WO2023022235A1 - 組み合わせ医薬 - Google Patents
組み合わせ医薬 Download PDFInfo
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- WO2023022235A1 WO2023022235A1 PCT/JP2022/031444 JP2022031444W WO2023022235A1 WO 2023022235 A1 WO2023022235 A1 WO 2023022235A1 JP 2022031444 W JP2022031444 W JP 2022031444W WO 2023022235 A1 WO2023022235 A1 WO 2023022235A1
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
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- A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
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- A61K39/461—Cellular immunotherapy characterised by the cell type used
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Definitions
- IAPs Inhibitor of apoptosis proteins
- the IAP family includes eight members: XIAP, cIAP1, cIAP2, NAIP, ILP2, ML-IAP, survivin, and BRUCE.
- Members of the IAP family have in common 1-3 copies of a zinc-coordinating domain of approximately 70 amino acids called the baculovirus IAP repeat (BIR) domain.
- BIR baculovirus IAP repeat
- the BIR domain binds to caspases such as caspases 3, 7, and 9 and has the effect of inhibiting apoptosis.
- IAP antagonists can treat tumors by inhibiting the binding of caspases to the BIR domain and inducing apoptosis.
- Known IAP antagonists include non-peptidomimetic small molecule antagonists such as trinapant (ASTX660) (eg, Patent Document 1), and second mitochondria-derived caspase activator (SMAC) mimetics such as birinapant, LCL161, and AT406.
- ASTX660 trinapant
- SMAC second mitochondria-derived caspase activator
- Adoptive immunotherapy using genetically modified immune cells is known as another approach to treating tumors.
- First-generation chimeric antigen receptors consist of a single-chain antibody capable of recognizing surface antigens of tumor cells, a transmembrane domain, and an intracellular signaling domain of the TCR complex CD3zeta that activates T cells.
- second-generation chimeric antigen receptors have been developed that link the intracellular signaling domain of the T-cell co-stimulatory molecule CD28.
- third-generation chimeric antigen receptors have been developed that link intracellular signaling domains from the tumor necrosis factor (TNF) receptor superfamily CD137 (4-1BB) or CD134 (OX40) in tandem. .
- TCR genes targeting tumor antigens such as gp100, MART-1, CEA, MAGE-A4, WT1, and NY-ESO-1 are known as nucleic acids encoding T cell receptors.
- One of the subjects of the present disclosure is to improve the therapeutic effect of genetically modified immunotherapy.
- the present disclosure typically includes the following aspects.
- Item 1. Formula (1) below: A pharmaceutical composition (or drug, medicament, or IAP inhibitor) containing a compound represented by said pharmaceutical composition (or drug, drug, or IAP inhibitor) administered in combination with immune cells that have been engineered to express a somatic or recombinant T-cell receptor. Section 1a. 2. The pharmaceutical composition (or agent, medicament, or IAP inhibitor) of paragraph 1, administered before, concurrently, or after administration of said immune cells.
- Item 2. A pharmaceutical composition comprising immune cells engineered to express a chimeric antigen receptor or a recombinant T-cell receptor, wherein: The pharmaceutical composition, which is administered in combination with a compound represented by, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. Section 2a.
- Item 3 The medicament according to item 2, which is administered before, simultaneously with, or after administration of the compound represented by formula (1), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
- Composition. Item 3. 1a or 2a, wherein said chimeric antigen receptor or recombinant T cell receptor specifically recognizes an antigen selected from CD19, integrin ⁇ 7, and NY-ESO-1.
- pharmaceutical composition of Item 4. The pharmaceutical composition according to Item 1 or 2 or Item 1a or 2a, wherein the chimeric antigen receptor or recombinant T cell receptor specifically recognizes activated integrin ⁇ 7.
- the immune cells are T cells or NK cells that have been modified to express a chimeric antigen receptor, and the chimeric antigen receptor is (1) an extracellular domain capable of recognizing an antigen, (2) a transmembrane domain, (3) intracellular signaling domains of co-stimulatory molecules, and (4) The pharmaceutical composition according to any one of Items 1 to 4, 1a, and 2a, which contains the intracellular signaling domain of CD3zeta.
- Items 1 to 4, 1a, and 2a which contains the intracellular signaling domain of CD3zeta.
- Item 6. The pharmaceutical composition according to Item 5, wherein the extracellular domain is an extracellular domain capable of recognizing CD19 or integrin ⁇ 7.
- Item 7. 7.
- the pharmaceutical composition of paragraph 5 or 6, wherein the transmembrane domain is the transmembrane domain of CD28 or CD8.
- said immune cells are T cells or NK cells modified to express a recombinant T cell receptor, said recombinant T cell receptor having a variable domain capable of recognizing NY-ESO-1 1 or 2, or the pharmaceutical composition of paragraphs 1a or 2a.
- said immune cells are T cells modified to express a chimeric antigen receptor that specifically recognizes CD19, T cells modified to express a chimeric antigen receptor that specifically recognizes integrin ⁇ 7, NK cells engineered to express a chimeric antigen receptor that specifically recognizes CD19 or T cells engineered to express a recombinant T cell receptor that specifically recognizes NY-ESO-1 Item 1 or 2, or the pharmaceutical composition according to Item 1a or 2a.
- Item 11 The pharmaceutical composition according to any one of Items 1 to 10, 1a and 2a for preventing and/or treating cancer.
- compositions of any of paragraphs 1-12, 1a, 2a, and 12a, wherein said immune cells are administered in an amount that is less than the dose when administered alone or is not effective alone.
- Item 14 Formula (1) below: A first agent containing a compound represented by, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a chimeric antigen receptor or a recombinant T cell receptor to express A kit comprising a second agent containing immune cells that have been modified to Section 14a. said first and second agents are in the same formulation and are administered at the same time, or said first and second agents are in different formulations and are administered simultaneously, separately or sequentially; 15. The kit of paragraph 14. Section 14b.
- kit of paragraphs 14 or 14a wherein said chimeric antigen receptor or recombinant T-cell receptor specifically recognizes an antigen selected from CD19, integrin ⁇ 7, and NY-ESO-1.
- Section 14c The kit of paragraph 14 or 14a, wherein said chimeric antigen receptor or recombinant T cell receptor specifically recognizes activated integrin ⁇ 7. Section 14d.
- the immune cells are T cells or NK cells that have been modified to express a chimeric antigen receptor, and the chimeric antigen receptor is (1) an extracellular domain capable of recognizing an antigen, (2) a transmembrane domain, (3) intracellular signaling domains of co-stimulatory molecules, and (4) The kit of any of paragraphs 14 and 14a-14c, containing the intracellular signaling domain of CD3zeta.
- Section 14e. The kit of paragraph 14d, wherein said extracellular domain is an extracellular domain capable of recognizing CD19 or integrin ⁇ 7.
- Section 14f The kit of paragraphs 14d or 14e, wherein said transmembrane domain is the transmembrane domain of CD28 or CD8.
- kits of any of paragraphs 14d-14f, wherein said co-stimulatory molecule is CD2, CD4, CD5, CD8 ⁇ , CD8 ⁇ , CD28, CD134 (OX40), CD137 (4-1BB), or CD278 (ICOS).
- Section 14h. wherein said immune cells are T cells or NK cells modified to express a recombinant T cell receptor, said recombinant T cell receptor having a variable domain capable of recognizing NY-ESO-1;
- said immune cells are T cells modified to express a chimeric antigen receptor that specifically recognizes CD19, T cells modified to express a chimeric antigen receptor that specifically recognizes integrin ⁇ 7, NK cells engineered to express a chimeric antigen receptor that specifically recognizes CD19 or T cells engineered to express a recombinant T cell receptor that specifically recognizes NY-ESO-1 14.
- the kit of claim 14 or 14a which is Section 14j.
- the compound represented by formula (1), its pharmaceutically acceptable salt, or its pharmaceutically acceptable solvate is 10 mg to 180 mg/day, which is less than the dose when administered alone.
- the immune cells are administered in an amount of 1 ⁇ 10 3 to 1 ⁇ 10 8 (viable cell count)/kg body weight/day, an amount lower than the dose when administered alone, or an amount not effective alone , paragraphs 14 and 14a-14k. Item 15.
- a method of preventing and/or treating cancer comprising: Formula (1) below for a subject in need of cancer prevention and/or treatment: A compound represented by, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, with immune cells modified to express a chimeric antigen receptor or a recombinant T cell receptor A method comprising administering in combination.
- the administering comprises administering the compound represented by formula (1), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, before, concurrently, or with the administration of the immune cells; 16.
- Section 15b Section 15b.
- the immune cells are T cells or NK cells that have been modified to express a chimeric antigen receptor, and the chimeric antigen receptor is (1) an extracellular domain capable of recognizing an antigen, (2) a transmembrane domain, (3) intracellular signaling domains of co-stimulatory molecules, and (4) The method of any of paragraphs 15 and 15a-15c, comprising the intracellular signaling domain of CD3zeta.
- Section 15f. The method of paragraphs 15d or 15e, wherein said transmembrane domain is the transmembrane domain of CD28 or CD8.
- said immune cells are T cells modified to express a chimeric antigen receptor that specifically recognizes CD19, T cells modified to express a chimeric antigen receptor that specifically recognizes integrin ⁇ 7, NK cells engineered to express a chimeric antigen receptor that specifically recognizes CD19 or T cells engineered to express a recombinant T cell receptor that specifically recognizes NY-ESO-1
- Section 15j. 10 mg to 180 mg/day of the compound represented by the above formula (1), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, which is less than the dose when administered alone The method of any of paragraphs 15 and 15a-15i, administered in an amount, or in an amount that is not effective alone. Section 15k.
- the immune cells are T cells or NK cells that have been modified to express a chimeric antigen receptor, and the chimeric antigen receptor is (1) an extracellular domain capable of recognizing an antigen, (2) a transmembrane domain, (3) intracellular signaling domains of co-stimulatory molecules, and (4) Use according to any one of items 16 and 16a-16c, which contains the intracellular signaling domain of CD3zeta.
- Section 16f. Use according to paragraphs 16d or 16e, wherein said transmembrane domain is the transmembrane domain of CD28 or CD8.
- co-stimulatory molecule is CD2, CD4, CD5, CD8 ⁇ , CD8 ⁇ , CD28, CD134 (OX40), CD137 (4-1BB), or CD278 (ICOS).
- said immune cells are T cells or NK cells modified to express a recombinant T cell receptor, said recombinant T cell receptor having a variable domain capable of recognizing NY-ESO-1 Use according to 16 or 16a.
- said immune cells are T cells modified to express a chimeric antigen receptor that specifically recognizes CD19, T cells modified to express a chimeric antigen receptor that specifically recognizes integrin ⁇ 7, NK cells engineered to express a chimeric antigen receptor that specifically recognizes CD19 or T cells engineered to express a recombinant T cell receptor that specifically recognizes NY-ESO-1 Use according to paragraphs 16 or 16a, wherein Section 16j. Use according to any of paragraphs 16 and 16a-16i, wherein said medicament is a medicament for preventing and/or treating cancer. Section 16k.
- the drug is the compound represented by the formula (1), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, administered alone at a dose of 10 mg to 180 mg/day Use according to any of paragraphs 16 and 16a-16j, which is a medicament for administration in an amount less than or not effective alone.
- the drug is 1 ⁇ 10 3 to 1 ⁇ 10 8 (viable cell count)/kg body weight/day, an amount lower than the dose when administered alone, or an amount that is not effective alone.
- Section 17a. The medicament is for administration before, simultaneously with, or after administration of the compound represented by formula (1), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. 18.
- Section 17b. Use according to paragraphs 17 or 17a, wherein said chimeric antigen receptor or recombinant T cell receptor specifically recognizes an antigen selected from CD19, integrin ⁇ 7 and NY-ESO-1.
- Section 17c Section 17c.
- chimeric antigen receptor or recombinant T cell receptor specifically recognizes activated integrin ⁇ 7.
- the immune cells are T cells or NK cells that have been modified to express a chimeric antigen receptor, and the chimeric antigen receptor is (1) an extracellular domain capable of recognizing an antigen, (2) a transmembrane domain, (3) intracellular signaling domains of co-stimulatory molecules, and (4) Use according to any one of items 17 and 17a-17c, which contains the intracellular signaling domain of CD3zeta.
- Section 17e. Use according to paragraph 17d, wherein said extracellular domain is an extracellular domain capable of recognizing CD19 or integrin ⁇ 7.
- Section 17f Use according to paragraphs 17d, wherein said extracellular domain is an extracellular domain capable of recognizing CD19 or integrin ⁇ 7.
- transmembrane domain is the transmembrane domain of CD28 or CD8.
- Section 17g Use according to any of paragraphs 17d-17f, wherein said co-stimulatory molecule is CD2, CD4, CD5, CD8 ⁇ , CD8 ⁇ , CD28, CD134 (OX40), CD137 (4-1BB), or CD278 (ICOS).
- Section 17h wherein said immune cells are T cells or NK cells modified to express a recombinant T cell receptor, said recombinant T cell receptor having a variable domain capable of recognizing NY-ESO-1 Use according to 17 or 17a.
- Section 17i Section 17i.
- said immune cells are T cells modified to express a chimeric antigen receptor that specifically recognizes CD19, T cells modified to express a chimeric antigen receptor that specifically recognizes integrin ⁇ 7, NK cells engineered to express a chimeric antigen receptor that specifically recognizes CD19 or T cells engineered to express a recombinant T cell receptor that specifically recognizes NY-ESO-1 Use according to paragraph 17 or 17a, wherein Section 17j. Use according to any of paragraphs 17 and 17a-17i, wherein said medicament is a medicament for preventing and/or treating cancer. Section 17k.
- the drug contains 1 ⁇ 10 3 to 1 ⁇ 10 8 (viable cell count)/kg body weight/day of the immune cells, an amount lower than the dose when administered alone, or an amount that is not effective alone Use according to any of paragraphs 17 and 17a-17j, which is a medicament for administration.
- the medicament is 10 mg to 180 mg/day, an amount less than the dose when administered alone, or an amount that is not effective alone, the compound represented by the above formula (1), or a pharmaceutically acceptable salt thereof , or a pharmaceutically acceptable solvate thereof, which is a medicament for administration.
- Formula (1) below used for administration in combination with immune cells that have been modified to express a chimeric antigen receptor or a recombinant T-cell receptor: A compound represented by, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
- Section 18a. 19 The compound of Item 18, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for administration before, concurrently with, or after administration of said immune cells.
- Section 18b Use according to paragraphs 18 or 18a, wherein said chimeric antigen receptor or recombinant T cell receptor specifically recognizes an antigen selected from CD19, integrin ⁇ 7 and NY-ESO-1. Section 18c.
- the immune cells are T cells or NK cells that have been modified to express a chimeric antigen receptor, and the chimeric antigen receptor is (1) an extracellular domain capable of recognizing an antigen, (2) a transmembrane domain, (3) intracellular signaling domains of co-stimulatory molecules, and (4) A compound, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof according to any one of Items 18 and 18a-18c, which contains the intracellular signaling domain of CD3zeta. Section 18e.
- Section 18f. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, of paragraph 18d or 18e, wherein said transmembrane domain is the transmembrane domain of CD28 or CD8.
- Section 18g. The compound of any of paragraphs 18d-18f, wherein said co-stimulatory molecule is CD2, CD4, CD5, CD8 ⁇ , CD8 ⁇ , CD28, CD134 (OX40), CD137 (4-1BB), or CD278 (ICOS); a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof; Section 18h.
- said immune cells are T cells or NK cells modified to express a recombinant T cell receptor, said recombinant T cell receptor having a variable domain capable of recognizing NY-ESO-1 A compound according to 18 or 18a, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
- Section 18i
- said immune cells are T cells modified to express a chimeric antigen receptor that specifically recognizes CD19, T cells modified to express a chimeric antigen receptor that specifically recognizes integrin ⁇ 7, NK cells engineered to express a chimeric antigen receptor that specifically recognizes CD19 or T cells engineered to express a recombinant T cell receptor that specifically recognizes NY-ESO-1
- the compound of paragraph 18 or 18a, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof which is Section 18j.
- Formula (1) below expressing a chimeric antigen receptor or recombinant T-cell receptor used for administration in combination with a compound represented by immune cells that have been modified to Section 19a. in paragraph 19, for administration before, simultaneously with, or after administration of the compound represented by formula (1), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof; Immune cells as indicated.
- Section 19b The immune cell of paragraph 19 or 19a, wherein said chimeric antigen receptor or recombinant T cell receptor specifically recognizes an antigen selected from CD19, integrin ⁇ 7, and NY-ESO-1. Section 19c.
- the immune cell of Paragraph 19 or 19a wherein said chimeric antigen receptor or recombinant T cell receptor specifically recognizes activated integrin ⁇ 7.
- Section 19d T cells or NK cells that have been modified to express a chimeric antigen receptor, wherein the chimeric antigen receptor is (1) an extracellular domain capable of recognizing an antigen, (2) a transmembrane domain, (3) intracellular signaling domains of co-stimulatory molecules, and (4) The immune cell of any one of Items 19 and 19a-19c, which contains the intracellular signaling domain of CD3zeta.
- Section 19e The immune cell of paragraph 19d, wherein said extracellular domain is an extracellular domain capable of recognizing CD19 or integrin ⁇ 7.
- Section 19f The immune cell of paragraph 19d, wherein said extracellular domain is an extracellular domain capable of recognizing CD19 or integrin ⁇ 7.
- Section 19g. The immune cell of any of paragraphs 19d-19f, wherein said co-stimulatory molecule is CD2, CD4, CD5, CD8 ⁇ , CD8 ⁇ , CD28, CD134 (OX40), CD137 (4-1BB), or CD278 (ICOS).
- Section 19h. wherein said immune cells are T cells or NK cells modified to express a recombinant T cell receptor, said recombinant T cell receptor having a variable domain capable of recognizing NY-ESO-1 The immune cell of 19 or 19a.
- said immune cells are T cells modified to express a chimeric antigen receptor that specifically recognizes CD19, T cells modified to express a chimeric antigen receptor that specifically recognizes integrin ⁇ 7, NK cells engineered to express a chimeric antigen receptor that specifically recognizes CD19 or T cells engineered to express a recombinant T cell receptor that specifically recognizes NY-ESO-1
- the immune cell of paragraph 19 or 19i which is Section 19j.
- the efficacy of pharmaceutical compositions containing trinapanth drugs or modified immune cells can be significantly increased.
- FIG. 1 is a graph showing the combined effect of Birinapant and CD19 CAR-T.
- FIG. 2 is a graph showing the combined effect of Tolinapant (meaning the (+)-L-lactate salt of the compound represented by formula (1) in this figure) and CD19 CAR-T. * indicates a combined effect test in a one-way model, with Tolinapant and CD19 CAR-T (1 ⁇ 10 5 cells/body) versus control (Tolinapant, CD19 CAR-T (1 ⁇ 10 5 cells/body), respectively) body) showed a significant (p ⁇ 0.05) effect.
- FIG. 1 is a graph showing the combined effect of Birinapant and CD19 CAR-T.
- FIG. 2 is a graph showing the combined effect of Tolinapant (meaning the (+)-L-lactate salt of the compound represented by formula (1) in this figure) and CD19 CAR-T. * indicates a combined effect test in a one-way model, with Tolinapant and CD19 CAR-T (1 ⁇ 10 5 cells/
- FIG. 3 is a graph showing the combined effect of Tolinapant (meaning the (+)-L-lactate salt of the compound represented by formula (1) in this figure) and CD19 CAR-T on low tumor burden.
- FIG. 4 is a graph showing the combined effect of LCL161 and CD19 CAR-T.
- FIG. 5 is a graph showing the combined effect of AT406 and CD19 CAR-T.
- Figure 6 shows the dosing regimen.
- FIG. 7 is a graph showing the combined effect of Tolinapant and active integrin ⁇ 7 CAR-T.
- FIG. 8 shows the dosing regimen.
- FIG. 9 is a graph showing the combined effect of Tolinapant and CD19 CAR-KHYG-1.
