from DC, ILC or general coronavirus/Mtb specific Tregs, etc.). Indeed, immune-controlling cells such as MDSCs play a dual role in the regulation of viral infection and subsequent onset of concurrent tissue damage (dorkoi et al 2019;Amodio et al, 2019). For example, MDSCs have been reported to terminate antiviral immunity to dengue, LP-BM5 retrovirus (in the mouse AIDS model), and SARS CoV-2 by inhibiting an effective antiviral T cell response. (Green et al, 2013; guo et al, 2019,Sacchi et al, 2020,Reizine et al, 2021). In the case of SARS CoV-2, elevated levels of MDSC are associated with severe disease because of increased arginase activity, which in turn leads to T cell hypoproliferation and lymphopenia (ameliorated by arginine supplementation) (Reizine et al 2021). And in (with Japanese etc.) Higher mortality in country compared to covd-19) the findings in european conducted studies, according to Takano et al, on japanese, polymorphonuclear (PMN) -MDSC that transiently dilate proliferation was observed in severe survivors of covd-19, but not in non-survivors. This situation reveals that: transient PMN-MDSCs help to regulate severe inflammation in patients with COVID-19 (Takano et al, 2021). As a control, activation of immunoregulatory cells and induction of expression of IL-10 mediated by extract a (also observed in the present invention implemented with PBMCs) occurred at an earlier stage than a strong memory Th1 response occurred. Thus, in addition to a potent Th1 response, activation of such an immunomodulatory pathway is also important to prevent concurrent tissue damage, which may occur in the event of a runaway of these potent immune responses. Consistent with the inventors' hypothesis, lessard et al found that: inflammatory LY6Chigh monocytes can be converted to LY6Clow patrol monocytes by treatment of mice with MDP, which can produce the immunomodulatory cytokines IL-10 and tgfβ in a NOD2 dependent manner while alleviating LPS-mediated inflammation in vivo (lesard et al, 2017). And, the Bio-plex analysis of the PBMC culture supernatant in the present invention showed that: RBD and extract a strongly induced expression of Th 1-inducible cytokines tnfα, IL-1α and IL-12 on day 3 (fig. 27). Indeed, shibuya et al report that IL-1α and TNFα are required for induction of Th1 responses induced by IL-12 by using an in vitro differentiation system, and TCRαβ transgenic mice specifically recognizing OVA or egg lysozyme (Shibuya et al, 1998). Furthermore, the expression of Th 1-related cytokines IL-2 and IFNγ was strongly induced by the combination of extract A and RBD on day 6, indicating that a strong Th1 response was induced (FIGS. 7 and S7). Nevertheless, extracts A and RBD also mediate the production of IL-17A from hBMC on day 6 after re-stimulation of RBD, which reveals induction of Th17 responses (FIG. 27). BCG vaccination or Mtb vaccine derived from BCG is known to induce Th17 responses, and since extract a contains antigens derived from Mtb, the expected outcome is related to the generation of Th17 responses mediated by extract a (Gopal et al 2012,De Cassan et al, 2010). On the other hand, I induced by BCG vaccine Expression of L-17A is one of the mechanisms necessary for Th1 response to occur by inhibiting Mtb-mediated inhibitors such as IL-10 secretion in vivo (golal et al 2012).
Bacterial and mushroom extracts (including Coley toxin) are thought to exhibit immune-boosting-based anti-tumor effects by stimulating natural immune receptors such as TLR4 (Thotathil and Jameson,2007;Mourits et al, 2018). On the contrary, the inventors and the like understand that: the Mtb hot water extract induces potent effects against diseases in animal models having BCG memory in advance, which induction is considered to include a mechanism of Mtb antigen-specific Th1 type T cell responses mediated by Mtb antigens as non-pathogenic antigen molecules derived from extract a, and cross-reacts with other diseases. Furthermore, the STING agonists derived from Mtb found in extract a are also important in mediating the effect of extract a against disease. Furthermore, by observing the effect of influenza vaccine on disease in influenza virus immunized animals, it can be shown that: the xenogeneic T cell response induced by non-pathogenic antigenic molecules is effective not only against specific tumors or infections, but also against the development of various types of pathogens of unrelated nature. In agreement with this, the inventors' data also demonstrate that extract A derived from Mtb can express or potentiate a heterogeneous T cell response that can cross-react with SARS-CoV-2 in SARS-CoV-2 insensitive individuals with pre-existing Mtb memory. Which indicates the following assumption: protective immune responses against SARS-CoV-2 can be induced by vaccination with substances derived from tubercle bacillus. In addition, it is considered that immunization (vaccination) with an pandemic pathogenic agent (e.g., SARS-CoV-2) supplemented with extract A as an adjuvant without performing BCG vaccination when combating pandemic such as COVID-19 is a safer method, considering that BCG is not suitable for repeated administration. The reason for this is that: for multiple systemic administration, extract a was safer than BCG. Especially in the case of humans, safety is of paramount importance. BCG history or vaccination history based on tuberculosis infection may bring about a local or systemic detrimental effect of immunization including spread of BCG infection to immunocompromised individuals (Venkataraman et al 2015;Whelan et al, 2009). However, extract a nonetheless is a favorable tool for immunotherapy against allergy administration as a powerful inducer of type 1 immunity. The reason for this is that: allergy-related type 2 immunity (Gieseck et al, 2018) can be reduced or avoided.
( Example 9: prevention and treatment of bacterial infections, reinfection prevention and treatment )
In this example, prevention, reinfection prevention, and/or treatment of bacterial infections were validated.
