JP6515182B2 - Wt1抗原ペプチドおよび免疫調節剤の併用 - Google Patents
Wt1抗原ペプチドおよび免疫調節剤の併用 Download PDFInfo
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- JP6515182B2 JP6515182B2 JP2017519401A JP2017519401A JP6515182B2 JP 6515182 B2 JP6515182 B2 JP 6515182B2 JP 2017519401 A JP2017519401 A JP 2017519401A JP 2017519401 A JP2017519401 A JP 2017519401A JP 6515182 B2 JP6515182 B2 JP 6515182B2
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- 229960000575 trastuzumab Drugs 0.000 description 1
- 229950007217 tremelimumab Drugs 0.000 description 1
- 229960003181 treosulfan Drugs 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- RTKIYFITIVXBLE-QEQCGCAPSA-N trichostatin A Chemical compound ONC(=O)/C=C/C(/C)=C/[C@@H](C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-QEQCGCAPSA-N 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 1
- 235000019801 trisodium phosphate Nutrition 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 102000015534 trkB Receptor Human genes 0.000 description 1
- 108010064880 trkB Receptor Proteins 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- 125000000430 tryptophan group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
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- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- YYSFXUWWPNHNAZ-PKJQJFMNSA-N umirolimus Chemical compound C1[C@@H](OC)[C@H](OCCOCC)CC[C@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 YYSFXUWWPNHNAZ-PKJQJFMNSA-N 0.000 description 1
- AHXICHPPXIGCBN-GPWPDEGDSA-N uqc681jjiv Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](OC(C)=O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)OC)C(=O)C1=CC=CC=C1 AHXICHPPXIGCBN-GPWPDEGDSA-N 0.000 description 1
- 229960002004 valdecoxib Drugs 0.000 description 1
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960000241 vandetanib Drugs 0.000 description 1
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
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- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 1
- 229950010644 vidofludimus Drugs 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 description 1
- 229960004982 vinblastine sulfate Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
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- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 1
- 229960002110 vincristine sulfate Drugs 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
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- 229960000922 vinflunine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229950005839 vinzolidine Drugs 0.000 description 1
- 229950001212 volociximab Drugs 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 229960000237 vorinostat Drugs 0.000 description 1
- 229960001771 vorozole Drugs 0.000 description 1
- XLMPPFTZALNBFS-INIZCTEOSA-N vorozole Chemical compound C1([C@@H](C2=CC=C3N=NN(C3=C2)C)N2N=CN=C2)=CC=C(Cl)C=C1 XLMPPFTZALNBFS-INIZCTEOSA-N 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001152—Transcription factors, e.g. SOX or c-MYC
- A61K39/001153—Wilms tumor 1 [WT1]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/82—Translation products from oncogenes
Description
免疫調節剤と併用される、WT1抗原ペプチドまたはその薬学上許容される塩を含む、癌を治療または予防するための医薬組成物。
項2.
WT1抗原ペプチドまたはその薬学上許容される塩と併用される、免疫調節剤を含む、癌を治療または予防するための医薬組成物。
項3.
免疫調節剤とWT1抗原ペプチドまたはその薬学上許容される塩とを含む、癌を治療または予防するための医薬組成物。
項4.
WT1抗原ペプチドがWT1キラーペプチドである、項1〜3のいずれかに記載の医薬組成物。
項5.
WT1キラーペプチドまたはその薬学上許容される塩が、
RMFPNAPYL (配列番号:2)、
CMTWNQMNL (配列番号:3)、
CYTWNQMNL (配列番号:4)、
ALLPAVPSL (配列番号:5)、
SLGEQQYSV (配列番号:6)、
RVPGVAPTL (配列番号:7)、
VLDFAPPGA、(配列番号:8)、
C−CMTWNQMNL (配列番号:9)(式中、CとCの間の結合はジスルフィド結合を表す。)、
C−CYTWNQMNL (配列番号:10)(式中、CとCの間の結合はジスルフィド結合を表す。)
RYFPNAPYL (配列番号:21)、および
YMFPNAPYL (配列番号:26)から選択されるいずれかのアミノ酸配列からなるペプチド;
前記配列番号2〜10、21および26から選択されるいずれかのアミノ酸配列において、1個〜数個のアミノ酸が、欠失、置換、および/または付加されたアミノ酸配列を含み且つCTL誘導活性を有するペプチド;もしくは
式(1):
で表される化合物、
式(2):
で表される化合物、および
式(3):
で表される化合物
からなる群から選択される化合物;またはその薬学上許容される塩である、項4に記載の医薬組成物。
項6.
WT1キラーペプチドまたはその薬学上許容される塩が、
RMFPNAPYL(配列番号:2)、
CMTWNQMNL (配列番号:3)、
CYTWNQMNL (配列番号:4)、
ALLPAVPSL (配列番号:5)、
C−CYTWNQMNL (配列番号:10)、および
YMFPNAPYL (配列番号:26)
から選択されるいずれかのアミノ酸配列からなるペプチド;もしくは
式(3):
で表される化合物;またはその薬学上許容される塩である、項5に記載の医薬組成物。
項7.
WT1ヘルパーペプチドまたはその薬学上許容される塩をさらに含む、項4〜6のいずれかに記載の医薬組成物。
項8.
WT1ヘルパーペプチドまたはその薬学上許容される塩と併用される、項4〜6のいずれかに記載の医薬組成物。
項9.
WT1ヘルパーペプチドまたはその薬学上許容される塩が、
以下:
KRYFKLSHLQMHSRKH (配列番号:11)、
SGQARMFPNAPYLPSCLES(配列番号:12)、
RSDELVRHHNMHQRNMTKL (配列番号:13)、
PGCNKRYFKLSHLQMHSRKHTG (配列番号:14)、
CNKRYFKLSHLQMHSRK (配列番号:15)、
CNKRYFKLSHLQMHSRKH (配列番号:16)、
CNKRYFKLSHLQMHSRKHTG (配列番号:17)、
WAPVLDFAPPGASAYGSL (配列番号:18)、
CWAPVLDFAPPGASAYGSL (配列番号:19)、
WAPVLDFAPPGASAYGSLC (配列番号:20)、および
SGQAYMFPNAPYLPSCLES (配列番号:37)
から選択されるいずれかのアミノ酸配列からなるペプチド;もしくは
前記配列番号11〜20から選択されるいずれかのアミノ酸配列において、1個〜数個のアミノ酸が、欠失、置換、および/または付加されたアミノ酸配列を含み且つヘルパーT細胞誘導活性を有するペプチド;またはその薬学上許容される塩である、項7または8に記載の医薬組成物。
項10.
WT1ヘルパーペプチドまたはその薬学上許容される塩が、
以下:
KRYFKLSHLQMHSRKH (配列番号:11)、
PGCNKRYFKLSHLQMHSRKHTG (配列番号:14)、
WAPVLDFAPPGASAYGSL (配列番号:18)、および
SGQAYMFPNAPYLPSCLES (配列番号:37)
から選択されるいずれかのアミノ酸配列からなるペプチドまたはその薬学上許容される塩である、項9に記載の医薬組成物。
項11.
WT1キラーペプチドまたはその薬学上許容される塩が、RMFPNAPYL(配列番号:2)またはその薬学上許容される塩であり、
WT1ヘルパーペプチドまたはその薬学上許容される塩が、KRYFKLSHLQMHSRKH(配列番号:11)またはその薬学上許容される塩である、項10に記載の医薬組成物。
項12.
WT1キラーペプチドまたはその薬学上許容される塩が、RMFPNAPYL(配列番号:2)またはその薬学上許容される塩であり、
WT1ヘルパーペプチドまたはその薬学上許容される塩が、PGCNKRYFKLSHLQMHSRKHTG(配列番号:14)またはその薬学上許容される塩である、項10に記載の医薬組成物。
項13.
WT1キラーペプチドまたはその薬学上許容される塩が、ALLPAVPSL(配列番号:5)またはその薬学上許容される塩であり、
WT1ヘルパーペプチドまたはその薬学上許容される塩が、KRYFKLSHLQMHSRKH(配列番号:11)またはその薬学上許容される塩である、項10に記載の医薬組成物。
項14.
WT1キラーペプチドまたはその薬学上許容される塩が、YMFPNAPYL(配列番号:26)またはその薬学上許容される塩であり、
WT1ヘルパーペプチドまたはその薬学上許容される塩が、SGQAYMFPNAPYLPSCLES(配列番号:37)またはその薬学上許容される塩である、項10に記載の医薬組成物。
項15.
WT1キラーペプチドまたはその薬学上許容される塩が、式(3):
で表される化合物またはその薬学上許容される塩であり、
WT1ヘルパーペプチドまたはその薬学上許容される塩が、WAPVLDFAPPGASAYGSL(配列番号:18)またはその薬学上許容される塩である、項10に記載の医薬組成物。
項16.
癌ワクチンとして使用される、項1〜15のいずれかに記載の医薬組成物。
項17.
免疫調節剤が、
(1)免疫チェックポイント阻害剤、
(2)共刺激分子アゴニスト剤、
(3)免疫活性化剤、および
(4)低分子阻害剤
からなる群から選択される1以上の薬剤である、項1〜16のいずれかに記載の医薬組成物。
項18.
免疫調節剤が抗体、核酸、タンパク質、ペプチドまたは低分子化合物である、項17に記載の医薬組成物。
項19.
免疫調節剤が、免疫チェックポイント阻害剤である、項17または18に記載の医薬組成物。
項20.
