WO2021106978A1 - 医薬組成物 - Google Patents
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- WO2021106978A1 WO2021106978A1 PCT/JP2020/043938 JP2020043938W WO2021106978A1 WO 2021106978 A1 WO2021106978 A1 WO 2021106978A1 JP 2020043938 W JP2020043938 W JP 2020043938W WO 2021106978 A1 WO2021106978 A1 WO 2021106978A1
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Definitions
- the present invention relates to a pharmaceutical composition. More specifically, it relates to a pharmaceutical composition in which an immunogenic substance is administered in combination with a Toll-like receptor agonist, a LAG-3 protein and an immune checkpoint inhibitor.
- Cancer vaccine therapy is a method of inducing a specific immune response against cancer cells in the patient's body by directly administering the cancer antigen to the patient to cause the cancer to regress.
- the cancer antigen to be administered to the patient the cancer antigen protein itself, the cancer antigen-derived peptide, the nucleic acid encoding them, the dendritic cell on which the cancer antigen is presented, the cancer cell itself, and the like are used.
- an adjuvant is also administered together with the cancer antigen.
- the adjuvant cytokines that stimulate various immunocompetent cells, Toll-like receptor (TLR) agonists, and the like are used.
- TLR Toll-like receptor
- lymphocyte activation gene 3 LAG-3 is also used as a vaccine adjuvant.
- Patent Document 1 discloses a drug in which a TLR3 agonist Poly I: C (polyinosin polycytidine acid) and a fusion protein of LAG-3 protein and IgG are used in combination with a cancer antigen-derived peptide. There is.
- TLR3 is one of the innate immune system molecules that recognizes virus-derived double-stranded RNA and promotes the production of type I interferon, which has a strong antiviral effect.
- Poly I: C is a double-stranded RNA analog known as a TLR3 agonist.
- LAG-3 binds to MHC class II molecules, exerts negative regulation on the proliferation of activated T cells and maintenance of T cell homeostasis, and plays an important role in the function of regulatory T cells (Treg). It is also known to be involved in the control of homeostasis of plasma cell dendritic cells.
- Immune checkpoint inhibitors are agents that inhibit the immunosuppressive system and activate anti-tumor immunity (Non-Patent Documents 1 to 3).
- Immune checkpoint inhibitors include anti-PD-1 antibody Nivolumab (Patent Document 2), pembrolizumab (Patent Document 3), and anti-PD-L1 antibody Atezolizumab (Patent Document 2).
- Document 4 Durvalumab (Patent Document 5), Avelumab (Patent Document 6), anti-CTLA-4 antibody, Ipilimumab (Patent Document 7), Tremelimumab (Patent Document 8). ) Etc. are known.
- the main object of the present invention is to provide a novel technique useful for cancer vaccine therapy.
- the present invention provides the following [1]-[84].
- [3] The pharmaceutical composition of [2], wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.
- at least one immunogenic substance is a peptide derived from at least one cancer antigen.
- the pharmaceutical composition of [8], wherein the at least one cancer antigen-derived peptide is an HSP70-derived peptide or a GPC3-derived peptide.
- the pharmaceutical composition [12] Toll-like receptor agonists and LAG-3 protein, its mutant or its derivative, With at least one immunogenic substance, Immune checkpoint inhibitors and However, the pharmaceutical composition according to any one of [1] to [10], which is contained as an active ingredient in a single preparation and is administered. [13] The pharmaceutical composition according to any one of [1]-[12] used for cancer vaccine therapy.
- the pharmaceutical composition of [33] wherein the cancer is hyposensitive or resistant to immune checkpoint inhibitors.
- the therapeutic method of [39], wherein the Toll-like receptor agonist is Poly I: C or a salt thereof.
- the treatment method of [40], wherein the Poly I: C is Poly ICLC.
- the therapeutic method according to any one of [36]-[41], wherein the LAG-3 protein, a mutant thereof or a derivative thereof is a fusion protein of LAG-3 protein and IgG.
- the therapeutic method of [43], wherein the at least one cancer antigen-derived peptide is an HSP70-derived peptide or a GPC3-derived peptide.
- Poly ICLC and LAG-3 protein and IgG fusion protein The HSP70-derived peptide consisting of the amino acid sequence shown in SEQ ID NO: 7 and Anti-PD-1 antibody and A therapeutic method characterized by administering the drug in combination to a subject.
- the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody or an anti-CTLA-4 antibody.
- the immune checkpoint inhibitor is an anti-PD-1 antibody.
- the method of any of [53]-[55], wherein the Toll-like receptor agonist is a Toll-like receptor 3 agonist or a Toll-like receptor 9 agonist.
- Poly ICLC and LAG-3 protein and IgG fusion protein The HSP70-derived peptide consisting of the amino acid sequence shown in SEQ ID NO: 7 and Anti-PD-1 antibody and A method of inducing a specific immune response against cancer cells, which comprises administering the drug in combination to a subject.
- the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody or an anti-CTLA-4 antibody.
- Use of [69] wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.
- [71] Use of either [68]-[70], wherein the Toll-like receptor agonist is a Toll-like receptor 3 agonist or a Toll-like receptor 9 agonist.
- [72] Use of [71], wherein the Toll-like receptor agonist is Poly I: C or a salt thereof.
- Use of [72], wherein the Poly I: C is Poly ICLC.
- Use of any of [68]-[73], wherein the LAG-3 protein, a mutant thereof or a derivative thereof is a fusion protein of LAG-3 protein and IgG.
- [75] Use of any of [68]-[74], wherein at least one immunogenic substance is at least one cancer antigen-derived peptide.
- Poly ICLC and LAG-3 protein and IgG fusion protein The HSP70-derived peptide consisting of the amino acid sequence shown in SEQ ID NO: 7 and Anti-PD-1 antibody and To produce a pharmaceutical composition, characterized in that they are administered in combination.
- the present invention provides a novel technique useful for cancer vaccine therapy.
- the vertical axis shows the tumor volume (mm 3 ), and the horizontal axis shows the number of days after melanoma cell transplantation (Test Example 1). Line breaks that occur before Day 28 mean mouse death.
- the change in the average value of the tumor volume of the mice in each experimental group is shown (Test Example 1).
- the vertical axis shows the tumor volume (mm 3 ), and the horizontal axis shows the number of days after melanoma cell transplantation (Day).
- the average value of the tumor volume of the mice of each experimental group on Day 21 and Day 28 is shown (Test Example 1).
- the scores of the search (lymphocyte) infiltration of the mice in each experimental group on Day 28 are shown (Test Example 1).
- the changes in the survival rate of the mice in each experimental group are shown (Test Example 2).
- the vertical axis shows the survival rate, and the horizontal axis shows the number of days (Day) after melanoma cell transplantation.
- the change in the average value of the tumor volume of the mice in each experimental group is shown (Test Example 3).
- the vertical axis shows the tumor volume (mm 3 ), and the horizontal axis shows the number of days after colorectal cancer cell transplantation (Day).
- the changes in the survival rate of the mice in each experimental group are shown (Test Example 3).
- the vertical axis shows the survival rate, and the horizontal axis shows the number of days (Day) after colorectal cancer cell transplantation.
- the changes in the survival rate of the mice in each experimental group are shown (Test Example 4).
- the vertical axis shows the survival rate, and the horizontal axis shows the number of days (Day) after colorectal cancer cell transplantation.
- the changes in the survival rate of the mice in each experimental group are shown (Test Example 5).
- the vertical axis shows the survival rate, and the horizontal axis shows the number of days (Day) after colorectal cancer cell transplantation.
- the pharmaceutical composition according to the present invention comprises a Toll-like receptor agonist, a LAG-3 protein, a mutant thereof or a derivative thereof (hereinafter, also referred to as “LAG-3 protein, etc.”), and at least one immunogenic substance. , It is characterized in that it is administered in combination with an immune checkpoint inhibitor.
- an immune checkpoint inhibitor By administering a Toll-like receptor agonist, LAG-3 protein, etc. and an immune checkpoint inhibitor in combination with an immunogenic substance, the Toll-like receptor agonist and only the LAG-3 protein and the immunogenic substance are administered.
- a synergistically superior immune effect can be obtained as compared with the administration of the immune checkpoint inhibitor alone or as compared with the administration of these alone.
- the pharmaceutical composition according to the present invention particularly comprises a Toll-like receptor agonist, a LAG-3 protein, a variant thereof or a derivative thereof (hereinafter, also referred to as “LAG-3 protein or the like”), and at least one cancer antigen. It is characterized in that the derived peptide and the immune checkpoint inhibitor are administered in combination.
- a Toll-like receptor agonist, LAG-3 protein, etc. and an immune checkpoint inhibitor in combination with a cancer antigen-derived peptide By administering a Toll-like receptor agonist, LAG-3 protein, etc. and an immune checkpoint inhibitor in combination with a cancer antigen-derived peptide, only the Toll-like receptor agonist, LAG-3 protein, and cancer antigen-derived peptide are administered. A synergistic and superior antitumor effect can be obtained as compared with the administration of or the administration of the immune checkpoint inhibitor alone, or as compared with the administration of these alone.
- a Toll-like receptor agonist, LAG-3 protein, etc. and an immune checkpoint inhibitor in combination with a cancer antigen-derived peptide a Toll-like receptor agonist, LAG-3 protein, and a cancer antigen-derived peptide can be administered.
- a high antitumor effect can be expected even at a low dose, which cannot be obtained when only the immunocheckpoint inhibitor is administered, when these are administered alone,
- the present invention also provides a pharmaceutical composition characterized in that a Toll-like receptor agonist, a LAG-3 protein or the like, and an immune checkpoint inhibitor are administered in combination.
- the pharmaceutical composition can be administered in combination with at least one immunogenic substance.
- the “immune checkpoint inhibitor” refers to an agent that inhibits the immunosuppressive system and activates tumor immunity.
- the immune checkpoint inhibitor is not particularly limited, and examples thereof include anti-PD-1 antibody, anti-PD-L1 antibody, and anti-CTLA-4 antibody.
- the immune checkpoint inhibitor is preferably an anti-PD-1 antibody and an anti-PD-L1 antibody, and more preferably an anti-PD-1 antibody.
- Anti-PD-1 antibody refers to PD-1 and its binding partners, PD-L1 and PD-, by specifically binding to PD-1 (Programmed cell death-1; CD279; PDCD1). Indicates an antibody that has the effect of reducing, inhibiting, and / or interfering with signal transduction resulting from interaction with L2.
- the anti-PD-1 antibody is not particularly limited as long as its clinical efficacy and safety have been confirmed, but preferably nivolumab (International Publication No. 2006/121168, etc.) and pembrolizumab. ) (International Publication No. 2008/156712, etc.).
- Anti-PD-L1 antibody refers to PD-L1 and its binding partner, PD-1 and PD-L1 by specifically binding to PD-L1 (Programmed cell death ligand 1; CD274; B7-H1). Indicates an antibody that has the effect of reducing, inhibiting, and / or interfering with signal transduction resulting from interaction with B7.1 (CD80).
- the anti-PD-L1 antibody is not particularly limited as long as its clinical efficacy and safety have been confirmed, but preferably atezolizumab (International Publication No. 2010/077634, etc.) and Durvalumab. ) (International Publication No. 2011/066389, etc.) and Avelumab (International Publication No. 2013/079174, etc.).
- Anti-CTLA-4 antibody is CTLA-4 and its binding partner, B7.1 (CD80), by specifically binding to CTLA-4 (Cytotoxic T-lymphocyte-associated protein 4; CD152).
- B7.1 CD80
- CTLA-4 Cytotoxic T-lymphocyte-associated protein 4
- B7.2 CD86
- the anti-CTLA-4 antibody is not particularly limited as long as its clinical efficacy and safety have been confirmed, but preferably Ipilimumab (International Publication No. 2001/014424, etc.) and Tremelimumab. ) (International Publication No. 2000/037504, etc.).
- a "Toll-like receptor agonist” is a molecule that, when bound to any Toll-like receptor (TLR), stimulates the TLR in the same manner as when a natural ligand binds to it. means.
- TLR agonists OncoImmunology 1: 5, 699-716; August 2012, OncoImmunology 2: 8, e25238; August 2013, Trends in Immunology, Vol.30, No.1, 23-32, Immunology 33, October 29, 2010 , 492-503, World Journal of Vaccines, 2011, 1, 33-78 and Onco Immunology 1: 6, 894-907; September 2012, known TLR agonists, and these known TLR agonists.
- TLR agonists include TLR1 agonists to TLR10 agonists.
- TLR3 agonists, TLR4 agonists, TLR7 agonists, TLR8 agonists, TLR9 agonists or TLR10 agonists can be used.
- the TLR agonist may be a TLR3 agonist or a TLR9 agonist in particular.