(method)
In the prevention of bacterial infections (e.g., bacterial conjunctivitis, etc.), a subject not suffering from bacterial infections is administered with an antigen that is a causative agent of bacterial infections and extract a.
In the prevention and/or treatment of recurrence of bacterial infections (e.g., bacterial conjunctivitis, etc.), extract a is administered to a subject who has suffered from a bacterial infection, and/or is suffering from a bacterial infection.
After administration, prognostic observation of bacterial infections in subjects is carried out by techniques customary in the art.
( Example 10: prevention and treatment of parasitic infections )
In this example, prevention, reinfection prevention, and/or treatment of parasitic infections were validated.
(method)
In the prevention of parasitic infections (e.g., acanthamoeba keratitis, etc.), a pathogen antigen of parasitic infections and extract a are administered to a subject not suffering from parasitic infections.
In the prevention and/or treatment of recurrence of parasitic infections (e.g., acanthamoeba keratitis, etc.), extract a is administered to a subject who has suffered from a parasitic infection, and/or is suffering from a parasitic infection.
After administration, prognostic observation of parasitic infection in the subject is carried out by techniques customary in the art.
( Example 11: infection prevention, disease onset prevention, reinfection prevention, and treatment of viral infections )
In this example, clinical trials of infection prevention, morbidity prevention, reinfection prevention, and/or treatment of viral infections are conducted.
(method)
(specificity of non-pathogenic antigen)
Peripheral Blood Mononuclear Cells (PBMCs) were isolated from the onset of viral infection, from the non-onset of viral infection (viral antigen was confirmed but asymptomatic or viral infection had healed), and from normal subjects. An antigen response profile is specified by determining the vaccination history, and/or infection history, of the subject. The history of vaccination and infection may include, but is not limited to, tuberculosis, malaria, yellow fever virus, smallpox virus, seed pox, measles/rubella, polio, MUMPS (adofurosis)/MUMPS, rotavirus infection, varicella (chicken pox), yellow fever, ebola virus (Ebola), west nile fever, haemophilus influenzae type b infection, pneumococcal infection, pertussis, japanese encephalitis, meningococcal infection, salmonella infection, pathogenic escherichia coli, toxoplasmosis, zika virus (Zika virus), herpes virus type 1, EBV/epstein-barr virus (herpes virus type 4), CMV/cytomegalovirus (herpes virus type 5), influenza (virus), MARS, rabies, diphtheria, and the like.
The PBMC isolated as described above (e.g., 1.0X10) are treated with extract A (0.01. Mu.g/mL to 1 mg/mL) or an extract comprising extract A (0.01. Mu.g/mL to 1 mg/mL) 4 Cell to 1.0X10 6 Cells) are stimulated for about 6 to 24 hours, and cytokine production (e.g., IFN-gamma, IL-2, and/or TNF-alpha, etc.) is determined by detection methods (e.g., ELISA, qPCR, FACS, etc.) that are conventional in the art. A subject whose cytokine production amount after stimulation is 2 times or more the cytokine production amount before stimulation is selected as a Responder (Responder). However, the selection of the subject is not necessarily performed.
(administration of extract A in the onset of viral infection or in subjects who have been cured of viral infection)
The clinical effectiveness was evaluated by administering extract a to subjects who developed viral infections, did not develop viral infections (no symptoms or cured viral infections were confirmed to have viral antigens), and were normal according to the following administration protocol.
The group is composed of: placebo or extract A (about 0.001 μg/1 to about 1 mg/1) or extract containing extract A (about 0.001 μg/1 to about 1mg/1 in terms of extract A) was used in 2 amounts
Number of subjects: about 100 to 1000
Route of application: SC (subcutaneous administration) or IM (intramuscular administration) or ID (intradermal administration)
Number of applications: about 1 time per day (week 1), about 1 time per week (week 2 and later)
During application: 1 time to about 1 year
Evaluation item: the virus clearance, time required for confirming the negative change of virus genome, fever period, time required for improving symptoms (fever, cough, pharyngalgia, headache, myalgia or arthralgia, cold or sweating, listlessness or tiredness, dyspnea, disturbance of consciousness, runny nose, chest pain, diarrhea, nausea and vomiting, etc.), severe and mortality, antibody change ratio in serum, artificial respirator/ECMO use, image improvement ratio, time-lapse-based WBC and white blood cell percentage, hemoglobin, platelet, creatinine, glucose, total bilirubin, ALT, PT, etc., patient ratio of each degree of severe based on sequence standard more than 1 item among items from the time required for improvement up to oxidation, the kind, frequency and severity of adverse events, the number and proportion of infected persons, the time from infection to onset, the time from appearance of symptoms to disappearance of PCR positives, the days from appearance of symptoms to improvement of symptoms, the presence or absence of severe symptoms (hospitalization with oxygen inhalation), the presence or absence of severe diseases (a state requiring mechanical ventilation, shock state, or ICU management necessary for organ failure other than lung), the fluctuation of serum antibody titer against antigen from baseline, the fluctuation of IFN- γ against antigen from baseline, the kind, frequency and severity of adverse events was taken as evaluation items.
(results)
All evaluation items can observe examples in which the group to which the non-pathogenic antigen was administered was more remarkably effective than the placebo group and was effective in the range of the amount in which the test was conducted.
(administration of pathogenic agent antigen and extract A in normal subjects)
In the case of normal subjects, the causative agent of viral infection, and extract a, were administered according to the following administration protocol, and the clinical effectiveness was evaluated.