免疫チェックポイント阻害剤が、
(1)CTLA−4、
(2)PD−1、
(3)LAG−3、
(4)BTLA、
(5)KIR、
(6)TIM−3、
(7)PD−L1、
(8)PD−L2、
(9)B7−H3、
(10)B7−H4、
(11)HVEM、
(12)GAL9、
(13)CD160、
(14)VISTA、
(15)BTNL2、
(16)TIGIT、
(17)PVR、
(18)BTN1A1、
(19)BTN2A2、
(20)BTN3A2、および
(21)CSF−1R
からなる群から選択される分子に対する1以上の薬剤である、項19に記載の医薬組成物。
項21.
免疫チェックポイント阻害剤が、CTLA−4、PD−1、LAG−3、TIM−3、BTLA、VISTA、HVEM、TIGIT、PVR、PD−L1およびCD160からなる群から選択される分子に対する1以上の薬剤である、項20に記載の医薬組成物。
項22.
免疫チェックポイント阻害剤が、PD−1またはPD−L1に対する薬剤である、項21に記載の医薬組成物。
項23.
免疫チェックポイント阻害剤が、CTLA−4に対する薬剤である、項21に記載の医薬組成物。
項24.
免疫チェックポイント阻害剤が、LAG−3に対する薬剤である、項21に記載の医薬組成物。
項25.
免疫チェックポイント阻害剤が、TIM−3に対する薬剤である、項21に記載の医薬組成物。
項26.
免疫チェックポイント阻害剤が、BTLAに対する薬剤である、項21に記載の医薬組成物。
項27.
免疫チェックポイント阻害剤が、HVEMに対する薬剤である、項21に記載の医薬組成物。
項28.
免疫チェックポイント阻害剤が、TIGITに対する薬剤である、項21に記載の医薬組成物。
項29.
免疫チェックポイント阻害剤が、PVRに対する薬剤である、項21に記載の医薬組成物。
項30.
免疫チェックポイント阻害剤が、CD160に対する薬剤である、項21に記載の医薬組成物。
項31.
免疫チェックポイント阻害剤が、CSF−1Rに対する薬剤である、項21に記載の医薬組成物。
項32.
免疫チェックポイント阻害剤が、抗体である、項19〜31のいずれかに記載の医薬組成物。
項33.
免疫チェックポイント阻害剤が、PD−1またはPD−L1に対する抗体である、項32に記載の医薬組成物。
項33.
PD−1に対する抗体が、ニボルマブまたはペンブロリズマブである、項33に記載の医薬組成物。
項34.
PD−L1に対する抗体が、Durvalumab、Atezolizumab(MPDL3280A)またはBMS−936559である、項33に記載の医薬組成物。
項35.
免疫調節剤が、共刺激分子アゴニスト剤である、項17または18に記載の医薬組成物。
項36.
共刺激分子アゴニスト剤が、
(1)4−1BB、
(2)4−1BB−L、
(3)OX40、
(4)OX40−L、
(5)GITR、
(6)CD28、
(7)CD40、
(8)CD40−L、
(9)ICOS、
(10)ICOS−L、
(11)LIGHT、および
(12)CD27
からなる群から選択される分子に対する1以上の薬剤である、項35に記載の医薬組成物。
項37.
共刺激分子アゴニスト剤が、4−1BB、OX40、GITR、CD40およびICOSからなる群から選択される分子に対する1以上の薬剤である、項36に記載の医薬組成物。
項38.
共刺激分子アゴニスト剤が、4−1BBに対する薬剤である、項37に記載の医薬組成物。
項39.
共刺激分子アゴニスト剤が、OX40に対する薬剤である、項37に記載の医薬組成物。
項40.
共刺激分子アゴニスト剤が、GITRに対する薬剤である、項37に記載の医薬組成物。
項41.
共刺激分子アゴニスト剤が、CD40に対する薬剤である、項37に記載の医薬組成物。
項42.
共刺激分子アゴニスト剤が、ICOSに対する薬剤である、項37に記載の医薬組成物。
項43.
共刺激分子アゴニスト剤が、抗体である、項35〜42のいずれかに記載の医薬組成物。
項44.
免疫調節剤が、免疫活性化剤である、項17または18に記載の医薬組成物。
項45.
免疫活性化剤が、Toll様受容体(TLR)作動薬である、項44に記載の医薬組成物。
項46.
TLR作動薬が、
(1)TLR1/2作動薬、
(2)TLR2作動薬、
(3)TLR3作動薬、
(4)TLR4作動薬、
(5)TLR5作動薬、
(6)TLR6/2作動薬、
(7)TLR7作動薬、
(8)TLR7/8作動薬、
(9)TLR7/9作動薬、
(10)TLR8作動薬、
(11)TLR9作動薬、および
(12)TLR11作動薬
からなる群から選択される1以上の薬剤である、項45に記載の医薬組成物。
項47.
TLR作動薬が、TLR3作動薬、TLR7作動薬、TLR7/8作動薬、およびTLR9作動薬からなる群から選択される1以上の薬剤である、請求項46に記載の医薬組成物。
項48.
Toll様受容体作動薬が、TLR3作動薬である、項47に記載の医薬組成物。
項49.
Toll様受容体作動薬が、TLR7作動薬である、項47に記載の医薬組成物。
項50.
Toll様受容体作動薬が、TLR7/8作動薬である、項47に記載の医薬組成物。
項51.
Toll様受容体作動薬が、TLR9作動薬である、項47に記載の医薬組成物。
項52.
Toll様受容体作動薬が、核酸である、項45〜51のいずれかに記載の医薬組成物。
項53.
免疫調節剤が、低分子阻害剤である、項17または18に記載の医薬組成物。
項54.
低分子阻害剤が、β―カテニン阻害剤、IDO阻害剤、COX−2阻害剤、CXCR4阻害剤、STAT3阻害剤およびマルチキナーゼ阻害剤からなる群から選択される1以上の薬剤である、項53に記載の医薬組成物。
項55.
低分子阻害剤が、β―カテニン阻害剤である、請求項54に記載の医薬組成物。
項56.
低分子阻害剤が、IDO阻害剤である、項54に記載の医薬組成物。
項57.
低分子阻害剤が、COX−2阻害剤である、項54に記載の医薬組成物。
項58.
低分子阻害剤が、CXCR4阻害剤である、項54に記載の医薬組成物。
項59.
低分子阻害剤が、STAT3阻害剤である、項54に記載の医薬組成物。
項60.
低分子阻害剤が、マルチキナーゼ阻害剤である、項54に記載の医薬組成物。
項61.
癌が、白血病、骨髄異形成症候群、多発性骨髄腫、悪性リンパ腫、胃癌、大腸癌、肺癌、乳癌、胚細胞癌、肝癌、皮膚癌、膀胱癌、前立腺癌、子宮癌、子宮頸癌、卵巣癌、脳腫瘍、骨癌、膵癌、頭頚部癌、皮膚または眼窩内悪性メラノーマ、直腸癌、肛門部癌、精巣癌、卵管のカルシノーマ、子宮内膜カルシノーマ、子宮頚部カルシノーマ、膣カルシノーマ、外陰部カルシノーマ、ホジキン病、非ホジキンリンパ腫、食道癌、小腸癌、内分泌系癌、甲状腺癌、副甲状腺癌、副腎癌、柔組織肉腫、尿道癌、陰茎癌、急性骨髄性白血病、慢性骨髄性白血病、急性リンパ芽球性白血病、慢性リンパ球性白血病を含む慢性または急性白血病、小児固形癌、リンパ球性リンパ腫、腎臓または尿管の癌、腎盂カルシノーマ、中枢神経系(CNS)腫瘍、原発性CNSリンパ腫、腫瘍新脈管形成、脊椎腫瘍、脳幹グリオーム、下垂体アデノーマ、カポシ肉腫、扁平上皮癌、扁平細胞癌、T細胞リンパ腫、多型性膠芽腫、悪性黒色腫、非小細胞肺がん、腎細胞癌およびアスベスト誘発癌からなる群から選択される、項1〜60のいずれかに記載の医薬組成物。
項62.
WT1抗原ペプチドと免疫調節剤とが同時に投与される、項1〜61のいずれかに記載の医薬組成物。
項63.
WT1抗原ペプチドと免疫調節剤とが別々に投与される、項1、2、および4〜61のいずれかに記載の医薬組成物。
項64.
WT1抗原ペプチドが免疫調節剤の投与前に投与される、項1、2、および4〜61のいずれかに記載の医薬組成物。
項65.
WT1抗原ペプチドが免疫調節剤の投与後に投与される、項1、2、および4〜61のいずれかに記載の医薬組成物。
項66.
癌を治療するための、項1〜66のいずれかに記載の医薬組成物。
項67.
薬学上許容される担体をさらに含む、項1〜66のいずれかに記載の医薬組成物。
項68.
項1〜67のいずれかに規定されるWT1抗原ペプチドまたはその薬学上許容される塩と免疫調節剤とを哺乳動物に投与することを含む、癌を治療または予防するための方法。
項69.
WT1抗原ペプチドまたはその薬学上許容される塩と免疫調節剤とを同時にまたは別々に投与する、項68に記載の方法。
項70.