- TLR1 agonist is meant a molecule that, when bound to TLR1, stimulates TLR1 in the same way as when a natural ligand binds to it. TLR1 recognizes lipoproteins and activates the innate immune system. Examples of TLR1 agonists include lipoprotein, Triacylated lipopeptides, Zymosan and the like.
- TLR2 agonist is meant a molecule that, when bound to TLR2, stimulates TLR2 in the same way as when a natural ligand binds to it. TLR2 recognizes Acylated lipopeptides and activates the innate immune system. Examples of TLR2 agonists include SMP-105, Acylated lipopeptides, Amphotericin B, Atypical LPS, Byglican, Forins, Glyco (phospho) lipids, Lipoteichoic acid, Peptidoglycan, Phenol soluble modulin and Zymosan.
- TLR3 agonist means a molecule that, when bound to TLR3, stimulates TLR3 in the same way as when a natural ligand binds to it. TLR3 recognizes virus-derived double-stranded RNA and activates the innate immune system.
- Poly I: C which is a synthetic double-stranded polynucleotide having a structure similar to that of double-stranded RNA, is known, but is not limited thereto.
- Poly I: C may be the salt thereof, for example, a sodium salt.
- Poly ICLC can be used as Poly I: C.
- RIBOX XOL can also be used as the TLR3 agonist.
- TLR3 agonists examples include Poly I: C, Poly ICLC (product name "Hiltonol”), RIBOXXOL, Ampligen, IPH-3102, cM362-139, cM362-140 and the like.
- Poly I: C is preferably used, but among Poly I: C, Poly ICLC (product name "Hiltonol") stabilized with Poly-Lysine and Carboxymethyl cellulose is more preferably used.
- TLR4 agonist means a molecule that, when bound to TLR4, stimulates TLR4 in the same way as when a natural ligand binds to it.
- TLR4 recognizes bacterial-derived lipopolysaccharide (LPS) and activates the innate immune system.
- MPL is known as a TLR4 agonist, but is not limited to this.
- MPL may be the salt thereof, for example, a sodium salt.
- Examples of TLR4 agonists include MPL, MPLA, OM-174 (CRX-527), Picibanil (OK-432) and ONO-4007.
- TLR5 agonist is meant a molecule that, when bound to TLR5, stimulates TLR5 in the same way as when a natural ligand binds to it. TLR5 recognizes bacterial flagellin and activates the innate immune system. As the TLR5 agonist, flagellin derived from various bacteria or a recombinant protein of flagellin is known, but the TLR5 agonist is not limited to this. Examples of the TLR5 agonist include CBLB502 and the like.
- TLR6 agonist is meant a molecule that, when bound to TLR6, stimulates TLR6 in the same way as when a natural ligand binds to it. TLR6 recognizes lipoproteins and activates the innate immune system. Examples of TLR6 agonists include Diacylated lipopeptides, Lipoproteins, Lipoteichoic acid and Zymosan.
- TLR7 agonist is meant a molecule that, when bound to TLR7, stimulates TLR7 in the same way as when a natural ligand binds to it.
- TLR8 agonist refers to a molecule that, when bound to TLR8, stimulates TLR8 in the same manner as when a natural ligand is bound to it.
- TLR7 and TLR8 recognize virus-derived single-stranded RNA and activate the innate immune system.
- Imiquimod is known as a TLR7 / 8 agonist, but is not limited to this.
- Imiquimod may be the salt thereof, for example a sodium salt.
- TLR7 / 8 agonists examples include Imiquimod (S-26308, R-837), Resimiquimod (R-848), 3M-052, 852A, VTX-1463, VTX-2337, AZD8848 (DSP-3025), ANA773 and Examples include TMX-101.
- TLR9 agonist means a molecule that, when bound to TLR9, stimulates TLR9 in the same way as when a natural ligand binds to it. TLR9 recognizes CpG DNA from bacteria and viruses and activates the innate immune system.
- CpG ODN is known as a TLR9 agonist, but is not limited to this.
- CpG ODN CpG oligodeoxynucleotide
- TLR9 agonists examples include CpG, CpG-28, CpG-685 (GNKG168), CpG-1826, CpG-7909 (PF-3512676, Agatolimod, promune®), ODN1585, IMO-2125, IMO-2055.
- CpG ODN such as (EMD1201081), ISS1018, MGN-1703, MGN-1706, AVE0675, QAX-935, SAR-21609, SD-101, and DIMS0150.
- TLR10 agonist is meant a molecule that, when bound to TLR10, stimulates TLR10 in the same way as when a natural ligand binds to it. TLR10 recognizes acylated lipopeptide and activates the innate immune system. Examples of the TLR10 agonist include acylated lipopeptide and the like.
- LAG-3 protein in the present invention, "LAG-3 protein, a mutant thereof or a derivative thereof” means a LAG-3 protein, a functional variant thereof or a functional derivative thereof.
- the derived animal species of the LAG-3 protein is not limited, but for example, it is preferable that the LAG-3 protein is derived from the same animal species as the subject to which the pharmaceutical composition according to the present invention is administered. Therefore, human LAG-3 can be used as long as the pharmaceutical composition according to the present invention is administered to humans.
- the LAG-3 protein is a protein having the amino acid sequence shown in NCBI Accession No. P18627.5.
- a functional variant of the LAG-3 protein is (i) a variant of LAG-3 consisting of an amino acid sequence in which one or several amino acids are added, substituted, or deleted in the amino acid sequence of LAG-3.
- Those having the functions of the LAG-3 protein necessary for exerting the effects of the present invention (ii) the amino acid sequence of LAG-3 and at least 80% or more, or 85% or more, 90% or more, 95
- a variant of LAG-3 consisting of an amino acid sequence having a sequence identity of% or more, 98% or more, and 99% or more, which has the function of LAG-3 necessary for exerting the effect of the present invention.
- amino acid is used in the broadest sense, and includes artificial amino acid variants and derivatives in addition to natural amino acids.
- Amino acids are natural proteinaceous L-amino acids; D-amino acids; chemically modified amino acids such as amino acid variants and derivatives; natural non-protein amino acids such as norleucine, ⁇ -alanine and ornithine; Examples thereof include chemically synthesized compounds having the properties known in the above.
- unnatural amino acids are ⁇ -methyl amino acids ( ⁇ -methylalanine, etc.), D-amino acids, histidine-like amino acids ( ⁇ -hydroxy-histidine, homohistidine, ⁇ -fluoromethyl-histidine, ⁇ -methyl-histidine, etc.) , Amino acids having excess methylene in the side chain (“homo” amino acids), amino acids in which the carboxylic acid functional group amino acids in the side chain are replaced with sulfonic acid groups (such as cysteine acid) and the like.
- homo amino acids amino acids having excess methylene in the side chain
- amino acids in which the carboxylic acid functional group amino acids in the side chain are replaced with sulfonic acid groups (such as cysteine acid) and the like.
- LAG-3 protein examples include fusion proteins of all or part of LAG-3 protein and other proteins or polypeptides, and proteins in which sugar chains and lipids are added to LAG-3 protein. Be done.
- An example of a functional derivative of the LAG-3 protein is a fusion protein of LAG-3 and IgG (LAG-3Ig).
- LAG-3Ig IgG
- Derivatives described in the Journal of Translational Medicine 2014, 12:97 are exemplified as functional derivatives of the LAG-3 protein.
- IMP321 as a functional derivative of the LAG-3 protein, IMP321 (LAG-3Ig), which is a fusion protein of LAG-3 and IgG, can be preferably used.
- the "immunogenic substance” broadly includes substances capable of inducing an immune response in the body of an animal. Immunogenics elicit a humoral and / or cell-mediated immune response such that administration to an individual enhances an antigen-specific immune response against the same or similar antigen encountered with the individual's immune system (ie,). It means an immunogenic) substance. Immunogenic substances can elicit cellular immune responses such as CD4 + T cell responses (eg, TH1, TH2 and / or TH17) and / or CD8 + T cell responses (eg, CTL responses).
- CD4 + T cell responses eg, TH1, TH2 and / or TH17
- CD8 + T cell responses eg, CTL responses
- immunogenic substances include proteins, glycoproteins, sugar chains, peptides and nucleic acids (DNA, RNA, etc.).
- the immunogenic substance may be a nucleic acid encoding a protein, glycoprotein or peptide expressible, an expression vector containing the nucleic acid, and a cell expressing the protein, glycoprotein, sugar chain or peptide.
- These immunogenic substances may be derived from pathogens such as viruses and bacteria and cancer.
- the pharmaceutical composition according to the present invention may contain one kind of immunogenic substance or may contain two or more kinds of immunogenic substances.
- the "cancer antigen-derived peptide” refers to (i) a peptide having a partial amino acid sequence of a cancer antigen protein, and (ii) addition, substitution or deletion of one or two amino acids in the amino acid sequence. Peptide having a sequence containing, which induces immunity to attack cancer cells, or (iii) sequence identity of 90% or more, 95% or more, 98% or more, or 99% or more with the amino acid sequence. A peptide that induces immunity that attacks cancer cells.
- the cancer antigen-derived peptide may consist of 8 or more and 11 or less amino acid residues.
- cancer antigen-derived peptide When a cancer antigen-derived peptide is administered subcutaneously to a patient, it is taken up by antigen-presenting cells such as dendritic cells and macrophages and presented on the cell surface together with HLA molecules. Cytotoxic T cell (CTL) progenitor cells that are reactive to the presented peptide are clonally proliferated, and the proliferated and differentiated mature CTLs migrate to cancer tissue via lymphatic flow. Mature CTLs attack cancer cells expressing peptides that have the same sequence as the administered peptides and induce apoptosis.
- CTL Cytotoxic T cell
- the HSP70-derived peptide as a cancer antigen-derived peptide is not particularly limited, and examples thereof include the peptides described in International Publication No. 2018/070069, and specifically, SEQ ID NOs: 1 to 15 Examples thereof include peptides containing 8 or more consecutive amino acid residues in the amino acid sequence represented by any of them and consisting of 11 or less amino acid residues.
- a HSP70-derived peptide having the amino acid sequence represented by any of SEQ ID NOs: 1 to 15 can be used, and an HSP70-derived peptide having the amino acid sequence represented by SEQ ID NO: 7 is more preferably used. Be done.
- the GPC3-derived peptide as a cancer antigen-derived peptide is not particularly limited, and examples thereof include the peptides described in International Publication No. 2018/070069, and specifically, SEQ ID NOs: 16 to 26. Examples thereof include peptides containing 8 or more consecutive amino acid residues in the amino acid sequence represented by any of them and consisting of 11 or less amino acid residues.
- a GPC3-derived peptide having the amino acid sequence represented by any of SEQ ID NOs: 16 to 26 can be used, and a GPC3-derived peptide having the amino acid sequence represented by SEQ ID NO: 16 is more preferably used. Be done.
- These antigen-derived peptides are disclosed as examples, and the cancer antigen-derived peptides used in the pharmaceutical composition according to the present invention are not limited to these antigen-derived peptides.
- the pharmaceutical composition according to the present invention may contain a cancer antigen-derived peptide derived from one type of cancer antigen protein, or may contain a cancer antigen-derived peptide derived from two or more types of cancer antigen proteins.
- the pharmaceutical composition according to the present invention particularly preferably contains an HSP70-derived peptide having the amino acid sequence represented by SEQ ID NO: 7 and a GPC3-derived peptide having the amino acid sequence represented by SEQ ID NO: 16.
- the pharmaceutical composition according to the present invention can be used for cancer vaccine therapy and can also be used as an anticancer agent.
- anti-cancer agent means an agent that can be used for the prevention or treatment of cancer.
- Cancer vaccine therapy can be used for the prevention or treatment of cancer.
- the prevention or treatment of cancer includes a decrease in tumor size, a delay or arrest of growth, an inhibition of cancer metastasis (delay or arrest), and an inhibition of cancer cell growth (delay or arrest). It means causing at least one of inhibition (delay or arrest) of recurrence of cancer and relief of one or more symptoms associated with cancer.
- Cancer is used in its broadest sense and is used for stellate cell tumor, oligodendroglioma, meningitis, neurofibroma, glioblastoma, coat tumor, nerve sheath tumor, neurofibrosarcoma, neuroblast.
- Celloma pituitary tumor (eg, pituitary adenoma), medulloblastoma, melanoma, brain tumor, prostate cancer, head and neck cancer, esophageal cancer, renal cancer, renal cell carcinoma, pancreatic cancer, breast cancer, lung cancer, colon Cancer, colon cancer, gastric cancer, skin cancer, ovarian cancer, bladder cancer, fibrosarcoma, squamous epithelial cancer, neuroectodermal, thyroid tumor, lymphoma, leukemia, multiple myeloma, hepatocellular carcinoma, mesenteric tumor and epidermoid cancer Etc., but are not limited to these.