The group is composed of:
(1) Placebo
(2) Extract A (about 0.001 μg/1 to about 1 mg/1) or extract containing extract A (about 0.001 μg/1 to about 1mg/1 in terms of extract A) was used in 2 amounts
(3) Individual causative agents of viral infections
(4) The causative agent of viral infection, extract A (about 0.001 μg/1 to about 1 mg/1) or extract containing extract A (about 0.001 μg/1 to about 1mg/1 in terms of extract A) is used in 2 amounts
Number of subjects: about 100 to 30,000
Route of application: SC (subcutaneous administration) or IM (intramuscular administration) or ID (intradermal administration)
Number of applications: 1 time (week 1), 1 time from week 1 to week 4 thereafter as needed
During application: 1 to 10 times (in the case of prevention, the tracking period after the end of administration is 1 month to 1 year or more)
Evaluation item: the number and proportion of the infected persons, the time from infection to onset, the time from appearance of symptoms to disappearance of PCR positives, the number of days from appearance of symptoms to improvement of symptoms, the presence or absence of serious illness (hospitalization with oxygen inhalation), the presence or absence of serious illness (state requiring mechanical ventilation, shock state, or ICU management necessary for organ failure other than lung), the fluctuation of serum antibody titer against antigen from baseline, the fluctuation of IFN- γ against antigen from baseline, the kind, frequency, and severity of adverse events were evaluated as evaluation items.
(results)
All evaluation items were observed: examples of non-pathogenic antigens that are administered in combination with viral infectious agents that are more significantly effective than either placebo or viral infectious agents alone, and that are effective in the range of amounts used in the test.
( Example 12: prevention and treatment of allergies, prevention of recurrence )
In this example, prevention, relapse prevention, and/or treatment of allergies were validated.
(method)
In the prevention of allergies (e.g., allergic conjunctivitis, etc.), an allergic pathogen antigen and extract a are administered to a subject who does not have an allergic pathogen antigen.
In the prevention and/or treatment of recurrence of allergies (e.g., allergic conjunctivitis, etc.), extract a is administered to a subject already having an allergic pathogenic antigen, and/or having an allergic pathogenic antigen.
After administration, prognostic observation of the allergic response in the subject is carried out by techniques customary in the art.
( Example 13: prevention and treatment of autoimmune diseases, relapse prevention and treatment )
In this example, prevention, relapse prevention, and/or treatment of autoimmune disease was validated.
(method)
In the prevention of autoimmune diseases (e.g., autoimmune uveitis), a pathogen antigen of an autoimmune disease and extract a are administered to a subject who does not have a pathogen antigen of an allergic reaction.
In the prevention and/or treatment of recurrence of an autoimmune disease (e.g., autoimmune uveitis), extract a is administered to a subject already having an antigen that is a causative agent of the autoimmune disease, and/or having an antigen that is a causative agent of the autoimmune disease.
After administration, prognostic observation of autoimmune disease in the subject is carried out by techniques customary in the art.
Example 14 preparation
(1) In the case of a single dose of only the antigen component of a non-pathogenic agent, which is neither derived nor cross-reactive with the pathogenic agent of the disease
A stock solution of extract A was prepared according to the method described in < preparation example >. The stock solution of the prepared extract a was diluted 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, 1,000-fold, 2,000-fold, 3,000-fold, 4,000-fold, 5,000-fold, 6,000-fold, 7,000-fold, 8,000-fold, 9,000-fold, 10,000-fold, 20,000-fold, 30,000-fold, 40,000-fold, 50,000-fold, 60,000-fold, 70,000-fold, 80,000-fold, 90,000-fold, or 100,000-fold, to a concentration suitable for administration. Thereafter, japanese pharmacopoeia sodium chloride was mixed so that the final concentration became 0.9%, sterilized by a method such as autoclave, and then formulated into a proper dosage form.
(2) In the case of a combination of a pathogenic antigen component (which is derived from and/or cross-reacts with a pathogenic agent of a target disease in a subject) and a non-pathogenic antigen component (which is neither derived from nor cross-reacts with a pathogenic agent of the disease)
The stock solution of extract A was diluted to a concentration suitable for administration according to the method described in < (1) for the case of a single dose of only non-pathogenic antigen component, which neither originates from nor cross-reacts with the pathogenic agent of the disease. Thereafter, japanese pharmacopoeia sodium chloride was mixed so that the final concentration became 0.9%. Thereafter, after sterilization by an autoclave or the like, spike proteins of coronaviruses are added so as to be at an appropriate final concentration, and the resulting composition is formulated into an appropriate dosage form.
Alternatively, extract A and coronavirus spike protein may be separate formulations, in which case extract A is formulated into an appropriate formulation according to the method described in < (1) single dose of non-pathogenic antigenic components (neither originating from nor cross-reacting with the pathogenic agent of the disease). The spike protein of coronavirus may be prepared and formulated in addition, and other company products may be used.
( Example 15: treatment/prevention including companion diagnosis )
An example of treatment and prevention with concomitant diagnosis of a subject (human) desiring to be vaccinated is shown.
Peripheral Blood Mononuclear Cells (PBMCs) are isolated from human subjects (which may include subjects suffering from viral infections, not suffering from viral infections (viral antigens are confirmed but asymptomatic or viral infections have been cured), and normal subjects) for which a vaccine effect or treatment based on the present invention is expected.
For the immunological memory (immune response) of the above-mentioned subject, the antigen response profile is specified by examination of tuberculosis infection by tuberculin reaction examination, gamma interferon release test or the like, mother and child health manual or its equivalent or medical record, other medical information (information recorded by the electronization of the subject stored in the cloud, electronic chip or the like may be used).