- Figure 10 shows the dosing regimen.
- composition A is a pharmaceutical composition containing a chimeric antigen receptor or a recombinant T cell receptor. It is preferable that the pharmaceutical composition is administered in combination with immune cells (which may be in the form of pharmaceutical composition B described below) modified to express It is preferably a pharmaceutical composition administered before, simultaneously with, or after.
- Pharmaceutical composition A may typically be an IAP antagonist, in particular an antagonist of XIAP, cIAP1 and cIAP2.
- Trinapant-type agents may take effect more rapidly when administered in combination with engineered immune cells compared to other IAP antagonists.
- A-1 The compound represented by trinapanth drug formula (1) accounts for 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, or 90% of the total amount. Greater than 95%, 99% or more, 99.5% or more, 99.9% or more, or 100% can exist as a single optical isomer.
- the pharmaceutically acceptable salt of the compound represented by formula (1) is preferably an acid addition salt.
- the acid addition salt may be an organic acid addition salt or an inorganic acid addition salt.
- Non-limiting examples of acid addition salts include acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (e.g.
- L-ascorbic acid L-aspartic acid
- benzenesulfonic acid benzoic acid
- 4 -acetamidobenzoic acid butanoic acid
- (+) camphoric acid camphor-sulfonic acid
- (+)-(1S)-camphor-10-sulfonic acid capric acid, caproic acid, caprylic acid
- cinnamic acid citric acid
- Cyclamic acid dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid (e.g.
- D-glucuronic acid D-glucuronic acid
- glutamic acid e.g. L-glutamic acid
- ⁇ -oxoglutaric acid glycolic acid, hippuric acid
- hydrohalic acid e.g. hydrobromic acid, hydrochloric acid, hydroiodic acid
- isethionic acid lactic acid (e.g.
- Non-limiting examples of the pharmaceutically acceptable solvates include water, methanol, ethanol, isopropanol, acetic acid, ethyl acetate, ethanolamine, dimethylsulfoxide (DMSO) and the like.
- composition A preferably contains pharmaceutically acceptable excipients as other ingredients.
- Pharmaceutically acceptable excipients include, for example, carriers (including solid carriers, semi-solid carriers, and liquid carriers), adjuvants, diluents, fillers or extenders, granulating agents, coating agents, release agents, Regulators, binders, disintegrants, lubricants, preservatives, antioxidants, buffers, suspending agents, thickeners, flavoring agents, stabilizers, surfactants, chelating agents, or other pharmaceutical compositions
- Examples include excipients commonly used in products.
- One type of pharmaceutically acceptable excipient may be used alone, or two or more types may be used in combination.
- Form pharmaceutical composition A includes liquid preparations (e.g. injections, eye drops, nasal drops, suspensions), solid preparations (e.g. tablets, granules, powders), and semi-solid preparations (e.g. ointments, suppositories) and other formulations known to those skilled in the art.
- liquid preparations e.g. injections, eye drops, nasal drops, suspensions
- solid preparations e.g. tablets, granules, powders
- semi-solid preparations e.g. ointments, suppositories
- composition A may be for oral or parenteral administration.
- Pharmaceutical composition A may be for topical administration.
- Pharmaceutical composition A may for example be for intraocular, aural, intranasal, sublingual, intrabronchial, intravenous, intramuscular, intraperitoneal, intrarectal, intravaginal or transdermal administration.
- Pharmaceutical composition A may be for injection.
- the dose of the trinapant-based drug can be appropriately selected according to the purpose of administration, the subject of administration and its condition.
- the lower limit of daily dosage per kg body weight of a subject is 0.01 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, or It may be 1 mg.
- the upper limit of the daily dosage per 1 kg of body weight of the subject can be selected as appropriate, for example, 10 mg, 9 mg, 8 mg, 7 mg, 6 mg, 5 mg, 4 mg, 3 mg, 2 mg, or 1 mg. There may be.
- the daily dosage may be 0.01 mg to 5 mg, 0.05 mg to 4 mg, or 0.1 mg to 3 mg per kg body weight of the subject.
- the daily dose may be, for example, 1 mg or more, 5 mg or more, 10 mg or more, 20 mg or more, 30 mg or more, 40 mg or more, 50 mg or more, 60 mg or more, 70 mg or more, 80 mg or more, 90 mg or more, or 100 mg or more; 500 mg or less, 400 mg or less, 300 mg or less, 200 mg or less, 190 mg or less, 180 mg or less, 170 mg or less, 160 mg or less, 150 mg or less, 140 mg or less, 130 mg or less, 120 mg or less, 110 mg or less, or 100 mg or less.
- daily doses can be 1 mg to 300 mg, 5 mg to 200 mg, or 10 mg to 180 mg.
- the dosage of the trinapanth drug may be an amount converted to the weight of the free form of trinapant (the compound represented by the above formula (1)), or or the actual weight of the solvate.
- the dosage of the trinapanth drug is the amount converted to the weight of the free form of trinapant. It may be administered in two or more doses (eg, two or three times) so that the daily dose falls within the above range, but administration in one dose is preferred.
- the dosage of the trinapant-based agent may be an amount that is less than the dosage when administered alone, or an amount that is not effective alone. Even when administered in such an amount, excellent efficacy can be exhibited in combination with the administration of modified immune cells.
- composition A can be administered at any frequency.
- pharmaceutical composition A can be administered once, twice, or three times daily, once every two days, once every three days, once every four days, once every five days, once every six days, It can be administered at a frequency of once a week, once every two weeks, once every three weeks, or once every four weeks.
- pharmaceutical composition A may continue administration at the frequency (eg, once a day) for a predetermined period (eg, 1 week, 2 weeks, 3 weeks, or 4 weeks), and then Administration may be discontinued for periods of time (eg, 1 week, 2 weeks, 3 weeks, or 4 weeks), and cycles of continued and discontinued administration may be repeated.
- the pharmaceutical composition A can be administered once a day for 7 days, followed by a cycle of discontinuing administration for 7 days, which can be performed once or twice.
- composition A is administered prior to administration of the modified immune cells, e.g. 30 minutes before, 1 hour before, 2 hours before, 3 hours before, 4 hours before, 5 hours before, 6 hours before, 7 hours before, 8 hours before, 9 hours before, 10 hours before, 11 hours before, 12 hours before It may be administered before, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week before. Pharmaceutical composition A may be administered concurrently with administration of the modified immune cells.
- composition A is administered after administration of the modified immune cells, for example, immediately after administration, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours 18 hours later, 24 hours later, 2 days later, 3 days later, 4 days later, 5 days later, 6 days later, or 1 week later.
- Pharmaceutical composition A may also be administered, for example, when tumor marker levels are above baseline levels after administration of the modified immune cells.
- Non-limiting examples of other agents include alkylating agents, DNA methylation inhibitors, antimetabolites (eg, pyrimidine antimetabolites, purine antimetabolites, antifolates), and the like.
- subjects for administration of pharmaceutical composition A include, but are not limited to, humans, dogs, cats, monkeys, sheep, horses, cows, mice, and rats.
- a subject to which pharmaceutical composition A is administered may be a subject to which modified immune cells are administered or to which the modified immune cells have been administered. It is preferable that the subject to be administered the pharmaceutical composition A is a subject (or an incipient patient or a recurrent patient) in need of prevention and/or treatment of an IAP-related disease, particularly cancer.
- compositions, manufacturing method, administration method, etc. of pharmaceutical composition A can be designed based on the description of, for example, WO2015/092420 (the entirety of which is incorporated herein by reference).
- composition A is not particularly limited in its use as long as it can enhance the effect of pharmaceutical composition B (therapeutic effect in gene-modified immunotherapy).
- Pharmaceutical composition A can be used, for example, to prevent and/or treat IAP-related diseases.
- prevention is used to include, for example, prevention of recurrence
- treatment is used to include, for example, prevention or delay of progression, alleviation, mitigation, and remission.
- IAP-related diseases include, for example, diseases involving cell accumulation (e.g. cancer, autoimmune disorders, inflammation, restenosis), disorders in which excessive apoptosis leads to cell loss (e.g.
- cancer represents “tumor” in a broad sense and can be used synonymously with “tumor”.
- the IAP-related disease is cancer.
- Cancer is characterized by XIAP, cIAP1, cIAP2, NAIP, ILP2, ML-IAP, survivin, and BRUCE, more specifically XIAP, cIAP1, cIAP2, and ML-IAP, more specifically XIAP, cIAP1, and cIAP2; Most specifically, it may be a cancer sensitive to the antagonism of any one or more IAPs selected from XIAP. The cancer may be relapsed or refractory cancer.
- Cancer may be solid cancer or blood cancer.
- Solid cancers may be of epithelial origin, mesenchymal origin, or other cancers.
- non-limiting examples of solid cancers include transitional cell carcinoma; cancer of the bladder and urinary tract; breast cancer; cancer; liver cancer (e.g. hepatocellular carcinoma, hepatoblastoma); gallbladder and biliary tract cancer (e.g. bile duct cancer); pancreatic cancer (e.g.
- pancreatic endocrine cancer such as metastatic pancreatic cancer, pancreatic exocrine cancer such as pancreatic ductal adenocarcinoma ); kidney cancer (e.g., renal cell carcinoma, nephroblastoma); lung cancer (e.g., adenocarcinoma, small cell lung cancer, non-small cell lung cancer, bronchoalveolar carcinoma, mesothelioma); cancer of the head and neck (e.g., Carcinoma of the tongue, mouth, larynx, pharynx, nasopharynx, tonsils, salivary glands, nasal cavities, sinuses, vision and appendages (e.g.
- retinoblastoma ovary, fallopian tubes, peritoneum, vagina, vulva , penile, cervical, myometrial, or endometrial cancer; thyroid cancer (e.g. medullary thyroid carcinoma, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, follicular thyroid carcinoma); adrenal carcinoma (e.g. adrenocortical carcinoma) ); prostate cancer (e.g. hormone refractory prostate cancer); skin cancer (e.g. melanoma (e.g.
- stage 3 and 4 malignant melanoma basal cell carcinoma, squamous cell carcinoma, head and neck squamous cell carcinoma (HNSCC) , keratoacanthocytoma, dysplastic nevus, mycosis fungoides), etc.
- solid cancers include Merkel cell carcinoma, metastatic non-small cell carcinoma, metastatic breast cancer, metastatic colon cancer, metastatic gastric cancer, metastatic non-genitourinary cancer, metastasis non-small cell lung cancer, metastatic ovarian cancer, metastatic renal cell carcinoma, HBV infection and related cancers, and vulvar disease.
- solid tumors include soft tissue sarcoma, osteosarcoma, fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, angiosarcoma, Kaposi's sarcoma, Ewing Soft fibrous, bone, or cartilage sarcomas such as sarcomas, synovial sarcoma, epithelioid sarcoma, gastrointestinal mesenchymal tumors, benign and malignant histiocytomas, and dermatofibrosarcoma protuberans.
- solid tumors include tumors of the central or peripheral nervous system (e.g., astrocytoma, glioma, glioblastoma, meningioma, brain tumor, brain ependymoma, fruiting tumor, schwannoma); endocrine tumors (e.g., pituitary tumor, adrenal tumor, pancreatic islet tumor, parathyroid tumor, carcinoid tumor, medullary carcinoma of the thyroid); germ cell and trophoblast Laminar tumors (e.g.
- teratoma teratoma, seminioma, dysgerminoma, hydatidiform mole, choriocarcinoma
- pediatric and embryonal tumors e.g. medulloblastoma, neuroblastoma, Wilms tumor, primitive congenital or otherwise syndromes (xeroderma pigmentosum) in which the patient becomes affected by malignancies.
- Non-limiting examples of hematological cancers include acute lymphocytic leukemia (ALL) (e.g. B-ALL, T-ALL), chronic lymphocytic leukemia (CLL) (e.g. hairy cell leukemia, prolymphocytic leukemia).
- ALL acute lymphocytic leukemia
- CLL chronic lymphocytic leukemia
- B-cell lymphomas e.g., diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), follicular lymphoma, Burkitt's lymphoma, mantle cell lymphoma, blastic leukemia; marginal zone B-cell lymphoma, high-grade B-cell lymphoma, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma); T-cell lymphoma (e.g., peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), adult T-cell lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, Sézary syndrome); natural killer [NK]-cell lymphoma; Hodgkin's lymphoma (HL); non-Hodgkin's lymphoma; MALT lymphoma; Primary cutaneous follicular lymphom
- the cancer is acute myeloid leukemia (AML), T-cell lymphoma (peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), adult T-cell leukemia-lymphoma (ATLL), chronic myelomonocytic hematologic cancer, including acute lymphoblastic leukemia (ALL), and diffuse large B-cell lymphoma (DLBCL), hi another embodiment, the cancer is a hematologic cancer, including multiple myeloma. is.
- AML acute myeloid leukemia
- PTCL peripheral T-cell lymphoma
- CTCL cutaneous T-cell lymphoma
- ATLL adult T-cell leukemia-lymphoma
- ALL acute lymphoblastic leukemia
- DLBCL diffuse large B-cell lymphoma
- the cancer is a hematologic cancer, including multiple myeloma. is.
- the cancer is head and neck squamous cell carcinoma (HNSCC), prostate cancer, pancreatic cancer, small cell lung cancer, non-small cell lung cancer, colon cancer, melanoma, rectal cancer, bladder, cervical cancer, and Solid tumors, including breast cancer.
- HNSCC head and neck squamous cell carcinoma
- prostate cancer pancreatic cancer
- small cell lung cancer non-small cell lung cancer
- colon cancer melanoma
- rectal cancer including breast cancer.
- bladder cervical cancer
- Solid tumors including breast cancer.
- a pharmaceutical composition containing immune cells that have been modified to express It is preferably a pharmaceutical composition that is administered at the same time as the drug, and more specifically, it is preferably a pharmaceutical composition that is administered before, at the same time as, or after administration of the trinapant drug.
- a chimeric antigen receptor (CAR) or recombinant T cell receptor (TCR) recognizes and binds to a specific antigen.
- the antigen is a tumor antigen.
- tumor antigens include 5T4, ⁇ 5 ⁇ 1-integrin, integrin ⁇ 7 (e.g. activated integrin ⁇ 7), 707-AP, AFP, ART-4, B7H4, BAGE, ⁇ -catenin/m, Bcr-abl.
- MN/C IX antibody CA125, CAMEL, CAP-1, CASP-8, CD4, CD19, CD20, CD22, CD25, CDC27/m, CD30, CD33, CD52, CD56, CD80, CD98, CDK4/m, CEA , CT, Cyp-B, DAM, EGFR, ErbB3, ELF2M, EMMPRIN, EpCam, ETV6-AML1, G250, GAGE, GnT-V, Gp100, HAGE, HER-2/new, HLA-A*0201-R170I, HPV -E7, HSP70-2M, HST-2, hTERT (or hTRT), iCE, IGF-1R, IL-2R, IL-5, KIAA0205, LAGE, LDLR/FUT, MAGE, MART-1/melan-A, MART -2/Ski, MC1R, myosin/m, MUC1, MUM-1, MUM-2,
- B-1.CAR CARs preferably contain an extracellular domain and an intracellular signaling domain.
- Extracellular domain The extracellular domain is not particularly limited as long as it can recognize (or bind or specifically bind to) an antigen.
- the extracellular domain preferably contains the antigen binding site of an antibody or the antigen (ligand) binding site of a receptor.
- the antigen-binding site of an antibody may be the entire region of an antibody or an antigen-binding fragment of an antibody.
- An antibody may be a monoclonal antibody or a polyclonal antibody.
- the antibody can be, for example, a murine antibody, a chimeric antibody, a humanized antibody, or a fully humanized antibody.
- the antigen-binding fragment is not particularly limited as long as it contains the H chain (heavy chain) and L chain (light chain) variable regions.
- Non-limiting examples of antigen-binding fragments include Fv, Fab, Fab', (Fab') 2 , scFv, scFv-Fc, diabody, triabody, tetrabody, minibody, nanobody, and the like.
- the antigen-binding site of the receptor may be the entire region of the receptor or the antigen-binding domain of the receptor.
- Receptors include, for example, TCRs such as TCR ⁇ , TCR ⁇ , TCR ⁇ , and TCR ⁇ ; natural cytotoxic receptors (NCR) of NK cells such as NKp30, NKp44, NKp46, etc., but not limited to.
- the extracellular domain preferably contains the antigen-binding site of an antibody, more preferably scFv, and is an anti-human CD19 antibody (e.g. FMC63) or an anti-human activated integrin ⁇ 7 antibody (e.g. : MMG49)-derived scFv is more preferable.
- scFv can be prepared by conventional methods. Non-limiting examples of such methods include U.S. Pat. No. 4,694,778, Science, vol. 242, pp. 423-442 (1988), Nature, vol. 334, p. 54454 (1989), Science, vol. 242 , pp. 1038-1041 (1988), Molecular Immunology, Vol. 34, No. 16-17, pp. 1157-1165 (1997).
- Antigens that can be recognized or bound by the extracellular domain are preferably tumor antigens.
- tumor antigens include 5T4, ⁇ 5 ⁇ 1-integrin, integrin ⁇ 7 (e.g. activated integrin ⁇ 7), 707-AP, AFP, ART-4, B7H4, BAGE, ⁇ -catenin/m, Bcr-abl.
- MN/C IX antibody CA125, CAMEL, CAP-1, CASP-8, CD4, CD19, CD20, CD22, CD25, CDC27/m, CD30, CD33, CD52, CD56, CD80, CD98, CDK4/m, CEA , CT, Cyp-B, DAM, EGFR, ErbB3, ELF2M, EMMPRIN, EpCam, ETV6-AML1, G250, GAGE, GnT-V, Gp100, HAGE, HER-2/new, HLA-A*0201-R170I, HPV -E7, HSP70-2M, HST-2, hTERT (or hTRT), iCE, IGF-1R, IL-2R, IL-5, KIAA0205, LAGE, LDLR/FUT, MAGE, MART-1/melan-A, MART -2/Ski, MC1R, myosin/m, MUC1, MUM-1, MUM-2,
- the tumor antigen is preferably CD19 or integrin ⁇ 7. In other embodiments, the tumor antigen is preferably CD19 or activated integrin ⁇ 7. In still other embodiments, it is preferred that the tumor antigen is activated integrin ⁇ 7.
- a CAR capable of recognizing or binding CD19 is referred to as "CD19 CAR”
- T cells and NK cells modified to express CD19 CAR are referred to as "CD19 CAR-T" and "CD19 CAR-NK", respectively.
- Examples of CD19 CAR-NK include CD19 CAR-KHYG-1.
- CARs capable of recognizing or binding to activated integrin ⁇ 7 include, for example, activated integrin ⁇ 7 CAR. (aITGB7 CAR-T)”.
- the extracellular domain is heavy chain CDR1 having the amino acid sequence (GVSLPDYG) set forth in SEQ ID NO:1, heavy chain CDR2 having the amino acid sequence (IWGSETT) set forth in SEQ ID NO:2, set forth in SEQ ID NO:3 heavy chain CDR3 having the amino acid sequence (AKHYYYGGSYAMDY), light chain CDR1 having the amino acid sequence shown in SEQ ID NO:4 (QDISKY), light chain CDR2 having the amino acid sequence shown in SEQ ID NO:5 (HTS), and SEQ ID NO:6 ( QQGNTLPYT) preferably contains a light chain CDR3 having the amino acid sequence shown in QQGNTLPYT).
- heavy chain CDRs 1-3 and light chain CDRs 1-3 are specified by homology search by IMGT/BlastSearch (http://www.imgt.org/blast/).
- the extracellular domain includes heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 1, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 2, heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 3, Binding of an antibody comprising a light chain CDR1 having the amino acid sequence shown in SEQ ID NO:4, a light chain CDR2 having the amino acid sequence shown in SEQ ID NO:5, and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO:6 to CD19 It is preferred to contain an antigen-binding site (especially scFv) of an antibody that competitively inhibits .