- the pharmaceutical composition according to the present invention may be particularly suitably applied to cancers for which existing treatment with an immune checkpoint inhibitor is inadequate (that is, cancers that are hyposensitive or resistant to an immune checkpoint inhibitor).
- cancers that are hyposensitive or resistant to immune checkpoint inhibitors are cancers in which T lymphocyte infiltration to the tumor site is unlikely to occur, and sufficient antitumor effect cannot be obtained by administration of anti-PD-1 antibody alone.
- Specific examples of cancers that are hyposensitive or resistant to immune checkpoint inhibitors include colon cancer, pancreatic cancer, gastric cancer, esophageal cancer, soft sarcoma, ovarian cancer, and breast cancer (excluding triple negative breast cancer). ), Cervical cancer, endometrial cancer, hepatocellular carcinoma, etc.
- the pharmaceutical composition according to the present invention can be applied to a subject as a systemic therapy, or can be locally applied to a cancer tissue to expect a therapeutic effect.
- Each component of an immunogenic substance and an immune checkpoint inhibitor such as a Toll-like receptor agonist and LAG-3 protein is contained as an active ingredient in a preparation different from the other one or more. Formulations may be administered simultaneously or at different times. Alternatively, each ingredient may be contained and administered as an active ingredient in a single formulation.
- Each component can be dissolved in a water-soluble solvent, formulated in the form of a pharmaceutically acceptable salt, and administered to a patient.
- a pharmaceutically acceptable salt forms are buffered at physiological pH in the form of physiologically acceptable water-soluble salts such as sodium salt, potassium salt, magnesium salt, calcium salt and the like. The form is mentioned.
- a water-insoluble solvent can also be used, and examples of such a water-insoluble solvent include alcohols such as ethanol and propylene glycol.
- the pharmaceutical composition can be orally or parenterally administered, and its dosage form is not particularly limited.
- Dosage forms of pharmaceutical compositions include, for example, liquids (eg injections), dispersants, suspensions, tablets, pills, powders, suppositories, powders, fine granules, granules, capsules, syrups. , Nasal drops, ear drops.
- parenteral administration for example, intraperitoneal administration, subcutaneous administration, intradermal administration, intramuscular administration, intravenous administration, or intranasal administration can be used.
- the therapeutically effective amount of the pharmaceutical composition can be appropriately determined according to the patient's symptoms, age, sex, body weight, sensitivity difference, administration method, administration plan, type of preparation and the like.
- the therapeutically effective amount per single dose is not particularly limited, but is, for example, 50-800 mg, preferably 100-400 mg, typically 200 mg of an immune checkpoint inhibitor.
- Toll-like receptor agonists such as 0.25-5.0 mg, preferably 0.5-2.5 mg, typically 1.26 mg.
- the amount of a cancer antigen-derived peptide is, for example, 0.5-8 mg, preferably 1-4 mg, and typically 2 mg per type.
- the anti-PD-1 antibody is, for example, 50-800 mg, preferably 100-400 mg, typically 200 mg.
- Toll-like receptor agonist, LAG-3 protein, etc. and an immune checkpoint inhibitor By administering a Toll-like receptor agonist, LAG-3 protein, etc. and an immune checkpoint inhibitor in combination with the immunogenic substance, only the Toll-like receptor agonist, LAG-3 protein, and the immunogenic substance were administered. In some cases, or when the therapeutically effective amounts of immunogenic substances, Toll-like receptor agonists, LAG-3 proteins, etc. and immune checkpoint inhibitors can be reduced as compared with the case where only immune checkpoint inhibitors are administered. is there. In particular, since immune checkpoint inhibitors are expensive, it is preferable from the viewpoint of patient burden and medical finance that the same immune effect can be expected at a lower dose.
- Each component may be administered at the same time, or when any one or more is different from the other one or more.
- a Toll-like receptor agonist, LAG-3 protein, etc. and a cancer antigen-derived peptide can be used as the first preparation
- the anti-PD-1 antibody can be used as the second preparation, which can be administered at different times.
- the administration plan of the first and second preparations can be made as follows.
- First product One cycle is 28 days (4 weeks). The first and second cycles are administered on days 1, 8, 15, and 22. The 3rd and 4th cycles are administered on the 1st and 15th days. After the 5th cycle, administer on the 1st day. Administration is performed subcutaneously at four locations, both axillae and both inguinal regions.
- Second product One cycle was 21 days (3 weeks). Administer intravenously on the first day of each cycle.
- the pharmaceutical composition according to the present invention can be formulated according to a known method.
- one or more of the components of the immunogenic substance and the immune checkpoint inhibitor, such as Toll-like receptor agonist and LAG-3 protein may be different from the other one or more.
- each component may be a single formulation.
- pharmaceutically acceptable carriers and additives for formulation, pharmaceutically acceptable carriers and additives (excipients, binders, dispersants, disintegrants, lubricants, solubilizers, solubilizers, colorants, flavoring agents, stabilizers, etc. Emulsifiers, suspending agents, absorption promoters, surfactants, pH regulators, preservatives, antioxidants, etc.) may be used.
- carriers and additives include pharmaceutically acceptable organic solvents such as water, saline, phosphate buffer, dextrose, glycerol, ethanol, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium carboxymethyl cellulose, etc.
- a surfactant such as polyoxyethylene lauryl ethers, sodium lauryl sulfate, or saponin is used as an absorption enhancer for improving the absorption of a poorly absorbable drug such as a peptide that is difficult to be absorbed through the mucosa.
- Bile acids such as glycocholic acid, deoxycholic acid, taurocholic acid
- Chelating agents such as EDTA and salicylic acids
- Fatty acids such as caproic acid, capric acid, lauric acid, oleic acid, linoleic acid and mixed micelles
- Enamine derivatives, N-acyl collagen peptides, N-acyl amino acids, cyclodextrins, chitosans, nitrogen monoxide donors and the like can be used.
- the pharmaceutical composition according to the present invention contains a peptide, it may be encapsulated or adsorbed in polylactic acid / glycolic acid (PLGA) microcapsules, porous hydroxyapatite fine particles, etc. to impart sustained release properties, and pulse-releasing ions.
- Percutaneous absorption may be performed using a Tophoresis patch system.
- the pharmaceutical composition according to the present invention may contain an additional adjuvant when used in cancer vaccine therapy.
- adjuvants include precipitation adjuvants such as aluminum hydroxide, sodium hydroxide, aluminum phosphate, calcium phosphate, alum, and carboxyvinyl polymers, as well as Freund complete adjuvant, Freund incomplete adjuvant, liquid paraffin, lanolin, etc.
- oil-based adjuvants such as Montanide ISA763AV and Montanide ISA51.
- the pharmaceutical composition according to the present invention may be used in combination with other anticancer agents, or may be combined with radiation therapy or surgical treatment.
- Other anti-cancer agents include adriamycin, daunomycin, mitomycin, cisplatin, vincristine, epirubicin, methotrexate, 5-fluorouracil, aclassinomycin, nitrogen mustard, cyclophosphamide, bleomycin, daunorubicin, doxorubicin, vincristine, vinblastine.
- the other anticancer agent may be administered to the subject separately or continuously at the same time as the pharmaceutical composition according to the present invention, or may be administered at different administration intervals.
- Cancer model mouse C57BL / 6 mouse with subcutaneously transplanted mouse melanoma cells (B16F10 cells, 1 x 10 5 )
- Poly ICLC Hiltonol® (Oncovir, Inc.), 50 ⁇ g / mouse LAG-3Ig: IMP321 (Immutep, Ltd.), 1 ⁇ g / mouse GP100 peptide: antigen epitope of B16F10 cells (SEQ ID NO: 27: EGSRNQDWL), 50 ⁇ g / mouse Anti-PD-1 antibody: InVivoPlus anti-m PD-1 (Bio X Cell, Cat.No .: BP0146, clone: RPM1-14), 100 ⁇ g / mouse
- Control group (1) No treatment
- Control group (2) Administer only anti-PD-1 antibody
- Control group (3) Administer only Poly ICLC, LAG-3Ig and GP100 peptide
- Test group (4) Poly ICLC, LAG -3Ig, GP100 peptide and anti-PD-1 antibody administered
- Control group (5) LAG-3Ig, GP100 peptide and anti-PD-1 antibody only administered
- Mouse melanoma cells (B16F10 cells, 1 ⁇ 10 5 cells) were transplanted subcutaneously into C57BL / 6 mice (Day 0).
- Poly ICLC, LAG-3Ig and GP100 peptides were subcutaneously administered on Day 0, 5, 12, 19, 26 (once a week) to a site different from the tumor transplant site.
- Anti-PD-1 antibody was intraperitoneally administered on Days 3, 5, 7, 10, 12, 14 (three times a week).
- Changes in tumor volume and mononuclear cell (lymphocyte) infiltration into the tumor site were evaluated by histopathological techniques. Tumor volume was determined by "(minor axis of the tumor tissue) (tumor tissue diameter) ⁇ 2/2". Lymphocyte infiltration was evaluated on a 3-point scale.
- FIG. 1 shows changes in tumor volume of mice in each experimental group.
- the vertical axis shows the tumor volume (mm 3 ), and the horizontal axis shows the number of days after melanoma cell transplantation (Day). Line breaks that occur before Day 28 mean mouse death.
- the number of mice that survived until Day 28 was 3 in the control group (1), 3 in the control group (2), 9 in the control group (3), 9 in the test group (4), and in the control group (5).
- FIG. 2 shows the change in the average value of the tumor volume of the mice in each experimental group.
- the vertical axis shows the tumor volume (mm 3 ), and the horizontal axis shows the number of days after melanoma cell transplantation (Day).
- FIG. 3 shows the average tumor volume of mice in each experimental group on Day 21 and Day 28.
- the control group (3) to which Poly ICLC, LAG-3Ig and GP100 peptide was administered had a significant anti-compliance compared to the untreated control group (1) and the control group (2) to which only the anti-PD-1 antibody was administered. A tumor effect was observed. In the control group (2) to which only the anti-PD-1 antibody was administered, tumor growth was hardly suppressed. Nevertheless, in the test group (4) in which the anti-PD-1 antibody was administered in addition to the Poly ICLC, LAG-3Ig and GP100 peptides, the control group (3) in which only the Poly ICLC, LAG-3Ig and GP100 peptides were administered. A more remarkable antitumor effect was observed.
- the average tumor volume in test group (4) was 64% less than control group (3) on Day 21 and 50% less than control group (3) on Day 28.
- Administration of Poly ICLC, LAG-3Ig and GP100 peptides in combination with anti-PD-1 antibody is synergistic compared to administration of Poly ICLC, LAG-3Ig and GP100 peptides alone or anti-PD-1 antibody alone. It was clarified that an excellent antitumor effect was exhibited. Such an excellent antitumor effect disappeared in the control group (5) to which only LAG-3Ig, GP100 peptide and anti-PD-1 antibody were administered.
- FIG. 4 shows the scores of quest (lymphocyte) infiltration of mice in each experimental group on Day 28.
- the degree of infiltration in the control group (3) to which Poly ICLC, LAG-3Ig and GP100 peptide was administered was higher than that in the untreated control group (1) and the control group (2) to which only the anti-PD-1 antibody was administered. Individuals with a higher score of 2 or 3 were found. In the control group (2) to which only the anti-PD-1 antibody was administered, almost no increase in infiltration was observed. Nevertheless, in the test group (4) in which the anti-PD-1 antibody was administered in addition to the Poly ICLC, LAG-3Ig and GP100 peptides, the control group (3) in which only the Poly ICLC, LAG-3Ig and GP100 peptides were administered. More remarkable lymphocyte infiltration was observed in comparison with the above.
- the cancer model mouse (melanoma B16F10 cells) used in this study has a low degree of lymphocyte infiltration into the tumor site, and it may be difficult to obtain an antitumor effect by administration of anti-PD-1 antibody alone.
- an immune checkpoint inhibitor such as an anti-PD-1 antibody with a Toll-like receptor agonist and LAG-3 protein and applying it to cancer vaccine therapy with a peptide derived from a cancer antigen. It is expected that a high antitumor effect can be obtained by inducing a specific immune response against cancer cells even in patients whose therapeutic effect is difficult to obtain by single administration.
- Test Example 2 Antitumor effect 2 in cancer model mice
- the test period of Test Example 1 was extended from 28 days to 2 months, and the survival rate of cancer model mice was evaluated.