The PBMC isolated as described above (e.g., 1.0X10) are treated with extract A (0.01. Mu.g/mL to 1 mg/mL) or an extract containing extract A (0.01. Mu.g/mL to 1 mg/mL) 4 Cell to 1.0X10 6 Cells) are stimulated for about 6 to 24 hours, and cytokine production (e.g., IFN-gamma, IL-2, and/or TNF-alpha, etc.) is determined by detection methods (e.g., ELISA, qPCR, FACS, etc.) that are conventional in the art. A human subject whose cytokine production after stimulation is a standard threshold (for example, 1.1 times or more, 1.2 times or more, 1.3 times or more, 1.4 times or more, 1.5 times or more, 1.6 times or more, 1.7 times or more, 1.8 times or more, 1.9 times or more, 2 times or more, 3 times or more, 4 times or more, 5 times or more, 6 times or more, 7 times or more, 8 times or more, 9 times or more, or 10 times or more, preferably 2 times or more) of the cytokine production before stimulation is selected as an inoculation subject.
The vaccination schedule may be suitably carried out, for example, additional immunizations may be carried out at appropriate times such as 1 week apart after administration.
(results)
It was confirmed that the infection was less likely to occur than before inoculation.
( Example 16: treatment/prevention including companion diagnosis )
An example of treatment/prevention with concomitant diagnosis for a subject (human) for whom preventive vaccination is determined is shown.
Peripheral Blood Mononuclear Cells (PBMCs) are isolated from human subjects (which may include subjects suffering from viral infections, not suffering from viral infections (viral antigens are confirmed but asymptomatic or viral infections have been cured), and normal subjects) for which a vaccine effect or treatment based on the present invention is expected.
The immune memory (immune response) of the subject is objectively checked by a tuberculin response test, a gamma interferon release test, or the like (if objectivity is ensured, an antigen response profile is specified by a mother-son health manual, an equivalent thereof, medical records, or other medical information (information recorded electronically by the subject and stored in a cloud, an electronic chip, or the like).
The PBMC isolated as described above (e.g., 1.0X10) are treated with extract A (0.01. Mu.g/mL to 1 mg/mL) or an extract containing extract A (0.01. Mu.g/mL to 1 mg/mL) 4 Cell to 1.0X10 6 Cells) are stimulated for about 6 to 24 hours, and cytokine production (e.g., IFN-gamma, IL-2, and/or TNF-alpha, etc.) is determined by detection methods (e.g., ELISA, qPCR, FACS, etc.) that are conventional in the art. A human subject whose cytokine production after stimulation is a standard threshold (for example, 1.1 times or more, 1.2 times or more, 1.3 times or more, 1.4 times or more, 1.5 times or more, 1.6 times or more, 1.7 times or more, 1.8 times or more, 1.9 times or more, 2 times or more, 3 times or more, 4 times or more, 5 times or more, 6 times or more, 7 times or more, 8 times or more, 9 times or more, or 10 times or more, preferably 2 times or more) of the cytokine production before stimulation is selected as an inoculation subject.
The vaccination schedule may be suitably carried out, for example, additional immunizations may be carried out at appropriate times such as 1 week apart after administration.
(results)
It was confirmed that the infection was less likely to occur than before inoculation.
( Example 17: treatment/prevention including companion diagnosis )
An example of treatment and prevention with concomitant diagnosis for a subject (human) desiring preventive vaccination is shown.
Peripheral Blood Mononuclear Cells (PBMCs) are isolated from human subjects (which may include subjects suffering from viral infections, not suffering from viral infections (viral antigens are confirmed but asymptomatic or viral infections have been cured), and normal subjects) for which a vaccine effect or treatment based on the present invention is expected.
By using tuberculin response test, the immunological memory (immune response) of the subject is objectively confirmed, thereby specifying the antigen response profile.
The PBMC isolated as described above (e.g., 1.0X10) are treated with extract A (0.01. Mu.g/mL to 1 mg/mL) or an extract containing extract A (0.01. Mu.g/mL to 1 mg/mL) 4 Up to 1.0X10 6 Cells) are stimulated for about 6 to 24 hours, and cytokine production (e.g., IFN-gamma, IL-2, and/or TNF-alpha, etc.) is determined by detection methods (e.g., ELISA, qPCR, FACS, etc.) that are conventional in the art. A human subject whose cytokine production after stimulation is a standard threshold (for example, 1.1 times or more, 1.2 times or more, 1.3 times or more, 1.4 times or more, 1.5 times or more, 1.6 times or more, 1.7 times or more, 1.8 times or more, 1.9 times or more, 2 times or more, 3 times or more, 4 times or more, 5 times or more, 6 times or more, 7 times or more, 8 times or more, 9 times or more, or 10 times or more, preferably 2 times or more) of the cytokine production before stimulation is selected as an inoculation subject.
The vaccination schedule may be suitably carried out, for example, additional immunizations may be carried out at appropriate times such as 1 week apart after administration.
(results)
It was confirmed that the infection was less likely to occur than before inoculation.
( Example 18: treatment/prevention including companion diagnosis )
An example of treatment and prevention with concomitant diagnosis for a subject (human) desiring preventive vaccination is shown.
Peripheral Blood Mononuclear Cells (PBMCs) are isolated from human subjects (which may include subjects suffering from viral infections, not suffering from viral infections (viral antigens are confirmed but asymptomatic or viral infections have been cured), and normal subjects) for which a vaccine effect or treatment based on the present invention is expected.