- an antigen-binding site especially scFv
- the extracellular domain is heavy chain CDR1 having the amino acid sequence (GYTFSSYW) set forth in SEQ ID NO:7, heavy chain CDR2 having the amino acid sequence (MLPGSGSS) set forth in SEQ ID NO:8, set forth in SEQ ID NO:9 heavy chain CDR3 having the amino acid sequence (ARGDGNYWYFDV), light chain CDR1 having the amino acid sequence set forth in SEQ ID NO: 10 (SSVGY), light chain CDR2 having the amino acid sequence set forth in SEQ ID NO: 11 (ATS), and SEQ ID NO: 12 ( It is preferred to contain a light chain CDR3 having the amino acid sequence shown in QQWSSDPPT).
- the extracellular domain includes heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 7, heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 8, heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 9, Binding of an antibody comprising a light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 10, a light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 11, and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 12 to CD19 It is preferred to contain an antigen-binding site (especially scFv) of an antibody that competitively inhibits .
- an antigen-binding site especially scFv
- the extracellular domain preferably contains an antigen-binding site of an antibody having an epitope in the region consisting of amino acid residues 20-109 of activated human integrin ⁇ 7.
- the antibody has affinity for activated human integrin ⁇ 7 and binds to myeloma cells but not to normal blood cells.
- Active integrin ⁇ 7 CAR-T (aITGB7 CAR-T) in the present invention is described in WO2017/026331 or Nature Medicine 23 12 2007 1436, which is incorporated herein in its entirety.
- identity refers to the degree of amino acid identity when two or more amino acid sequences to be compared are optimally aligned.
- the identity of amino acid sequences is determined, for example, by the default ( It can be calculated using the parameters of the initial setting).
- conservative substitution means substitution of one or more amino acids with another amino acid so as not to substantially alter the function or properties of the protein.
- Non-limiting examples of conservative substitutions include the group of nonpolar amino acids (hydrophobic amino acids): alanine (A), valine (V), leucine (L), isoleucine (I), proline (P), phenylalanine ( F), substitutions in methionine (M), tryptophan (W), the group of polar amino acids (neutral amino acids): glycine (G), asparagine (N), glutamine (Q), serine (S), threonine (T), Substitutions in tyrosine (Y), cysteine (C), groups of acidic amino acids: aspartic acid (D), substitutions in glutamic acid (E), groups of basic amino acids: lysine (K), arginine (R), histidine (H). and the like.
- the equilibrium dissociation constant (K D ), which represents the binding affinity of the extracellular domain to an antigen, may be, for example, 1 ⁇ M or less, 500 nM or less, or 100 nM or less, or 0.1 pM or more, 0.5 pM or more, or 1 pM or more. There may be. Equilibrium dissociation constants can be determined, for example, by SPR measurements or BiacoreTM analysis.
- the extracellular domain may contain the antigen binding site of an antibody, or the antigen (ligand) binding site of a receptor, as well as the extracellular domains of other proteins.
- Non-limiting examples of such other proteins include CD3 ⁇ , CD3 ⁇ , CD4, CD5, CD8, CD9, CD16, CD22, CD28, CD33, CD37, CD64, CD80, CD86, CD134 (OX40), CD137, CD154, T cell co-receptors such as CD278 (ICOS) and the like.
- the extracellular domain of said other protein is preferably the extracellular domain of CD28.
- the extracellular domain of said other protein has the amino acid sequence shown in SEQ ID NO: 13: IEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKP, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, Amino acid sequences with 97% or more, 98% or more, or 99% or more identity, or 1 to 3 amino acid deletions, substitutions (e.g., conservative substitutions), insertions, and/or with respect to the amino acid sequences or an added amino acid sequence.
- the intracellular signaling domain is not particularly limited as long as it can transmit a signal into the cell when the extracellular domain recognizes an antigen.
- the intracellular signaling domain comprises sequences capable of antigen-dependent primary activation (primary cytoplasmic signaling sequences) and sequences capable of antigen-independent secondary activation or co-stimulation (secondary cytoplasmic signaling sequences).
- the primary cytoplasmic signaling sequence may have a signaling motif known as an immunoreceptor tyrosine-based activation motif (ITAM) (Nature, vol. 338, pp. 383-384 (1989)), and/ Alternatively, it may have a signaling motif known as an immunoreceptor tyrosine-based inhibitory motif (ITIM) (J Immunol., vol. 162, No. 2, pp. 897-902 (1999)).
- ITAM immunoreceptor tyrosine-based activation motif
- ITIM immunoreceptor tyrosine-based inhibitory motif
- the intracellular signaling domain with the primary cytoplasmic signaling sequence preferably has one or more ITAMs and also preferably has an exogenous STAT3-associated motif.
- intracellular signaling domains include intracellular signaling domains of CD3 ⁇ , FcR ⁇ , FcR ⁇ , CD3 ⁇ , CD3 ⁇ , CD3 ⁇ , CD5, CD22, CD79a, CD79b, CD66d, and the like.
- said intracellular signaling domain is preferably the intracellular signaling domain of CD3zeta.
- the intracellular signaling domain has the amino acid sequence shown in SEQ ID NO: 14: RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, Amino acid sequences with 97% or more, 98% or more, or 99% or more identity, or 1 to 3 amino acid deletions, substitutions (e.g., conservative substitutions), insertions, and/or with respect to the amino acid sequences or an added amino acid sequence.
- the intracellular signaling domain with secondary cytoplasmic signaling sequences is preferably the intracellular signaling domain of one or more co-stimulatory molecules.
- co-stimulatory molecules include CD2, CD4, CD5, CD8 ⁇ , CD8 ⁇ , CD28, CD134 (OX40), CD137 (4-1BB), CD154, CD278 (ICOS), and the like.
- said intracellular signaling domain is the intracellular signaling domain of CD28 and/or the intracellular signaling domain of CD137(4-1BB), preferably the intracellular signaling domain of CD28. is more preferred.
- the intracellular signaling domain has the amino acid sequence shown in SEQ ID NO: 15: RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, Amino acid sequences with 97% or more, 98% or more, or 99% or more identity, or 1 to 3 amino acid deletions, substitutions (e.g., conservative substitutions), insertions, and/or with respect to the amino acid sequences or an added amino acid sequence.
- CARs may have additional intracellular signaling domains other than those described above.
- a CAR may have a domain that induces cytokine (eg, IL-12) expression.
- a CAR may also include the intracellular domain of a cytokine receptor (eg, an IL-2R beta chain fragment). Additional intracellular signaling domains may be inserted, for example, between the intracellular signaling domain of the co-stimulatory molecule and the primary cytoplasmic signaling sequence.
- Transmembrane domain CAR preferably contains a transmembrane domain between the extracellular domain and the intracellular signaling domain.
- a transmembrane domain can be a transmembrane domain from any polypeptide having one or more transmembrane sequences.
- the polypeptide may be a naturally occurring polypeptide or an artificial polypeptide.
- transmembrane domains from naturally occurring polypeptides include TCRs such as TCR ⁇ , TCR ⁇ ; CD3 ⁇ , CD3 ⁇ , CD4, CD5, CD8, CD9, CD16, CD22, CD28, CD33, CD37, CD64, CD80 T cell co-receptors such as CD86, CD134 (OX40), CD137, CD154, CD278 (ICOS); transmembrane domains of TNF receptors such as GITR;
- the artificial polypeptide-derived transmembrane domain is preferably a polypeptide that mainly contains hydrophobic residues such as leucine and valine. Also, the transmembrane domain preferably has a phenylalanine, tryptophan, and valine triplet at each end.
- the transmembrane domain is preferably CD28 or the transmembrane domain of CD8, more preferably the transmembrane domain of CD28.
- the transmembrane domain has the amino acid sequence shown in SEQ ID NO: 16: FWVLVVVGGVLACYSLLVTVAFIIFWV, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, Amino acid sequences with 97% or more, 98% or more, or 99% or more identity, or 1-3 amino acid deletions, substitutions (e.g., conservative substitutions), insertions, and/or with respect to the amino acid sequences or an added amino acid sequence.
- Linker Sequence or Spacer Domain CAR may have a linker sequence or spacer domain between the extracellular domain and the transmembrane domain or between the transmembrane domain and the intracellular signaling domain. good.
- the linker sequence or spacer domain is not particularly limited as long as it has the function of connecting two domains.
- the linker sequence preferably contains 10 amino acids or less, preferably 2 amino acids or more.
- Spacer domains preferably contain no more than 300, no more than 200, no more than 100, or no more than 50 amino acids, preferably no more than 10, no more than 15, no more than 20, or no more than 25 amino acids. is preferred.
- the linker sequence is preferably selected from a continuous glycine-serine sequence, the amino acid sequence shown in SEQ ID NO: 17 (GSTSGSGKPGSGEGSTKG), the amino acid sequence shown in SEQ ID NO: 18 (GSTSGGGSGGGSGGGGSS), and the like.
- the spacer domain preferably has a sequence that promotes binding between CAR and antigen and enhances signal transduction to cells.
- sequences preferably contain cysteines, charged amino acids, serines or threonines within potential glycosylation sites, and the like.
- Non-limiting examples of spacer domains include CD8 ⁇ , CD8 ⁇ , CD28, portions of IgG4 (eg, hinge regions), and the like.
- the CAR may have a leader sequence (signal peptide sequence) at the N-terminus.
- the signal peptide sequence preferably contains 15 amino acids or more, preferably 30 amino acids or less.
- Non-limiting examples of signal peptides include signal peptides of the aforementioned proteins with intracellular signaling domains.
- the signal peptide may be the GM-CSFR signal peptide, the oncostatin M signal peptide, or signal peptides such as CD8a, IL-2, IL-3.
- it may be an Ig heavy chain signal sequence (VHCAMP).
- the signal peptide may be of human or non-human origin, such as insect cell or virus origin.
- the leader sequence (signal peptide sequence) has the amino acid sequence shown in SEQ ID NO: 19: MLLLVTSLLLCELPHPAFLLIP, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, Amino acid sequences with 97% or more, 98% or more, or 99% or more identity, or 1 to 3 amino acid deletions, substitutions (e.g., conservative substitutions), insertions, and/or with respect to the amino acid sequences or an added amino acid sequence.
- the CAR comprises, in order from the N-terminal side, scFv derived from an anti-human CD19 antibody (e.g. FMC63) or an anti-human activated integrin ⁇ 7 antibody (e.g. MMG49), a CD28 extracellular domain, a CD28 transmembrane domain, It preferably contains a CD28 intracellular signaling domain and a CD3 ⁇ intracellular signaling domain, and the N-terminal side of scFv derived from an anti-human CD19 antibody (eg, FMC63) or an anti-human activated integrin ⁇ 7 antibody (eg, MMG49) It is also preferred to further contain the GM-CSFR signal peptide in the .
- an anti-human CD19 antibody e.g. FMC63
- an anti-human activated integrin ⁇ 7 antibody e.g. MMG49
- the CAR has the amino acid sequence shown in SEQ ID NO: 20 (GenBank Accession No. HM852952.1): MLLLVTSLLLCELPHPAFLLIPDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEGSTKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSAAAIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAY
- the CAR has the amino acid sequence shown in SEQ ID NO:21: MDFQVQIFSFLLISASVIMSRGQIVLSQSPAILSASPGEKVTMTCRASSSVGYMHWFQQKPGSSPKPWIYATSNLASGVPARFSGSESGTSYSLTISRVEAEDAATYYCQQWSSDPPTFGGGTKLEIKRGSTSGSGKPGSGEGSQVQLQQSGAELMKPGASVKISCKASGYTFSSYWIEWVKQRPGHGLEWIGEMLPGSGSSNYNEKFKGKATFTADTSSNTAYMQLSSLTSEDSAVYYCARGDGNYWYFDVWGAGTTVTVSSAAAIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQN
- CAR may be multimerized such as dimerized.
- dimerizing CARs via disulfide bonds it is preferable to insert a cysteine into the spacer domain and/or the transmembrane domain of the CAR.
- the recombinant TCR may be a heterodimer composed of ⁇ and ⁇ chains, or a heterodimer composed of ⁇ and ⁇ chains.
- Each chain has a variable domain (V domain) and a constant domain (C domain) and has three CDRs in the V domain, namely CDR1, CDR2 and CDR3, the three CDR sequences recognizing or Designed to connect.
- a recombinant TCR can recognize (or bind) any antigen.
- a recombinant TCR can have a variable domain capable of recognizing an antigen.
- Antigens include, for example, the same antigens as described in B-1-1.
- the antigen is preferably a tumor antigen, preferably gp100, MART-1, CEA, MAGE-A1, MAGE-A3, MAGE-A4, WT1, or NY-ESO-1.
- the antigen is preferably human leukocyte antigen A (HLA-A)-restricted, HLA-A * 02-restricted (e.g., HLA-A * 02:01-restricted, HLA-A * 02:06-restricted) or More preferably, it is HLA-A * 24-restricted (eg, HLA-A * 24:02-restricted).
- HLA-A human leukocyte antigen A
- HLA-A * 02-restricted e.g., HLA-A * 02:01-restricted, HLA-A * 02:06-restricted
- HLA-A * 24-restricted e.g, HLA-A * 24:02-restricted
- Recombinant TCRs are HLA-A * 02-restricted gp100-specific TCR, HLA-A * 02-restricted MART-1-specific TCR, HLA-A * 02-restricted MAGE-A3-specific TCR, HLA-A * 02 It may be a NY-ESO-1-restricted TCR, a HLA-A * 24-restricted MAGE-A4-specific TCR, or an HLA-A * 24-restricted WT1-specific TCR.
- a TCR capable of recognizing or binding to NY-ESO-1 is referred to as "NY-ESO-1 TCR”
- T cells modified to express NY-ESO-1 TCR are referred to as "NY-ESO-1 TCR”.
- -T T cells modified to express NY-ESO-1 TCR
- the equilibrium dissociation constant (K D ), which represents the binding affinity of the recombinant TCR to the antigen, may be, for example, 100 ⁇ M or less, 10 ⁇ M or less, 1 ⁇ M or less, 500 nM or less, or 100 nM or less, and 0.1 pM or more, 0.5 pM. or more, or 1 pM or more.
- Equilibrium dissociation constants can be determined, for example, by SPR measurements or BiacoreTM analysis.
- Immune cells modified to express CAR or recombinant TCR Immune cells modified to express CAR (e.g., CAR-T cells, CAR-NK cells) contain CAR-expressing nucleic acids ( immune cells containing nucleic acid constructs). Similarly, immune cells that have been modified to express a recombinant TCR (eg, TCR-T cells) are preferably immune cells that contain recombinant TCR-expressing nucleic acids (including nucleic acid constructs).
- CAR or nucleic acid for expression of recombinant TCR preferably contains a promoter in addition to the nucleic acid encoding CAR or recombinant TCR.
- promoters include pol II promoters such as CMV promoter, EF1 promoter, SV40 promoter, MSCV promoter; tryptophan promoters such as trc and tac; lac promoter; T7 promoter; T5 promoter; arabinose-inducible promoter; cold shock promoter; tetracycline-inducible promoter; ubiquitin promoter;
- CAR or recombinant TCR expression nucleic acid may further contain other elements.
- other elements include origins of replication, enhancer sequences, terminator sequences, reporter protein coding sequences, drug resistance gene coding sequences, and the like.
- Recombinant TCR-expressing nucleic acids include sequences that suppress the expression of endogenous TCRs (e.g., endogenous TCR ⁇ -chain and siRNA against the ⁇ chain).
- CAR or recombinant TCR expression nucleic acid may be in the form of a vector.
- the vector may be a non-viral vector, it is preferably a viral vector.
- Non-limiting examples of viral vectors include retroviral vectors (including oncoretroviral vectors, lentiviral vectors, and pseudotyped vectors), adenoviral vectors, adeno-associated viral (AAV) vectors, simian viral vectors, vaccinia virus. vectors or Sendai virus vectors, Epstein-Barr virus (EBV) vectors, HSV vectors and the like. Viral vectors can also be replication-deficient viral vectors so that they do not self-replicate in infected cells.
- Immune cells are not particularly limited as long as they can be modified to express CAR or recombinant TCR.
- Non-limiting examples of immune cells include monocytes, macrophages, T cells, B cells, NK cells. In one embodiment, the immune cells are preferably T cells or NK cells.
- Non-limiting examples of T cells include CD4 positive T cells (e.g. helper T cells), CD8 positive T cells (e.g. cytotoxic T cells), natural killer T cells, regulatory T cells (Treg), naive T cells, effector T cells, memory T cells, tumor infiltrating lymphocytes (TIL), ⁇ T cells, ⁇ T cells.
- an immune cell can be a cell population, which cell population can be, for example, a cell population containing peripheral blood mononuclear cells (PBMC).
- PBMC peripheral blood mononuclear cells
- Immune cells may be differentiated from hematopoietic stem cells, but are derived from living organisms, for example, those collected from living organisms (peripheral blood, cord blood, bone marrow, lymph nodes, spleen, etc.), or from living organisms. It is preferably obtained by collecting and expanding the culture.
- the immune cells may be autologous immune cells (immune cells of a subject to which pharmaceutical composition B is administered) or allogeneic immune cells. In the case of alloimmune cells, it is preferred that the HLA types are matched.
- immune cells may be stimulated with soluble or membrane-bound anti-CD3 antibodies (eg, OKT3 or mOKT3) and/or APCs (eg, artificial APCs) prior to transduction.
- APCs may express membrane-type anti-CD3 monoclonal antibodies.
- B-3-3 Transduction of CAR or Recombinant TCR Expressing Nucleic Acid into Immune Cells
- methods for transducing immune cells with CAR or recombinant TCR expressing nucleic acid include the virus infection method and the calcium phosphate method. , lipofection, microinjection, electroporation, and the like, but are not limited to these.
- Non-limiting examples of modified immune cells include T cells modified to express CD19 CAR (e.g. Gilead Yescarta (axicabtagene ciloleucel) from Novartis, Kymriah (tisagenlecleucel) from Novartis, Breyanzi (lisocabtagene maraleucel) from Bristol-Myers Squibb, TBI-1501 from Takara Bio Inc., UCART19/ALLO-501 from Nihon Servier), BCMA CAR T cells engineered to express CD98 CAR (e.g.
- T cells engineered to express CD98 CAR e.g. 2018/0230212 (incorporated herein by reference in its entirety)
- T cells engineered to express activated integrin ⁇ 7 CAR examples include T cells engineered to express CARs as described in US Patent Application Publication No. 2018/0230216, which is incorporated herein by reference in its entirety.
- TCR-T cells include NY-ESO-1-specific TCR-T cells (e.g., Tmunity's NY-ESO-1 TCR-T Triple Knockout TCR (NYCE), Takara Bio Inc.'s TBI-1301), MAGE-A4-specific TCR-T cells (e.g. Adaptimmune ADP-A2M4 SPEAR T-cells), MAGE-A3 and/or MAGE-A6-specific TCR-T cells (e.g. Kite/Gilead Sciences' KITE-718) can be mentioned.
- NY-ESO-1-specific TCR-T cells e.g., Tmunity's NY-ESO-1 TCR-T Triple Knockout TCR (NYCE), Takara Bio Inc.'s TBI-1301
- MAGE-A4-specific TCR-T cells e.g. Adaptimmune ADP-A2M4 SPEAR T-cells
- the engineered immune cells are T cells that have been engineered to express a CAR that specifically recognizes CD19, a CAR that specifically recognizes integrin ⁇ 7 (e.g., activated integrin ⁇ 7).
- Engineered T cells, NK cells engineered to express a CAR that specifically recognizes CD19, or T cells engineered to express a recombinant TCR that specifically recognizes NY-ESO-1 is preferably
- composition B preferably contains pharmaceutically acceptable excipients as other ingredients.
- Pharmaceutically acceptable excipients include, for example, the same excipients as described in A-2.
- pharmaceutically acceptable excipients include carriers (e.g. sterile water, saline), stabilizers, antioxidants (e.g. ascorbic acid), buffers (e.g. phosphate, citric acid). acid), preservatives, surfactants (e.g. polyethylene glycol, Tween), chelating agents (e.g. EDTA), sugars or sugar alcohols (e.g. glucose, mannose, sucrose, mannitol), amino acids (e.g.