- Cancer model mouse C57BL / 6 mouse with subcutaneously transplanted mouse melanoma cells (B16F10 cells, 1 x 10 5 )
- Poly ICLC Hiltonol® (Oncovir, Inc.), 50 ⁇ g / mouse LAG-3Ig: IMP321 (Immutep, Ltd.), 1 ⁇ g / mouse GP100 peptide: antigen epitope of B16F10 cells (SEQ ID NO: 27: EGSRNQDWL), 50 ⁇ g / mouse Anti-PD-1 antibody: InVivoPlus anti-m PD-1 (Bio X Cell, Cat.No .: BP0146, clone: RPM1-14), 100 ⁇ g / mouse
- Control group (1) No treatment
- Control group (2) Administer only anti-PD-1 antibody
- Control group (3) Administer only Poly ICLC, LAG-3Ig and GP100 peptide
- Test group (4) Poly ICLC, LAG -3Ig, GP100 peptide and anti-PD-1 antibody administered
- Control group (5) LAG-3Ig, GP100 peptide and anti-PD-1 antibody only administered
- Mouse melanoma cells (B16F10 cells, 1 ⁇ 10 5 cells) were transplanted subcutaneously into C57BL / 6 mice (Day 0).
- Poly ICLC, LAG-3Ig and GP100 peptides were subcutaneously administered on Day 0, 5, 12, 19, 26 (once a week) to a site different from the tumor transplant site.
- Anti-PD-1 antibody was intraperitoneally administered on Days 3, 5, 7, 10, 12, 14 (three times a week).
- FIG. 5 shows changes in the survival rate of mice in each experimental group.
- the vertical axis shows the survival rate, and the horizontal axis shows the number of days (Day) after melanoma cell transplantation.
- the maximum survival time of the test group (4) was Day 56, and the maximum survival days of the control group (2) and the control group (3) were Day 39 and Day 46, respectively.
- Administration of Poly ICLC, LAG-3Ig and GP100 peptides in combination with anti-PD-1 antibody is synergistic compared to administration of Poly ICLC, LAG-3Ig and GP100 peptides alone or anti-PD-1 antibody alone. It was clarified that an excellent effect of extending the number of survival days was exhibited. In addition, such an excellent effect of extending the survival period disappeared in the control group (5) to which only LAG-3Ig, GP100 peptide and anti-PD-1 antibody were administered.
- Cancer model mouse C57BL / 6 mouse with subcutaneously transplanted mouse colon cancer cells (MC38 cells, 1 x 10 6 )
- Poly ICLC Hiltonol® (Oncovir, Inc.), 50 ⁇ g / mouse LAG-3Ig: IMP321 (Immutep, Ltd.), 1 ⁇ g / mouse MC38 peptide: A mixture of Reps1 (SEQ ID NO: 28: AQLANDVVL), Adpgk (SEQ ID NO: 29: ASMTNMELM), Dpagt1 (SEQ ID NO: 30: SIIVFNLL), which are antigen epitopes of MC38 cells, 50 ⁇ g / mouse Anti-PD-1 antibody: InVivoPlus anti-m PD-1 (Bio X Cell, Cat.No .: BP0146, clone: RPM1-14), 100 ⁇ g / mouse
- Control group (1) No treatment
- Control group (2) Administer only anti-PD-1 antibody
- Control group (3) Administer only Poly ICLC, LAG-3Ig and MC38 peptide
- Test group (4) Poly ICLC, LAG -3Ig, MC38 peptide and anti-PD-1 antibody administered
- Mouse colon cancer cells (MC38 cells, 1 x 10 6 cells) were transplanted subcutaneously into C57BL / 6 mice (Day 0).
- Poly ICLC, LAG-3Ig and MC38 peptides were subcutaneously administered on Days 5, 12 and 19 to a site different from the tumor transplant site.
- Anti-PD-1 antibody was intraperitoneally administered on Days 5, 12, and 19. Changes in tumor volume were evaluated by a histopathological method in the same manner as in Test Example 1.
- FIG. 6 shows the change in the average value of the tumor volume of the mice in each experimental group.
- the vertical axis shows the tumor volume (mm 3 ), and the horizontal axis shows the number of days after colorectal cancer cell transplantation (Day).
- FIG. 7 shows changes in the survival rate of mice in each experimental group. The vertical axis shows the survival rate, and the horizontal axis shows the number of days (Day) after colorectal cancer cell transplantation.
- the tumor size of the control group (3) to which Poly ICLC, LAG-3Ig and MC38 peptide was administered was larger than that of the untreated control group (1) and the control group (2) to which only the anti-PD-1 antibody was administered. Suppression was observed.
- the test group (4) in which the anti-PD-1 antibody was administered in addition to the Poly ICLC, LAG-3Ig and MC38 peptides was further compared with the control group (3) in which only the Poly ICLC, LAG-3Ig and MC38 peptides were administered. Tumor size was suppressed.
- Test Example 4 Antitumor effect 4 in cancer model mice
- the dose of anti-PD-1 antibody in Test Example 3 was changed from 100 ⁇ g / mouse to 66.7 ⁇ g / mouse, and the antitumor effect was evaluated.
- the dose of anti-PD-1 antibody in humans is about 10 mg / kg body weight at a time (see, for example, N Engl J Med 2015; 372: 2509-2520), which is a mouse dose of 200 ⁇ g / kg in terms of body weight. Corresponds to mouse. Therefore, the above dose of 66.7 ⁇ g / mouse corresponds to 1/3 of the normal dose in humans.
- Cancer model mouse C57BL / 6 mouse with subcutaneously transplanted mouse colon cancer cells (MC38 cells, 1 x 10 6 )
- Poly ICLC Hiltonol® (Oncovir, Inc.), 50 ⁇ g / mouse LAG-3Ig: IMP321 (Immutep, Ltd.), 1 ⁇ g / mouse MC38 peptide: A mixture of Reps1 (SEQ ID NO: 28: AQLANDVVL), Adpgk (SEQ ID NO: 29: ASMTNMELM), Dpagt1 (SEQ ID NO: 30: SIIVFNLL), which are antigen epitopes of MC38 cells, 50 ⁇ g / mouse Anti-PD-1 antibody: InVivoPlus anti-m PD-1 (Bio X Cell, Cat.No .: BP0146, clone: RPM1-14), 66.7 ⁇ g / mouse
- Control group (1) No treatment
- Control group (2) Administer only anti-PD-1 antibody
- Control group (3) Administer only Poly ICLC, LAG-3Ig and MC38 peptide
- Test group (4) Poly ICLC, LAG -3Ig, MC38 peptide and anti-PD-1 antibody administered
- Mouse colon cancer cells (MC38 cells, 1 x 10 6 cells) were transplanted subcutaneously into C57BL / 6 mice (Day 0).
- Poly ICLC, LAG-3Ig and MC38 peptides were subcutaneously administered on Days 5, 12 and 19 to a site different from the tumor transplant site.
- Anti-PD-1 antibody was intraperitoneally administered on Days 5, 12, and 19. Changes in tumor volume were evaluated by a histopathological method in the same manner as in Test Example 1.
- FIG. 8 shows changes in the survival rate of mice in each experimental group.
- the vertical axis shows the survival rate, and the horizontal axis shows the number of days (Day) after colorectal cancer cell transplantation.
- test group (4) which received anti-PD-1 antibody in addition to Poly ICLC, LAG-3Ig and MC38 peptides, 100% of the individuals survived on Day 46. In contrast, the survival rates on Day 46 of the control group (3) to which Poly ICLC, LAG-3Ig and MC38 peptides were administered and the control group (2) to which only the anti-PD-1 antibody was administered were 60% and 30 respectively. %Met. Furthermore, in test group (4), 40% of the individuals survived on Day 53. In contrast, the survival rates of Day 53 in the control group (3) and the control group (2) were 10% and 10%, respectively.
- Cancer model mouse C57BL / 6 mouse with subcutaneously transplanted mouse colon cancer cells (MC38 cells, 1 x 10 6 )
- Poly ICLC Hiltonol® (Oncovir, Inc.), 0 or 50 ⁇ g / mouse LAG-3Ig: IMP321 (Immutep, Ltd.), 1 ⁇ g or 10 ⁇ g / mouse MC38 peptide: A mixture of Reps1 (SEQ ID NO: 28: AQLANDVVL), Adpgk (SEQ ID NO: 29: ASMTNMELM), Dpagt1 (SEQ ID NO: 30: SIIVFNLL), which are antigen epitopes of MC38 cells, 50 ⁇ g / mouse Anti-PD-1 antibody: InVivoPlus anti-m PD-1 (Bio X Cell, Cat.No .: BP0146,
- Control group (1) Untreated test group (4): Poly ICLC, LAG-3Ig, MC38 peptide and anti-PD-1 antibody administered
- Control group (5) LAG-3Ig (1 ⁇ g), MC38 peptide and anti-PD- Administer only 1 antibody
- Control group (6) Administer only LAG-3Ig (10 ⁇ g), MC38 peptide and anti-PD-1 antibody
- Mouse colon cancer cells (MC38 cells, 1 x 10 6 cells) were transplanted subcutaneously into C57BL / 6 mice (Day 0).
- Poly ICLC, LAG-3Ig and MC38 peptides were subcutaneously administered on Days 5, 12 and 19 to a site different from the tumor transplant site.
- Anti-PD-1 antibody was intraperitoneally administered on Days 5, 12, and 19. Changes in tumor volume were evaluated by a histopathological method in the same manner as in Test Example 1.
- FIG. 9 shows changes in the survival rate of mice in each experimental group.
- the vertical axis shows the survival rate, and the horizontal axis shows the number of days (Day) after colorectal cancer cell transplantation.
- Phase I / II clinical trial of peptide vaccine CYT001 HSP70-derived peptide, GPC3-derived peptide, Poly ICLC, LAG-3Ig
- Anti-PD-1 antibody in patients with unresectable advanced hepatocellular carcinoma
- Phase I / II study (safety / efficacy study)
- Target patients Patients with advanced hepatocellular carcinoma (44 cases) who meet any of the following conditions are targeted. -Histologically or cytologically diagnosed as hepatocellular carcinoma.
- Anti-PD-1 antibody 200 mg is administered intravenously at a time.
- CYT001 One cycle is 28 days (4 weeks). The first and second cycles are administered on days 1, 8, 15, and 22. The 3rd and 4th cycles are administered on the 1st and 15th days. After the 5th cycle, administer on the 1st day. Administration is performed subcutaneously at four locations, both axillae and both inguinal regions.
- Anti-PD-1 antibody One cycle was 21 days (3 weeks). Administer intravenously on the first day of each cycle.
- an excellent antitumor effect is exhibited by administering a combination of an anti-PD-1 antibody with PolyICLC, LAG-3Ig and a peptide derived from a cancer antigen.
- a therapeutic effect can be obtained by administration of an immune checkpoint inhibitor alone. It is expected that even in difficult patients, a high antitumor effect can be obtained by inducing a specific immune response against cancer cells.