The immune memory (immune response) of the above subjects was targeted to specific antigen response profiles by gamma interferon release assays.
The PBMC isolated as described above (e.g., 1.0X10) are treated with extract A (0.01. Mu.g/mL to 1 mg/mL) or an extract containing extract A (0.01. Mu.g/mL to 1 mg/mL) 4 Cell to 1.0X10 6 Cells) are stimulated for about 6 to 24 hours, and cytokine production (e.g., IFN-gamma, IL-2, and/or TNF-alpha, etc.) is determined by detection methods (e.g., ELISA, qPCR, FACS, etc.) that are conventional in the art. A human subject whose cytokine production after stimulation is a standard threshold (for example, 1.1 times or more, 1.2 times or more, 1.3 times or more, 1.4 times or more, 1.5 times or more, 1.6 times or more, 1.7 times or more, 1.8 times or more, 1.9 times or more, 2 times or more, 3 times or more, 4 times or more, 5 times or more, 6 times or more, 7 times or more, 8 times or more, 9 times or more, or 10 times or more, preferably 2 times or more) of the cytokine production before stimulation is selected as an inoculation subject.
The vaccination schedule may be suitably carried out, for example, additional immunizations may be carried out at appropriate times such as 1 week apart after administration.
(results)
It was confirmed that the infection was less likely to occur than before inoculation.
(annotation)
In view of the foregoing, the application has been exemplified using its preferred embodiments, it is to be understood that the application should be construed solely in view of the claims. Patents, patent applications, and other documents cited in this specification are to be understood as being incorporated by reference into this specification as if the content itself were specifically set forth in this specification. The present application claims priority from International application PCT/JP2021/005951 filed by International Business office at 2021, month 2, month 17 and Japanese patent application No. 2021-208598 filed by Japanese patent office at 2021, month 12, month 22, and is understood to be incorporated herein by reference in its entirety.
Industrial applicability
The present application provides a method for preventing and treating diseases such as infections based on a mechanism which has not been conventionally known.
Claims (110)
1. A composition for preventing or treating an infectious disease, an allergic reaction and/or an autoimmune disease, comprising a non-pathogenic antigen component which is neither derived from nor cross-reactive with a pathogenic agent of the infectious disease, allergic reaction and/or autoimmune disease in a subject,
The composition has the following characteristics:
1) Confirming that the subject has an immune response against the non-pathogenic agent;
2) In the event that the subject has the immune response, the composition is administered to the subject.
2. A composition for preventing or treating an infectious disease, comprising a non-pathogenic antigenic component which is neither derived from nor cross-reactive with a pathogenic agent of the infectious disease of a subject,
the composition has the following characteristics:
1) Confirming that the subject has an immune response against the non-pathogenic agent;
2) In the event that the subject has the immune response, the composition is administered to the subject.
3. A composition for preventing or treating an infection other than tuberculosis in a subject, wherein the composition comprises a hot water extract of Bacillus tuberculosis or a portion thereof,
the composition has the following characteristics:
1) Confirming that the subject has an immune response against tuberculosis;
2) In the event that the subject has the immune response, the composition is administered to the subject.
4. A composition according to claim 3, wherein the hot water extract of mycobacterium tuberculosis or a part thereof is a hot water extract of human mycobacterium tuberculosis qingshan B strain.
5. Composition according to claim 3 or 4, wherein the hot water extract of tubercle bacillus or a part thereof is extract a.
6. The composition of any one of claims 1 to 5, wherein the composition is administered in an amount effective to produce IL-10.
7. The composition of any one of claims 1 to 6, wherein the infection is a viral infection.
8. The composition of any one of claims 1 to 7, wherein the infection is a viral infection associated with a coronavirus.
9. The composition of any one of claims 1 to 8, wherein the immune response is objectively confirmed.
10. The composition of claim 9, wherein the objective confirmation of the immune response is confirmed by a tuberculin response test or a gamma interferon release test-based test, or objective information contained in a mother-son health manual or equivalent thereof, medical records, or other medical information.
11. The composition of any one of claims 1 to 10, wherein the immune response is examined by a tuberculin response test or a gamma interferon release test.
12. The composition according to any one of claims 1 to 10, wherein the non-pathogenic antigen component, or a hot water extract of tubercule bacillus or a part thereof, is administered to the subject in advance in case the subject does not have the immune response, and then the composition is administered to the subject in case it is confirmed that the subject has the immune response.
13. The composition of claim 11, wherein the prior administration is repeated until the subject has the immune response.
14. The composition of claim 11 or 12, wherein the prior administration is administration before or after the infection is afflicted.
15. The composition of claim 13, wherein the prior administration is administration after the infection is afflicted with.
16. The composition according to any one of claims 1 to 14, wherein the composition is administered in the presence of a pathogenic antigen component derived from and/or cross-reactive with the pathogenic agent.
17. A composition for preventing or treating a disease comprising a non-pathogenic antigen component that is neither derived from nor cross-reactive with a pathogenic agent of the disease, the composition being administered in the presence of a pathogenic antigen component that is derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject.
18. The composition of claim 17, wherein the pathogenic agent comprises a foreign substance to the subject.
19. The composition of claim 17 or 18, wherein the causative agent of the disease comprises causative agent of an infectious disease, causative agent of an allergic reaction, causative agent of an autoimmune disease, or poison.
20. The composition of any one of claims 17 to 19, wherein the disease is an infection.
21. The composition of any one of claims 17 to 20, wherein the subject has an immunological memory for the non-pathogenic antigenic component.