項1〜67のいずれかに規定されるWT1抗原ペプチドまたはその薬学上許容される塩と免疫調節剤とを含む、癌を治療または予防するためのキット。
WT1抗原ペプチドまたはその薬学上許容される塩と免疫調節剤とを哺乳動物に投与することを含む、癌を治療または予防するための方法;
免疫調節剤と併用される、癌の治療または予防における使用のための、WT1抗原ペプチドまたはその薬学上許容される塩;
WT1抗原ペプチドまたはその薬学上許容される塩と併用される、癌の治療または予防における使用のための、免疫調節剤;
免疫調節剤と併用される、癌を治療または予防するための医薬の製造のため、WT1抗原ペプチドまたはその薬学上許容される塩の使用;
WT1抗原ペプチドまたはその薬学上許容される塩と併用される、癌を治療または予防するための医薬の製造のため、免疫調節剤の使用;および
癌を治療または予防するための医薬の製造のため、WT1抗原ペプチドまたはその薬学上許容される塩および免疫調節剤の使用。
WT1抗原ペプチドまたはその薬学上許容される塩と免疫チェックポイント阻害剤とを哺乳動物に投与することを含む、癌を治療または予防するための方法;
免疫チェックポイント阻害剤と併用される、癌の治療または予防における使用のための、WT1抗原ペプチドまたはその薬学上許容される塩;
WT1抗原ペプチドまたはその薬学上許容される塩と併用される、癌の治療または予防における使用のための、免疫チェックポイント阻害剤;
免疫チェックポイント阻害剤と併用される、癌を治療または予防するための医薬の製造のため、WT1抗原ペプチドまたはその薬学上許容される塩の使用;
WT1抗原ペプチドまたはその薬学上許容される塩と併用される、癌を治療または予防するための医薬の製造のため、免疫チェックポイント阻害剤の使用;および
癌を治療または予防するための医薬の製造のため、WT1抗原ペプチドまたはその薬学上許容される塩および免疫チェックポイント阻害剤の使用。
AlaまたはA:アラニン残基
ArgまたはR:アルギニン残基
AsnまたはN:アスパラギン残基
AspまたはD:アスパラギン酸残基
CysまたはC:システイン残基
GlnまたはQ:グルタミン残基
GluまたはE:グルタミン酸残基
GlyまたはG:グリシン残基
HisまたはH:ヒスチジン残基
IleまたはI:イソロイシン残基
LeuまたはL:ロイシン残基
LysまたはK:リジン残基
MetまたはM:メチオニン残基
PheまたはF:フェニルアラニン残基
ProまたはP:プロリン残基
SerまたはS:セリン残基
ThrまたはT:スレオニン残基
TrpまたはW:トリプトファン残基
TyrまたはY:チロシン残基
ValまたはV:バリン残基
Abu:2−アミノ酪酸残基(α−アミノ酪酸残基とも言う)
Orn:オルニチン残基
Cit:シトルリン残基
RMFPNAPYL (配列番号:2)、
CMTWNQMNL (配列番号:3)、
CYTWNQMNL (配列番号:4)、
ALLPAVPSL (配列番号:5)、
SLGEQQYSV (配列番号:6)、
RVPGVAPTL (配列番号:7)、
VLDFAPPGA (配列番号:8)、
C−CMTWNQMNL (配列番号:9)(式中、CとCの間の結合はジスルフィド結合を表す。)、および
C−CYTWNQMNL (配列番号:10)(式中、CとCの間の結合はジスルフィド結合を表す。)
から選択されるいずれかのアミノ酸配列を含むペプチド、並びに配列番号:2〜10から選択されるいずれかのアミノ酸配列中にアミノ酸残基の改変を含有する改変アミノ酸配列を含み且つCTL誘導活性を有するペプチドが挙げられる。好ましくは、配列番号:2〜10から選択されるいずれかのアミノ酸配列からなるペプチド、および配列番号:2〜10から選択されるいずれかのアミノ酸配列中にアミノ酸残基の改変を含有する改変アミノ酸配列からなり且つCTL誘導活性を有するペプチドが挙げられる。より好ましくは、配列番号:2〜10から選択されるいずれかのアミノ酸配列からなるペプチドが挙げられる。さらにより好ましくは、配列番号:2〜6、8および10から選択されるいずれかのアミノ酸配列からなるペプチドが挙げられる。
RMFPNAPYL (配列番号:2)の改変キラーペプチドである、
RYFPNAPYL (配列番号:21)(国際公開第03/106682号参照)、
FMFPNAPYL (配列番号:22)、
RLFPNAPYL (配列番号:23)、
RMMPNAPYL (配列番号:24)、
RMFPNAPYV (配列番号:25)および
YMFPNAPYL (配列番号:26)(国際公開第2009/072610号参照);
CMTWNQMNL (配列番号:3)の改変キラーペプチドである、
CYTWNQMNL (配列番号:4)(国際公開第02/79253号参照)、
Xaa-Met-Thr-Trp-Asn-Gln-Met-Asn-Leu (配列番号:27)、
(本配列中XaaはSerまたはAlaを表す)および
Xaa-Tyr-Thr-Trp-Asn-Gln-Met-Asn-Leu (配列番号:28)
(本配列中XaaはSer、Ala、Abu、Arg、Lys、Orn、Cit、Leu、PheまたはAsnを表す)(国際公開2004/026897号参照);
ALLPAVPSL (配列番号:5)の改変キラーペプチドである、
AYLPAVPSL (配列番号:29)(国際公開第2003/106682号参照);
SLGEQQYSV (配列番号:6)の改変キラーペプチドである、
FLGEQQYSV (配列番号:30)、
SMGEQQYSV (配列番号:31)および
SLMEQQYSV (配列番号:32)(国際公開第2009/072610号参照);並びに
RVPGVAPTL (配列番号:7)の改変キラーペプチドである、
RYPGVAPTL (配列番号:33)(国際公開第2003/106682号参照)。
式(1):
で表される化合物、
式(2):
で表される化合物、または
式(3):
で表される化合物
である。
KRYFKLSHLQMHSRKH (配列番号:11)、
SGQARMFPNAPYLPSCLES(配列番号:12)、
RSDELVRHHNMHQRNMTKL (配列番号:13)、
PGCNKRYFKLSHLQMHSRKHTG (配列番号:14)、
CNKRYFKLSHLQMHSRK (配列番号:15)、
CNKRYFKLSHLQMHSRKH (配列番号:16)、
CNKRYFKLSHLQMHSRKHTG (配列番号:17)、
WAPVLDFAPPGASAYGSL (配列番号:18)、
CWAPVLDFAPPGASAYGSL (配列番号:19)、
WAPVLDFAPPGASAYGSLC (配列番号:20)、
SGQARMFPNAPYLPSC (配列番号:34)、
SGQAYMFPNAPYLPSC (配列番号:35)、
SGQARMFPNAPYLPSCLES (配列番号:36)、
SGQAYMFPNAPYLPSCLES (配列番号:37)、
PGCNKRYFKLSHLQMHSRK (配列番号:38)、
PGCNKRYFKLSHLQMHSRKH (配列番号:39)、PGCNKRYFKLSHLQMHSRKHTG (配列番号:40)、
QARMFPNAPYLPSCL (配列番号:44)、
LKGVAAGSSSSVKWT (配列番号:45)および
RYFKLSHLQMHSRKH (配列番号:46)
から選択されるいずれかのアミノ酸配列を含むペプチド、および配列番号:11〜20、34〜40および44〜46から選択されるいずれかのアミノ酸配列中にアミノ酸残基の改変を含有する改変アミノ酸配列を含み且つヘルパーT細胞誘導活性を有するペプチド、が挙げられる。好ましくは、配列番号:11〜20および34〜40から選択されるいずれかのアミノ酸配列からなるペプチド、および配列番号:11〜20および34〜40から選択されるいずれかのアミノ酸配列中にアミノ酸残基の改変を含有する改変アミノ酸配列からなり且つヘルパーT細胞誘導活性を有するペプチドが挙げられる。より好ましくは、配列番号:11〜20および34〜40から選択されるいずれかのアミノ酸配列からなるペプチドであり、さらにより好ましくは、配列番号:11〜20から選択されるいずれかのアミノ酸配列からなるペプチドが挙げられる。
SGQARMFPNAPYLPSCLES (配列番号:36)の改変ヘルパーペプチドである、
SGQAYMFPNAPYLPSCLES (配列番号:37)(国際公開第2007/120673号参照)、
SGQARMFPNAPYLPSC (配列番号:34)および
SGQAYMFPNAPYLPSC (配列番号:35);並びに
PGCNKRYFKLSHLQMHSRKHTG (配列番号:40)の改変ヘルパーペプチドである、
PGCNKRYFKLSHLQMHSRK (配列番号:38)、
PGCNKRYFKLSHLQMHSRKH (配列番号:39)、
KRYFKLSHLQMHSRKH (配列番号:11)、
CNKRYFKLSHLQMHSRK (配列番号:15)、
CNKRYFKLSHLQMHSRKH (配列番号:16)および
CNKRYFKLSHLQMHSRKHTG (配列番号:17)。
RMFPNAPYL (配列番号:2)、
CMTWNQMNL (配列番号:3)、
CYTWNQMNL (配列番号:4)、
ALLPAVPSL (配列番号:5)、
SLGEQQYSV (配列番号:6)、
RVPGVAPTL (配列番号:7)、