- glycine glutamine, asparagine, arginine, lysine
- polypeptides or proteins e.g., serum albumin, gelatin, immunoglobulin
- adjuvants e.g., adjuvants such as aluminum hydroxide.
- the lower limit of the dose of immune cells whose administration has been modified can be appropriately selected according to the purpose of administration, the subject of administration, the condition thereof, and the like.
- the lower limit of daily dosage is 1 ⁇ 10 2 , 5 ⁇ 10 2 , 1 ⁇ 10 3 , 2 ⁇ 10 3 , 3 ⁇ 10 3 viable cells per 1 kg body weight of the subject. , 4x10 3 , 5x10 3 , 6x10 3, 7x10 3 , 8x10 3 , 9x10 3 , 1x10 4 , 2x10 4 , 3 4 x 10, 4 4 x 10 , 4 5 x 10, 4 6 x 10, 4 7 x 10 , 4 8 x 10, 4 9 x 10, or 5 1 x 10 good too.
- the upper limit of the daily dose can also be appropriately selected in the same manner as the lower limit .
- the daily dose is 1 ⁇ 10 3 to 1 ⁇ 10 8 viable cells, 5 ⁇ 10 3 to 5 ⁇ 10 7 , or 1 ⁇ 10 4 to 1 ⁇ 10 3 per 1 kg body weight of the subject. It may be 1 ⁇ 10 7 pieces.
- the daily dosage may be divided into two or more times (eg, two or three times) so that the daily dose falls within the above range, or may be divided into two days depending on the case.
- the dose of the modified immune cells may be an amount that is less than the dose when administered alone, or an amount that is not effective alone. Even when administered in such an amount, excellent efficacy can be exhibited in combination with the administration of the trinapant drug.
- composition B can be administered at any frequency.
- pharmaceutical composition B can be administered once, twice, or three times daily, once every two days, once every three days, once every four days, once every five days, once every six days, It can be administered at a frequency of once a week, once every two weeks, once every three weeks, or once every four weeks.
- pharmaceutical composition B may continue administration at the frequency (eg, once a day) for a predetermined period (eg, 1 week, 2 weeks, 3 weeks, or 4 weeks), and then Administration may be discontinued for periods of time (eg, 1 week, 2 weeks, 3 weeks, or 4 weeks), and cycles of continued and discontinued administration may be repeated.
- the administration of pharmaceutical composition B comprises (1) administering pharmaceutical composition B (or modified immune cells), (2) pharmaceutical composition B ( or modified immune cells), and administering a new pharmaceutical composition B (or modified immune cells) prepared using immune cells obtained from the subject after administration of (3) ( It preferably includes repeating 2).
- composition B is administered before administration of the trinapant drug, for example, immediately before administration, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 20 minutes, 30 minutes before, 1 hour before, 2 hours before, 3 hours before, 4 hours before, 5 hours before, 6 hours before, 7 hours before, 8 hours before, 9 hours before, 10 hours before, 11 hours before, 12 hours before, It may be administered 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week before. Pharmaceutical composition B may be administered at the same time as administration of the trinapant drug.
- composition B is administered after administration of the trinapant drug, for example, immediately, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 20 minutes, 30 minutes after administration. After, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, It may be administered 18 hours later, 24 hours later, 2 days later, 3 days later, 4 days later, 5 days later, 6 days later, or 1 week later. Pharmaceutical composition B may also be administered, for example, after administration of a trinapant drug and when tumor marker levels are above baseline levels.
- Non-limiting examples of other agents include alkylating agents, DNA methylation inhibitors, antimetabolites (eg, pyrimidine antimetabolites, purine antimetabolites, antifolates), and the like.
- the administration target of pharmaceutical composition B includes, for example, those same as those of pharmaceutical composition A.
- a subject to be administered pharmaceutical composition B may be a subject to which a trinapant drug is administered or has been administered. It is preferable that the subject to be administered the pharmaceutical composition B is a subject (or an incipient patient or a recurrent patient) in need of prevention and/or treatment of an IAP-related disease, particularly cancer.
- compositions, manufacturing method, administration method, etc. of pharmaceutical composition B can be designed based on the description of, for example, WO1993/019163 (the entirety of which is incorporated herein by reference).
- composition B is not particularly limited in its use, as long as it is used in combination with pharmaceutical composition A in such a manner that its efficacy (therapeutic effect in gene-modified immunotherapy) can be enhanced.
- Pharmaceutical composition B is preferably, for example, a disease, typically cancer, which is the target of genetically modified immunotherapy.
- cancer include those exemplified for pharmaceutical composition A.
- Kits Kits of the present disclosure comprise a first agent containing a compound represented by Formula (1), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a chimeric antigen It is preferred to have a second agent containing immune cells that have been modified to express the receptor or recombinant T cell receptor.
- the first agent preferably consists of pharmaceutical composition A
- the second agent preferably consists of pharmaceutical composition B.
- the first agent and the second agent may be in the same formulation and administered simultaneously, or in different formulations and administered simultaneously, separately, or sequentially.
- Test cells 1.1.1 Test cells 1-1) Cell name: CD19 CAR-T (manufactured by Takara Bio Inc.) 1-2) Origin: Human peripheral blood-derived T cells 1-3) Source: ACCUCELL, etc. Characteristics: T cells induced by stimulating commercially available human PMBC with anti-CD3 antibody (Clone; OKT3) and proliferating in medium containing IL-2 (250 U/mL) Leader sequence, single-chain variable fragment (scFv) sequence connecting the heavy and light chain variable regions of anti-human CD19 antibody (Clone; FMC63), linker sequence, extracellular domain/transmembrane domain/intracellular domain of CD28 molecule and a sequence connecting the intracellular region of the CD3 ⁇ molecule using a retroviral vector, proliferated, cultured, and cryopreserved.
- scFv single-chain variable fragment
- scFv single-chain variable fragment
- Serum Fetal Bovine Serum i) Concentration: 10% ii) Source: Sigma-Aldrich c) Additives: Penicillin-streptomycin mixture solution i) Concentration: 100 Units/mL penicillin, 100 ⁇ g/mL streptomycin ii) Source: Nacalai Tesque, Inc. d) Cytokine: Recombinant Human IL-2 i) Concentration: 100 U/mL ii) Source: PeproTech Characteristics: KHYG-1, a human NK-like cell line, was transfected with a CD19 CAR retroviral vector, grown, sorted by FCM for positive cells, expanded again, and cryopreserved.
- Control cells 1-1) Cell line name: Control-T cells (human T cells) 1-2) Origin: Human peripheral blood PBMC 1-3) Source: ACCUCELL, etc. Characteristics: Commercially available human PBMCs were stimulated with anti-CD3 antibody (Clone; OKT3) and anti-CD28 antibody (Clone; 28.2) and proliferated in medium containing IL-2 (100 U/mL). , Cryopreserved cells after culture.
- Serum Fetal Bovine Serum i) Concentration: 10% ii) Source: Sigma-Aldrich c) Additives: Penicillin-streptomycin mixture solution i) Concentration: 100 Units/mL penicillin, 100 ⁇ g/mL streptomycin ii) Source: Nacalai Tesque, Inc. d) Cytokine: Recombinant Human IL-2 i) Concentration: 100 U/mL ii) Source: PeproTech
- cell diluent used was 47% bicarbon infusion, 20% low-molecular-weight dextran sugar injection, 28% human serum albumin 25%, and 5% dimethylsulfoxide. After all solutions were mixed, they were stored in a deep freezer (set temperature -80°C) until use.
- Cryopreserved active integrin ⁇ 7 CAR-T was rapidly thawed in a constant temperature bath at 37°C, suspended in cell diluent, and centrifuged (800 xg, 5 minutes, 4°C) to remove the supernatant. . After resuspending the cells in the cell diluent, a portion of the suspension was taken, dead cells were stained with AOPI Staining Solution, and the number of viable cells was counted using a hemocytometer. A cell diluent was prepared to 0.1 mL/body according to the group composition based on the results of measuring the number of viable cells. The prepared cell suspension was stored in ice water until administration.
- Control-T was rapidly thawed in a constant temperature bath at 37°C, suspended in a cell diluent, and centrifuged (800 xg, 5 minutes, 4°C) to remove the supernatant. After resuspending the cells in the cell diluent, a portion of the suspension was taken, dead cells were stained with AOPI Staining Solution, and the number of viable cells was counted using a hemocytometer.
- a cell diluent was prepared to 0.1 mL/body according to the group composition based on the results of measuring the number of viable cells. The prepared cell suspension was stored in ice water until administration.
- Cryopreserved CD19 CAR-KHYG-1 and KHYG-1 were rapidly thawed in a constant temperature bath at 37°C, suspended in medium, and centrifuged (150 xg, 5 minutes, 20°C) to remove the supernatant. bottom. After resuspending the cells in the medium, the whole amount was seeded in a flask and cultured at 37°C in the presence of 5% CO 2 . After the start of culture, the morphology and growth state of the cells were observed under a microscope, and the cells were cultured until subconfluent. Subconfluent cell suspensions were passaged into culture flasks containing fresh medium.
- a required amount of each cell suspension cultured to a subconfluent state was collected, washed three times with D-PBS (-) by centrifugation, and then resuspended in serum-free RPMI1640. After resuspension, a portion of the cell suspension was taken, dead cells were stained with AOPI staining solution, and the number of viable cells was counted using a hemacytometer. Based on the results of measuring the viable cell count of cells, a cell diluent was prepared so as to have a concentration of 0.1 mL/body according to the group composition. The administration solution after preparation was stored in ice water until administration.
- Test substance 1 represents the (+)-L-lactate salt of the compound represented by formula (1) for this example only. Storage conditions: refrigerated, protected from light
- Tolinapant was prepared to be 16 mg / kg based on previous reports (Reference 1: Mol Cancer Ther. 2018 July; 17(7): 1381-1391; Reference 2: Oncoimmunology 2020 January 9;9(1):1710398). Tolinapant was weighed in a required amount so as to be 1.6 mg/mL, and then dissolved in distilled water to make it colorless and transparent. The administration solution was dispensed into sterilized tubes, protected from light and stored frozen until administration.
- Birinpant was prepared to 12 mg/kg based on previous reports (Reference 3: Jessica Michie, et al., Cancer Immunol Res. 2019;7(2):183-192 ). After weighing the necessary amount of Birinpant to 1.2 mg/mL, it was suspended in previously prepared captisol. The suspension was prepared by grinding using an agate mortar until a uniform fine suspension was obtained. The administration solution was dispensed into sterilized tubes and stored in a low-temperature room (set temperature: 4°C) shielded from light until administration.
- LCL161 was prepared to be 30 mg / kg based on previous reports (Reference 4: Peter J Houghton et al., Pediatr Blood Cancer. 2012;58(4):636-639 ). After weighing the required amount of LCL161 to 3 mg/mL, it was dissolved in a previously prepared sodium acetate solution to make it colorless and transparent. The administration solution was dispensed into sterilized tubes and stored in a low-temperature room (set temperature: 4°C) shielded from light until administration.
- AT406 was prepared to 100 mg / kg based on previous reports (Reference 5: Melissa K Brunckhorst et al., Cancer Biology & Therapy. 2012;13(9):804- 811).
- AT406 was first prepared as a 200 mg/mL DMSO solution. Next, a required amount was taken so as to obtain 10 mg/mL, and suspended in a previously prepared hypromellose solution. The suspension was prepared by grinding with an agate mortar until a uniform fine suspension was obtained.
- the administration solution was dispensed into sterilized tubes and stored in a low-temperature room (set temperature: 4°C) shielded from light until administration.
- Serum Fetal Bovine Serum i) Concentration: 10% ii) Source: Nichirei Biosciences c) Additives: Penicillin-streptomycin mixed solution i) Concentration: 100 Units/mL penicillin, 100 ⁇ g/mL streptomycin ii) Source: Nacalai Tesque Co., Ltd.
- MM.1S-luc2 1) Cell line name: MM.1S 2) Origin: Multiple Myeloma 3) Obtained from: ATCC (established luc2 strain after obtaining) 4) Culture conditions: RPMI1640 medium containing 10% inactivation (56°C, 30 minutes treatment) fetal bovine serum, CO2 incubator (37°C, 5% CO2 ) a) Culture medium: RPMI1640 i) Source: Nacalai Tesque Co., Ltd.
- Serum Fetal Bovine Serum i) Concentration: 10% ii) Source: Sigma-Aldrich c) Additives: Penicillin-streptomycin mixed solution i) Concentration: 100 Units/mL penicillin, 100 ⁇ g/mL streptomycin ii) Source: Nacalai Tesque Co., Ltd.
- A375 Cell line name: A375 2) Origin: Malignant melanoma 3) Source: ATCC CRL-1619 4) Culture conditions: DMEM medium containing 10% inactivation (56°C, 30 minutes treatment) fetal bovine serum, CO2 incubator (37°C, 5% CO2 ) a) Culture medium: DMEM i) Source: Nacalai Tesque Co., Ltd.
- Serum Fetal Bovine Serum i) Concentration: 10% ii) Source: Sigma-Aldrich c) Additives: Penicillin-streptomycin mixed solution i) Concentration: 100 Units/mL penicillin, 100 ⁇ g/mL streptomycin ii) Source: Nacalai Tesque Co., Ltd.
- NALM6 Cell line name: NALM6 2) Origin: Acute Lymphoblastic Leukemia 3) Obtained from: ATCC CRL-3273 4) Culture conditions: RPMI1640 medium containing 10% inactivation (56°C, 30 minutes treatment) fetal bovine serum, CO2 incubator (37°C, 5% CO2 ) a) Culture medium: RPMI1640 i) Source: Nacalai Tesque Co., Ltd.
- Serum Fetal Bovine Serum i) Concentration: 10% ii) Source: Sigma-Aldrich c) Additives: Penicillin-streptomycin mixed solution i) Concentration: 100 Units/mL penicillin, 100 ⁇ g/mL streptomycin ii) Source: Nacalai Tesque Co., Ltd.
- Test method 1.4.1 Test method for combination use of IAP antagonist and CD19 CAR-T NOG mice produced by Invivo Science Co., Ltd. were received at 6 weeks of age, and at 7 weeks of age, tumor cells were intravenously transplanted to produce tumor-bearing mice. . 20 mg/kg busulfex (BSF) was administered intraperitoneally the day before transplantation. During the breeding period, 5 animals are housed at a time, temperature 24°C (actual measurement: 19.7-25.0°C), humidity 50% (actual measurement: 38.6-58.5%), lighting 12 hours/day (8:00AM to 8:00PM). They were reared in a P2A breeding room set to .
- BSF busulfex
- mice (Clea Japan, CL-2) and autoclave-sterilized tap water in a water bottle.
- the CD19 CAR-T cells to be administered were iv administered once on the same day as grouping according to the group composition.
- Administration of the IAP antagonist was also started on the same day as the grouping, and was administered po or ip according to the group composition table.
- the evaluation period was 3 to 4 weeks, and grouping and pharmacological evaluation were performed using the tumor luminescence value obtained by IVIS (trademark) as an indicator. IVISTM luminescence measurements and body weight measurements were performed twice a week.
- mice Clea Japan, CL-2
- mice Clea Japan, CL-2
- Control-T cells and activated integrin ⁇ 7 CAR-T (aITGB7 CAR-T) cells to be administered were iv administered once on the same day as grouping according to the group composition.
- Administration of Tolinapant was also started on the same day as the grouping, and po administration was performed daily according to the group composition table.
- the evaluation period was until Day 14 or Day 21, and grouping and pharmacological evaluation were performed using the tumor luminescence value by IVIS as an index. Measurement of luminescence value with IVIS and body weight measurement were carried out twice a week.
- the NY-ESO-1 TCR-T cells to be administered were iv administered once on the same day as the grouping according to the group composition.
- Tolinapant the same day as the grouping was used as the start date of administration, and po administration was performed according to the group composition table.
- the evaluation period was 2 weeks, and grouping and pharmacological evaluation were performed based on the results of tumor diameter measurement using vernier calipers. Tumor diameter measurements and body weight measurements were performed twice a week.
- mice Clea Japan, CL-2
- the CD19 CAR KHYG-1 cells and KHYG-1 cells to be administered were intratumorally administered a total of 4 times after grouping according to the group composition.
- Administration of Tolinapant was also started on the same day as the grouping, and was orally administered every day according to the group composition table.
- the evaluation period was up to Day 17, and grouping and pharmacological evaluation were performed using the tumor volume measured with a vernier caliper as an index. Tumor volume measurements and body weight measurements were performed twice weekly prior to each dose.
- Subconfluent cell suspensions were passaged into culture flasks containing fresh medium (passage 2). After thawing, cells that were passaged 3 or more times were used for transplantation. The volume of the culture solution to be subcultured was 1/10 to 1/3 of the volume of the new medium. The cell suspension cultured to a subconfluent state was washed three times with D-PBS (-) by centrifugation, and then resuspended in serum-free RPMI1640. In the case of NALM6-luc2, after resuspension, a portion of the cell suspension was taken, dead cells were stained with AOPI Staining Solution, and the number of viable cells was counted with a hemocytometer.
- RPMI1640 It was diluted with RPMI1640 to prepare 1 ⁇ 10 7 cells/mL based on the measurement result of the viable cell count of the cells. Similarly, in the low tumor load system, the cells were diluted with serum-free RPMI1640 to 1 ⁇ 10 6 cells/mL. In the case of MM.1S-luc2, after resuspension, a portion of the cell suspension was taken, dead cells were stained with AOPI Staining Solution, and the number of viable cells was counted with a hemocytometer. It was diluted with RPMI1640 to prepare 3 ⁇ 10 7 cells/mL based on the results of measuring the viable cell count of the cells.
- NALM6 In the case of NALM6, after resuspension, a portion of the cell suspension was taken, dead cells were stained with AOPI Staining Solution, and the number of viable cells was counted with a hemocytometer. It was diluted with RPMI1640 to prepare 1 ⁇ 10 8 cells/mL based on the measurement result of the viable cell count of the cells. An equal volume of the prepared cell suspension was mixed with a scaffold Matrigel (Corning (trademark) high-concentration Matrigel basement membrane matrix) to obtain a final suspension for transplantation (5 ⁇ 10 7 cells/mL). The prepared cell suspension was stored in ice water until transplantation.
- a scaffold Matrigel Corning (trademark) high-concentration Matrigel basement membrane matrix
- A375 Cell Suspension for Transplantation Cells were cultured in a CO 2 incubator (5% CO 2 , 37° C.) using a culture medium (hereinafter referred to as medium).
- medium a culture medium
- the cryopreserved A375 cell line was quickly thawed in a constant temperature bath at 37°C, suspended in a medium, and centrifuged (150 xg, 5 minutes, 20°C) to remove the supernatant. After resuspending the cells in the medium, the whole amount was seeded in a dish and cultured at 37°C in the presence of 5% CO 2 .
- the morphology and growth state of the cells were observed under a microscope, and the cells were cultured until subconfluent (first passage). Remove the supernatant from the subconfluent dish, wash with D-PBS(-) (Nacalai Tesque), add trypsin-EDTA (Nacalai Tesque), remove and collect the cells, and centrifuge (4°C, 1200 rpm). , 5 minutes). The cells were suspended in DMEM medium and the number of viable cells was measured using AOPI staining solution. They were then seeded at a cell density suitable for the dish size and cultured in a CO2 incubator (passage 2). Cells that were passaged 3 or more times were used for transplantation.
- the cultured cells were detached and collected with trypsin-EDTA and centrifuged (4°C, 1200 rpm, 5 minutes). After removing the supernatant, D-PBS(-) was added to resuspend, and similarly centrifuged to wash the cells. This washing operation was repeated two more times. A portion of the cell suspension was measured for the number of viable cells using AOPI staining solution, and D-PBS(-) was used to prepare a cell suspension of 1 ⁇ 10 7 cells/mL. The prepared cell suspension was stored on ice until transplantation.