22. The composition of any one of claims 17 to 21, wherein the composition comprises the pathogenic antigen component.
23. The composition of any one of claims 17 to 22, wherein the composition is for use in preventing the disease.
24. The composition of any one of claims 17 to 23, wherein the composition prevents or treats the disease in a form that is not accompanied by or reduces an immune overreaction.
25. The composition of any one of claims 17 to 24, wherein the composition is administered in a form effective for controlling cellular immunity, which is cellular immunity to a causative agent of the disease.
26. The composition of any one of claims 17 to 25, wherein the presence or absence of a pathogenic agent antigen component in the subject is confirmed and, in the absence, the pathogenic agent antigen component is administered together with the non-pathogenic agent antigen component, the pathogenic agent antigen component being derived from and/or cross-reactive with a pathogenic agent of a target disease.
27. The composition of any one of claims 17 to 26, wherein the disease is an infection, allergy or autoimmune disease.
28. The composition of any one of claims 17 to 27, wherein the disease is a viral or bacterial infection.
29. The composition of any one of claims 17 to 28, wherein the disease is a viral infection.
30. The composition of any one of claims 17 to 29, wherein the disease is an infection associated with a coronavirus.
31. The composition of any one of claims 17 to 30, wherein the pathogenic antigen component is a molecule that is at least partially present on the surface of a pathogenic agent of a target disease.
32. The composition of any one of claims 17 to 31, wherein the non-pathogenic antigenic component is a hot water extract of mycobacterium tuberculosis or a portion thereof.
33. The composition of any one of claims 17 to 32, wherein the non-pathogenic antigenic component is a hot water extract of human mycobacterium tuberculosis qingshan B strain or a portion thereof.
34. The composition of any one of claims 17 to 33, wherein the non-pathogenic antigen component is extract a.
35. A composition according to any one of claims 17 to 34, wherein the non-pathogenic antigen component comprises a STING agonist derived from mycobacterium tuberculosis, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb associated antigen, a component capable of biosynthesis of STING agonists in human cells, or a NOD2 agonist.
36. The composition of any one of claims 17 to 35, wherein the non-pathogenic antigen component comprises a STING agonist derived from mycobacterium tuberculosis, the STING agonist being c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing 2'3' -cGAMP in human cytoplasm mediated by cGAS.
37. The composition of any one of claims 17 to 36, wherein the non-pathogenic antigen component is administered more than twice.
38. The composition of any one of claims 17 to 37, wherein the composition has the following characteristics:
1) Identifying the subject as having an immune response against the non-pathogenic agent;
2) In the event that the subject has the immune response, the composition is administered to the subject.
39. The composition of claim 38, wherein the immune response is objectively confirmed.
40. The composition of claim 38 or 39, wherein the objective confirmation of the immune response is confirmed by a tuberculin response test or a gamma interferon release test-based test, or objective information contained in a mother-son health manual or equivalent thereof, medical records, or other medical information.
41. The composition of any one of claims 38 to 40, wherein the immune response is examined by a tuberculin response test or a gamma interferon release test.
42. The composition of any one of claims 38 to 41, wherein the non-pathogenic antigen component or a hot water extract of tubercule bacillus or a portion thereof is administered to the subject in advance in the event that the subject does not have the immune response, and then the composition is administered to the subject in the event that the subject is confirmed to have the immune response.
43. The composition of claim 42, wherein said pre-administration is repeated until said subject has said immune response.
44. The composition of claim 42 or 43, wherein the prior administration is administration prior to or after the infection is afflicted with.
45. The composition of any one of claims 42 to 44, wherein the prior administration is administration after the infection is afflicted with.
46. A combination, characterized in that it is a combination of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject, and a non-pathogenic antigen component derived from or cross-reactive with neither the pathogenic agent of the disease.
47. The combination of claim 46, wherein the pathogenic antigen component comprises a pathogenic agent of an infectious disease, a pathogenic agent of an allergic reaction, a pathogenic agent of an autoimmune disease, or a poison.
48. The combination of claim 46 or 47, wherein the pathogenic antigen component is a bacterium, a virus, or a protozoan or a portion thereof.
49. The combination of any one of claims 46 to 48, wherein the pathogenic antigen component is a virus or a part thereof.
50. The combination of any one of claims 46 to 49, wherein the pathogenic antigen component is a virus belonging to the family coronaviridae or a portion thereof.
51. The combination of any one of claims 46 to 50, wherein the pathogenic agent is a virus belonging to the family selected from the group consisting of rhinoviruses, adenoviruses, coronaviruses, RS viruses, influenza viruses, parainfluenza viruses and enteroviruses.
52. The combination of any one of claims 46 to 51, wherein the pathogenic agent is a virus belonging to the genus coronavirus b.
53. The combination of any one of claims 46 to 51, wherein the pathogenic agent is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2.
54. The combination of any one of claims 46 to 51, wherein the pathogenic agent is SARS-CoV-2 virus.
55. The combination of any one of claims 46 to 49, wherein the non-pathogenic antigen component is a hot water extract of mycobacterium tuberculosis or a portion thereof.
56. The combination of any one of claims 46 to 55, wherein the non-pathogenic antigen component is a hot water extract of strain B of human mycobacterium tuberculosis or a portion thereof.
57. The combination of any one of claims 46 to 56, wherein the non-pathogenic antigen component is a hot water extract of mycobacterium tuberculosis or a portion thereof.
58. The combination of any one of claims 46 to 57, wherein the non-pathogenic antigen component is a hot water extract of strain B of human mycobacterium tuberculosis or a portion thereof.