VLDFAPPGA、(配列番号:8)、
C−CMTWNQMNL (配列番号:9)(式中、CとCの間の結合はジスルフィド結合を表す。)、および
C−CYTWNQMNL (配列番号:10)(式中、CとCの間の結合はジスルフィド結合を表す。)から選択されるいずれかのアミノ酸配列からなるペプチド;
前記配列番号2〜10から選択されるいずれかのアミノ酸配列において、1個〜数個のアミノ酸が、欠失、置換、および/または付加されたアミノ酸配列を含み且つCTL誘導活性を有するペプチド;または
式(1)〜(3)で表される化合物の、酸付加塩および塩基付加塩が挙げられる。例えば、酸付加塩としては、塩酸塩、臭化水素酸塩、硫酸塩、ヨウ化水素酸塩、硝酸塩、リン酸塩などの無機酸塩、クエン酸塩、シュウ酸塩、酢酸塩、ギ酸塩、プロピオン酸塩、安息香酸塩、トリフルオロ酢酸塩、マレイン酸塩、酒石酸塩、メタンスルホン酸塩、ベンゼンスルホン酸塩、パラトルエンスルホン酸塩などの有機酸塩が挙げられ、塩基付加塩としては、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩、アンモニウム塩などの無機塩基塩、トリエチルアンモニウム塩、トリエタノールアンモニウム塩、ピリジニウム塩、ジイソプロピルアンモニウム塩などの有機塩基塩などが挙げられ、さらにはアルギニン、アスパラギン酸、グルタミン酸などの塩基性あるいは酸性アミノ酸といったアミノ酸塩が挙げられる。
KRYFKLSHLQMHSRKH (配列番号:11)、
SGQARMFPNAPYLPSCLES(配列番号:12)、
RSDELVRHHNMHQRNMTKL (配列番号:13)、
PGCNKRYFKLSHLQMHSRKHTG (配列番号:14)、
CNKRYFKLSHLQMHSRK (配列番号:15)、
CNKRYFKLSHLQMHSRKH (配列番号:16)、
CNKRYFKLSHLQMHSRKHTG (配列番号:17)、
WAPVLDFAPPGASAYGSL (配列番号:18)、
CWAPVLDFAPPGASAYGSL (配列番号:19)および
WAPVLDFAPPGASAYGSLC (配列番号:20)
から選択されるいずれかのアミノ酸配列からなるペプチド;または
前記配列番号11〜20から選択されるいずれかのアミノ酸配列において、1個〜数個のアミノ酸が、欠失、置換、および/または付加されたアミノ酸配列を含み且つヘルパーT細胞誘導活性を有するペプチドの、酸付加塩および塩基付加塩が挙げられる。例えば、酸付加塩としては、塩酸塩、臭化水素酸塩、硫酸塩、ヨウ化水素酸塩、硝酸塩、リン酸塩などの無機酸塩、クエン酸塩、シュウ酸塩、酢酸塩、ギ酸塩、プロピオン酸塩、安息香酸塩、トリフルオロ酢酸塩、マレイン酸塩、酒石酸塩、メタンスルホン酸塩、ベンゼンスルホン酸塩、パラトルエンスルホン酸塩などの有機酸塩が挙げられ、塩基付加塩としては、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩、アンモニウム塩などの無機塩基塩、トリエチルアンモニウム塩、トリエタノールアンモニウム塩、ピリジニウム塩、ジイソプロピルアンモニウム塩などの有機塩基塩などが挙げられ、さらにはアルギニン、アスパラギン酸、グルタミン酸などの塩基性あるいは酸性アミノ酸といったアミノ酸塩が挙げられる。
RMFPNAPYL 酢酸塩、
CMTWNQMNL 酢酸塩、
CYTWNQMNL 酢酸塩、
ALLPAVPSL 酢酸塩、
SLGEQQYSV 酢酸塩、
RVPGVAPTL 酢酸塩、
VLDFAPPGA 酢酸塩、
C−CMTWNQMNL 酢酸塩、
C−CYTWNQMNL 酢酸塩、
SGQARMFPNAPYLPSCLES 酢酸塩、
RSDELVRHHNMHQRNMTKL 酢酸塩、
PGCNKRYFKLSHLQMHSRKHTG 酢酸塩、
CNKRYFKLSHLQMHSRK 酢酸塩、
CNKRYFKLSHLQMHSRKH 酢酸塩、
CNKRYFKLSHLQMHSRKHTG 酢酸塩、
WAPVLDFAPPGASAYGSL 酢酸塩、
CWAPVLDFAPPGASAYGSL 酢酸塩、
WAPVLDFAPPGASAYGSLC 酢酸塩、
RMFPNAPYL トリフルオロ酢酸塩、
CMTWNQMNL トリフルオロ酢酸塩、
CYTWNQMNL トリフルオロ酢酸塩、
ALLPAVPSL トリフルオロ酢酸塩、
SLGEQQYSV トリフルオロ酢酸塩、
RVPGVAPTL トリフルオロ酢酸塩、
VLDFAPPGA トリフルオロ酢酸塩、
C−CMTWNQMNL トリフルオロ酢酸塩、
C−CYTWNQMNL トリフルオロ酢酸塩、
SGQARMFPNAPYLPSCLES トリフルオロ酢酸塩、
RSDELVRHHNMHQRNMTKL トリフルオロ酢酸塩、
PGCNKRYFKLSHLQMHSRKHTG トリフルオロ酢酸塩、
CNKRYFKLSHLQMHSRK トリフルオロ酢酸塩、
CNKRYFKLSHLQMHSRKH トリフルオロ酢酸塩、
CNKRYFKLSHLQMHSRKHTG トリフルオロ酢酸塩、
WAPVLDFAPPGASAYGSL トリフルオロ酢酸塩、
CWAPVLDFAPPGASAYGSL トリフルオロ酢酸塩、および
WAPVLDFAPPGASAYGSLC トリフルオロ酢酸塩
が挙げられる。
ヒト末梢血単核球からの腫瘍抗原ペプチド特異的細胞傷害性T細胞誘導に対する免疫チェックポイント阻害剤の併用効果
WT1抗原ペプチド特異的CTLのペプチドに対する免疫応答性に対する免疫チェックポイント阻害剤の作用
WT1キラーペプチドおよびWT1ヘルパーペプチドのカクテルワクチンを投与したマウス脾細胞における免疫チェックポイント分子の発現変化
本試験に使用したHLA−A*02:01遺伝子導入マウス(C57BL/6CrHLA−A2.1DR1)は、マウスのMHCを欠損し、ヒトのMHCであるHLA−A02:01とマウスMHCであるH−2DbとのキメラHLAと、HLA−DRB1*01:01とを発現するマウスである(Eur J Immunol.2004;34:3060-9)。本マウスを用いることで、ヒトのHLA−A*02:01に結合し得るペプチドでCTLを誘導することが可能である。また、ヒトのHLA−DRB1*01:01に結合し得るペプチドでヘルパーT細胞を誘導し、CTL誘導増強効果を評価することも可能である。
WT1抗原ペプチド特異的T細胞の腫瘍細胞に対する免疫応答性における免疫チェックポイント阻害剤の作用
実施例3と同様にWT1キラーペプチドおよびWT1ヘルパーペプチドを含む組成物を等量のモンタナイドと混合しエマルション化させたのち、HLA−A*02:01遺伝子導入マウスの尾根部皮内に投与した(マウス1匹の1回の免疫につき、1mgのWT1キラーペプチドと0.75mgのWT1ヘルパーペプチドを投与)。最終投与の1週間後にマウスをCO2ガスにより安楽死させたのち脾臓を摘出し、Complete T-cell medeium(以下CTM)を用いて脾細胞懸濁液を調製した。WT1キラーペプチド(配列番号:2)をDMSOで40mg/mLに溶解し、さらにCTMで500μg/mLに希釈した。調製した脾細胞の一部にこのペプチド溶液を添加し、最終濃度100μg/mLで約1時間、37℃、5% CO2下に静置した。CTMで余分なペプチドを洗浄後、ペプチドパルスした脾細胞と非ペプチドパルス脾細胞を1:10の割合で混合した。この脾細胞懸濁液に抗PD−1抗体(Bio X cell社製、クローンRMP1-14)、またはアイソタイプコントロール抗体(Bio X cell社製、Rat IgGa, κ)を10μg/mLで添加し、37℃、5% CO2下で5日間培養した。培養した脾細胞を10%FBS含有RPMI1640培地で洗浄し、Responder細胞とした。次に、WT1キラーペプチド(配列番号:2)をDMSOで40mg/mLに溶解し、さらに10%FBS含有RPMI1640培地で100μg/mLに希釈した。マウスリンパ腫由来細胞株EL4 S3- Rob(Eur J Immunol.1990;20:171-7)にHHD(ヒトHLA−A*02:01分子のα3ドメインをマウスMHCクラスI分子H−2Dbのα3ドメインと置換したキメラHLA分子)を安定発現させた細胞株(J Exp Med.1997;185:2043-51)(以下、EL4HHD)を上記のペプチド含有RPMI1640培地、またはペプチド非含有RPMI1640培地で懸濁し、約1時間、37℃、5% CO2下に静置した。10%FBS含有RPMI1640培地で余分なペプチドを洗浄し、Stimulator細胞とした。U底96穴プレートにStimulator細胞であるEL4HHDを1×105細胞/穴、Responder細胞である5日間培養した脾細胞を5×105細胞/穴で播種して混合し、37℃、5% CO2下で24時間培養した。この培養上清中に含まれるマウスIFN−γの濃度をELISAキット(R&D Systems)で測定した。
WT1抗原ペプチド特異的T細胞のペプチドおよび腫瘍細胞に対する免疫応答性における各種併用剤の作用