- the transplantation site (right armpit) was shaved with a safety razor by the day before tumor transplantation in order to facilitate the transplantation operation and subsequent observation of tumor growth.
- the cell suspension was subcutaneously injected into the axilla without anesthesia using an insulin syringe with a 26G needle (1 mL, Terumo Corporation) at 1 ⁇ 10 6 cells/0.1 mL/body. A cell suspension was implanted.
- the transplantation site (right axilla) was shaved with a safety razor by the day before tumor transplantation in order to facilitate the transplantation operation and subsequent observation of tumor growth.
- the cell suspension was subcutaneously injected into the axilla under anesthesia using an insulin syringe (1 mL, Terumo Corporation) equipped with a 26G injection needle to obtain 5 ⁇ 10 6 cells/0.1 mL/body. A cell suspension was implanted.
- mice were assigned to 5 animals per group by a stratified random sampling method using the tumor size index. After grouping, individual identification was performed by marking the mouse tail.
- Method of administration A suspension of CD19 CAR-T cells was administered into the tail vein at the time of grouping. The dose was calculated by counting the number of CD19 CAR-T viable cells, and administered once at 0.1 mL/body according to the group composition table. A 27G mijector was used for administration.
- aITGB7 CAR-T activated integrin ⁇ 7 CAR-T
- Control-T cells were administered to the tail vein at the time of grouping. The dose was determined by counting the number of viable aITGB7 CAR-T cells, preparing a cell density suspension according to the group composition table, and administering 0.1 mL/body once. A 27G mijector was used for administration.
- NY-ESO-1 TCR-T cell suspension was administered through the tail vein.
- the dose was determined by counting the number of NY-ESO-1 TCR-T viable cells, preparing a cell density suspension according to the group composition table, and administering 0.1 mL/body once. A 27G mijector was used for administration.
- Birinapant was administered intraperitoneally at 10 mL/kg according to the group composition table, and Tolinapant, LCL161 and AT406 were also orally administered at 10 mL/kg using a sonde according to the group composition table.
- Tolinapant, LCL161 and AT406 were also orally administered at 10 mL/kg using a sonde according to the group composition table.
- an insulin syringe with a 26G needle was used, and for oral administration, the needle was replaced with a sonde.
- Tumor diameter was measured by measuring the minor axis and major axis using an electronic vernier caliper (Mitutoyo). After tumor cell implantation, the tumor diameter was measured twice a week.
- tumor volume (TV) was calculated using the following formula.
- TV L x W2 x 1/2 where TV is tumor volume (mm 3 ) L: Length (mm) W: Minor diameter (mm)
- Body weight was measured on the day of grouping and on the day of necropsy, and twice a week during the dosing period.
- AT406 showed a transition of combined effect similar to that of Tolinapant, but since the speed of effect was different, the differentiation between AT406 and Tolinapant was verified by the AUC of the combined result and the maximum tumor burden (luminescence value).
- the AUC of the concomitant data up to Day 17 was able to obtain significance associated with concomitant use of Tolinapant, and similar results were obtained on Day 14 (Tables 9 and 10).
- a significant difference was also obtained between AT406 and Tolinapant in the maximum tumor burden (Table 11). From the above, it was confirmed that Tolinapant exhibits a higher efficacy-enhancing effect in combination with CAR-T cells than other IAP antagonists.
- trinapant drugs are also remarkably superior in efficacy enhancing effect in combination with modified immune cells including CAR-T cells, TCR-T cells, and CAR-NK cells.
- target CAR antigen-expressing tumor cells eg, CD19-positive NALM6
- cytokines eg, TNF- ⁇
- coexistence of cytokines produced from CAR-T and Tolinapant induces cell death (e.g., apoptosis) not only in antigen-expressing cells but also in antigen-negative tumor cells (e.g., CD19-negative NALM6).
- Such non-contact induction of cell death in tumor cells can exert anti-tumor effects even against tumor cells that have escaped antigens and tumor cells that have metastasized to sites where modified immune cells cannot approach. Be expected.
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Abstract
Description
項1.
下記式(1):
項1a.
前記免疫細胞の投与の前、同時、又は後に投与される、項1に記載の医薬組成物(又は薬剤、医薬、もしくはIAP阻害剤)。
項2.
キメラ抗原受容体又は組換えT細胞受容体を発現するように改変された免疫細胞を含有する医薬組成物であって、下記式(1):
項2a.
前記式(1)で表される化合物、その薬学的に許容可能な塩、又はその薬学的に許容可能な溶媒和物の投与の前、同時、又は後に投与される、項2に記載の医薬組成物。
項3.
前記キメラ抗原受容体又は組換えT細胞受容体が、CD19、インテグリンβ7、及びNY-ESO-1から選択される抗原を特異的に認識する、項1又は2、或いは、項1a又は2aに記載の医薬組成物。
項4.
前記キメラ抗原受容体又は組換えT細胞受容体が、活性型インテグリンβ7を特異的に認識する、項1又は2、或いは、項1a又は2aに記載の医薬組成物。
項5.
前記免疫細胞がキメラ抗原受容体を発現するように改変されたT細胞又はNK細胞であり、前記キメラ抗原受容体が、
(1) 抗原を認識可能な細胞外ドメイン、
(2) 膜貫通ドメイン、
(3) 共刺激分子の細胞内シグナル伝達ドメイン、及び
(4) CD3ζの細胞内シグナル伝達ドメイン
を含有する、項1~4、1a、及び2aのいずれかに記載の医薬組成物。
項6.
前記細胞外ドメインが、CD19又はインテグリンβ7を認識可能な細胞外ドメインである、項5に記載の医薬組成物。
項7.
前記膜貫通ドメインが、CD28又はCD8の膜貫通ドメインである、項5又は6に記載の医薬組成物。
項8.
前記共刺激分子が、CD2、CD4、CD5、CD8α、CD8β、CD28、CD134(OX40)、CD137(4-1BB)、又はCD278(ICOS)である、項5~7のいずれかに記載の医薬組成物。
項9.
前記免疫細胞が組換えT細胞受容体を発現するように改変されたT細胞又はNK細胞であり、前記組換えT細胞受容体が、NY-ESO-1を認識可能な可変ドメインを有する、項1又は2、或いは、項1a又は2aに記載の医薬組成物。
項10.
前記免疫細胞が、CD19を特異的に認識するキメラ抗原受容体を発現するように改変されたT細胞、インテグリンβ7を特異的に認識するキメラ抗原受容体を発現するように改変されたT細胞、CD19を特異的に認識するキメラ抗原受容体を発現するように改変されたNK細胞、又はNY-ESO-1を特異的に認識する組換えT細胞受容体を発現するように改変されたT細胞である、項1又は2、或いは、項1a又は2aに記載の医薬組成物。
項11.
癌を予防及び/又は治療するための、項1~10、1a、及び2aのいずれかに記載の医薬組成物。
項12.
前記式(1)で表される化合物、その薬学的に許容可能な塩、又はその薬学的に許容可能な溶媒和物が、10mg~180mg/日で投与される、項1~11、1a、及び2aのいずれかに記載の医薬組成物。
項12a.
前記式(1)で表される化合物、その薬学的に許容可能な塩、又はその薬学的に許容可能な溶媒和物が、単独で投与する場合の投与量よりも少ない量、又は単独では有効でない量で投与される、項1~11、1a、及び2aのいずれかに記載の医薬組成物。
項13.
前記免疫細胞が、1×103個~1×108個(生細胞数)/kg体重/日で投与される、項1~12、1a、2a、及び12aのいずれかに記載の医薬組成物。
項13a.
前記免疫細胞が、単独で投与する場合の投与量よりも少ない量、又は単独では有効でない量で投与される、項1~12、1a、2a、及び12aのいずれかに記載の医薬組成物。
項14.
下記式(1):
項14a.
前記第一剤及び第二剤は、同一の製剤にあり、同時に投与される、或いは
前記第一剤及び第二剤は、異なる製剤にあり、同時に、別々に、又は連続的に投与される、
項14に記載のキット。
項14b.
前記キメラ抗原受容体又は組換えT細胞受容体が、CD19、インテグリンβ7、及びNY-ESO-1から選択される抗原を特異的に認識する、項14又は14aに記載のキット。
項14c.
前記キメラ抗原受容体又は組換えT細胞受容体が、活性型インテグリンβ7を特異的に認識する、項14又は14aに記載のキット。
項14d.
前記免疫細胞がキメラ抗原受容体を発現するように改変されたT細胞又はNK細胞であり、前記キメラ抗原受容体が、
(1) 抗原を認識可能な細胞外ドメイン、
(2) 膜貫通ドメイン、
(3) 共刺激分子の細胞内シグナル伝達ドメイン、及び
(4) CD3ζの細胞内シグナル伝達ドメイン
を含有する、項14及び14a~14cのいずれかに記載のキット。
項14e.
前記細胞外ドメインが、CD19又はインテグリンβ7を認識可能な細胞外ドメインである、項14dに記載のキット。
項14f.
前記膜貫通ドメインが、CD28又はCD8の膜貫通ドメインである、項14d又は14eに記載のキット。
項14g.
前記共刺激分子が、CD2、CD4、CD5、CD8α、CD8β、CD28、CD134(OX40)、CD137(4-1BB)、又はCD278(ICOS)である、項14d~14fのいずれかに記載のキット。
項14h.
前記免疫細胞が組換えT細胞受容体を発現するように改変されたT細胞又はNK細胞であり、前記組換えT細胞受容体が、NY-ESO-1を認識可能な可変ドメインを有する、請求項14又は14aに記載のキット。
項14i.
前記免疫細胞が、CD19を特異的に認識するキメラ抗原受容体を発現するように改変されたT細胞、インテグリンβ7を特異的に認識するキメラ抗原受容体を発現するように改変されたT細胞、CD19を特異的に認識するキメラ抗原受容体を発現するように改変されたNK細胞、又はNY-ESO-1を特異的に認識する組換えT細胞受容体を発現するように改変されたT細胞である、請求項14又は14aに記載のキット。
項14j.
癌を予防及び/又は治療するための、項14及び14a~14iのいずれかに記載のキット。
項14k.
前記式(1)で表される化合物、その薬学的に許容可能な塩、又はその薬学的に許容可能な溶媒和物が、10mg~180mg/日、単独で投与する場合の投与量よりも少ない量、又は単独では有効でない量で投与される、項14及び14a~14jのいずれかに記載のキット。
項14L.
前記免疫細胞が、1×103個~1×108個(生細胞数)/kg体重/日、単独で投与する場合の投与量よりも少ない量、又は単独では有効でない量で投与される、項14及び14a~14kのいずれかに記載のキット。
項15.
癌を予防及び/又は治療する方法であって、
癌の予防及び/又は治療を必要とする対象に、下記式(1):
項15a.
前記投与することが、前記式(1)で表される化合物、その薬学的に許容可能な塩、又はその薬学的に許容可能な溶媒和物を、前記免疫細胞の投与の前、同時、又は後に投与することである、項15に記載の方法。
項15b.
前記キメラ抗原受容体又は組換えT細胞受容体が、CD19、インテグリンβ7、及びNY-ESO-1から選択される抗原を特異的に認識する、項15又は15aに記載の方法。
項15c.
前記キメラ抗原受容体又は組換えT細胞受容体が、活性型インテグリンβ7を特異的に認識する、項15又は15aに記載の方法。
項15d.
前記免疫細胞がキメラ抗原受容体を発現するように改変されたT細胞又はNK細胞であり、前記キメラ抗原受容体が、
(1) 抗原を認識可能な細胞外ドメイン、
(2) 膜貫通ドメイン、
(3) 共刺激分子の細胞内シグナル伝達ドメイン、及び
(4) CD3ζの細胞内シグナル伝達ドメイン
を含有する、項15及び15a~15cのいずれかに記載の方法。
項15e.
前記細胞外ドメインが、CD19又はインテグリンβ7を認識可能な細胞外ドメインである、項15dに記載の方法。
項15f.
前記膜貫通ドメインが、CD28又はCD8の膜貫通ドメインである、項15d又は15eに記載の方法。
項15g.
前記共刺激分子が、CD2、CD4、CD5、CD8α、CD8β、CD28、CD134(OX40)、CD137(4-1BB)、又はCD278(ICOS)である、項15d~15fのいずれかに記載の方法。
項15h.
前記免疫細胞が組換えT細胞受容体を発現するように改変されたT細胞又はNK細胞であり、前記組換えT細胞受容体が、NY-ESO-1を認識可能な可変ドメインを有する、項15又は15aに記載の方法。
項15i.
前記免疫細胞が、CD19を特異的に認識するキメラ抗原受容体を発現するように改変されたT細胞、インテグリンβ7を特異的に認識するキメラ抗原受容体を発現するように改変されたT細胞、CD19を特異的に認識するキメラ抗原受容体を発現するように改変されたNK細胞、又はNY-ESO-1を特異的に認識する組換えT細胞受容体を発現するように改変されたT細胞である、項15又は15aに記載の方法。
項15j.
前記式(1)で表される化合物、その薬学的に許容可能な塩、又はその薬学的に許容可能な溶媒和物を、10mg~180mg/日、単独で投与する場合の投与量よりも少ない量、又は単独では有効でない量で投与する、項15及び15a~15iのいずれかに記載の方法。
項15k.
前記免疫細胞を、1×103個~1×108個(生細胞数)/kg体重/日、単独で投与する場合の投与量よりも少ない量、又は単独では有効でない量で投与する、項15及び15a~15jのいずれかに記載の方法。
項16.
キメラ抗原受容体又は組換えT細胞受容体を発現するように改変された免疫細胞と組み合わせて投与するための医薬の調製のための、下記式(1):
項16a.
前記医薬が、前記免疫細胞の投与の前、同時、又は後に投与するための医薬である、項16に記載の使用。
項16b.
前記キメラ抗原受容体又は組換えT細胞受容体が、CD19、インテグリンβ7、及びNY-ESO-1から選択される抗原を特異的に認識する、項16又は16aに記載の使用。
項16c.
前記キメラ抗原受容体又は組換えT細胞受容体が、活性型インテグリンβ7を特異的に認識する、項16又は16aに記載の使用。
項16d.
前記免疫細胞がキメラ抗原受容体を発現するように改変されたT細胞又はNK細胞であり、前記キメラ抗原受容体が、
(1) 抗原を認識可能な細胞外ドメイン、
(2) 膜貫通ドメイン、
(3) 共刺激分子の細胞内シグナル伝達ドメイン、及び
(4) CD3ζの細胞内シグナル伝達ドメイン
を含有する、項16及び16a~16cのいずれかに記載の使用。
項16e.
前記細胞外ドメインが、CD19又はインテグリンβ7を認識可能な細胞外ドメインである、項16dに記載の使用。
項16f.
前記膜貫通ドメインが、CD28又はCD8の膜貫通ドメインである、項16d又は16eに記載の使用。
項16g.
前記共刺激分子が、CD2、CD4、CD5、CD8α、CD8β、CD28、CD134(OX40)、CD137(4-1BB)、又はCD278(ICOS)である、項16d~16fのいずれかに記載の使用。
項16h.
前記免疫細胞が組換えT細胞受容体を発現するように改変されたT細胞又はNK細胞であり、前記組換えT細胞受容体が、NY-ESO-1を認識可能な可変ドメインを有する、項16又は16aに記載の使用。
項16i.
前記免疫細胞が、CD19を特異的に認識するキメラ抗原受容体を発現するように改変されたT細胞、インテグリンβ7を特異的に認識するキメラ抗原受容体を発現するように改変されたT細胞、CD19を特異的に認識するキメラ抗原受容体を発現するように改変されたNK細胞、又はNY-ESO-1を特異的に認識する組換えT細胞受容体を発現するように改変されたT細胞である、項16又は16aに記載の使用。
項16j.
前記医薬が、癌を予防及び/又は治療するための医薬である、項16及び16a~16iのいずれかに記載の使用。
項16k.
前記医薬が、前記式(1)で表される化合物、その薬学的に許容可能な塩、又はその薬学的に許容可能な溶媒和物を10mg~180mg/日、単独で投与する場合の投与量よりも少ない量、又は単独では有効でない量で投与するための医薬である、項16及び16a~16jのいずれかに記載の使用。
項16L.
前記医薬が、1×103個~1×108個(生細胞数)/kg体重/日、単独で投与する場合の投与量よりも少ない量、又は単独では有効でない量の前記免疫細胞と組み合わせて投与するための医薬である、項16及び16a~16kのいずれかに記載の使用。
項17.
下記式(1):
項17a.
前記医薬が、前記式(1)で表される化合物、その薬学的に許容可能な塩、又はその薬学的に許容可能な溶媒和物の投与の前、同時、又は後に投与するための医薬である、項17に記載の使用。
項17b.
前記キメラ抗原受容体又は組換えT細胞受容体が、CD19、インテグリンβ7、及びNY-ESO-1から選択される抗原を特異的に認識する、項17又は17aに記載の使用。
項17c.
前記キメラ抗原受容体又は組換えT細胞受容体が、活性型インテグリンβ7を特異的に認識する、項17又は17aに記載の使用。
項17d.
前記免疫細胞がキメラ抗原受容体を発現するように改変されたT細胞又はNK細胞であり、前記キメラ抗原受容体が、
(1) 抗原を認識可能な細胞外ドメイン、
(2) 膜貫通ドメイン、
(3) 共刺激分子の細胞内シグナル伝達ドメイン、及び
(4) CD3ζの細胞内シグナル伝達ドメイン
を含有する、項17及び17a~17cのいずれかに記載の使用。
項17e.
前記細胞外ドメインが、CD19又はインテグリンβ7を認識可能な細胞外ドメインである、項17dに記載の使用。
項17f.
前記膜貫通ドメインが、CD28又はCD8の膜貫通ドメインである、項17d又は17eに記載の使用。
項17g.
前記共刺激分子が、CD2、CD4、CD5、CD8α、CD8β、CD28、CD134(OX40)、CD137(4-1BB)、又はCD278(ICOS)である、項17d~17fのいずれかに記載の使用。
項17h.
前記免疫細胞が組換えT細胞受容体を発現するように改変されたT細胞又はNK細胞であり、前記組換えT細胞受容体が、NY-ESO-1を認識可能な可変ドメインを有する、項17又は17aに記載の使用。
項17i.
前記免疫細胞が、CD19を特異的に認識するキメラ抗原受容体を発現するように改変されたT細胞、インテグリンβ7を特異的に認識するキメラ抗原受容体を発現するように改変されたT細胞、CD19を特異的に認識するキメラ抗原受容体を発現するように改変されたNK細胞、又はNY-ESO-1を特異的に認識する組換えT細胞受容体を発現するように改変されたT細胞である、項17又は17aに記載の使用。
項17j.
前記医薬が、癌を予防及び/又は治療するための医薬である、項17及び17a~17iのいずれかに記載の使用。
項17k.
前記医薬が、前記免疫細胞を1×103個~1×108個(生細胞数)/kg体重/日、単独で投与する場合の投与量よりも少ない量、又は単独では有効でない量で投与するための医薬である、項17及び17a~17jのいずれかに記載の使用。
項17L.
前記医薬が、10mg~180mg/日、単独で投与する場合の投与量よりも少ない量、又は単独では有効でない量の、前記式(1)で表される化合物、その薬学的に許容可能な塩、又はその薬学的に許容可能な溶媒和物と組み合わせて投与するための医薬である、項17及び17a~17kのいずれかに記載の使用。
項18.
キメラ抗原受容体又は組換えT細胞受容体を発現するように改変された免疫細胞と組み合わせて投与するために用いられる、下記式(1):
項18a.
前記免疫細胞の投与の前、同時、又は後に投与するために用いられる、項18に記載の化合物、その薬学的に許容可能な塩、又はその薬学的に許容可能な溶媒和物。
項18b.
前記キメラ抗原受容体又は組換えT細胞受容体が、CD19、インテグリンβ7、及びNY-ESO-1から選択される抗原を特異的に認識する、項18又は18aに記載の使用。
項18c.
前記キメラ抗原受容体又は組換えT細胞受容体が、活性型インテグリンβ7を特異的に認識する、項18又は18aに記載の使用。
項18d.