- SEQ ID NO: 1 Amino acid sequence of HSP70-derived peptide
- SEQ ID NO: 2 Amino acid sequence of HSP70-derived peptide
- SEQ ID NO: 3 Amino acid sequence of HSP70-derived peptide
- SEQ ID NO: 4 Amino acid sequence of HSP70-derived peptide
- SEQ ID NO: 5 Amino acid sequence of HSP70-derived peptide
- SEQ ID NO: 6 Amino acid sequence of HSP70-derived peptide
- SEQ ID NO: 7 Amino acid sequence of HSP70-derived peptide
- SEQ ID NO: 8 Amino acid sequence of HSP70-derived peptide
- SEQ ID NO: 9 Amino acid sequence of HSP70-derived peptide
- SEQ ID NO: 10 Amino acid sequence of HSP70-derived peptide
- SEQ ID NO: 11 Amino acid sequence of HSP70-derived peptide
- SEQ ID NO: 12 Amino acid sequence of
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Abstract
Description
アジュバントとしては、各種の免疫担当細胞を刺激するサイトカインやToll様受容体(TLR)アゴニスト等が利用されている。
また、リンパ球活性化遺伝子3(lymphocyte activation gene 3: LAG-3)もワクチン用アジュバントとして用いられている。
特許文献1には、がん抗原由来ペプチドに、TLR3アゴニストであるPoly I:C(ポリイノシンポリシチジン酸)と、LAG-3タンパク質とIgGとの融合タンパク質と、を併用する医薬が開示されている。TLR3は、ウイルス由来の二本鎖RNAを認識し、強い抗ウイルス作用を示すI型インターフェロンの産生を促す自然免疫系分子の一つである。Poly I:Cは、TLR3アゴニストとして知られる二本鎖RNAアナログである。また、LAG-3は、MHCクラスII分子と結合し、活性化T細胞の増殖やT細胞の恒常性維持において負の制御を行い、制御性T細胞(Treg)の機能において重要な役割を担うことや、形質細胞用樹状細胞の恒常性の制御にも関与することが知られている。
[1] Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体又はその誘導体と、
少なくとも免疫原性物質と、
免疫チェックポイント阻害剤と、
が、組み合わされて投与されることを特徴とする医薬組成物。
[2] 免疫チェックポイント阻害剤が、抗PD-1抗体、抗PD-L1抗体又は抗CTLA-4抗体である、[1]の医薬組成物。
[3] 免疫チェックポイント阻害剤が、抗PD-1抗体である、[2]の医薬組成物。
[4] 前記Toll様受容体アゴニストが、Toll様受容体3アゴニスト又はToll様受容体9アゴニストである、[1]-[3]のいずれかの医薬組成物。
[5] 前記Toll様受容体アゴニストが、Poly I:C又はその塩である、[4]の医薬組成物。
[6] 前記Poly I:Cが、Poly ICLCである、[5]の医薬組成物。
[7] 前記LAG-3タンパク質、その変異体又はその誘導体が、LAG-3タンパク質とIgGの融合タンパク質である、[1]-[6]のいずれかの医薬組成物。
[8] 少なくとも1種の免疫原性物質が、少なくとも1種のがん抗原由来ペプチドである、[1]-[7]のいずれかの医薬組成物。
[9] 前記少なくとも1種のがん抗原由来ペプチドが、HSP70由来ペプチド又はGPC3由来ペプチドである、[8]の医薬組成物。
[10] 前記HSP70由来ペプチドが配列番号7に示すアミノ酸配列からなり、前記GPC3由来ペプチドが配列番号16に示すアミノ酸配列からなる、[9]の医薬組成物。
[11] Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体又はその誘導体と、
少なくとも1種の免疫原性物質と、
免疫チェックポイント阻害剤と、
のいずれか1以上が、他の1以上と別異の製剤に有効成分として含有され、それらの製剤が同時に又は異なる時間に投与されることを特徴とする、[1]-[10]のいずれかの医薬組成物。
[12] Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体又はその誘導体と、
少なくとも1種の免疫原性物質と、
免疫チェックポイント阻害剤と、
が、単一の製剤に有効成分として含有され、投与されることを特徴とする、[1]-[10]のいずれかの医薬組成物。
[13] がんワクチン療法に用いられる、[1]-[12]のいずれかの医薬組成物。
[14] 抗がん剤である、[1]-[12]のいずれかの医薬組成物。
[15] がんが、免疫チェックポイント阻害剤に低感受性又は抵抗性である、[13]又は[14]の医薬組成物。
[16] Poly ICLCと、
LAG-3タンパク質とIgGの融合タンパク質と、
配列番号7に示すアミノ酸配列からなるHSP70由来ペプチドと、
抗PD-1抗体と、
が、組み合わされて投与されることを特徴とする医薬組成物。
[17] Poly ICLCと、
LAG-3タンパク質とIgGの融合タンパク質と、
配列番号16に示すアミノ酸配列からなるGPC3由来ペプチドと、
抗PD-1抗体と、
が、組み合わされて投与されることを特徴とする医薬組成物。
LAG-3タンパク質、その変異体又はその誘導体と、
免疫チェックポイント阻害剤と、
が、組み合わせて投与されることを特徴とする医薬組成物。
[19] 免疫チェックポイント阻害剤が、抗PD-1抗体、抗PD-L1抗体又は抗CTLA-4抗体である、[18]の医薬組成物。
[20] 免疫チェックポイント阻害剤が、抗PD-1抗体である、[19]の医薬組成物。
[21] 前記Toll様受容体アゴニストが、Toll様受容体3アゴニスト又はToll様受容体9アゴニストである、[18]-[20]のいずれかの医薬組成物。
[22] 前記Toll様受容体アゴニストが、Poly I:C又はその塩である、[21]のいずれかの医薬組成物。
[23] 前記Poly I:Cが、Poly ICLCである、[22]の医薬組成物。
[24] 前記LAG-3タンパク質、その変異体又はその誘導体が、LAG-3タンパク質とIgGの融合タンパク質である、[18]-[23]のいずれかの医薬組成物。
[25] Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体又はその誘導体と、
免疫チェックポイント阻害剤と、
のいずれか1以上が、他の1以上と別異の製剤に有効成分として含有され、それらの製剤が同時に又は異なる時間に投与されることを特徴とする、[18]-[24]のいずれかの医薬組成物。
[26] Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体又はその誘導体と、
免疫チェックポイント阻害剤と、
が、単一の製剤に有効成分として含有され、投与されることを特徴とする、[18]-[24]のいずれかの医薬組成物。
[27] がんワクチン療法に用いられる、[18]-[26]のいずれかの医薬組成物。
[28] がんが、免疫チェックポイント阻害剤に低感受性又は抵抗性である、[27]の医薬組成物。
[29] さらに、少なくとも1種の免疫原性物質と組み合わされて投与されることを特徴とする、[18]-[28]のいずれかの医薬組成物。
[30] 少なくとも1種の免疫原性物質が、少なくとも1種のがん抗原由来ペプチドである、[29]の医薬組成物。
[31] 前記少なくとも1種のがん抗原由来ペプチドが、HSP70由来ペプチド又はGPC3由来ペプチドである、[30]の医薬組成物。
[32] 前記HSP70由来ペプチドが配列番号7に示すアミノ酸配列からなり、前記GPC3由来ペプチドが配列番号16に示すアミノ酸配列からなる、[31]の医薬組成物。
[33] 抗がん剤である、[30]-[32]のいずれかの医薬組成物。
[34] がんが、免疫チェックポイント阻害剤に低感受性又は抵抗性である、[33]の医薬組成物。
[35] Poly ICLCと、
LAG-3タンパク質とIgGの融合タンパク質と、
抗PD-1抗体と、
が、組み合わされて投与されることを特徴とする医薬組成物。
LAG-3タンパク質、その変異体又はその誘導体と、
少なくとも1種の免疫原性物質と、
免疫チェックポイント阻害剤と、
を、対象に組み合わされて投与することを特徴とする治療方法。
[37] 免疫チェックポイント阻害剤が、抗PD-1抗体、抗PD-L1抗体又は抗CTLA-4抗体である、[36]の治療方法。
[38] 免疫チェックポイント阻害剤が、抗PD-1抗体である、[37]の治療方法。
[39] 前記Toll様受容体アゴニストが、Toll様受容体3アゴニスト又はToll様受容体9アゴニストである、[36]-[38]のいずれかの治療方法。
[40] 前記Toll様受容体アゴニストが、Poly I:C又はその塩である、[39]の治療方法。
[41] 前記Poly I:Cが、Poly ICLCである、[40]の治療方法。
[42] 前記LAG-3タンパク質、その変異体又はその誘導体が、LAG-3タンパク質とIgGの融合タンパク質である、[36]-[41]のいずれかの治療方法。
[43] 少なくとも1種の免疫原性物質が、少なくとも1種のがん抗原由来ペプチドである、[36]-[42]のいずれかの治療方法。
[44] 前記少なくとも1種のがん抗原由来ペプチドが、HSP70由来ペプチド又はGPC3由来ペプチドである、[43]の治療方法。
[45] 前記HSP70由来ペプチドが配列番号7に示すアミノ酸配列からなり、前記GPC3由来ペプチドが配列番号16に示すアミノ酸配列からなる、[44]の治療方法。
[46] Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体又はその誘導体と、
少なくとも1種の免疫原性物質と、
免疫チェックポイント阻害剤と、
のいずれか1以上が、他の1以上と別異の製剤に有効成分として含有され、それらの製剤が同時に又は異なる時間に投与されることを特徴とする、[36]-[45]のいずれかの治療方法。
[47] Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体又はその誘導体と、
少なくとも1種の免疫原性物質と、
免疫チェックポイント阻害剤と、
が、単一の製剤に有効成分として含有され、投与されることを特徴とする、[36]-[45]のいずれかの治療方法。
[48] がんワクチン療法である、[36]-[47]のいずれかの治療方法。
[49] がんのための、[36]-[47]のいずれかの治療方法。
[50] がんが、免疫チェックポイント阻害剤に低感受性又は抵抗性である、[48]又は[49]の治療方法。
[51] Poly ICLCと、
LAG-3タンパク質とIgGの融合タンパク質と、
配列番号7に示すアミノ酸配列からなるHSP70由来ペプチドと、
抗PD-1抗体と、
を、対象に組み合わされて投与することを特徴とする治療方法。
[52] Poly ICLCと、
LAG-3タンパク質とIgGの融合タンパク質と、
配列番号16に示すアミノ酸配列からなるGPC3由来ペプチドと、
抗PD-1抗体と、
を、対象に組み合わされて投与することを特徴とする治療方法。
LAG-3タンパク質、その変異体又はその誘導体と、
少なくとも1種のがん抗原由来ペプチドと、
免疫チェックポイント阻害剤と、
を、対象に組み合わされて投与することを特徴とする、がん細胞に対する特異的な免疫応答を誘導する方法。
[54] 免疫チェックポイント阻害剤が、抗PD-1抗体、抗PD-L1抗体又は抗CTLA-4抗体である、[53]の方法。
[55] 免疫チェックポイント阻害剤が、抗PD-1抗体である、[54]の方法。
[56] 前記Toll様受容体アゴニストが、Toll様受容体3アゴニスト又はToll様受容体9アゴニストである、[53]-[55]のいずれかの方法。
[57] 前記Toll様受容体アゴニストが、Poly I:C又はその塩である、[53]-[56]のいずれかの方法。
[58] 前記Poly I:Cが、Poly ICLCである、[57]の方法。
[59] 前記LAG-3タンパク質、その変異体又はその誘導体が、LAG-3タンパク質とIgGの融合タンパク質である、[53]-[58]のいずれかの方法。
[60] 前記少なくとも1種のがん抗原由来ペプチドが、HSP70由来ペプチド又はGPC3由来ペプチドである、[53]-[59]のいずれかの方法。
[61] 前記HSP70由来ペプチドが配列番号7に示すアミノ酸配列からなり、前記GPC3由来ペプチドが配列番号16に示すアミノ酸配列からなる、[60]の方法。
[62] Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体又はその誘導体と、
少なくとも1種のがん抗原由来ペプチドと、
免疫チェックポイント阻害剤と、
のいずれか1以上が、他の1以上と別異の製剤に有効成分として含有され、それらの製剤が同時に又は異なる時間に投与されることを特徴とする、[53]-[61]のいずれかの方法。