WT1キラーペプチド(式(3)の化合物)およびWT1ヘルパーペプチド(配列番号:18)を含む組成物を等量のモンタナイドと混合しエマルション化させたのち、HLA−A*02:01遺伝子導入マウスの尾根部皮内に投与した(マウス1匹につき、0.5mgのWT1キラーペプチドと0.375mgのWT1ヘルパーペプチドを投与)。投与の1週間後にマウスをCO2ガスにより安楽死させたのち脾臓を摘出し、CTMを用いて脾細胞懸濁液を調製した。WT1キラーペプチド(配列番号:2)をDMSOで40mg/mLに溶解した。脾細胞の一部に調製したWT1キラーペプチド溶液を添加し、最終濃度100μg/mLで約1時間、37℃、5%CO2下に静置した。CTMで余分なペプチドを洗浄後、ペプチドパルスした脾細胞と非ペプチドパルス細胞を1:10の割合で混合し、U底96穴プレートに3.85×105細胞/穴で播種した。腫瘍細胞として、マウスルイス肺がん由来細胞株LLCにHHDおよびWT1キラーペプチド(配列番号:2)を安定発現させた細胞株(本明細書中、LLC―HHD―WT1腫瘍細胞とも記載する)にX線(50Gy)照射した後に最終濃度100ng/mLのマウスリコンビナントIFN―γの存在下で約2日間培養し、CTMで洗浄した。このLLC−HHD−WT1腫瘍細胞を、脾細胞を播種したU底96穴プレートに5×104細胞/穴あるいは3.5×104細胞/穴で播種して混合し、CTM(培地)、あるいはアイソタイプコントロール抗体、あるいは免疫チェックポイント阻害剤、あるいは共刺激分子アゴニスト抗体、あるいはTLR作動薬、あるいはβ―カテニン阻害剤を添加して37℃、5%CO2下で約3日間培養した。免疫チェックポイント阻害剤としては抗PD−1抗体(BioLegend社、クローン29F.1A12)、抗TIM−3抗体(BioLegend社、クローンRMT3-23)、抗CD160抗体(eBioscience社、クローンeBioCNX46-3)、抗LAG−3抗体(BioLegend社、クローンC9B7W)、抗BTLA抗体(BioLegend社、クローン6A6)、抗PD−L1抗体(eBiosciecne社、クローンMIH5)、抗HVEM抗体(BioLegend社、クローンHMHV-1B18)、抗VISTA抗体(BioLegend社、クローンMH5A)、抗PVR抗体(Hycult Biotech社、クローン3F1)を最終濃度10μg/mLで用いた。共刺激分子アゴニスト抗体としては抗4−1BB抗体(Bio X Cell社、クローンLOB12.3)、抗OX−40抗体(Bio X Cell社、クローンOX-86)、抗GITR抗体(BioLegend社、クローンDTA-1)、抗CD−40抗体(BioLegend社、クローン1C10)を最終濃度30μg/mLで用いた。抗PD―1抗体、抗TIM−3抗体、抗CD160抗体、および抗CD−40抗体に対応するアイソタイプコントロール抗体としてRat IgG2aκ(BD Pharmingen社)を、抗PD−L1抗体および抗PVR抗体に対応するアイソタイプコントロール抗体としてRat IgG2a(Bio X Cell社)を、抗BTLA抗体、抗HVEM抗体、および抗VISTA抗体に対応するアイソタイプコントロール抗体としてArmenian Hamster IgG(eBioscience社)を、抗LAG−3抗体、抗4−1BB抗体および抗OX−40抗体に対応するアイソタイプコントロール抗体としてRat IgG1κ(eBiosciecne社)を、抗GITR抗体に対応するアイソタイプコントロール抗体としてRat IgG2b(Bio X Cell社)を用いた。TLR作動薬としてはTLR3作動薬であるPolyI:C HMW(GEヘルスケア、最終濃度30μg/mL)およびPolyI:C LMW(GeneDesign、最終濃度30μg/mL)、TLR7作動薬であるImiquimod(最終濃度10μg/mL)、TLR7/8作動薬であるR848(最終濃度1μmol/L)、およびTLR9作動薬であるCpG−ODN−D19(最終濃度1μmol/L)、CpG−ODN−1826(最終濃度1μmol/L)、およびCpG−ODN−C583(最終濃度1μmol/L)を用いた。β―カテニン阻害剤としてはXAV939を最終濃度5μmol/Lで用いた。この培養上清中に含まれるマウスIFN―γの濃度をELISAキット(R&D Systems)で測定した。
担がん生体由来のWT1抗原ペプチド特異的T細胞の免疫活性における各種併用剤の作用
マウスリンパ腫細胞株EL4にHLA−A2402/Kb(ヒトHLA−A*24:02分子のα3ドメインをマウスMHCクラスI分子H−2Kbのα3ドメインと置換したキメラHLA分子)およびWT1キラーペプチド(配列番号:4)を安定発現させた細胞株(本明細書中、EL4―A24/Kb―WT1腫瘍細胞とも記載する)をハンクス平衡塩溶液中に浮遊させ、HLA−A*24:02遺伝子導入マウスの腹側部皮内に移植した(マウス1匹につき、3×105個あるいは5×105個)。腫瘍細胞を移植した1日後および8日後に、WT1キラーペプチド(式(3)の化合物)およびWT1ヘルパーペプチド(配列番号:18)を含む組成物を等量のモンタナイドと混合しエマルション化させたのち、HLA−A*24:02遺伝子導入マウスの前肢付け根皮内および後肢付け根皮内に2か所に分けて投与した(マウス1匹に対する1回の投与につき、1mgのWT1キラーペプチドと0.75mgのWT1ヘルパーペプチドを投与)。腫瘍移植15日後にマウスをCO2ガスにより安楽死させたのち脾臓を摘出し、CTMを用いて脾細胞懸濁液を調製した。この脾細胞をU底96穴プレートに3.85×105細胞/穴で播種し、CTM、あるいはアイソタイプコントロール抗体、あるいは免疫チェックポイント阻害剤、あるいは共刺激分子アゴニスト抗体を添加して37℃、5%CO2下で約3日間培養した。免疫チェックポイント阻害剤としては抗PD−1抗体(BioLegend社、クローン29F.1A12)、抗CTLA―4抗体(BioLegend社、クローンUC10-4B9)、抗TIGIT抗体(Bio X Cell社、クローン1G9)を最終濃度30μg/mLで用いた。共刺激分子アゴニスト抗体としては抗ICOS抗体(BioLegend社、クローンC398.4A)を最終濃度30μg/mLで用いた。抗PD―1抗体に対応するアイソタイプコントロール抗体としてRat IgG2aκ(BD Pharmingen社)を、抗CTLA−4抗体および抗ICOS抗体に対応するアイソタイプコントロール抗体としてArmenian Hamster IgG(eBioscience社)を、抗TIGIT抗体に対応するアイソタイプコントロール抗体としてMouse IgG1(Bio X Cell社)を用いた。この培養上清中に含まれるマウスIFN―γの濃度をELISAキット(R&D Systems)で測定した。
WT1抗原ペプチド特異的T細胞のペプチドおよび腫瘍細胞に対する免疫応答性における各種併用剤の作用
WT1キラーペプチド(配列番号:2)およびWT1ヘルパーペプチド(配列番号:11)を含む組成物を等量のモンタナイドと混合しエマルション化させたのち、HLA−A*02:01遺伝子導入マウスの尾根部皮内に投与した(マウス1匹につき、0.3mgのWT1キラーペプチドと0.3mgのWT1ヘルパーペプチドを投与)。投与の1週間後にマウスをCO2ガスにより安楽死させたのち脾臓を摘出し、CTMを用いて脾細胞懸濁液を調製した。WT1キラーペプチド(配列番号:2)をDMSOで40mg/mLに溶解した。脾細胞の一部に調製したWT1キラーペプチド溶液を添加し、最終濃度100μg/mLで約1時間、37℃、5%CO2下に静置した。CTMで余分なペプチドを洗浄後、ペプチドパルスした脾細胞と非ペプチドパルス細胞を1:10の割合で混合し、U底96穴プレートに3.85×105細胞/穴で播種した。腫瘍細胞として、LLC―HHD―WT1腫瘍細胞にX線(50Gy)照射した後に最終濃度100ng/mLのマウスリコンビナントIFN―γの存在下で約2日間培養し、CTMで洗浄した。このLLC−HHD−WT1腫瘍細胞を、脾細胞を播種したU底96穴プレートに3.5×104細胞/穴で播種して混合し、CTM、あるいはアイソタイプコントロール抗体、あるいは免疫チェックポイント阻害剤、あるいは共刺激分子アゴニスト抗体を添加して37℃、5%CO2下で約3日間培養した。免疫チェックポイント阻害剤としては抗PD−1抗体(BioLegend社、クローン29F.1A12)、抗B7−H4抗体(BioLegend社、クローンHMH4-5G1)、抗PD−L1抗体(eBiosciecne社、クローンMIH5)を最終濃度30μg/mLで用いた。共刺激分子アゴニスト抗体としては抗4−1BB抗体(Bio X Cell社、クローンLOB12.3)、抗OX−40抗体(Bio X Cell社、クローンOX-86)を最終濃度30μg/mLで用いた。抗PD―1抗体に対応するアイソタイプコントロール抗体としてRat IgG2aκ(BD Pharmingen社)を、抗PD−L1抗体に対応するアイソタイプコントロール抗体としてRat IgG2a(Bio X Cell社)を、抗B7−H4抗体に対応するアイソタイプコントロール抗体としてArmenian Hamster IgG(eBioscience社)を、抗4−1BB抗体および抗OX−40抗体に対応するアイソタイプコントロール抗体としてRat IgG1κ(eBiosciecne社)を用いた。この培養上清中に含まれるマウスIFN―γの濃度をELISAキット(R&D Systems)で測定した。
WT1抗原ペプチド特異的T細胞のペプチドおよび腫瘍細胞に対する免疫応答性における各種併用剤の作用