前記免疫細胞がキメラ抗原受容体を発現するように改変されたT細胞又はNK細胞であり、前記キメラ抗原受容体が、
(1) 抗原を認識可能な細胞外ドメイン、
(2) 膜貫通ドメイン、
(3) 共刺激分子の細胞内シグナル伝達ドメイン、及び
(4) CD3ζの細胞内シグナル伝達ドメイン
を含有する、項18及び18a~18cのいずれかに記載の化合物、その薬学的に許容可能な塩、又はその薬学的に許容可能な溶媒和物。
項18e.
前記細胞外ドメインが、CD19又はインテグリンβ7を認識可能な細胞外ドメインである、項18dに記載の化合物、その薬学的に許容可能な塩、又はその薬学的に許容可能な溶媒和物。
項18f.
前記膜貫通ドメインが、CD28又はCD8の膜貫通ドメインである、項18d又は18eに記載の化合物、その薬学的に許容可能な塩、又はその薬学的に許容可能な溶媒和物。
項18g.
前記共刺激分子が、CD2、CD4、CD5、CD8α、CD8β、CD28、CD134(OX40)、CD137(4-1BB)、又はCD278(ICOS)である、項18d~18fのいずれかに記載の化合物、その薬学的に許容可能な塩、又はその薬学的に許容可能な溶媒和物。
項18h.
前記免疫細胞が組換えT細胞受容体を発現するように改変されたT細胞又はNK細胞であり、前記組換えT細胞受容体が、NY-ESO-1を認識可能な可変ドメインを有する、項18又は18aに記載の化合物、その薬学的に許容可能な塩、又はその薬学的に許容可能な溶媒和物。
項18i.
前記免疫細胞が、CD19を特異的に認識するキメラ抗原受容体を発現するように改変されたT細胞、インテグリンβ7を特異的に認識するキメラ抗原受容体を発現するように改変されたT細胞、CD19を特異的に認識するキメラ抗原受容体を発現するように改変されたNK細胞、又はNY-ESO-1を特異的に認識する組換えT細胞受容体を発現するように改変されたT細胞である、項18又は18aに記載の化合物、その薬学的に許容可能な塩、又はその薬学的に許容可能な溶媒和物。
項18j.
癌を予防及び/又は治療するために用いられる、項18及び18a~18iのいずれかに記載の化合物、その薬学的に許容可能な塩、又はその薬学的に許容可能な溶媒和物。
項18k.
10mg~180mg/日、単独で投与する場合の投与量よりも少ない量、又は単独では有効でない量で投与するために用いられる、項18及び18a~18jのいずれかに記載の化合物、その薬学的に許容可能な塩、又はその薬学的に許容可能な溶媒和物。
項18L.
1×103個~1×108個(生細胞数)/kg体重/日、単独で投与する場合の投与量よりも少ない量、又は単独では有効でない量の前記免疫細胞と組み合わせて投与するために用いられる、項18及び18a~18kのいずれかに記載の化合物、その薬学的に許容可能な塩、又はその薬学的に許容可能な溶媒和物。
項19.
下記式(1):
項19a.
前記式(1)で表される化合物、その薬学的に許容可能な塩、又はその薬学的に許容可能な溶媒和物の投与の前、同時、又は後に投与するために用いられる、項19に記載の免疫細胞。
項19b.
前記キメラ抗原受容体又は組換えT細胞受容体が、CD19、インテグリンβ7、及びNY-ESO-1から選択される抗原を特異的に認識する、項19又は19aに記載の免疫細胞。
項19c.
前記キメラ抗原受容体又は組換えT細胞受容体が、活性型インテグリンβ7を特異的に認識する、項19又は19aに記載の免疫細胞。
項19d.
キメラ抗原受容体を発現するように改変されたT細胞又はNK細胞であり、前記キメラ抗原受容体が、
(1) 抗原を認識可能な細胞外ドメイン、
(2) 膜貫通ドメイン、
(3) 共刺激分子の細胞内シグナル伝達ドメイン、及び
(4) CD3ζの細胞内シグナル伝達ドメイン
を含有する、項19及び19a~19cのいずれかに記載の免疫細胞。
項19e.
前記細胞外ドメインが、CD19又はインテグリンβ7を認識可能な細胞外ドメインである、項19dに記載の免疫細胞。
項19f.
前記膜貫通ドメインが、CD28又はCD8の膜貫通ドメインである、項19d又は19eに記載の免疫細胞。
項19g.
前記共刺激分子が、CD2、CD4、CD5、CD8α、CD8β、CD28、CD134(OX40)、CD137(4-1BB)、又はCD278(ICOS)である、項19d~19fのいずれかに記載の免疫細胞。
項19h.
前記免疫細胞が組換えT細胞受容体を発現するように改変されたT細胞又はNK細胞であり、前記組換えT細胞受容体が、NY-ESO-1を認識可能な可変ドメインを有する、項19又は19aに記載の免疫細胞。
項19i.
前記免疫細胞が、CD19を特異的に認識するキメラ抗原受容体を発現するように改変されたT細胞、インテグリンβ7を特異的に認識するキメラ抗原受容体を発現するように改変されたT細胞、CD19を特異的に認識するキメラ抗原受容体を発現するように改変されたNK細胞、又はNY-ESO-1を特異的に認識する組換えT細胞受容体を発現するように改変されたT細胞である、項19又は19iに記載の免疫細胞。
項19j.
癌を予防及び/又は治療するために用いられる、項19及び19a~19iのいずれかに記載の免疫細胞。
項19k.
1×103個~1×108個(生細胞数)/kg体重/日、単独で投与する場合の投与量よりも少ない量、又は単独では有効でない量で投与するために用いられる、項19及び19a~19jのいずれかに記載の免疫細胞。
項19L.
10mg~180mg/日、単独で投与する場合の投与量よりも少ない量、又は単独では有効でない量の、前記式(1)で表される化合物、その薬学的に許容可能な塩、又はその薬学的に許容可能な溶媒和物と組み合わせて投与するために用いられる、項19及び19a~19kのいずれかに記載の免疫細胞。
本開示のトリナパント系薬剤を含有する医薬組成物(以下、「医薬組成物A」と称する。)は、キメラ抗原受容体又は組換えT細胞受容体を発現するように改変された免疫細胞(後述の医薬組成物Bの形態であってもよい。)と組み合わせて投与される医薬組成物であることが好ましく、具体的には、前記免疫細胞の投与の前、同時、又は後に投与される医薬組成物であることが好ましい。医薬組成物Aは、典型的にはIAPアンタゴニストであることができ、特にXIAP、cIAP1、及びcIAP2のアンタゴニストであることができる。トリナパント系薬剤は、例えば、他のIAPアンタゴニストと比較して、改変された免疫細胞と組み合わせて投与したときに、より迅速に効能を発揮し得る。
式(1)で表される化合物は、総量の55%以上、60%以上、65%以上、70%以上、75%以上、80%以上、85%以上、90%以上、95%以上、99%以上、99.5%以上、99.9%以上、又は100%が単一の光学異性体として存在し得る。
医薬組成物Aは、他の成分として、薬学的に許容可能な賦形剤を含有することが好ましい。薬学的に許容可能な賦形剤としては、例えば、担体(固体担体、半固体担体、及び液体担体を含む)、補助剤、希釈剤、充填剤又は増量剤、造粒剤、コーティング剤、放出制御剤、結合剤、崩壊剤、滑沢剤、保存剤、抗酸化剤、緩衝剤、沈殿防止剤、増粘剤、矯味矯臭剤、安定剤、界面活性剤、キレート剤、又はその他の医薬組成物で慣用されている賦形剤などが挙げられる。薬学的に許容可能な賦形剤は1種を単独で用いてもよく、2種以上を組み合わせて用いてもよい。
医薬組成物Aは、液状製剤(例:注射剤、点眼剤、点鼻剤、懸濁剤)、固形製剤(例:錠剤、顆粒剤、散剤)、半固形製剤(例:軟膏剤、坐剤)、及びその他当業者に公知の製剤形態のいずれであってもよい。
医薬組成物Aは、経口投与用であっても非経口投与用であってもよい。医薬組成物Aは、局所投与用であってもよい。医薬組成物Aは、例えば、眼内、耳、鼻腔内、舌下、気管支内、静脈内、筋肉内、腹腔内、直腸内、膣内、又は経皮投与用であってもよい。医薬組成物Aは、注射用であってもよい。
医薬組成物Aは、医薬組成物Bの効果(遺伝子改変免疫療法における治療効果)を増強し得る用途で用いる限り、その用途は特に制限されない。医薬組成物Aは、例えばIAP関連疾患の予防及び/又は治療に用いることができる。本明細書において、「予防」は、例えば再発防止を包含する意味で用い、「治療」は、例えば進行の防止又は遅延、軽減、緩和、及び寛解を包含する意味で用いる。IAP関連疾患としては、例えば、細胞蓄積に関わる疾患(例:癌、自己免疫障害、炎症、再狭窄)、過剰アポトーシスが細胞の損失をもたらす障害(例:アルツハイマー病、パーキンソン病、ハンチントン病、筋萎縮性側索硬化症などの神経変性、虚血、脳卒中、心筋梗塞、心不全、骨粗鬆症、AIDS)などが挙げられる。本明細書において、「癌」は広義的な意味で「腫瘍」を表し、「腫瘍」と同義で使用し得る。IAP関連疾患は癌であることが好ましい。癌は、XIAP、cIAP1、cIAP2、NAIP、ILP2、ML-IAP、サバイビン、及びBRUCE、より具体的にはXIAP、cIAP1、cIAP2、及びML-IAP、さらに具体的にはXIAP、cIAP1、及びcIAP2、最も具体的にはXIAPから選択される1以上のいずれかのIAPの拮抗作用に対して感受性を有する癌であり得る。癌は、再発又は難治性の癌であってもよい。
本開示の、キメラ抗原受容体(CAR)又は組換えT細胞受容体(TCR)を発現するように改変された免疫細胞を含有する医薬組成物(以下、「医薬組成物B」と称する。)は、トリナパント系薬剤(医薬組成物Aの形態であってもよい。)と組み合わせて投与される医薬組成物であることが好ましく、具体的には、前記トリナパント系薬剤の投与の前、同時、又は後に投与される医薬組成物であることが好ましい。
CARは、細胞外ドメイン及び細胞内シグナル伝達ドメインを含有することが好ましい。
細胞外ドメインは、抗原を認識(又は抗原に結合もしくは特異的に結合)し得る限り、特に限定されない。細胞外ドメインは、抗体の抗原結合部位、又は受容体の抗原(リガンド)結合部位を含有することが好ましい。
また、当該細胞外ドメインは、配列番号1に示されるアミノ酸配列を有する重鎖CDR1、配列番号2に示されるアミノ酸配列を有する重鎖CDR2、配列番号3に示されるアミノ酸配列を有する重鎖CDR3、配列番号4に示されるアミノ酸配列を有する軽鎖CDR1、配列番号5に示されるアミノ酸配列を有する軽鎖CDR2、及び配列番号6に示されるアミノ酸配列を有する軽鎖CDR3を含む抗体のCD19への結合を競合的に阻害する抗体の抗原結合部位(特にscFv)を含有することが好ましい。
また、当該細胞外ドメインは、配列番号7に示されるアミノ酸配列を有する重鎖CDR1、配列番号8に示されるアミノ酸配列を有する重鎖CDR2、配列番号9に示されるアミノ酸配列を有する重鎖CDR3、配列番号10に示されるアミノ酸配列を有する軽鎖CDR1、配列番号11に示されるアミノ酸配列を有する軽鎖CDR2、及び配列番号12に示されるアミノ酸配列を有する軽鎖CDR3を含む抗体のCD19への結合を競合的に阻害する抗体の抗原結合部位(特にscFv)を含有することが好ましい。
IEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKP、
当該アミノ酸配列に対して70%以上、75%以上、80%以上、85%以上、90%以上、91%以上、92%以上、93%以上、94%以上、95%以上、96%以上、97%以上、98%以上、又は99%以上の同一性を有するアミノ酸配列、或いは
当該アミノ酸配列に対して1~3個のアミノ酸が欠失、置換(例:保存的置換)、挿入、及び/又は付加したアミノ酸配列
であることが好ましい。
細胞内シグナル伝達ドメインは、細胞外ドメインが抗原を認識した際、細胞内にシグナルを伝達することが可能なものである限り、特に限定されない。一実施形態において、細胞内シグナル伝達ドメインは、抗原依存的な一次活性化が可能な配列(一次細胞質シグナル伝達配列)及び抗原非依存的な二次活性化又は共刺激が可能な配列(二次細胞質シグナル伝達配列)を有することが好ましい。
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR、
当該アミノ酸配列に対して70%以上、75%以上、80%以上、85%以上、90%以上、91%以上、92%以上、93%以上、94%以上、95%以上、96%以上、97%以上、98%以上、又は99%以上の同一性を有するアミノ酸配列、或いは
当該アミノ酸配列に対して1~3個のアミノ酸が欠失、置換(例:保存的置換)、挿入、及び/又は付加したアミノ酸配列
であることが好ましい。
RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS、
当該アミノ酸配列に対して70%以上、75%以上、80%以上、85%以上、90%以上、91%以上、92%以上、93%以上、94%以上、95%以上、96%以上、97%以上、98%以上、又は99%以上の同一性を有するアミノ酸配列、或いは
当該アミノ酸配列に対して1~3個のアミノ酸が欠失、置換(例:保存的置換)、挿入、及び/又は付加したアミノ酸配列
であることが好ましい。
CARは、細胞外ドメインと細胞内シグナル伝達ドメインとの間に膜貫通ドメインを含有することが好ましい。膜貫通ドメインは、1以上の膜貫通配列を有する任意のポリペプチド由来の膜貫通ドメインであることができる。当該ポリペプチドは天然ポリペプチドであっても人工ポリペプチドであってもよい。
FWVLVVVGGVLACYSLLVTVAFIIFWV、
当該アミノ酸配列に対して70%以上、75%以上、80%以上、85%以上、90%以上、91%以上、92%以上、93%以上、94%以上、95%以上、96%以上、97%以上、98%以上、又は99%以上の同一性を有するアミノ酸配列、或いは
当該アミノ酸配列に対して1~3個のアミノ酸が欠失、置換(例:保存的置換)、挿入、及び/又は付加したアミノ酸配列
であることが好ましい。
CARは、細胞外ドメインと膜貫通ドメインの間、又は、膜貫通ドメインと細胞内シグナル伝達ドメインの間に、リンカー配列又はスペーサードメインを有していてもよい。
MLLLVTSLLLCELPHPAFLLIP、
当該アミノ酸配列に対して70%以上、75%以上、80%以上、85%以上、90%以上、91%以上、92%以上、93%以上、94%以上、95%以上、96%以上、97%以上、98%以上、又は99%以上の同一性を有するアミノ酸配列、或いは
当該アミノ酸配列に対して1~3個のアミノ酸が欠失、置換(例:保存的置換)、挿入、及び/又は付加したアミノ酸配列
であることが好ましい。
MLLLVTSLLLCELPHPAFLLIPDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEGSTKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSAAAIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR、
配列番号1~6に示されるアミノ酸配列を有し、且つ、配列番号20に示されるアミノ酸配列に対して70%以上、75%以上、80%以上、85%以上、90%以上、91%以上、92%以上、93%以上、94%以上、95%以上、96%以上、97%以上、98%以上、又は99%以上の同一性を有するアミノ酸配列、或いは
配列番号1~6に示されるアミノ酸配列を有し、且つ、配列番号20に示されるアミノ酸配列に対して1~3個のアミノ酸が欠失、置換(例:保存的置換)、挿入、及び/又は付加したアミノ酸配列
であることが好ましい。
MDFQVQIFSFLLISASVIMSRGQIVLSQSPAILSASPGEKVTMTCRASSSVGYMHWFQQKPGSSPKPWIYATSNLASGVPARFSGSESGTSYSLTISRVEAEDAATYYCQQWSSDPPTFGGGTKLEIKRGSTSGSGKPGSGEGSQVQLQQSGAELMKPGASVKISCKASGYTFSSYWIEWVKQRPGHGLEWIGEMLPGSGSSNYNEKFKGKATFTADTSSNTAYMQLSSLTSEDSAVYYCARGDGNYWYFDVWGAGTTVTVSSAAAIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR、
配列番号7~12に示されるアミノ酸配列を有し、且つ、配列番号21に示されるアミノ酸配列に対して70%以上、75%以上、80%以上、85%以上、90%以上、91%以上、92%以上、93%以上、94%以上、95%以上、96%以上、97%以上、98%以上、又は99%以上の同一性を有するアミノ酸配列、或いは
配列番号7~12に示されるアミノ酸配列を有し、且つ、配列番号21に示されるアミノ酸配列に対して1~3個のアミノ酸が欠失、置換(例:保存的置換)、挿入、及び/又は付加したアミノ酸配列
であることが好ましい。
組換えTCRはα鎖及びβ鎖で構成されるヘテロダイマーであってもよく、γ鎖及びδ鎖で構成されるヘテロダイマーであってもよい。各鎖は可変ドメイン(Vドメイン)及び定常ドメイン(Cドメイン)を有し、Vドメインに3つのCDR、すなわち、CDR1、CDR2、及びCDR3を有しており、3つのCDR配列が抗原を認識又は結合し得るように設計されている。
CARを発現するように改変された免疫細胞(例:CAR-T細胞、CAR-NK細胞)は、CAR発現用核酸(核酸構築物を含む)を含有する免疫細胞であることが好ましい。同様に、組換えTCRを発現するように改変された免疫細胞(例:TCR-T細胞)は、組換えTCR発現用核酸(核酸構築物を含む)を含有する免疫細胞であることが好ましい。
CAR又は組換えTCR発現用核酸は、CAR又は組換えTCRをコードする核酸に加えて、プロモーターを含有することが好ましい。プロモーターの非限定的な例としては、CMVプロモーター、EF1プロモーター、SV40プロモーター、MSCVプロモーターなどのpol II系プロモーター;trcやtacなどのトリプトファンプロモーター;lacプロモーター;T7プロモーター;T5プロモーター;T3プロモーター;SP6プロモーター;アラビノース誘導プロモーター;コールドショックプロモーター;テトラサイクリン誘導性プロモーター;ユビキチンプロモーターなどが挙げられる。
免疫細胞は、CAR又は組換えTCRを発現するように改変し得るものであれば、特に限定されない。免疫細胞の非限定的な例としては、単球、マクロファージ、T細胞、B細胞、NK細胞が挙げられる。一実施形態において、免疫細胞はT細胞又はNK細胞であることが好ましい。T細胞の非限定的な例としては、CD4陽性T細胞(例:ヘルパーT細胞)、CD8陽性T細胞(例:細胞傷害性T細胞)、ナチュラルキラーT細胞、制御性T細胞(Treg)、ナイーブT細胞、エフェクターT細胞、メモリーT細胞、腫瘍浸潤リンパ球(TIL)、αβT細胞、γδT細胞が挙げられる。典型的には、免疫細胞は細胞集団であることができ、当該細胞集団は、例えば末梢血単核細胞(PBMC)を含有する細胞集団であってもよい。免疫細胞は、造血幹細胞から分化させたものであってもよいが、生体に由来するもの、例えば、生体(末梢血、臍帯血、骨髄、リンパ節、脾臓など)から採取したもの、又は生体から採取して拡大培養したものであることが好ましい。免疫細胞は、自家免疫細胞(医薬組成物Bを投与する対象の免疫細胞)であってもよく、他家免疫細胞であってもよい。他家免疫細胞の場合、HLAの型が一致していることが好ましい。
CAR又は組換えTCR発現用核酸を免疫細胞に形質導入する方法としては、例えば、ウイルス感染法、カルシウムリン酸法、リポフェクション法、マイクロインジェクション法、エレクトロポレーション法などが挙げられるが、これらに限定されない。