[63] Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体又はその誘導体と、
少なくとも1種のがん抗原由来ペプチドと、
免疫チェックポイント阻害剤と、
が、単一の製剤に有効成分として含有され、投与されることを特徴とする、[53]-[61]のいずれかの方法。
[64] がん治療のための、[53]-[63]のいずれかの方法。
[65] がんが、免疫チェックポイント阻害剤に低感受性又は抵抗性である、[64]の方法。
[66] Poly ICLCと、
LAG-3タンパク質とIgGの融合タンパク質と、
配列番号7に示すアミノ酸配列からなるHSP70由来ペプチドと、
抗PD-1抗体と、
を、対象に組み合わされて投与することを特徴とする、がん細胞に対する特異的な免疫応答を誘導する方法。
[67] Poly ICLCと、
LAG-3タンパク質とIgGの融合タンパク質と、
配列番号16に示すアミノ酸配列からなるGPC3由来ペプチドと、
抗PD-1抗体と、
を、対象に組み合わされて投与することを特徴とする、がん細胞に対する特異的な免疫応答を誘導する方法。
LAG-3タンパク質、その変異体又はその誘導体と、
少なくとも1種の免疫原性物質と、
免疫チェックポイント阻害剤と、
が、組み合わされて投与されることを特徴とする医薬組成物の製造のための、
Toll様受容体アゴニスト、
LAG-3タンパク質、その変異体又はその誘導体、
少なくとも1種の免疫原性物質、又は
免疫チェックポイント阻害剤、
の使用。
[69] 免疫チェックポイント阻害剤が、抗PD-1抗体、抗PD-L1抗体又は抗CTLA-4抗体である、[68]の使用。
[70] 免疫チェックポイント阻害剤が、抗PD-1抗体である、[69]の使用。
[71] 前記Toll様受容体アゴニストが、Toll様受容体3アゴニスト又はToll様受容体9アゴニストである、[68]-[70]のいずれかの使用。
[72] 前記Toll様受容体アゴニストが、Poly I:C又はその塩である、[71]の使用。
[73] 前記Poly I:Cが、Poly ICLCである、[72]の使用。
[74] 前記LAG-3タンパク質、その変異体又はその誘導体が、LAG-3タンパク質とIgGの融合タンパク質である、[68]-[73]のいずれかの使用。
[75] 少なくとも1種の免疫原性物質が、少なくとも1種のがん抗原由来ペプチドである、[68]-[74]のいずれかの使用。
[76] 前記少なくとも1種のがん抗原由来ペプチドが、HSP70由来ペプチド又はGPC3由来ペプチドである、[75]の使用。
[77] 前記HSP70由来ペプチドが配列番号7に示すアミノ酸配列からなり、前記GPC3由来ペプチドが配列番号16に示すアミノ酸配列からなる、[76]の使用。
[78] Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体又はその誘導体と、
少なくとも1種の免疫原性物質と、
免疫チェックポイント阻害剤と、
のいずれか1以上が、他の1以上と別異の製剤に有効成分として含有されることを特徴とする、[68]-[77]のいずれかの使用。
[79] Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体又はその誘導体と、
少なくとも1種の免疫原性物質と、
免疫チェックポイント阻害剤と、
が、単一の製剤に有効成分として含有されることを特徴とする、[68]-[77]のいずれかの使用。
[80] 前記医薬組成物が、がんワクチン療法に用いられる、[68]-[79]のいずれかの使用。
[81] 前記医薬組成物が、抗がん剤である、[68]-[79]のいずれかの使用。
[82] がんが、免疫チェックポイント阻害剤に低感受性又は抵抗性である、[80]又は[81]の使用。
[83] Poly ICLCと、
LAG-3タンパク質とIgGの融合タンパク質と、
配列番号7に示すアミノ酸配列からなるHSP70由来ペプチドと、
抗PD-1抗体と、
が、組み合わされて投与されることを特徴とする医薬組成物を製造するための、
Poly ICLC、
LAG-3タンパク質とIgGの融合タンパク質、
配列番号16に示すアミノ酸配列からなるHSP70由来ペプチド、又は
抗PD-1抗体、
の使用。
[84] Poly ICLCと、
LAG-3タンパク質とIgGの融合タンパク質と、
配列番号7に示すアミノ酸配列からなるGPC3由来ペプチドと、
抗PD-1抗体と、
が、組み合わされて投与されることを特徴とする医薬組成物を製造するための、
Poly ICLC、
LAG-3タンパク質とIgGの融合タンパク質、
配列番号16に示すアミノ酸配列からなるGPC3由来ペプチド、又は
抗PD-1抗体、
の使用。
免疫原性物質に、Toll様受容体アゴニスト、LAG-3タンパク質等及び免疫チェックポイント阻害剤を組み合わせて投与することにより、Toll様受容体アゴニストと、LAG-3タンパク質及び免疫原性物質のみの投与又は免疫チェックポイント阻害剤のみの投与に比して、あるいはこれらの単独投与に比して相乗的な優れた免疫効果が得られる。また、免疫原性物質に、Toll様受容体アゴニスト、LAG-3タンパク質等及び免疫チェックポイント阻害剤を組み合わせて投与することにより、Toll様受容体アゴニスト、LAG-3タンパク質及び免疫原性物質のみを投与した場合又は免疫チェックポイント阻害剤のみを投与した場合、あるいはこれらを単独で投与した場合には効果を得られないような低用量でも、高い免疫効果を期待できる。
本発明に係る医薬組成物は、特に、Toll様受容体アゴニストと、LAG-3タンパク質、その変異体又はその誘導体(以下「LAG-3タンパク質等」とも称する)と、少なくとも1種のがん抗原由来ペプチドと、免疫チェックポイント阻害剤とが組み合わされて投与されることを特徴とする。
がん抗原由来ペプチドに、Toll様受容体アゴニスト、LAG-3タンパク質等及び免疫チェックポイント阻害剤を組み合わせて投与することにより、Toll様受容体アゴニストと、LAG-3タンパク質及びがん抗原由来ペプチドのみの投与又は免疫チェックポイント阻害剤のみの投与に比して、あるいはこれらの単独投与に比して相乗的な優れた抗腫瘍効果が得られる。また、がん抗原由来ペプチドに、Toll様受容体アゴニスト、LAG-3タンパク質等及び免疫チェックポイント阻害剤を組み合わせて投与することにより、Toll様受容体アゴニスト、LAG-3タンパク質及びがん抗原由来ペプチドのみを投与した場合又は免疫チェックポイント阻害剤のみを投与した場合、あるいはこれらを単独で投与した場合には効果を得られないような低用量でも、高い抗腫瘍効果を期待できる。
免疫チェックポイント阻害剤に、Toll様受容体アゴニストとLAG-3タンパク質を組み合わせて、免疫原性物質によるがんワクチン療法に適用することで、免疫チェックポイント阻害剤の単独投与では治療効果を得られ難い患者においても、高い免疫効果を期待できる。
免疫チェックポイント阻害剤に、Toll様受容体アゴニストとLAG-3タンパク質を組み合わせて、特にがん抗原由来ペプチドによるがんワクチン療法に適用することで、免疫チェックポイント阻害剤の単独投与では治療効果を得られ難い患者においても、がん細胞に対する特異的な免疫応答を誘導して、高い抗腫瘍効果を期待できる。
本発明において、「免疫チェックポイント阻害剤」とは、免疫抑制系を阻害し、腫瘍免疫を活性化する薬剤を示す。
抗PD-1抗体としては、臨床での有効性と安全性が確認されていれば特に制限はないが、好適には、ニボルマブ(Nivolumab)(国際公開第2006/121168号等)及びペムブロリズマブ(Pembrolizumab)(国際公開第2008/156712号等)を挙げることができる。
抗PD-L1抗体としては、臨床での有効性と安全性が確認されていれば特に制限はないが、好適には、アテゾリズマブ(Atezolizumab)(国際公開第2010/077634号等)、デュルバルマブ(Durvalumab)(国際公開第2011/066389号等)及びアベルマブ(Avelumab)(国際公開第2013/079174号等)を挙げることができる。
抗CTLA-4抗体としては、臨床での有効性と安全性が確認されていれば特に制限はないが、好適には、イピリムマブ(Ipilimumab)(国際公開第2001/014424号等)及びトレメリムマブ(Tremelimumab)(国際公開第2000/037504号等)を挙げることができる。
本発明において、「Toll様受容体アゴニスト(TLRアゴニスト)」とは、いずれかのToll様受容体(TLR)に結合すると、TLRに天然のリガンドが結合したときと同じように刺激を与える分子を意味する。
TLRアゴニストとしては、OncoImmunology 1:5, 699-716; August 2012、OncoImmunology 2:8, e25238; August 2013、Trends in Immunology, Vol.30, No.1, 23-32、Immunity 33, October 29, 2010, 492-503、World Journal of Vaccines, 2011, 1, 33-78並びにOncoImmunology 1:6, 894-907; September 2012に記載されるようなTLRのアゴニストが知られており、これら公知のTLRのアゴニストを用いることができる。
TLRアゴニストとして、TLR1アゴニスト~TLR10アゴニストが挙げられるが、例えば、TLR3アゴニスト、TLR4アゴニスト、TLR7アゴニスト、TLR8アゴニスト、TLR9アゴニスト又はTLR10アゴニストとすることができる。TLRアゴニストは、特にTLR3アゴニスト又はTLR9アゴニストであってよい。
TLR1アゴニストとしては、例えば、lipoprotein、Triacylated lipopeptides及びZymosan等が挙げられる。
TLR2アゴニストとしては、例えば、SMP-105, Acylated lipopeptides、Amphotericin B、Atypical LPS、Byglican、Forins、Glyco(phospho)lipids、Lipoteichoic acid、Peptidoglycan、Phenol soluble modulin及びZymosan等が挙げられる。
TLR3アゴニストとしては、二本鎖RNAに構造が似た合成二本鎖ポリヌクレオチドのPoly I:Cが知られているがこれに限定されない。Poly I:Cはその塩であってもよく、例えばナトリウム塩とすることができる。また、Poly I:Cとしては、Poly ICLCを用いることもできる。TLR3アゴニストとしては、RIBOXXOLを用いることもできる。
TLR3アゴニストとしては、例えば、Poly I:C、Poly ICLC (製品名「Hiltonol」)、RIBOXXOL、Ampligen、IPH-3102、cM362-139、及びcM362-140等が挙げられる。
TLR3アゴニストとしては、好ましくはPoly I:Cが用いられるが、Poly I:Cの中でも、Poly-LysineとCarboxymethylcelluloseで安定化させたPoly ICLC (製品名「Hiltonol」)がより好ましく用いられる。
TLR4アゴニストとしては、例えば、MPL、MPLA、OM-174 (CRX-527)、Picibanil (OK-432)及びONO-4007等が挙げられる。
TLR5アゴニストとしては、例えば、CBLB502等が挙げられる。
TLR6アゴニストとしては、例えば、Diacylated lipopeptides、Lipoproteins、Lipoteichoic acid及びZymosan等が挙げられる。
また、「TLR8アゴニスト」とは、TLR8に結合すると、TLR8に天然のリガンドが結合したときと同じように刺激を与える分子をいう。
TLR7及びTLR8は、ウイルス由来の一本鎖RNAを認識し、自然免疫系を活性化する。TLR7/8アゴニストとしては、Imiquimodが知られているがこれに限定されない。Imiquimodはその塩であってもよく、例えばナトリウム塩とすることができる。
TLR7/8アゴニストとしては、例えば、Imiquimod (S-26308, R-837)、Resimiquimod (R-848)、3M-052、852A、VTX-1463、VTX-2337、AZD8848 (DSP-3025)、ANA773及びTMX-101等が挙げられる。
TLR9アゴニストとしては、例えば、CpG、CpG-28、CpG-685 (GNKG168)、CpG-1826、CpG-7909 (PF-3512676, Agatolimod, promune(登録商標))、ODN1585、IMO-2125、IMO-2055 (EMD1201081)、ISS1018、MGN-1703、MGN-1706、AVE0675、QAX-935、SAR-21609、SD-101、及びDIMS0150等のCpG ODNが挙げられる。
TLR10アゴニストとしては、例えば、acylated lipopeptide等が挙げられる。
本発明において、「LAG-3タンパク質、その変異体又はその誘導体」とは、LAG-3タンパク質、その機能的な変異体又はその機能的な誘導体を意味する。LAG-3タンパク質は、由来動物種は限定されないが、例えば、本発明に係る医薬組成物を投与する対象と同じ動物種に由来するタンパク質とすることが好ましい。したがって、本発明に係る医薬組成物がヒトに投与されるものであれば、ヒトLAG-3を用いることができる。LAG-3タンパク質は、ヒトの場合、NCBI Accession No. P18627.5に示されるアミノ酸配列を有するタンパク質である。