WT1キラーペプチド(配列番号:2)およびWT1ヘルパーペプチド(配列番号:14)を含む組成物を等量のモンタナイドと混合しエマルション化させたのち、HLA−A*02:01遺伝子導入マウスの尾根部皮内に投与した(マウス1匹につき、0.3mgのWT1キラーペプチドと0.3mgのWT1ヘルパーペプチドを投与)。投与の1週間後にマウスをCO2ガスにより安楽死させたのち脾臓を摘出し、CTMを用いて脾細胞懸濁液を調製した。WT1キラーペプチド(配列番号:2)をDMSOで40mg/mLに溶解した。脾細胞の一部に調製したWT1キラーペプチド溶液を添加し、最終濃度100μg/mLで約1時間、37℃、5%CO2下に静置した。CTMで余分なペプチドを洗浄後、ペプチドパルスした脾細胞と非ペプチドパルス細胞を1:10の割合で混合し、U底96穴プレートに3.85×105細胞/穴で播種した。腫瘍細胞として、LLC―HHD―WT1腫瘍細胞にX線(50Gy)照射した後に最終濃度100ng/mLのマウスリコンビナントIFN―γの存在下で約2日間培養し、CTMで洗浄した。このLLC−HHD−WT1腫瘍細胞を、脾細胞を播種したU底96穴プレートに3.5×104細胞/穴で播種して混合し、CTM、あるいはアイソタイプコントロール抗体、あるいは免疫チェックポイント阻害剤、あるいは共刺激分子アゴニスト抗体を添加して37℃、5%CO2下で約3日間培養した。免疫チェックポイント阻害剤としては抗PD−1抗体(BioLegend社、クローン29F.1A12)、抗B7−H4抗体(BioLegend社、クローンHMH4-5G1)、抗PD−L1抗体(eBiosciecne社、クローンMIH5)を最終濃度30μg/mLで用いた。共刺激分子アゴニスト抗体としては抗4−1BB抗体(Bio X Cell社、クローンLOB12.3)、抗OX−40抗体(Bio X Cell社、クローンOX-86)を最終濃度30μg/mLで用いた。抗PD−1抗体に対応するアイソタイプコントロール抗体としてRat IgG2aκ(BD Pharmingen社)を、抗PD−L1抗体に対応するアイソタイプコントロール抗体としてRat IgG2a(Bio X Cell社)を、抗B7−H4抗体に対応するアイソタイプコントロール抗体としてArmenian Hamster IgG(eBioscience社)を、抗4−1BB抗体および抗OX−40抗体に対応するアイソタイプコントロール抗体としてRat IgG1κ(eBiosciecne社)を用いた。この培養上清中に含まれるマウスIFN−γの濃度をELISAキット(R&D Systems)で測定した。
WT1抗原ペプチド特異的T細胞のペプチドおよび腫瘍細胞に対する免疫応答性における各種併用剤の作用
WT1キラーペプチド(配列番号:26)およびWT1ヘルパーペプチド(配列番号:37)を含む組成物を等量のモンタナイドと混合しエマルション化させたのち、HLA−A*02:01遺伝子導入マウスの尾根部皮内に投与した(マウス1匹につき、0.234mgのWT1キラーペプチドと0.234mgのWT1ヘルパーペプチドを投与)。投与の1週間後にマウスをCO2ガスにより安楽死させたのち脾臓を摘出し、CTMを用いて脾細胞懸濁液を調製した。WT1キラーペプチド(配列番号:26)をDMSOで40mg/mLに溶解した。脾細胞の一部に調製したWT1キラーペプチド溶液を添加し、最終濃度100μg/mLで約1時間、37℃、5%CO2下に静置した。CTMで余分なペプチドを洗浄後、ペプチドパルスした脾細胞と非ペプチドパルス細胞を1:10の割合で混合し、U底96穴プレートに3.85×105細胞/穴で播種した。腫瘍細胞として、LLC―HHD―WT1腫瘍細胞にX線(50Gy)照射した後に最終濃度100ng/mLのマウスリコンビナントIFN―γの存在下で約2日間培養し、CTMで洗浄した。このLLC−HHD−WT1腫瘍細胞を、脾細胞を播種したU底96穴プレートに3.5×104細胞/穴で播種して混合し、CTM、あるいはアイソタイプコントロール抗体、あるいは免疫チェックポイント阻害剤を添加して37℃、5%CO2下で約3日間培養した。免疫チェックポイント阻害剤としては抗PD−1抗体(BioLegend社、クローン29F.1A12)、抗PD−L1抗体(eBiosciecne社、クローンMIH5)を最終濃度30μg/mLで用いた。抗PD−1抗体に対応するアイソタイプコントロール抗体としてRat IgG2aκ(BD Pharmingen社)を、抗PD−L1抗体に対応するアイソタイプコントロール抗体としてRat IgG2a(Bio X Cell社)を用いた。この培養上清中に含まれるマウスIFN−γの濃度をELISAキット(R&D Systems)で測定した。
WT1抗原ペプチド特異的T細胞のペプチドおよび腫瘍細胞に対する免疫応答性における各種併用剤の作用
WT1キラーペプチド(配列番号:5)およびWT1ヘルパーペプチド(配列番号:11)を含む組成物を等量のモンタナイドと混合しエマルション化させたのち、HLA−A*02:01遺伝子導入マウスの尾根部皮内に投与した(マウス1匹につき、0.3mgのWT1キラーペプチドと0.3mgのWT1ヘルパーペプチドを投与)。投与の1週間後にマウスをCO2ガスにより安楽死させたのち脾臓を摘出し、CTMを用いて脾細胞懸濁液を調製した。WT1キラーペプチド(配列番号:5)をDMSOで40mg/mLに溶解した。脾細胞の一部に調製したWT1キラーペプチド溶液を添加し、最終濃度100μg/mLで約1時間、37℃、5%CO2下に静置した。CTMで余分なペプチドを洗浄後、ペプチドパルスした脾細胞と非ペプチドパルス細胞を1:10の割合で混合し、U底96穴プレートに3.85×105細胞/穴で播種した。腫瘍細胞として、LLC―HHD―WT1腫瘍細胞にX線(50Gy)照射した後に最終濃度100ng/mLのマウスリコンビナントIFN―γの存在下で約2日間培養し、CTMで洗浄した。このLLC−HHD−WT1腫瘍細胞を、脾細胞を播種したU底96穴プレートに3.5×104細胞/穴で播種して混合し、CTM、あるいはアイソタイプコントロール抗体、あるいは免疫チェックポイント阻害剤、あるいは共刺激分子アゴニスト抗体を添加して37℃、5%CO2下で約3日間培養した。免疫チェックポイント阻害剤としては抗PD−1抗体(BioLegend社、クローン29F.1A12)、抗B7−H4抗体(BioLegend社、クローンHMH4-5G1)、抗PD−L1抗体(eBiosciecne社、クローンMIH5)を最終濃度30μg/mLで用いた。共刺激分子アゴニスト抗体としては抗4−1BB抗体(Bio X Cell社、クローンLOB12.3)、抗OX−40抗体(Bio X Cell社、クローンOX-86)、抗GITR抗体(BioLegend社、クローンDTA-1)を最終濃度30μg/mLで用いた。抗PD―1抗体に対応するアイソタイプコントロール抗体としてRat IgG2aκ(BD Pharmingen社)を、抗PD−L1抗体に対応するアイソタイプコントロール抗体としてRat IgG2a(Bio X Cell社)を、抗B7−H4抗体に対応するアイソタイプコントロール抗体としてArmenian Hamster IgG(eBioscience社)を、抗4−1BB抗体および抗OX−40抗体に対応するアイソタイプコントロール抗体としてRat IgG1κ(eBiosciecne社)を、抗GITR抗体に対応するアイソタイプコントロール抗体としてRat IgG2b(Bio X Cell社)を用いた。この培養上清中に含まれるマウスIFN―γの濃度をELISAキット(R&D Systems)で測定した。
免疫チェックポイント阻害剤によるイン・ビボ腫瘍増殖抑制効果に対するワクチンの増強効果
本試験に使用したHLA−A*24:02遺伝子導入マウス(C57BL/6CrHLA−A24/Kb)は、ヒトのMHCであるHLA−A24:02とマウスMHCであるH−2KbとのキメラHLAを発現するマウスである(Int. J. Cancer 2002;100:565-570)。本マウスを用いることで、ヒトのHLA−A*24:02に結合し得るペプチドでCTLを誘導することが可能である。
免疫チェックポイント阻害剤によるイン・ビボ腫瘍増殖抑制効果に対するワクチンの増強効果
カクテルワクチンで誘導したWT1抗原ペプチド特異的T細胞のペプチドおよび腫瘍細胞に対する免疫応答性における各種併用剤の作用
WT1キラーペプチド(式(3)の化合物)およびWT1ヘルパーペプチド(配列番号:18)を含む組成物を等量のモンタナイドと混合しエマルション化させたのち、HLA−A*02:01遺伝子導入マウスの尾根部皮内に投与した(マウス1匹につき、0.5mgのWT1キラーペプチドと0.375mgのWT1ヘルパーペプチドを投与)。あるいは、WT1キラーペプチド(式(3)の化合物)を含む組成物を等量のモンタナイドと混合しエマルション化させたのち、HLA−A*02:01遺伝子導入マウスの尾根部皮内に投与した(マウス1匹につき、0.5mgのWT1キラーペプチドを投与)。投与の1週間後にマウスをCO2ガスにより安楽死させたのち脾臓を摘出し、CTMを用いて脾細胞を調製した。この脾細胞をFITC標識抗CD8抗体(BD Pharmingen社)およびPE標識されたWT1キラーペプチド(配列番号:2)に対するHLAテトラマー試薬(MBL社)で染色し、フローサイトメーターを用いてキラーペプチド特異的CTLの解析を行った。