改変免疫細胞のうちCAR-T細胞の非限定的な例としては、CD19 CARを発現するように改変されたT細胞(例:ギリアド社のYescarta(axicabtagene ciloleucel)、ノバルティス社のKymriah(tisagenlecleucel)、ブリストル・マイヤーズ スクイブ社のBreyanzi(lisocabtagene maraleucel)、タカラバイオ株式会社のTBI-1501、日本セルヴィエ社のUCART19/ALLO-501)、BCMA CARを発現するように改変されたT細胞(例:セルジーン社のbb2121, ide-cel、ヤンセンファーマ社のJNJ-68284528)、CD98 CARを発現するように改変されたT細胞(例:米国特許出願公開第2018/0230212号(参照することによりその全体が明細書に組み込まれる)に記載のCARを発現するように改変されたT細胞)、活性型インテグリンβ7 CARを発現するように改変されたT細胞(例:米国特許出願公開第2018/0230216号(参照することによりその全体が明細書に組み込まれる)に記載のCARを発現するように改変されたT細胞)が挙げられる。TCR-T細胞の非限定的な例としては、NY-ESO-1特異的TCR-T細胞(例:Tmunity社のNY-ESO-1 TCR-T Triple Knockout TCR (NYCE)、タカラバイオ株式会社のTBI-1301)、MAGE-A4特異的TCR-T細胞(例:Adaptimmune社のADP-A2M4 SPEAR T-cells)、MAGE-A3及び/又はMAGE-A6特異的TCR-T細胞(例:Kite/Gilead Sciences社のKITE-718)が挙げられる。一実施形態において、改変免疫細胞は、CD19を特異的に認識するCARを発現するように改変されたT細胞、インテグリンβ7(例えば活性型インテグリンβ7)を特異的に認識するCARを発現するように改変されたT細胞、CD19を特異的に認識するCARを発現するように改変されたNK細胞、又はNY-ESO-1を特異的に認識する組換えTCRを発現するように改変されたT細胞であることが好ましい。
医薬組成物Bは、他の成分として、薬学的に許容可能な賦形剤を含有することが好ましい。薬学的に許容可能な賦形剤としては、例えばA-2に記載の賦形剤と同じものが挙げられる。一実施形態において、薬学的に許容可能な賦形剤は、担体(例:滅菌水、生理食塩水)、安定剤、抗酸化剤(例:アスコルビン酸)、緩衝剤(例:リン酸、クエン酸などの有機酸)、保存剤、界面活性剤(例:ポリエチレングリコール、Tween)、キレート剤(例:EDTA)、糖又は糖アルコール(例:グルコース、マンノース、スクロース、マンニトール)、アミノ酸(例:グリシン、グルタミン、アスパラギン、アルギニン、リシン)、ポリペプチド又はタンパク質(例:血清アルブミン、ゼラチン、免疫グロブリン)、及びアジュバント(例:水酸化アルミニウムなどのアジュバント)からなる群より選択される少なくとも一種である。
改変された免疫細胞の投与量の下限は、投与目的、投与対象及びその状態などに応じて適宜選択することができる。例えば、1日投与量の下限は、対象の体重1kg当たり、生細胞数として、1×102個、5×102個、1×103個、2×103個、3×103個、4×103個、5×103個、6×103個、7×103個、8×103個、9×103個、1×104個、2×104個、3×104個、4×104個、5×104個、6×104個、7×104個、8×104個、9×104個、又は1×105個であってもよい。また、1日投与量の上限も、下限と同様に適宜選択することができ、例えば、対象の体重1kg当たり、生細胞数として、1×109個、5×108個、1×108個、5×107個、1×107個、5×106個、又は1×106個であってもよい。例えば、1日投与量は、対象の体重1kg当たり、生細胞数として、1×103個~1×108個、5×103個~5×107個、又は1×104個~1×107個であってもよい。1日投与量が前記範囲になるように2回以上(例:2回又は3回)に分けて投与してもよいし、場合により2日に分けて投与してもよい。改変された免疫細胞の投与量は、単独で投与する場合の投与量よりも少ない量、又は単独では有効でない量であってもよい。このような量で投与した場合であっても、トリナパント系薬剤の投与と相まって優れた効能を発揮し得る。
医薬組成物Bは、医薬組成物Aと組み合わせてその薬効(遺伝子改変免疫療法における治療効果)が増強し得る態様で用いられる限り、その用途は特に制限されない。医薬組成物Bは、例えば、遺伝子改変免疫療法の対象となる疾患、典型的には癌であることが好ましい。癌の非限定的な例としては、医薬組成物Aで例示したものと同様のものが挙げられる。
本開示のキットは、式(1)で表される化合物、その薬学的に許容可能な塩、又はその薬学的に許容可能な溶媒和物を含有する第一剤、並びに、キメラ抗原受容体又は組換えT細胞受容体を発現するように改変された免疫細胞を含有する第二剤を備えることが好ましい。
1.1 被験細胞
1.1.1 被験細胞
1-1) 細胞名:CD19 CAR-T(タカラバイオ株式会社製)
1-2) 由来:ヒト末梢血由来T細胞
1-3) 入手先:ACCUCELL 等
特性:市販ヒトPMBCを抗CD3抗体(Clone; OKT3)で刺激し、さらにIL-2(250 U/mL)含有培地で増殖させることで誘導したT細胞に、リーダー配列、抗ヒトCD19抗体(Clone; FMC63)の重鎖及び軽鎖Variable Regionを繋げたsingle-chain variable fragment(scFv)配列、リンカー配列、CD28分子の細胞外領域・膜貫通領域・細胞内領域を含む配列、及びCD3ζ分子の細胞内領域を繋いだ配列をレトロウイルスベクターを用いて導入し、増殖、培養後、凍結保存された細胞。
2-2) 由来:ヒト末梢血由来T細胞
2-3) 入手先:ACCUCELL 等
特性:市販ヒトPMBCを抗CD3抗体(Clone; OKT3)及び抗CD28抗体(Clone; 28.2)で刺激し、さらにIL-2(100 U/mL)含有培地で増殖させることで誘導したT細胞に、抗ヒト活性型インテグリンβ7抗体(Clone; MMG49)の重鎖及び軽鎖Variable Regionを繋げたsingle-chain variable fragment(scFv)配列、リーダー配列、リンカー配列、CD28分子の細胞外領域・膜貫通領域・細胞内領域を含む配列、及びCD3ζ分子の細胞内領域を繋いだ配列を、レトロウイルスベクターを用いて導入し、増殖、培養後、凍結保存された細胞。
3-2) 由来:ヒト末梢血由来T細胞
3-3) 入手先:ACCUCELL 等
特性:市販ヒトPMBCを抗CD3抗体(Clone; OKT3)及び抗CD28抗体(Clone; 28.2)で刺激し、さらにIL-2(100 U/mL)含有培地で増殖させることで誘導したT細胞に、HLA-A*02:01拘束性NY-ESO-1を特異的に認識するT細胞受容体(TCR)α鎖及びβ鎖、並びに内在性のTCR α鎖及びβ鎖遺伝子に干渉するsiRNAを発現するレトロウイルスベクターMS3II-NYESO1-siTCR(特許第5969468号)を感染させることにより遺伝子改変されたT細胞(特許第5271901号、特許第5828861号)。作製後、凍結保存された細胞。
4-2) 由来:ヒトNK様細胞
4-3) 入手先:JCRB
入手後CD19 CAR発現株を樹立
4-4) 培養条件:10%非働化(56℃、30分処理)ウシ胎児血清ならびに以下の添加物、サイトカインを含むRPMI1640培地、CO2インキュベーター(37℃、5% CO2)
a) 培養液:RPMI1640
i) 入手先:ナカライテスク株式会社
b) 血清:ウシ胎児血清
i) 濃度:10%
ii) 入手先:シグマアルドリッチ
c) 添加物:ペニシリン-ストレプトマイシン混合溶液
i) 濃度:100 Units/mL ペニシリン、100 μg/mL ストレプトマイシン
ii) 入手先:ナカライテスク株式会社
d) サイトカイン:Recombinant Human IL-2
i) 濃度:100 U/mL
ii) 入手先:PeproTech
特性:ヒトNK様細胞株であるKHYG-1にCD19 CARレトロウイルスベクターを用いて遺伝子導入し、増殖させたのちFCMで陽性細胞をソーティング、再度拡大培養後、凍結保存した細胞。
1-1) 細胞株名:Control-T細胞(ヒトT細胞)
1-2) 由来:ヒト末梢血PBMC
1-3) 入手先:ACCUCELL 等
特性:市販ヒトPBMCを抗CD3抗体(Clone; OKT3)及び抗CD28抗体(Clone; 28.2)で刺激し、さらにIL-2(100 U/mL)含有培地で増殖、培養後、凍結保存された細胞。
2-2) 由来:ヒトNK様細胞
2-3) 入手先:JCRB
2-4) 培養条件:10%非働化(56℃、30分処理)ウシ胎児血清ならびに以下の添加物、サイトカインを含むRPMI1640培地、CO2インキュベーター(37℃、5% CO2)
a) 培養液:RPMI1640
i) 入手先:ナカライテスク株式会社
b) 血清:ウシ胎児血清
i) 濃度:10%
ii) 入手先:シグマアルドリッチ
c) 添加物:ペニシリン-ストレプトマイシン混合溶液
i) 濃度:100 Units/mL ペニシリン、100 μg/mL ストレプトマイシン
ii) 入手先:ナカライテスク株式会社
d) サイトカイン:Recombinant Human IL-2
i) 濃度:100 U/mL
ii) 入手先:PeproTech
細胞希釈液は47%ビカーボン輸液、20%低分子デキストラン糖注、28%ヒト血清アルブミン25%、5%ジメチルスルホキシドを用いた。全ての溶液を混合後、使用するまでディープフリーザー(設定温度-80℃)に保存した。
1) 凍結保存されたCD19 CAR-Tを37℃の恒温槽にて急速融解後、細胞希釈液に懸濁し、遠心(800×g、5分、4℃)により上清を除去した。細胞を細胞希釈液に再懸濁した後、懸濁液の一部を取りAOPI Staining Solutionにて死細胞を染色し、血球測定装置Cellometer Auto 2000 Cell Viability Counter(Nexcelom Bioscience社製)を用いて生細胞数をカウントした。細胞の生細胞数の測定結果から群構成に従い0.1 mL/bodyとなるよう細胞希釈液で調製した。調製後の細胞懸濁液は、投与時まで氷水中で保存した。
各投与日はサブコンフルエントの状態まで培養した各細胞懸濁液を必要量回収し、遠心操作によりD-PBS (-)で3回洗浄したのち無血清のRPMI1640にて再懸濁した。再懸濁後、細胞懸濁液の一部を取りAOPI staining solutionにて死細胞を染色し、血球測定装置を用いて生細胞数をカウントした。細胞の生細胞数の測定結果から群構成に従い0.1 mL/bodyとなるよう細胞希釈液で調製した。調製後の投与液は、投与時まで氷水中で保存した。
基本媒体としてTolinapantは蒸留水、Birinapantはカプチゾール、LCL161は酢酸ナトリウム、ならびにAT406はヒプロメロースを用いた。
カプチゾールは必要量を秤量後、蒸留水にて溶解、12.5%カプチゾール溶液となるよう調製しBirinapantの溶媒とした。
酢酸ナトリウムは3M 酢酸ナトリウム緩衝液(pH5.2)に0.1 M塩酸を加えpHを4.3~4.6の範囲内になるようあわせてLCL161の溶媒とした。
ヒプロメロースは必要量を秤量後PBSにて溶解、1%ヒプロメロース溶液を調製した。溶解後、オートクレーブをかけたのち0.1%相当量のTween 80を加えて溶解しAT406の溶媒とした。
すべての媒体は薬剤調製まで低温室(設定温度4℃)に保存した。
Tolinapantの調製は既報に基づき16 mg/kgとなるよう調製した(参考文献1:Mol Cancer Ther. 2018 July; 17(7): 1381-1391;参考文献2:Oncoimmunology, 2020 January 9; 9(1):1710398)。Tolinapantは1.6 mg/mLとなるよう必要量秤量後、蒸留水で無色透明に溶解させた。投与液は滅菌済みチューブに分注し、投与まで遮光し冷凍保存した。
Birinapantの調製は既報に基づき12 mg/kgとなるよう調製した(参考文献3:Jessica Michie, et al., Cancer Immunol Res. 2019;7(2):183-192)。Birinapantは1.2 mg/mLとなるよう必要量秤量後、事前に調製したカプチゾールで懸濁した。懸濁はメノウ乳鉢を用いて均一な細かい懸濁液になるまで磨りつぶし作製した。投与液は滅菌済みチューブに分注し、投与まで遮光し低温室(設定温度4℃)に保存した。
LCL161の調製は既報に基づき30 mg/kgとなるよう調製した(参考文献4:Peter J Houghton et al., Pediatr Blood Cancer. 2012;58(4):636-639)。LCL161は3 mg/mLとなるよう必要量秤量後、事前に調製した酢酸ナトリウム溶液で無色透明に溶解させた。投与液は滅菌済みチューブに分注し、投与まで遮光し低温室(設定温度4℃)に保存した。
AT406の調製は既報に基づき100 mg/kgとなるよう調製した(参考文献5:Melissa K Brunckhorst et al., Cancer Biology & Therapy. 2012;13(9):804-811)。AT406は初めに200 mg/mL DMSO溶液を調製した。次に10 mg/mLとなるよう必要量を分取し、事前に調製したヒプロメロース溶液で懸濁した。懸濁はメノウ乳鉢を用いて均一な細かい懸濁液になるまで磨りつぶし作製した。投与液は滅菌済みチューブに分注し、投与まで遮光し低温室(設定温度4℃)に保存した。
1.3.1 使用細胞
1.3.1.1 NALM6-luc2
1) 細胞株名:NALM6-luc2
2) 由来:Acute Lymphoblastic Leukemia
3) 入手先:ATCC CRL-3273
入手後:luc2株を樹立
4) 培養条件:10%非働化(56℃、30分処理)ウシ胎児血清を含むRPMI1640培地、CO2インキュベーター(37℃、5% CO2)
a) 培養液:RPMI1640
i) 入手先:ナカライテスク株式会社
b) 血清:ウシ胎児血清
i) 濃度:10%
ii) 入手先:ニチレイバイオサイエンス
c) 添加物:ペニシリン-ストレプトマイシン混合溶液
i) 濃度:100 Units/mL ペニシリン、100 μg/mL ストレプトマイシン
ii) 入手先:ナカライテスク株式会社
1) 細胞株名:MM.1S
2) 由来:Multiple Myeloma
3) 入手先:ATCC(入手後にluc2株を樹立)
4) 培養条件:10%非働化(56℃、30分処理)ウシ胎児血清を含むRPMI1640培地、CO2インキュベーター(37℃、5% CO2)
a) 培養液:RPMI1640
i) 入手先:ナカライテスク株式会社
b) 血清:ウシ胎児血清
i) 濃度:10%
ii) 入手先:シグマアルドリッチ
c) 添加物:ペニシリン-ストレプトマイシン混合溶液
i) 濃度:100 Units/mL ペニシリン、100 μg/mL ストレプトマイシン
ii) 入手先:ナカライテスク株式会社
1) 細胞株名:A375
2) 由来:Malignant Melanoma
3) 入手先:ATCC CRL-1619
4) 培養条件:10%非働化(56℃、30分処理)ウシ胎児血清を含むDMEM培地、CO2インキュベーター(37℃、5% CO2)
a) 培養液:DMEM
i) 入手先:ナカライテスク株式会社
b) 血清:ウシ胎児血清
i) 濃度:10%
ii) 入手先:シグマアルドリッチ
c) 添加物:ペニシリン-ストレプトマイシン混合溶液
i) 濃度:100 Units/mL ペニシリン、100 μg/mL ストレプトマイシン
ii) 入手先:ナカライテスク株式会社
1) 細胞株名:NALM6
2) 由来:Acute Lymphoblastic Leukemia
3) 入手先:ATCC CRL-3273
4) 培養条件:10%非働化(56℃、30分処理)ウシ胎児血清を含むRPMI1640培地、CO2インキュベーター(37℃、5% CO2)
a) 培養液:RPMI1640
i) 入手先:ナカライテスク株式会社
b) 血清:ウシ胎児血清
i) 濃度:10%
ii) 入手先:シグマアルドリッチ
c) 添加物:ペニシリン-ストレプトマイシン混合溶液
i) 濃度:100 Units/mL ペニシリン、100 μg/mL ストレプトマイシン
ii) 入手先:ナカライテスク株式会社
1) 種/系統:マウス/NOD/Shi-scid,IL-2RγKO Jic (NOG)
2) 微生物学的グレイド:specific pathogen-free (SPF)
3) 入手先:インビボサイエンス(株)
4) 週齢(入荷時):6週齢
5) 飼育条件
下記の条件に設定された環境下で、動物の飼育を行った。
a) 温度: 23 ± 3℃
b) 湿度: 55 ± 15%
c) 照明:照明時間:午前8時 ~ 午後8時
消灯時間:午後8時 ~ 午前8時
d) 餌及び水:自由摂取、CL-2 (固型飼料、放射線滅菌済、日本クレア株式会社)、オートクレーブ滅菌した水道水
1.3.4.1 Tolinapant
IAPアンタゴニストの試験で一般的に用いられるヒト乳癌細胞株MDA-MB-231異種移植マウス系において効果を示す用法用量(16 mg/kg、連日経口投与)から設定した(参考文献1及び2)。また本試験系であるNALM6-luc2においては、同じレジメンで効果を全く示さなかったことを確認した。
CAR-TとBirinapantの併用論文より用法用量を設定(12 mg/kg、週2回腹腔内投与)した(参考文献3)。また本試験系であるNALM6-luc2においては、同じレジメンで効果を全く示さなかったことを確認した。
既報の最低用量(30 mg/kg、週2回経口投与)を参考にした(参考文献4)。本試験系であるNALM6-luc2においては30 mg/kg、週2回経口投与で効果を示さない一方、半数以上の死亡例が認められたことを確認した。このことから用法用量を週1回経口投与に下げた設定(30 mg/kg、週1回経口投与)とした。
既報よりヒト卵巣がん細胞株OVCAR異種移植マウス系、ならびにヒト乳癌細胞株MDA-MB-231異種移植マウス系において効果を示す用法用量から休薬なしの最大投与量(100 mg/kg、連日経口投与)を設定した(参考文献5;参考文献6:Qian Cai, et al., Med Chem. 2011;54(8):2714-2726)。また本試験系であるNALM6-luc2においては、同じレジメンで効果を全く示さなかったことを確認した。
膠芽腫細胞株の皮下腫瘍マウスモデルにおいて、KHYG-1を用いたEv CAR-KHYG-1の薬理試験では1×107 cells/body、週2回(計3回)の腫瘍内投与が実施され(参考文献7:Nakazawa T, et al., Anticancer Res. 2020;40(6):3231-3237)、また胃がん細胞株を用いたFOLR1 CAR-KHYG-1では週1回(計2回)の腫瘍内投与が実施されている(参考文献8:Minsung Kim, et al., PLoS One. 2018;13(6):e0198347)。
1.4.1 IAPアンタゴニストとCD19 CAR-Tの併用試験方法
インビボサイエンス株式会社で生産されたNOGマウスを6週齢で入荷し、7週齢で腫瘍細胞を静脈内移植して担癌マウスを作製した。移植の前日に20 mg/kgのブスルフェクス(BSF)を腹腔内投与した。飼育期間中は、5匹ずつ収容し、温度24℃(実測:19.7~25.0℃)、湿度50%(実測:38.6~58.5%)、照明12時間/1日(8:00AMから8:00PM)に設定したP2A飼育室で飼育した。その間、放射線滅菌したマウス用固型飼料(日本クレア、CL-2)および給水瓶に入れたオートクレーブ滅菌水道水を自由に摂取させた。
投与するCD19 CAR-T細胞は群構成に従い、1回、群分けと同一日にiv投与した。IAPアンタゴニストにおいても群分けと同一日に投与を開始し、群構成表に従ってpoまたはip投与した。
評価期間は3週ないし4週間とし、IVIS(商標)による腫瘍発光値を指標に群分けと薬理評価を行った。IVIS(商標)での発光値の測定ならびに体重測定は週2回実施した。