本明細書において「1又は数個」とは、1個、2個、3個、4個、5個、6個、7個、8個、9個、又は10個を意味する。
LAG-3タンパク質の機能的な誘導体としては、具体的には、LAG-3とIgGとの融合タンパク質であるIMP321 (LAG-3Ig)を好適に用いることができる。
本発明において、「免疫原性物質」は、動物の体内で免疫応答を誘導可能な物質を広く包含する。免疫原性物質は、個体への投与によって、個体の免疫系と遭遇した同一又は類似抗原に対する抗原特異的免疫応答が増大するように、液性及び/又は細胞性免疫応答を誘発する(すなわち、免疫原性)物質を意味する。免疫原性物物質は、CD4+T細胞応答(例えば、TH1、TH2及び/若しくはTH17)並びに/又はCD8+T細胞応答(例えば、CTL応答)などの細胞性免疫応答を誘発できる。
本発明において、「がん抗原由来ペプチド」は、(i) がん抗原タンパク質の一部のアミノ酸配列を有するペプチド、(ii) 当該アミノ酸配列において1又は2個のアミノ酸の付加、置換又は欠失を含む配列を有するペプチドであって、がん細胞を攻撃する免疫を誘導するもの、又は(iii) 当該アミノ酸配列と90%以上、95%以上、98%以上、又は99%以上の配列同一性を有するペプチドであって、がん細胞を攻撃する免疫を誘導するものをいう。がん抗原由来ペプチドは、8以上11以下のアミノ酸残基からなるものとしてもよい。がん抗原由来ペプチドが患者の皮下に投与されると、樹状細胞やマクロファージ等の抗原提示細胞に取り込まれ、細胞表面にHLA分子とともに提示される。提示されたペプチドに反応性を示す細胞傷害性T細胞(CTL)前駆細胞がクローン増殖し、増殖・分化した成熟CTLがリンパ流を経由してがん組織に移動する。成熟CTLは、投与されたペプチドと同じ配列を有するペプチド発現しているがん細胞を攻撃し、アポトーシスを誘導する。
HSP70由来ペプチドは、特に配列番号1~15のいずれかで表されるアミノ酸配列を有するHSP70由来ペプチドを用いることができ、配列番号7で表されるアミノ酸配列を有するHSP70由来ペプチドがより好適に用いられる。
がん抗原由来ペプチドとしてのGPC3由来ペプチドとしては、特に限定されるものではないが、例えば、国際公開第2018/070069号に記載のペプチドが挙げられ、具体的には、配列番号16~26のいずれかで表されるアミノ酸配列における連続した8以上のアミノ酸残基を含み、且つ11以下のアミノ酸残基から成るペプチドが挙げられる。
GPC3由来ペプチドは、特に配列番号16~26のいずれかで表されるアミノ酸配列を有するGPC3由来ペプチドを用いることができ、配列番号16で表されるアミノ酸配列を有するGPC3由来ペプチドがより好適に用いられる。
これら抗原由来ペプチドは、例示として開示されるものであって、本発明に係る医薬組成物に用いられるがん抗原由来ペプチドが、これら抗原由来ペプチドに限定されるものではない。
本発明に係る医薬組成物は、がんワクチン療法に使用することができ、抗がん剤として使用することもできる。ここで、「抗がん剤」は、がんの予防又は治療に用いることができる剤を意味する。
本発明に係る医薬組成物は、特に、免疫チェックポイント阻害剤による既存治療で効果不十分ながん(すなわち、免疫チェックポイント阻害剤に低感受性又は抵抗性のがん)に好適に適用され得る。
免疫チェックポイント阻害剤に低感受性又は抵抗性のがんとしては、腫瘍部位へのTリンパ球の浸潤が生じ難く、抗PD-1抗体の単独投与では十分な抗腫瘍効果が得られないがんが挙げられる。免疫チェックポイント阻害剤に低感受性又は抵抗性のがんとしては、具体的には、大腸がん、すい臓がん、胃がん、食道がん、軟部肉腫、卵巣がん、乳がん(トリプルネガティブ乳がんを除く)、子宮頚部がん、子宮内膜がん、肝細胞がん等がある。
1回投与あたりの治療有効量は、特に限定されないが、免疫チェックポイント阻害剤で例えば50-800 mg、好ましくは100-400 mg、典型的には200 mgとされる。
Toll様受容体アゴニストで例えば0.25-5.0 mg、好ましくは0.5-2.5 mg、典型的には1.26 mgとされる。
LAG-3タンパク質等で例えば0.25-30mg、好ましくは0.5-15 mg、典型的には1 mgとされる。
がん抗原由来ペプチドで1種類あたり例えば0.5-8 mg、好ましくは1-4 mg、典型的には2 mgとされる。
抗PD-1抗体で例えば50-800 mg、好ましくは100-400 mg、典型的には200 mgとされる。
第1製剤:
1サイクルを28日(4週間)とする。
第1サイクル及び第2サイクルは、1, 8, 15, 22日目に投与する。
第3サイクル及び第4サイクルは、1, 15日目に投与する。
第5サイクル以降は、1日目に投与する。
投与は、両腋窩及び両鼠経部の4ヶ所に分けて皮下に行う。
第2製剤:
1サイクルを21日(3週間)とした。
各サイクルの1日目に、経静脈投与する。
この際、Toll様受容体アゴニスト、LAG-3タンパク質等、免疫原性物質及び免疫チェックポイント阻害剤の各成分は、いずれか1以上が、他の1以上と別異の製剤とされてよい。あるいは、各成分が、単一の製剤とされてもよい。
本発明に係る医薬組成物がペプチドを含む場合、ポリ乳酸・グリコール酸(PLGA)マイクロカプセルや多孔性ヒドロキシアパタイト微粒子等に封入又は吸着させて徐放性を付与してもよく、パルス放出型イオントフォレシス貼付剤システムを利用して経皮吸収させてもよい。
他の抗がん剤は、本発明に係る医薬組成物と同時に、別々に、あるいは連続して対象に投与されてもよいし、それぞれの投与間隔を変えて投与されてもよい。
本発明に係る医薬組成物の抗腫瘍作用を、がんモデルマウスを用いて試験した。
がんモデルマウス:マウスメラノーマ細胞(B16F10細胞、1×105個)を皮下移植したC57BL/6マウス
Poly ICLC:Hiltonol(登録商標)(Oncovir, Inc.)、50μg/mouse
LAG-3Ig:IMP321(Immutep, Ltd.)、1μg/mouse
GP100ペプチド:B16F10細胞の抗原エピトープ(配列番号27:EGSRNQDWL)、50μg/mouse
抗PD-1抗体:InVivoPlus anti m PD-1(Bio X Cell, Cat.No.: BP0146, クローン:RPM1-14)、100μg/mouse
各群10頭で以下の(1)~(5)の実験群を設けた。
対照群(1):無処置
対照群(2):抗PD-1抗体のみを投与
対照群(3):Poly ICLC、LAG-3Ig及びGP100ペプチドのみを投与
試験群(4):Poly ICLC、LAG-3Ig、GP100ペプチド及び抗PD-1抗体を投与
対照群(5):LAG-3Ig、GP100ペプチド及び抗PD-1抗体のみを投与
C57BL/6マウスの皮下にマウスメラノーマ細胞(B16F10細胞、1×105個)を移植した(Day 0)。
Poly ICLC、LAG-3Ig及びGP100ペプチドは、Day 0, 5, 12, 19, 26(1週間に1回)に、腫瘍移植部位とは異なる部位へ皮下投与した。
抗PD-1抗体は、Day 3, 5, 7, 10, 12, 14(1週間に3回)に、腹腔内投与した。
病理組織学的手法により腫瘍体積の変化と腫瘍部位への単核球(リンパ球)浸潤を評価した。腫瘍体積は、「(腫瘍組織の長径)×(腫瘍組織の短径)2/2」により求めた。リンパ球浸潤は、3段階のスコア化して評価した。
図1は、各実験群のマウスの腫瘍体積の変化を示す。縦軸は腫瘍体積(mm3)を、横軸はメラノーマ細胞移植後の日数(Day)を示す。Day 28よりも前に生じている線の途切れは、マウスの死亡を意味する。Day 28まで生存したマウスは、対照群(1)で3頭、対照群(2)で3頭、対照群(3)で9頭、試験群(4)で9頭、対照群(5)で6頭であった。
図2は、各実験群のマウスの腫瘍体積の平均値の変化を示す。縦軸は腫瘍体積(mm3)を、横軸はメラノーマ細胞移植後の日数(Day)を示す。
図3は、Day 21及びDay 28における各実験群のマウスの腫瘍体積の平均値を示す。
抗PD-1抗体のみを投与した対照群(2)では、腫瘍の増殖抑制はほとんどみられなかった。にもかかわらず、Poly ICLC、LAG-3Ig及びGP100ペプチドに加えて抗PD-1抗体を投与した試験群(4)では、Poly ICLC、LAG-3Ig及びGP100ペプチドのみを投与した対照群(3)に比してさらに顕著な抗腫瘍効果が認められた。試験群(4)の腫瘍の平均体積は、Day 21で対照群(3)に比して64%減、Day 28では対照群(3)に比して50%減であった。Poly ICLC、LAG-3Ig及びGP100ペプチドに抗PD-1抗体を組み合わせて投与することにより、Poly ICLC、LAG-3Ig及びGP100ペプチドのみの投与あるいは抗PD-1抗体のみの投与に比して相乗的な優れた抗腫瘍効果が奏されることが明らかとなった。
なお、このような優れた抗腫瘍効果は、LAG-3Ig、GP100ペプチド及び抗PD-1抗体のみを投与した対照群(5)では消失した。
抗PD-1抗体のみを投与した対照群(2)では、浸潤の亢進はほとんどみられなかった。にもかかわらず、Poly ICLC、LAG-3Ig及びGP100ペプチドに加えて抗PD-1抗体を投与した試験群(4)では、Poly ICLC、LAG-3Ig及びGP100ペプチドのみを投与した対照群(3)に比してさらに顕著なリンパ球浸潤が認められた。Poly ICLC、LAG-3Ig及びGP100ペプチドに抗PD-1抗体を組み合わせて投与することにより、Poly ICLC、LAG-3Ig及びGP100ペプチドのみの投与あるいは抗PD-1抗体のみの投与に比して優位なリンパ球浸潤が引き起こされることが明らかとなった。
なお、このような優位なリンパ球浸潤の増強効果は、LAG-3Ig、GP100ペプチド及び抗PD-1抗体のみを投与した対照群(5)では消失した。
試験例1の試験期間を28日から2か月に延長し、がんモデルマウスの生存率の評価を行った。
がんモデルマウス:マウスメラノーマ細胞(B16F10細胞、1×105個)を皮下移植したC57BL/6マウス
Poly ICLC:Hiltonol(登録商標)(Oncovir, Inc.)、50μg/mouse
LAG-3Ig:IMP321(Immutep, Ltd.)、1μg/mouse
GP100ペプチド:B16F10細胞の抗原エピトープ(配列番号27:EGSRNQDWL)、50μg/mouse
抗PD-1抗体:InVivoPlus anti m PD-1(Bio X Cell, Cat.No.: BP0146, クローン:RPM1-14)、100μg/mouse
各群10頭で以下の(1)~(5)の実験群を設けた。
対照群(1):無処置
対照群(2):抗PD-1抗体のみを投与
対照群(3):Poly ICLC、LAG-3Ig及びGP100ペプチドのみを投与
試験群(4):Poly ICLC、LAG-3Ig、GP100ペプチド及び抗PD-1抗体を投与
対照群(5):LAG-3Ig、GP100ペプチド及び抗PD-1抗体のみを投与
C57BL/6マウスの皮下にマウスメラノーマ細胞(B16F10細胞、1×105個)を移植した(Day 0)。
Poly ICLC、LAG-3Ig及びGP100ペプチドは、Day 0, 5, 12, 19, 26(1週間に1回)に、腫瘍移植部位とは異なる部位へ皮下投与した。
抗PD-1抗体は、Day 3, 5, 7, 10, 12, 14(1週間に3回)に、腹腔内投与した。
図5は、各実験群のマウスの生存率の変化を示す。縦軸は生存率を、横軸はメラノーマ細胞移植後の日数(Day)を示す。
にもかかわらず、Poly ICLC、LAG-3Ig及びGP100ペプチドに加えて抗PD-1抗体を投与した試験群(4)では、抗PD-1抗体のみを投与した対照群(2)及びPoly ICLC、LAG-3Ig及びGP100ペプチドのみを投与した対照群(3)に比して顕著な生存日数の伸長が認められた。試験群(4)の最大生存日数はDay 56あり、対照群(2)及び対照群(3)の最大生存日数はそれぞれDay 39、Day 46であった。Poly ICLC、LAG-3Ig及びGP100ペプチドに抗PD-1抗体を組み合わせて投与することにより、Poly ICLC、LAG-3Ig及びGP100ペプチドのみの投与あるいは抗PD-1抗体のみの投与に比して相乗的な優れた生存日数の伸長効果が奏されることが明らかとなった。
なお、このような優れた生存日数の伸長効果は、LAG-3Ig、GP100ペプチド及び抗PD-1抗体のみを投与した対照群(5)では消失した。
がんモデルマウスに移植するがん細胞をマウスメラノーマ細胞(B16F10細胞からマウス大腸がん細胞(MC38細胞)に替えて抗腫瘍作用を評価した。
がんモデルマウス:マウス大腸がん細胞(MC38細胞、1×106個)を皮下移植したC57BL/6マウス
Poly ICLC:Hiltonol(登録商標)(Oncovir, Inc.)、50μg/mouse
LAG-3Ig:IMP321(Immutep, Ltd.)、1μg/mouse
MC38ペプチド:MC38細胞の抗原エピトープであるReps1(配列番号28:AQLANDVVL), Adpgk(配列番号29:ASMTNMELM), Dpagt1(配列番号30:SIIVFNLL)の混合物、50μg/mouse
抗PD-1抗体:InVivoPlus anti m PD-1(Bio X Cell, Cat.No.: BP0146, クローン:RPM1-14)、100μg/mouse
各群5頭で以下の(1)~(4)の実験群を設けた。
対照群(1):無処置
対照群(2):抗PD-1抗体のみを投与
対照群(3):Poly ICLC、LAG-3Ig及びMC38ペプチドのみを投与