フローサイトメトリー解析の結果、WT1キラーペプチド(式(3)の化合物)およびWT1ヘルパーペプチド(配列番号:18)を含むワクチン(以下、カクテルワクチンaとする)を投与したマウスの脾細胞は、WT1キラーペプチド(式(3)の化合物)のみを含むワクチン(以下、キラーワクチンaとする)を投与したマウスの脾細胞と比べて、1.9倍のWT1キラーペプチド(配列番号:2)特異的CTLを含んでいた(図27)。これらの脾細胞をWT1キラーペプチド(配列番号:2)の添加下で培養したところ、カクテルワクチンaを投与したマウスの脾細胞は、キラーワクチンaを投与したマウスの脾細胞と比べて、2倍のIFN―γ産生量を示した(図28)。一方で、これらの脾細胞を腫瘍細胞と混合した上で、WT1キラーペプチド(配列番号:2)非添加下あるいは添加下で培養したところ、腫瘍細胞と混合しなかった場合(図28)と比較して脾細胞からのIFN−γ産生量は抑制されたが、カクテルワクチンaを投与したマウスの脾細胞は、キラーワクチンaを投与したマウスの脾細胞と比べて、WT1キラーペプチド(配列番号:2)非添加下では6.9倍、WT1キラーペプチド(配列番号:2)添加下では12倍のIFN―γ産生量を示した(図29)。これらの結果より、キラーワクチンaを投与したマウスの脾細胞中に含まれるCTLは、カクテルワクチンaを投与したマウスの脾細胞中に含まれるCTLと比べて、腫瘍細胞による抑制を強く受けることが示された。更には、腫瘍細胞の存在下でWT1キラーペプチドに加えて免疫チェックポイント阻害剤(図30)、共刺激分子アゴニスト抗体(図31)、あるいはβ―カテニン阻害剤(図32)を添加したところ、これらの併用剤によってカクテルワクチンaを投与したマウスの脾細胞は実施例5と同様に著しく活性化したが、キラーワクチンaを投与したマウスの脾細胞はほとんど活性化されなかった。これらの結果より、腫瘍中において、免疫チェックポイント阻害剤、共刺激分子アゴニスト剤、β―カテニン阻害剤によってWT1抗原ペプチド特異的CTLのWT1ペプチドおよび腫瘍細胞に対する反応性が増強されるためには、投与されるWT1ワクチンにキラーペプチドとヘルパーペプチドの双方が含まれていることが重要であることが明らかとなった。
カクテルワクチンで誘導したWT1抗原ペプチド特異的T細胞のペプチドおよび腫瘍細胞に対する免疫応答性における各種併用剤の作用
WT1キラーペプチド(配列番号:2)およびWT1ヘルパーペプチド(配列番号:11)を含む組成物を等量のモンタナイドと混合しエマルション化させたのち、HLA−A*02:01遺伝子導入マウスの尾根部皮内に投与した(マウス1匹につき、0.3mgのWT1キラーペプチドと0.3mgのWT1ヘルパーペプチドを投与)。あるいは、WT1キラーペプチド(配列番号:2)を含む組成物を等量のモンタナイドと混合しエマルション化させたのち、HLA−A*02:01遺伝子導入マウスの尾根部皮内に投与した(マウス1匹につき、0.3mgのWT1キラーペプチドを投与)。投与の1週間後にマウスをCO2ガスにより安楽死させたのち脾臓を摘出し、CTMを用いて脾細胞を調製した。この脾細胞をFITC標識抗CD8抗体(BD Pharmingen社)およびPE標識されたWT1キラーペプチド(配列番号:2)に対するHLAテトラマー試薬(MBL社)で染色し、フローサイトメーターを用いてキラーペプチド特異的CTLの解析を行った。
フローサイトメトリー解析の結果、WT1キラーペプチド(配列番号:2)およびWT1ヘルパーペプチド(配列番号:11)を含むワクチン(以下、カクテルワクチンbとする)を投与したマウスの脾細胞は、WT1キラーペプチド(配列番号:2)のみを含むワクチン(以下、キラーワクチンbとする)を投与したマウスの脾細胞と比べて、1.3倍のWT1キラーペプチド(配列番号:2)特異的CTLを含んでいた(図33)。これらの脾細胞をWT1キラーペプチド(配列番号:2)の添加下で培養したところ、カクテルワクチンbを投与したマウスの脾細胞は、キラーワクチンbを投与したマウスの脾細胞と比べて、2.6倍のIFN―γ産生量を示した(図34A−B)。これらの脾細胞を腫瘍細胞の存在下でWT1キラーペプチドに加えて免疫チェックポイント阻害剤(図35−37)あるいは共刺激分子アゴニスト抗体(図38−39)を添加して培養したところ、これらの併用剤によってカクテルワクチンbを投与したマウスの脾細胞は実施例7と同様に著しく活性化したが、キラーワクチンbを投与したマウスの脾細胞はほとんど活性化されなかった。これらの結果より、腫瘍中において、免疫チェックポイント阻害剤、共刺激分子アゴニスト剤によってWT1抗原ペプチド特異的CTLのWT1ペプチドおよび腫瘍細胞に対する反応性が増強されるためには、投与されるWT1ワクチンにキラーペプチドとヘルパーペプチドの双方が含まれていることが重要であることが明らかとなった。
配列番号:3 ペプチド
配列番号:4 ペプチド
配列番号:5 ペプチド
配列番号:6 ペプチド
配列番号:7 ペプチド
配列番号:8 ペプチド
配列番号:9 ペプチド
配列番号:10 ペプチド
配列番号:11 ペプチド
配列番号:12 ペプチド
配列番号:13 ペプチド
配列番号:14 ペプチド
配列番号:15 ペプチド
配列番号:16 ペプチド
配列番号:17 ペプチド
配列番号:18 ペプチド
配列番号:19 ペプチド
配列番号:20 ペプチド
配列番号:21 ペプチド
配列番号:22 ペプチド
配列番号:23 ペプチド
配列番号:24 ペプチド
配列番号:25 ペプチド
配列番号:26 ペプチド
配列番号:27 ペプチド
配列番号:28 ペプチド
配列番号:29 ペプチド
配列番号:30 ペプチド
配列番号:31 ペプチド
配列番号:32 ペプチド
配列番号:33 ペプチド
配列番号:34 ペプチド
配列番号:35 ペプチド
配列番号:36 ペプチド
配列番号:37 ペプチド
配列番号:38 ペプチド
配列番号:39 ペプチド
配列番号:40 ペプチド
配列番号:41 ペプチド
配列番号:42 ペプチド
配列番号:43 ペプチド
配列番号:44 ペプチド
配列番号:45 ペプチド
配列番号:46 ペプチド
Claims (18)
- 免疫調節剤と併用される、WT1抗原ペプチドまたはその薬学上許容される塩を含む、癌を治療または予防するための医薬組成物であって、WT1ヘルパーペプチドまたはその薬学上許容される塩をさらに含むか、WT1ヘルパーペプチドまたはその薬学上許容される塩と併用され、
WT1抗原ペプチドが、
式(3):
で表される化合物またはその薬学上許容される塩であり、
WT1ヘルパーペプチドまたはその薬学上許容される塩が、
以下:
KRYFKLSHLQMHSRKH (配列番号:11)、
SGQARMFPNAPYLPSCLES(配列番号:12)、
RSDELVRHHNMHQRNMTKL (配列番号:13)、
PGCNKRYFKLSHLQMHSRKHTG (配列番号:14)、
CNKRYFKLSHLQMHSRK (配列番号:15)、
CNKRYFKLSHLQMHSRKH (配列番号:16)、
CNKRYFKLSHLQMHSRKHTG (配列番号:17)、
WAPVLDFAPPGASAYGSL (配列番号:18)、
CWAPVLDFAPPGASAYGSL (配列番号:19)、
WAPVLDFAPPGASAYGSLC (配列番号:20)、および
SGQAYMFPNAPYLPSCLES (配列番号:37)
から選択されるいずれかのアミノ酸配列からなるペプチドまたはその薬学上許容される塩であり、
免疫調節剤が、抗体および核酸から選択される免疫チェックポイント阻害剤であり、
免疫チェックポイント阻害剤が、
(1)CTLA−4、
(2)PD−1、
(3)LAG−3、
(4)BTLA、
(5)KIR、
(6)TIM−3、
(7)PD−L1、
(8)PD−L2、
(9)B7−H3、
(10)B7−H4、
(11)HVEM、
(12)GAL9、
(13)CD160、
(14)VISTA、
(15)BTNL2、
(16)TIGIT、
(17)PVR、
(18)BTN1A1、
(19)BTN2A2、および
(20)BTN3A2
からなる群から選択される分子に対する1以上の薬剤である、医薬組成物。 - WT1抗原ペプチドまたはその薬学上許容される塩と併用される、免疫調節剤を含む、癌を治療または予防するための医薬組成物であって、WT1ヘルパーペプチドまたはその薬学上許容される塩をさらに含むか、WT1ヘルパーペプチドまたはその薬学上許容される塩と併用され、
WT1抗原ペプチドが、
式(3):
で表される化合物またはその薬学上許容される塩であり、
WT1ヘルパーペプチドまたはその薬学上許容される塩が、
以下:
KRYFKLSHLQMHSRKH (配列番号:11)、
SGQARMFPNAPYLPSCLES(配列番号:12)、
RSDELVRHHNMHQRNMTKL (配列番号:13)、
PGCNKRYFKLSHLQMHSRKHTG (配列番号:14)、
CNKRYFKLSHLQMHSRK (配列番号:15)、
CNKRYFKLSHLQMHSRKH (配列番号:16)、
CNKRYFKLSHLQMHSRKHTG (配列番号:17)、
WAPVLDFAPPGASAYGSL (配列番号:18)、
CWAPVLDFAPPGASAYGSL (配列番号:19)、