59. The combination of any one of claims 46 to 57, wherein the hot water extract of mycobacterium tuberculosis or a portion thereof is extract a.
60. The combination of any one of claims 46 to 57, wherein the hot water extract of tubercule bacillus or a portion thereof comprises a STING agonist, lpqH, Y1269, PPD, CMV pp65 overlapping peptide, mtb associated antigen, STING agonist or NOD2 agonist derived from tubercule bacillus.
61. A combination according to any one of claims 46 to 57, wherein the hot water extract of tubercule bacillus, or a portion thereof, comprises a STING agonist derived from tubercule bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
62. The combination of claim 55 or 56, wherein the non-pathogenic antigen component is administered more than twice.
63. The combination of any one of claims 55 to 62, wherein the pathogenic antigen component is a pathogenic agent of an infection and the non-pathogenic antigen component functions as an adjuvant when the pathogenic antigen component is used as a vaccine.
64. The combination of any one of claims 46 to 63, wherein the combination has the following characteristics:
1) Identifying the subject as having an immune response against the non-pathogenic agent;
2) In the event that the subject has the immune response, one or both of the combinations are administered to the subject.
65. The combination of claim 64, wherein the immune response is objectively confirmed.
66. The combination of claim 64 or 65, wherein the objective confirmation of the immune response is confirmed by a tuberculin response test or a test based on a gamma interferon release test, or objective information contained in a mother-son health manual or equivalent thereof, medical records, or other medical information.
67. The combination of any one of claims 64 to 66, wherein the immune response is examined by a tuberculin response test or a gamma interferon release test.
68. The combination of any one of claims 64-67, wherein the non-pathogenic antigen component or a hot water extract of mycobacterium tuberculosis or a portion thereof is administered to the subject in advance in the event that the subject does not have the immune response, and then the combination is administered to the subject in the event that the subject is confirmed to have the immune response.
69. The combination of claim 68, wherein the prior administration is repeated until the subject has the immune response.
70. The combination of claim 68 or 69, wherein the prior administration is administration prior to or after the infection is afflicted with.
71. The combination of any of claims 68-70, wherein the prior administration is administration after the infection is afflicted with.
72. A medicament for preventing or treating a disease, comprising a combination of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject and a non-pathogenic antigen component derived from or cross-reactive with neither the pathogenic agent of the disease.
73. The medicament of claim 72, wherein the medicament further comprises the features of any one or more of claims 64 to 71.
74. A kit for preventing or treating a disease, comprising a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease in a subject, and a non-pathogenic antigen component that is neither derived from nor cross-reactive with a pathogenic agent of the disease.
75. The kit of claim 74, wherein the kit further comprises the features of any one or more of claims 64 to 71.
76. A method for preventing or treating a disease in a subject, comprising the steps of:
administering to the subject an effective amount of a non-pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of the disease in the subject in the presence of a pathogenic antigen component that is neither derived from nor cross-reactive with a pathogenic agent of the disease.
77. The method of claim 76, wherein the method further comprises the features of any one or more of claims 64 to 71.
78. A method for preventing or treating a disease in a subject, comprising the steps of:
administering to the subject an effective amount of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of the disease; and
administering to the subject an effective amount of a non-pathogenic antigen component that is neither derived from nor cross-reactive with a pathogenic agent of the disease.
79. The method of claim 78, wherein the method further comprises the features of any one or more of claims 64 to 71.
80. A composition for relieving or transforming the inhibition of regulatory T cells (Treg), wherein,
inhibition of regulatory T cells (Tregs) refers to inhibiting the activity of a pathogenic agent against an infection, allergy and/or autoimmune disease in a subject or against a cell infected with or comprising the pathogenic agent,
the composition comprises a non-pathogenic antigen component that is neither derived from nor cross-reactive with a pathogenic agent of an infectious, allergic and/or autoimmune disease that is a target to which the subject has an immunological memory.
81. The composition of claim 80, wherein said Treg is transformed in said subject by the presence in said subject of a pathogenic antigen component derived from and/or cross-reactive with a pathogenic agent of a target disease, said effector T cell (Teff) being directed against a pathogenic agent of the disease or a cell comprising a pathogenic agent of the infection.
82. The composition of claim 80 or 81, wherein the subject has an immune memory against the pathogenic agent and/or a factor that cross-reacts with the pathogenic agent.
83. The composition of any one of claims 80 to 82, wherein the composition further comprises the features of any one or more of claims 64 to 71.
84. A composition for preventing or treating an infection in a subject, wherein the composition comprises an antigen component specific for a component different from a causative agent of the infection in the subject.
85. A composition for preventing or treating an infection in a subject, wherein the composition comprises an antigenic component derived from the subject that is different from a pathogen of a past infection of the infection, and is substantially free of a causative agent of the infection or a portion thereof.
86. A composition for preventing or treating an infection other than tuberculosis, comprising a tubercle bacillus extract.
87. A composition for controlling immune enhancement against a causative agent of an infection other than tuberculosis in a subject when the subject is exposed to the causative agent, comprising a mycobacterium tuberculosis extract.
88. A composition for preventing or treating an infection, allergy or autoimmune disease in a subject, characterized in that,
the composition comprising an antigen component specific in the subject, said antigen component being neither derived from nor cross-reactive with a causative agent of the infectious disease, allergy or autoimmune disease,
the antigenic component is a protein or a portion thereof, or a peptide, and is capable of controlling an immune response mediated by CD4 positive T cells,
the infection, allergy or autoimmune disease includes a disease that can be prevented or treated by an immune response mediated by CD4 positive T cells,
here, it is confirmed whether the subject can control an immune response against an infectious disease, an allergic reaction, or an autoimmune disease mediated by CD4 positive T cells, and the composition is administered in a case where the subject can control an immune response against an infectious disease, an allergic reaction, or an autoimmune disease mediated by CD4 positive T cells.