インビボサイエンス株式会社で生産されたNOGマウスを6週齢で入荷し、7週齢で腫瘍細胞を静脈内移植して担癌マウスを作製した。マウスは尾に番号を付けて識別した。飼育期間中は、5匹ずつ収容し、温度24℃(実測:19.7~25.0℃)、湿度50%(実測:38.6~58.5%)、照明12時間/1日(8:00AMから8:00PM)に設定したP2A飼育室で飼育した。その間、放射線滅菌したマウス用固型飼料(日本クレア、CL-2)および給水瓶に入れたオートクレーブ滅菌水道水を自由に摂取させた。
投与するControl-T細胞ならびに活性型インテグリンβ7 CAR-T(aITGB7 CAR-T)細胞は群構成に従い、1回、群分けと同一日にiv投与した。Tolinapantにおいても群分けと同一日に投与を開始し、群構成表に従って連日po投与した。
評価期間はDay 14またはDay 21までとし、IVISによる腫瘍発光値を指標に群分けと薬理評価を行った。IVISでの発光値の測定ならびに体重測定は週2回実施した。
インビボサイエンス株式会社で生産されたNOGマウスを6週齢で入荷し、7週齢で腫瘍細胞を皮下移植して担癌マウスを作製した。マウスは尾に番号を付けて識別した。飼育期間中は、5匹ずつ収容し、温度23℃、湿度55%、照明12時間/1日(8:00AMから8:00PM)に設定したP2A飼育室で飼育した。その間、放射線滅菌したマウス用固型飼料(日本クレア、CL-2)および給水瓶に入れたオートクレーブ滅菌水道水を自由に摂取させた。
投与するNY-ESO-1 TCR-T細胞は群構成に従い、1回、群分けと同一日にiv投与した。Tolinapantにおいても群分けと同一日を投与開始日とし、群構成表に従ってpo投与した。
評価期間は2週間とし、ノギスを用いた腫瘍径測定の結果から群分けと薬理評価を行った。腫瘍径測定ならびに体重測定は週2回実施した。
インビボサイエンス株式会社で生産されたNOGマウスを6週齢で入荷し、7週齢で腫瘍細胞をマトリゲルを用いて皮下移植し担癌マウスを作製した。マウスは尾に番号を付けて識別した。飼育期間中は、5匹ずつ収容し、温度24℃(実測:19.7~25.0℃)、湿度50%(実測:38.6~58.5%)、照明12時間/1日(8:00AMから8:00PM)に設定したP2A飼育室で飼育した。その間、放射線滅菌したマウス用固型飼料(日本クレア、CL-2)および給水瓶に入れたオートクレーブ滅菌水道水を自由に摂取させた。
投与するCD19 CAR KHYG-1細胞ならびにKHYG-1細胞は群構成に従い、群分け後、計4回、腫瘍内投与した。Tolinapantにおいても群分けと同一日に投与を開始し、群構成表に従って連日経口投与した。
評価期間はDay 17までとし、ノギスによる腫瘍体積を指標に群分けと薬理評価を行った。腫瘍体積測定ならびに体重測定は週2回、各投与前に実施した。
1.4.1.1 RPMI1640培地の調製
500 mLのRPMI1640培地に、非働化(56℃、30分処理)したウシ胎児血清を50 mL、抗生物質を5 mL加え培養用培地とした。一方、KHYG-1細胞ならびにCD19 CAR-KHYG-1細胞は、さらにIL-2を終濃度が100 U/mLとなるよう加えたものを培養用培地とした。それぞれは使用するまで低温室(設定温度4℃)に保存した。
500 mLのDMEM培地に、非働化(56℃、30分処理)したウシ胎児血清を50 mL、及び抗生物質を5 mL加え、使用するまで低温室(設定温度4℃)に保存した。
1.4.2.1 移植用NALM6-luc2、MM.1S-luc2、及びNALM6細胞懸濁液の調製
細胞の培養は、培養用培地(以下、培地)を用いてCO2インキュベーター内(5% CO2、37℃)で培養した。凍結保存された細胞株を37℃の恒温槽にて急速融解後、培地に懸濁し、遠心(150×g、5分、20℃)により上清を除去した。細胞を培地に再懸濁後、全量をフラスコに播種して、37℃、5% CO2存在下で培養した。培養開始後、顕微鏡にて細胞の形態及び増殖状態を観察し、サブコンフルエントになるまで培養した(継代1回目)。サブコンフルエントの細胞懸濁液を新しい培地が入った培養フラスコへ継代した(継代2回目)。融解後、3回以上継代培養した細胞を移植に使用した。継代する培養液量は、新しい培地の液量に対して1/10~1/3量の培養液とした。
サブコンフルエントの状態まで培養した細胞懸濁液を遠心操作によりD-PBS (-)で3回洗浄したのち無血清のRPMI1640にて再懸濁した。
NALM6-luc2の場合、再懸濁後、細胞懸濁液の一部を取りAOPI Staining Solutionにて死細胞を染色し、血球測定装置にて生細胞数をカウントした。細胞の生細胞数の測定結果から1×107 cells/mLとなるようRPMI1640で希釈し調製した。同様に、低腫瘍量の系においては1×106 cells/mLとなるよう無血清のRPMI1640で希釈し調製した。
MM.1S-luc2の場合、再懸濁後、細胞懸濁液の一部を取りAOPI Staining Solutionにて死細胞を染色し、血球測定装置にて生細胞数をカウントした。細胞の生細胞数の測定結果から3×107 cells/mLとなるようRPMI1640で希釈し調製した。
NALM6の場合、再懸濁後、細胞懸濁液の一部を取りAOPI Staining Solutionにて死細胞を染色し、血球測定装置にて生細胞数をカウントした。細胞の生細胞数の測定結果から1×108 cells/mLとなるようRPMI1640で希釈し調製した。調製した細胞懸濁液は足場となるマトリゲル(Corning(商標) 高濃度マトリゲル基底膜マトリックス)と等量混和し、最終的な移植用懸濁液(5×107 cells/mL)とした。
調製後の細胞懸濁液は、移植時まで氷水中で保存した。
細胞の培養は、培養用培地(以下、培地)を用いてCO2インキュベーター内(5% CO2、37℃)で培養した。凍結保存されたA375細胞株を37℃の恒温槽にて急速融解後、培地に懸濁し、遠心(150×g、5分、20℃)により上清を除去した。細胞を培地に再懸濁後、全量をディッシュに播種して、37℃、5% CO2存在下で培養した。培養開始後、顕微鏡にて細胞の形態及び増殖状態を観察し、サブコンフルエントになるまで培養した(継代1回目)。サブコンフルエントのディッシュの上清を除き、D-PBS(-)(ナカライテスク)を用いて洗浄し、トリプシン-EDTA(ナカライテスク)を加え、細胞を剥離回収し、遠心処理(4℃、1200 rpm、5分間)した。DMEM培地で懸濁し、AOPI staining solutionを用いて生細胞数を測定した。そしてディッシュサイズに適した細胞密度で播種し、CO2インキュベーターで培養した(継代2回目)。3回以上継代培養した細胞を移植に使用した。
培養した細胞をトリプシン-EDTAで剥離回収し、遠心処理(4℃、1200 rpm、5分間)した。上清を除去後、D-PBS(-)を加えて再懸濁し、同様に遠心分離して細胞を洗浄した。この洗浄操作を更に2回繰り返した。細胞懸濁液の一部をAOPI staining solutionを用いて生細胞数を測定後、D-PBS(-)を用いて1×107 cells/mLの細胞懸濁液を調製した。調製後の細胞懸濁液は、移植時まで氷中で保存した。
1.4.3.1 NALM6-luc2移植
保定器具を用いてマウスを保定後、無麻酔下の動物の尾静脈に27Gのマイジェクター(1 mL、テルモ株式会社)を用いて1×106 cells/0.1 mL/bodyの細胞懸濁液を移植した。また低腫瘍量の系においては1×105 cells/0.1 mL/bodyの細胞懸濁液を移植した。
保定器具を用いてマウスを保定後、無麻酔下の動物の尾静脈に27Gのマイジェクター(1 mL、テルモ株式会社)を用いて3×106 cells/0.1 mL/bodyの細胞懸濁液を移植した。
皮下移植群は、移植操作、及びその後の腫瘍増殖の観察を容易にするために、腫瘍移植前日までに安全剃刀を用いて移植部位(右腋窩部)を剃毛した。担癌マウスを作製するため、無麻酔下で細胞懸濁液を腋窩皮下へ26G注射針付きインスリン用注射筒(1 mL、テルモ株式会社)を用いて1×106 cells/0.1 mL/bodyの細胞懸濁液を移植した。
皮下移植群は、移植操作、及びその後の腫瘍増殖の観察を容易にするために、腫瘍移植前日までに安全剃刀を用いて移植部位(右腋窩部)を剃毛した。担癌マウスを作製するため、無麻酔下で細胞懸濁液を腋窩皮下へ26G注射針付きインスリン用注射筒(1 mL、テルモ株式会社)を用いて5×106 cells/0.1 mL/bodyの細胞懸濁液を移植した。
1.4.4.1 NALM6-luc2移植後の群分け
図6の投与レジメンに従い、ブスルフェクスで処置した翌日にNALM6-luc2を移植し、3日目にIn-VivoイメージングシステムIVIS(商標) Lumina X5(Perkin Elmer社)を用いて発光値を測定し、その発光値を指標にSAS software R9.4(SAS Institute Japan)を用い、層別無作為抽出法にて1群5匹に割り付けた。
図9の投与レジメンに従い、移植後、7日目にIn-VivoイメージングシステムIVIS(商標) Lumina X5(Perkin Elmer社)を用いて発光値を測定し、その発光値を指標にSAS software R9.4(SAS Institute Japan)を用い、層別無作為抽出法にて1群5匹に割り付けた。群分け後は、マウス尾部へのマーキングを行うことによって個体識別を行った。
移植後、8日目に腫瘍の長径と短径を測定し、腫瘍体積を算出した。SAS software R9.4 (SAS Institute Japan)を用い、腫瘍サイズ指標にして、層別無作為抽出法にて1群5匹に割り付けた。群分け後は、マウス尾部へのマーキングを行うことによって個体識別を行った。
移植後、21日目に腫瘍の長径と短径を測定し、腫瘍体積を算出した。SAS software R9.4(SAS Institute Japan)を用い、腫瘍サイズ指標にして、層別無作為抽出法にて1群5匹に割り付けた。群分け後は、マウス尾部へのマーキングを行うことによって個体識別を行った。
1) CD19 CAR-T細胞の懸濁液は尾静脈へ群分け時に投与した。投与量はCD19 CAR-T生細胞数をカウントし、群構成表に従い0.1 mL/bodyで1回投与した。投与には27Gのマイジェクターを用いた。
1.4.6.1 腫瘍発光値(Photones/sec)の測定
VivoGloTM-luciferin(プロメガ)をD-PBS(-)で30 mg/mLになるように溶解後、-20℃で遮光冷凍保存した。測定当日、溶解させたVivoGloTM-luciferin を等量のD-PBS(-)で希釈した。試験に用いるまで遮光下室温で保存した。予め測定した体重を基に、VivoGloTM-luciferinを10 mL/kgの容量で腹腔内投与し、投与20分後にIVIS(商標)Imaging Systemを用いて腫瘍の発光値を測定した。測定にはIVIS(商標)Lumina X5を用いた。図1~5及び7において、縦軸のTotal Flux [p/s]は、腫瘍発光値(Photones/sec)を意味する。
腫瘍径の測定は、電子ノギス(ミツトヨ)を用いて短径と長径を測定した。腫瘍細胞移植後、週2回腫瘍径の測定を行った。
腫瘍径の測定結果を基に、次式を用いて腫瘍体積(TV:tumor volume)を算出した。
TV = L×W2×1/2
ただし
TV:腫瘍体積(mm3)
L:長径(mm)
W:短径(mm)
体重は、群分け日と剖検日、投与期間中は週2回、測定を行った。
腫瘍発光値又は腫瘍体積
体重
体重変化
各データは、Microsoft Excel 2013を用いて、要約統計量(平均値及び標準偏差および標準誤差)を算出した。統計解析を伴うデータはSASソフトウェアR9.4(SAS Institute Japan)を用いて行った。有意性はp < 0.05 と定義した。
2.1 IAPアンタゴニストとCD19 CAR-Tの併用試験
2.1.1 BirinapantとCD19 CAR-Tの併用試験
CD19 CAR-T単独と比較して、BirinapantとCD19 CAR-Tの併用で抗腫瘍効果を高めることはなかった(図1)。
TolinapantとCD19 CAR-Tの併用によりDay7以降で有意な併用効果を認めた。1×105 cellsのCD19 CAR-TにTolinapantを併用した際、Day14で1×106 cells CD19 CAR-T単独効果と同等、それ以降ではさらに上回る腫瘍の退縮を認めた(図2)。
TolinapantとCD19 CAR-Tの併用により強い併用効果を認めた。1×105 cellsのCD19 CAR-TにTolinapantを併用した際、Day17で1×106 cells CD19 CAR-T単独と同等の効果を示し、2×104 cellsのCD19 CAR-TにTolinapantを併用した際には、Day21で1×106 cells CD19 CAR-T単独と同等の効力が得られ、実質50倍以上のCAR-T細胞数削減の可能性を示唆する結果であった(図3)。
LCL161とCD19 CAR-Tの併用によりDay7以降で併用効果を認めた。ただしLCL161の毒性が高く、半数以上の動物がLCL161によって死亡した。1×105 cellsのCD19 CAR-TにLCL161を併用した際、Day14以降で1×106 cells CD19 CAR-T単独効果と同等になり、最大効力においてもTolinapantに比べ乏しかった(図4)。
一方、AT406はCD19 CAR-Tの併用によりDay10以降で併用効果を認めた。1×105 cellsのCD19 CAR-TにAT406を併用した際、Day14以降で1×106 cells CD19 CAR-T単独効果と同等になった(図5)。
Tolinapantと3×104 cells aITGB7 CAR-Tの組み合わせの効果について21日間の評価を行い有意な併用効果を認めた。3×104 cells aITGB7 CAR-T単独投与群においてDay 14以降で抗腫瘍効果を示し始めた一方、Tolinapantとの組み合わせにおいてはDay 11以降、明らかな退縮を示し、有意な相乗効果を認めた(図7)。
3×106 cells/bodyのNY-ESO-1 TCR-TとTolinapantの併用群は、Day 15の腫瘍体積について、それぞれの単剤群に対して有意差が認められた。1×107 cells/bodyのNY-ESO-1 TCR-T単独投与群は、3×106 cells/bodyのNY-ESO-1 TCR-T単独投与群よりも高い抗腫瘍効果を示し、Day 7以降においては、Day 0を下回る腫瘍量となったものの、その組み合わせ群においては、さらに高い退縮が確認され、併用することによる相乗効果が示された。
TolinapantとCD19 CAR-KHYG-1の組み合わせの効果について17日間の評価を行い有意な併用効果を認めた。CD19 CAR-KHYG-1ならびにTolinapantの単独投与では抗腫瘍効果を示さない一方、2製剤の組み合わせにおいてはDay 7以降明らかな増殖抑制効果を示し、Day 17では有意な併用効果を認めた(図9)。
Tolinapantを含むIAPアンタゴニスト単独ではNALM6(B-ALL)及びMM.1S(MM)に対する効力は認められなかった。一方、Tolinapant + CD19 CAR-T、Tolinapant + 活性型インテグリンβ7 CAR-T(aITGB7 CAR-T)、Tolinapant + NY-ESO-1 TCR-T、及びTolinapant + CD19 CAR-KHYG-1の併用活性は再現性の高い有意な結果を得た。他のIAPアンタゴニストであるAT406、LCL161もCD19 CAR-Tとの併用効果を認めたが、LCL161においては体重減少及び死亡例が確認できる毒性が認められた。また最大効果においてもTolinapantの併用が優位であった。次いでAT406はTolinapantと似た併用効果推移を示したが、効果のスピードが異なることから併用結果のAUC、ならびに最大腫瘍量(発光値)によってAT406とTolinapantの差別化を検証した。その解析で、Day17までの併用データのAUCにおいて、Tolinapant併用に伴う有意性を得ることができ、Day14でも同様の結果が得られた(表9、表10)。同じく最大腫瘍量においてもAT406とTolinapantで有意差を得ることができた(表11)。
以上より、Tolinapantが他のIAPアンタゴニストよりも高いCAR-T細胞との併用における薬効増強作用を示すことが確認された。これにより、トリナパント系薬剤が、CAR-T細胞、TCR-T細胞、及びCAR-NK細胞を含む改変免疫細胞との併用における薬効増強作用においても顕著に優れることが示唆された。
また、in vitroにおいて、本実施例のCAR-Tが標的CAR抗原発現腫瘍細胞(例えばCD19陽性NALM6)と反応することで、サイトカイン(例えばTNF-α)が産生されることを確認している。さらに、CAR-Tから産生されるサイトカインとTolinapantが共存した場合、抗原発現細胞だけでなく抗原陰性腫瘍細胞(例えばCD19陰性NALM6)に対しても細胞死(例えばアポトーシス)を誘導させることが確認されている。このような腫瘍細胞に対する非接触的な細胞死の誘導により、抗原エスケープが生じた腫瘍細胞や、改変免疫細胞がアプローチできない部位に転移した腫瘍細胞に対しても、抗腫瘍効果を発揮することが期待される。
Claims (17)
- 前記キメラ抗原受容体又は組換えT細胞受容体が、CD19、インテグリンβ7、及びNY-ESO-1から選択される抗原を特異的に認識する、請求項1又は2に記載の医薬組成物。
- 前記キメラ抗原受容体又は組換えT細胞受容体が、活性型インテグリンβ7を特異的に認識する、請求項1又は2に記載の医薬組成物。
- 前記免疫細胞がキメラ抗原受容体を発現するように改変されたT細胞又はNK細胞であり、前記キメラ抗原受容体が、
(1) 抗原を認識可能な細胞外ドメイン、
(2) 膜貫通ドメイン、
(3) 共刺激分子の細胞内シグナル伝達ドメイン、及び
(4) CD3ζの細胞内シグナル伝達ドメイン
を含有する、請求項1~4のいずれかに記載の医薬組成物。 - 前記細胞外ドメインが、CD19又はインテグリンβ7を認識可能な細胞外ドメインである、請求項5に記載の医薬組成物。
- 前記膜貫通ドメインが、CD28又はCD8の膜貫通ドメインである、請求項5又は6に記載の医薬組成物。
- 前記共刺激分子が、CD2、CD4、CD5、CD8α、CD8β、CD28、CD134(OX40)、CD137(4-1BB)、又はCD278(ICOS)である、請求項5~7のいずれかに記載の医薬組成物。
- 前記免疫細胞が組換えT細胞受容体を発現するように改変されたT細胞又はNK細胞であり、前記組換えT細胞受容体が、NY-ESO-1を認識可能な可変ドメインを有する、請求項1又は2に記載の医薬組成物。
- 前記免疫細胞が、CD19を特異的に認識するキメラ抗原受容体を発現するように改変されたT細胞、インテグリンβ7を特異的に認識するキメラ抗原受容体を発現するように改変されたT細胞、CD19を特異的に認識するキメラ抗原受容体を発現するように改変されたNK細胞、又はNY-ESO-1を特異的に認識する組換えT細胞受容体を発現するように改変されたT細胞である、請求項1又は2に記載の医薬組成物。
- 癌を予防及び/又は治療するための、請求項1~10のいずれかに記載の医薬組成物。
- 前記式(1)で表される化合物、その薬学的に許容可能な塩、又はその薬学的に許容可能な溶媒和物が、10mg~180mg/日で投与される、請求項1~11のいずれかに記載の医薬組成物。
- 前記免疫細胞が、1×103個~1×108個(生細胞数)/kg体重/日で投与される、請求項1~12のいずれかに記載の医薬組成物。
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