試験群(4):Poly ICLC、LAG-3Ig、MC38ペプチド及び抗PD-1抗体を投与
C57BL/6マウスの皮下にマウス大腸がん細胞(MC38細胞、1×106個)を移植した(Day 0)。
Poly ICLC、LAG-3Ig及びMC38ペプチドは、Day 5, 12, 19に、腫瘍移植部位とは異なる部位へ皮下投与した。
抗PD-1抗体は、Day 5, 12, 19に、腹腔内投与した。
試験例1と同様に病理組織学的手法により腫瘍体積の変化を評価した。
図6は、各実験群のマウスの腫瘍体積の平均値の変化を示す。縦軸は腫瘍体積(mm3)を、横軸は大腸がん細胞移植後の日数(Day)を示す。
図7は、各実験群のマウスの生存率の変化を示す。縦軸は生存率を、横軸は大腸がん細胞移植後の日数(Day)を示す。
Poly ICLC、LAG-3Ig及びMC38ペプチドに加えて抗PD-1抗体を投与した試験群(4)では、Poly ICLC、LAG-3Ig及びMC38ペプチドのみを投与した対照群(3)に比してさらに腫瘍サイズが抑制された。
Poly ICLC、LAG-3Ig及びMC38ペプチドに抗PD-1抗体を組み合わせて投与することにより、Poly ICLC、LAG-3Ig及びMC38ペプチドのみの投与あるいは抗PD-1抗体のみの投与に比して相乗的な優れた抗腫瘍効果が奏されることが明らかとなった。
さらに、試験群(4)ではDay 50でも40%の個体が生存した。これに対して、対照群(3)及び対照群(2)では全ての個体が死亡した。
Poly ICLC、LAG-3Ig及びMC38ペプチドに抗PD-1抗体を組み合わせて投与することにより、Poly ICLC、LAG-3Ig及びMC38ペプチドのみの投与あるいは抗PD-1抗体のみの投与に比して優れた生存日数の伸長効果が奏されることが明らかとなった。
試験例3における抗PD-1抗体の投与量を100μg/mouseから66.7μg/mouseに変更し、抗腫瘍作用を評価した。
なお、ヒトにおける抗PD-1抗体の投与量は1回10mg/kg体重程度されており(例えばN Engl J Med 2015; 372:2509-2520参照)、これは体重換算でマウスの投与量200μg/mouseに相当する。したがって、上記66.7μg/mouseの投与量は、ヒトの通常投与量の1/3量に相当する。
がんモデルマウス:マウス大腸がん細胞(MC38細胞、1×106個)を皮下移植したC57BL/6マウス
Poly ICLC:Hiltonol(登録商標)(Oncovir, Inc.)、50μg/mouse
LAG-3Ig:IMP321(Immutep, Ltd.)、1μg/mouse
MC38ペプチド:MC38細胞の抗原エピトープであるReps1(配列番号28:AQLANDVVL), Adpgk(配列番号29:ASMTNMELM), Dpagt1(配列番号30:SIIVFNLL)の混合物、50μg/mouse
抗PD-1抗体:InVivoPlus anti m PD-1(Bio X Cell, Cat.No.: BP0146, クローン:RPM1-14)、66.7μg/mouse
各群5頭で以下の(1)~(4)の実験群を設けた。
対照群(1):無処置
対照群(2):抗PD-1抗体のみを投与
対照群(3):Poly ICLC、LAG-3Ig及びMC38ペプチドのみを投与
試験群(4):Poly ICLC、LAG-3Ig、MC38ペプチド及び抗PD-1抗体を投与
C57BL/6マウスの皮下にマウス大腸がん細胞(MC38細胞、1×106個)を移植した(Day 0)。
Poly ICLC、LAG-3Ig及びMC38ペプチドは、Day 5, 12, 19に、腫瘍移植部位とは異なる部位へ皮下投与した。
抗PD-1抗体は、Day 5, 12, 19に、腹腔内投与した。
試験例1と同様に病理組織学的手法により腫瘍体積の変化を評価した。
図8は、各実験群のマウスの生存率の変化を示す。縦軸は生存率を、横軸は大腸がん細胞移植後の日数(Day)を示す。
さらに、試験群(4)ではDay 53でも40%の個体が生存した。これに対して、対照群(3)及び対照群(2)でのDay 53の生存率はそれぞれ10%、10%であった。
Poly ICLC、LAG-3Ig及びMC38ペプチドに抗PD-1抗体を組み合わせて投与することにより、Poly ICLC、LAG-3Ig及びMC38ペプチドのみの投与あるいは抗PD-1抗体のみの投与に比して優れた生存日数の伸長効果が奏されることが明らかとなった。
実験群としてPoly ICLCを投与しない群を設け、抗腫瘍作用を評価した。
[材料]
がんモデルマウス:マウス大腸がん細胞(MC38細胞、1×106個)を皮下移植したC57BL/6マウス
Poly ICLC:Hiltonol(登録商標)(Oncovir, Inc.)、0又は50μg/mouse
LAG-3Ig:IMP321(Immutep, Ltd.)、1μg又は10μg/mouse
MC38ペプチド:MC38細胞の抗原エピトープであるReps1(配列番号28:AQLANDVVL), Adpgk(配列番号29:ASMTNMELM), Dpagt1(配列番号30:SIIVFNLL)の混合物、50μg/mouse
抗PD-1抗体:InVivoPlus anti m PD-1(Bio X Cell, Cat.No.: BP0146, クローン:RPM1-14)、66.7μg/mouse
各群5頭で以下の(1)~(4)の実験群を設けた。
対照群(1):無処置
試験群(4):Poly ICLC、LAG-3Ig、MC38ペプチド及び抗PD-1抗体を投与
対照群(5):LAG-3Ig(1μg)、MC38ペプチド及び抗PD-1抗体のみを投与
対照群(6):LAG-3Ig(10μg)、MC38ペプチド及び抗PD-1抗体のみを投与
C57BL/6マウスの皮下にマウス大腸がん細胞(MC38細胞、1×106個)を移植した(Day 0)。
Poly ICLC、LAG-3Ig及びMC38ペプチドは、Day 5, 12, 19に、腫瘍移植部位とは異なる部位へ皮下投与した。
抗PD-1抗体は、Day 5, 12, 19に、腹腔内投与した。
試験例1と同様に病理組織学的手法により腫瘍体積の変化を評価した。
図9は、各実験群のマウスの生存率の変化を示す。縦軸は生存率を、横軸は大腸がん細胞移植後の日数(Day)を示す。
以下のプロトコルにしたがって、本発明に係る医薬組成物の抗腫瘍作用を第I/II相臨床試験において評価する。
切除不能な進行肝細胞癌患者を対象としたペプチドワクチンCYT001(HSP70由来ペプチド、GPC3由来ペプチド、Poly ICLC、LAG-3Ig)と抗PD-1抗体併用の第I/II相臨床試験
[試験デザイン]
Simonの2段階デザイン("Optimal two-stage designs for phase II clinical trials.", Simon R, Control Clin. Trials., 1989, 10(1):1-10)に基づく、オープンラベルかつシングルアームの第I/II相試験(安全性/有効試験)
[対象患者]
以下のいずれを満たす進行肝細胞癌の患者(44症例)を対象とする。
・組織学的又は細胞学的に肝細胞癌と診断されている。
・切除不能。
・標準治療不能あるいは不応。
・HLA-A遺伝子の対立遺伝子型がHLA-A*24:02, HLA-A*02:01又はHLA-A*02:06。
・身体状態が良好(Eastern Cooperative Oncology Group(ECOG)のパフォーマンスステータス(PS)が0または1)である。
・肝臓状態が良好(Child-Pugh scoreがA)である。
[治験薬]
CYT001:1回あたり1.7mlを皮下投与。1.7ml中HSP70由来ペプチド(配列番号16)2 mg、GPC3由来ペプチド(配列番号7)2 mg、Poly ICLC(Hiltonol(登録商標))1.26 mg、LAG-3Ig(IMP321)1 mgを含む。
抗PD-1抗体:1回あたり200mgを経静脈投与。
[投与計画]
CYT001:
1サイクルを28日(4週間)とする。
第1サイクル及び第2サイクルは、1, 8, 15, 22日目に投与する。
第3サイクル及び第4サイクルは、1, 15日目に投与する。
第5サイクル以降は、1日目に投与する。
投与は、両腋窩及び両鼠経部の4ヶ所に分けて皮下に行う。
抗PD-1抗体:
1サイクルを21日(3週間)とした。
各サイクルの1日目に、経静脈投与する。
配列番号2:HSP70由来ペプチドのアミノ酸配列
配列番号3:HSP70由来ペプチドのアミノ酸配列
配列番号4:HSP70由来ペプチドのアミノ酸配列
配列番号5:HSP70由来ペプチドのアミノ酸配列
配列番号6:HSP70由来ペプチドのアミノ酸配列
配列番号7:HSP70由来ペプチドのアミノ酸配列
配列番号8:HSP70由来ペプチドのアミノ酸配列
配列番号9:HSP70由来ペプチドのアミノ酸配列
配列番号10:HSP70由来ペプチドのアミノ酸配列
配列番号11:HSP70由来ペプチドのアミノ酸配列
配列番号12:HSP70由来ペプチドのアミノ酸配列
配列番号13:HSP70由来ペプチドのアミノ酸配列
配列番号14:HSP70由来ペプチドのアミノ酸配列
配列番号15:HSP70由来ペプチドのアミノ酸配列
配列番号16:GPC3由来ペプチドのアミノ酸配列
配列番号17:GPC3由来ペプチドのアミノ酸配列
配列番号18:GPC3由来ペプチドのアミノ酸配列
配列番号19:GPC3由来ペプチドのアミノ酸配列
配列番号20:GPC3由来ペプチドのアミノ酸配列
配列番号21:GPC3由来ペプチドのアミノ酸配列
配列番号22:GPC3由来ペプチドのアミノ酸配列
配列番号23:GPC3由来ペプチドのアミノ酸配列
配列番号24:GPC3由来ペプチドのアミノ酸配列
配列番号25:GPC3由来ペプチドのアミノ酸配列
配列番号26:GPC3由来ペプチドのアミノ酸配列
配列番号27:GP100ペプチドのアミノ酸配列
配列番号28:Reps1ペプチドのアミノ酸配列
配列番号29:Adpgkペプチドのアミノ酸配列
配列番号30:Dpagt1ペプチドのアミノ酸配列
Claims (17)
- Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体又はその誘導体と、
少なくとも1種の免疫原性物質と、
免疫チェックポイント阻害剤と、
が、組み合わされて投与されることを特徴とする医薬組成物。 - 免疫チェックポイント阻害剤が、抗PD-1抗体、抗PD-L1抗体又は抗CTLA-4抗体である、請求項1に記載の医薬組成物。
- 前記Toll様受容体アゴニストが、Toll様受容体3アゴニスト又はToll様受容体9アゴニストである、請求項1又は2に記載の医薬組成物。
- 前記Toll様受容体アゴニストが、Poly I:C又はその塩である、請求項3に記載の医薬組成物。
- 前記Poly I:Cが、Poly ICLCである、請求項4に記載の医薬組成物。
- 前記LAG-3タンパク質、その変異体又はその誘導体が、LAG-3タンパク質とIgGの融合タンパク質である、請求項1-5のいずれか一項に記載の医薬組成物。
- 少なくとも1種の免疫原性物質が、少なくとも1種のがん抗原由来ペプチドである、請求項1-6のいずれか一項に記載の医薬組成物。
- 前記少なくとも1種のがん抗原由来ペプチドが、HSP70由来ペプチド又はGPC3由来ペプチドである、請求項7に記載の医薬組成物。
- 前記HSP70由来ペプチドが配列番号7に示すアミノ酸配列からなり、前記GPC3由来ペプチドが配列番号16に示すアミノ酸配列からなる、請求項8に記載の医薬組成物。
- Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体又はその誘導体と、
免疫原性物質と、
免疫チェックポイント阻害剤と、
のいずれか1以上が、他の1以上と別異の製剤に有効成分として含有され、それらの製剤が同時に又は異なる時間に投与されることを特徴とする、請求項1-9のいずれか一項に記載の医薬組成物。 - Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体又はその誘導体と、
免疫原性物質と、
免疫チェックポイント阻害剤と、
が、単一の製剤に有効成分として含有され、投与されることを特徴とする、請求項1-9のいずれか一項に記載の医薬組成物。 - がんワクチン療法に用いられる、請求項1-11のいずれか一項に記載の医薬組成物。
- 抗がん剤である、請求項1-11のいずれか一項に記載の医薬組成物。
- がんが、免疫チェックポイント阻害剤に低感受性又は抵抗性である、請求項12又は13に記載の医薬組成物。
- Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体又はその誘導体と、
免疫チェックポイント阻害剤と、
が、組み合わせて投与されることを特徴とする医薬組成物。 - さらに、少なくとも1種の免疫原性物質と組み合わされて投与されることを特徴とする、請求項14に記載の医薬組成物。
- 少なくとも1種の免疫原性物質が、少なくとも1種のがん抗原由来ペプチドである、請求項16に記載の医薬組成物。
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EP4066852A4 (en) | 2024-05-22 |
TW202128155A (zh) | 2021-08-01 |
US20220401540A1 (en) | 2022-12-22 |
JPWO2021106978A1 (ja) | 2021-06-03 |
AU2020394122A1 (en) | 2022-06-09 |
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