89. A composition for preventing or treating an infection in a subject, characterized in that,
the composition comprising an antigen component specific for a component different from a causative agent of the infection in the subject,
the infection comprises a viral infection and the method comprises,
the antigenic component is a protein or a portion thereof, or a peptide, and is capable of controlling an immune response mediated by CD4 positive T cells,
the viral infections include diseases which can be prevented or treated by an immune response mediated by CD4 positive T cells,
here, it is confirmed whether the subject can control an antiviral immune response mediated by CD4 positive T cells, and the composition is administered in a case where the subject can control an antiviral immune response mediated by CD4 positive T cells.
90. The composition of any one of claims 84 to 89, wherein the composition further comprises the features of any one or more of claims 64 to 71.
91. A method of making or otherwise providing a composition for preventing or treating an infection, allergy or autoimmune disease in a subject, wherein the method comprises the steps of:
step a) identifying an antigenic component specific to the subject, said antigenic component being neither derived from nor cross-reactive with a causative agent of the infection, allergy or autoimmune disease;
Step B), determining whether the antigen component has an immunological memory in the subject, and selecting an antigen component having the immunological memory; and
step C) manufacturing or otherwise providing the selected antigen component.
92. A method for determining whether an antigenic component specific to a subject, said antigenic component being neither derived from nor cross-reactive with a causative agent of an infectious disease, allergy or autoimmune disease in the subject, can prevent or treat the infectious disease, allergy or autoimmune disease in the subject, the method comprising the steps of:
step B) is a step of specifying whether or not the antigen component has an immunological memory in the subject, and in the case of having the immunological memory, is specified to be capable of preventing or treating an infection, an allergy or an autoimmune disease in the subject.
93. A method for preventing or treating an infection, allergy or autoimmune disease, comprising the steps of:
step a), obtaining an antigen responsiveness profile of the subject;
step b) of specifying an antigen component or a combination of antigen components based on the antigen responsiveness profile, wherein the antigen component or the combination of antigen components is specified based on whether the subject now exhibits an immune responsiveness or has previously exhibited an immune responsiveness; and
Step c) administering to the subject the antigen component or combination of antigen components identified in step b) in an amount sufficient to control an immune response in the subject.
94. The method of any one of claims 91 to 93, wherein the method further comprises the features of any one or more of claims 64 to 71.
95. An adjuvant for a vaccine against an infectious disease, comprising a hot water extract of tubercle bacillus or a part thereof.
96. An adjuvant for a vaccine against an infectious disease comprising a STING agonist.
97. An adjuvant for a vaccine against an infectious disease of a viral infection, comprising a STING agonist.
98. An adjuvant according to claim 95, wherein the hot water extract of mycobacterium tuberculosis or a portion thereof is a hot water extract of human mycobacterium tuberculosis qingshan B strain or a portion thereof.
99. An adjuvant according to claim 95 or 98, wherein the hot water extract of mycobacterium tuberculosis or a portion thereof is extract a.
100. An adjuvant according to any one of claims 95 to 99, wherein the hot water extract of mycobacterium tuberculosis or a portion thereof comprises a STING agonist, lpqH, Y1269, PPD, cmpp 65 overlapping peptide, mtb associated antigen, STING agonist or NOD2 agonist derived from mycobacterium tuberculosis.
101. An adjuvant according to any one of claims 95 to 100, wherein the hot water extract of tubercule bacillus, or a portion thereof, comprises a STING agonist derived from tubercule bacillus, which is c-di-AMP, c-di-GMP, 3' -cGAMP, 2'3' -cGAMP, and/or dsDNA capable of producing the STING agonist in human cytoplasm mediated by cGAS.
102. An adjuvant according to any one of claims 95 to 101, wherein the causative agent of infection is a bacterium, virus or protozoan.
103. An adjuvant according to any one of claims 95 to 102, wherein the causative agent of infection is a virus.
104. An adjuvant according to any one of claims 95 to 103, wherein the causative agent of infection is a virus belonging to the family coronaviridae.
105. An adjuvant according to any one of claims 95 to 104, wherein the causative agent of the infection is a virus belonging to a family selected from the group consisting of rhinovirus, adenovirus, coronavirus, RS virus, influenza virus, parainfluenza virus and enterovirus.
106. An adjuvant according to any one of claims 95 to 105, wherein the causative agent of infection is a virus belonging to the genus coronavirus.
107. An adjuvant according to any one of claims 95-106, wherein the causative agent of the infection is a virus selected from the group consisting of HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and SARS-CoV-2.
108. An adjuvant according to any one of claims 95 to 107, wherein the causative agent of infection is SARS-CoV-2 virus.
109. An adjuvant according to any one of claims 95 to 108, wherein the adjuvant further comprises the features of any one or more of claims 64 to 71.
110. An adjuvant according to any one of claims 95 to 108, wherein the adjuvant converts innate immunity into acquired immunity.
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| JPPCT/JP2021/005951 | 2021-02-17 | ||
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| JP2021208598 | 2021-12-22 | ||
| PCT/JP2022/006212 WO2022176920A1 (en) | 2021-02-17 | 2022-02-16 | New treatment and prevention based on new method for controlling cellular immunity |
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