WAPVLDFAPPGASAYGSLC (配列番号:20)、および
SGQAYMFPNAPYLPSCLES (配列番号:37)
から選択されるいずれかのアミノ酸配列からなるペプチドまたはその薬学上許容される塩であり、
免疫調節剤が、抗体および核酸から選択される免疫チェックポイント阻害剤であり、
免疫チェックポイント阻害剤が、
(1)CTLA−4、
(2)PD−1、
(3)LAG−3、
(4)BTLA、
(5)KIR、
(6)TIM−3、
(7)PD−L1、
(8)PD−L2、
(9)B7−H3、
(10)B7−H4、
(11)HVEM、
(12)GAL9、
(13)CD160、
(14)VISTA、
(15)BTNL2、
(16)TIGIT、
(17)PVR、
(18)BTN1A1、
(19)BTN2A2、および
(20)BTN3A2
からなる群から選択される分子に対する1以上の薬剤である、医薬組成物。 - 免疫調節剤とWT1抗原ペプチドまたはその薬学上許容される塩とを含む、癌を治療または予防するための医薬組成物であって、WT1ヘルパーペプチドまたはその薬学上許容される塩をさらに含むか、WT1ヘルパーペプチドまたはその薬学上許容される塩と併用され、
WT1抗原ペプチドが、
式(3):
で表される化合物またはその薬学上許容される塩であり、
WT1ヘルパーペプチドまたはその薬学上許容される塩が、
以下:
KRYFKLSHLQMHSRKH (配列番号:11)、
SGQARMFPNAPYLPSCLES(配列番号:12)、
RSDELVRHHNMHQRNMTKL (配列番号:13)、
PGCNKRYFKLSHLQMHSRKHTG (配列番号:14)、
CNKRYFKLSHLQMHSRK (配列番号:15)、
CNKRYFKLSHLQMHSRKH (配列番号:16)、
CNKRYFKLSHLQMHSRKHTG (配列番号:17)、
WAPVLDFAPPGASAYGSL (配列番号:18)、
CWAPVLDFAPPGASAYGSL (配列番号:19)、
WAPVLDFAPPGASAYGSLC (配列番号:20)、および
SGQAYMFPNAPYLPSCLES (配列番号:37)
から選択されるいずれかのアミノ酸配列からなるペプチドまたはその薬学上許容される塩であり、
免疫調節剤が、抗体および核酸から選択される免疫チェックポイント阻害剤であり、
免疫チェックポイント阻害剤が、
(1)CTLA−4、
(2)PD−1、
(3)LAG−3、
(4)BTLA、
(5)KIR、
(6)TIM−3、
(7)PD−L1、
(8)PD−L2、
(9)B7−H3、
(10)B7−H4、
(11)HVEM、
(12)GAL9、
(13)CD160、
(14)VISTA、
(15)BTNL2、
(16)TIGIT、
(17)PVR、
(18)BTN1A1、
(19)BTN2A2、および
(20)BTN3A2
からなる群から選択される分子に対する1以上の薬剤である、医薬組成物。 - 癌ワクチンとして使用される、請求項1〜3のいずれかに記載の医薬組成物。
- 免疫チェックポイント阻害剤が、CTLA−4、PD−1、LAG−3、TIM−3、BTLA、VISTA、HVEM、TIGIT、PVR、B7−H4、PD−L1およびCD160からなる群から選択される分子に対する1以上の薬剤である、請求項1〜4のいずれかに記載の医薬組成物。
- 免疫チェックポイント阻害剤が、CTLA−4、PD−1、LAG−3、BTLA、VISTAおよびPD−L1からなる群から選択される分子に対する1以上の薬剤である、請求項5に記載の医薬組成物。
- 免疫チェックポイント阻害剤が、PD−1またはPD−L1に対する薬剤である、請求項6に記載の医薬組成物。
- 免疫チェックポイント阻害剤が、抗体である、請求項5〜7のいずれかに記載の医薬組成物。
- 免疫チェックポイント阻害剤が、PD−1またはPD−L1に対する抗体である、請求項8に記載の医薬組成物。
- PD−1に対する抗体が、ニボルマブまたはペンブロリズマブである、請求項9に記載の医薬組成物。
- PD−L1に対する抗体が、Durvalumab、MPDL3280AまたはBMS−936559である、請求項9に記載の医薬組成物。
- 癌が、白血病、骨髄異形成症候群、多発性骨髄腫、悪性リンパ腫、胃癌、大腸癌、肺癌、乳癌、胚細胞癌、肝癌、皮膚癌、膀胱癌、前立腺癌、子宮癌、子宮頸癌、卵巣癌、脳腫瘍、骨癌、膵癌、頭頚部癌、皮膚または眼窩内悪性メラノーマ、直腸癌、肛門部癌、精巣癌、卵管のカルシノーマ、子宮内膜カルシノーマ、子宮頚部カルシノーマ、膣カルシノーマ、外陰部カルシノーマ、ホジキン病、非ホジキンリンパ腫、食道癌、小腸癌、内分泌系癌、甲状腺癌、副甲状腺癌、副腎癌、柔組織肉腫、尿道癌、陰茎癌、急性骨髄性白血病、慢性骨髄性白血病、急性リンパ芽球性白血病、慢性リンパ球性白血病を含む慢性または急性白血病、小児固形癌、リンパ球性リンパ腫、腎臓または尿管の癌、腎盂カルシノーマ、中枢神経系(CNS)腫瘍、原発性CNSリンパ腫、腫瘍新脈管形成、脊椎腫瘍、脳幹グリオーム、下垂体アデノーマ、カポシ肉腫、扁平上皮癌、扁平細胞癌、T細胞リンパ腫、多型性膠芽腫、悪性黒色腫、非小細胞肺がん、腎細胞癌およびアスベスト誘発癌からなる群から選択される、請求項1〜11のいずれかに記載の医薬組成物。
- WT1抗原ペプチドと免疫調節剤とが同時に投与される、請求項1〜12のいずれかに記載の医薬組成物。
- WT1抗原ペプチドと免疫調節剤とが別々に投与される、請求項1、2、および4〜12のいずれかに記載の医薬組成物。
- WT1抗原ペプチドが免疫調節剤の投与前に投与される、請求項1、2、および4〜12のいずれかに記載の医薬組成物。
- WT1抗原ペプチドが免疫調節剤の投与後に投与される、請求項1、2、および4〜12のいずれかに記載の医薬組成物。
- 薬学上許容される担体をさらに含む、請求項1〜16のいずれかに記載の医薬組成物。
- 請求項1〜3のいずれかに規定されるWT1抗原ペプチドまたはその薬学上許容される塩と、請求項1〜3および5〜11のいずれかに規定される免疫調節剤とを含み、請求項1〜3のいずれかに規定されるWT1ヘルパーペプチドまたはその薬学上許容される塩をさらに含むか、前記WT1ヘルパーペプチドまたはその薬学上許容される塩と併用される、癌を治療または予防するためのキット。
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CA2511538C (en) * | 2002-12-30 | 2013-11-26 | 3M Innovative Properties Company | Immunostimulatory combinations |
DE602004023476D1 (de) * | 2003-01-15 | 2009-11-19 | Chugai Pharmaceutical Co Ltd | Dimerisiertes peptid |
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US20040197312A1 (en) * | 2003-04-02 | 2004-10-07 | Marina Moskalenko | Cytokine-expressing cellular vaccine combinations |
AU2004255470B2 (en) * | 2003-07-10 | 2010-08-19 | Cytos Biotechnology Ag | Packaged virus-like particles |
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JP5427027B2 (ja) * | 2006-05-03 | 2014-02-26 | ザ・リージェンツ・オブ・ザ・ユニバーシティ・オブ・コロラド,ア・ボディー・コーポレイト | Cd40アゴニスト抗体/i型インターフェロン相乗性アジュバントの結合体、それを含む複合体、および細胞性免疫を強化する治療としてのその使用 |
GB0620894D0 (en) * | 2006-10-20 | 2006-11-29 | Univ Southampton | Human immune therapies using a CD27 agonist alone or in combination with other immune modulators |
DK2370593T3 (en) * | 2008-11-28 | 2016-07-04 | Univ Emory | A method for determining the effect of PD-1 Antagonists |
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BR112012026227A2 (pt) * | 2010-04-13 | 2020-08-04 | Celldex Therapeutics, Inc. | anticorpo monoclonal humano ou humanizado, molécula biespecífica, vetor de expressão, célula transformada, composição, e, usos de um anticorpo |
CN103157108B (zh) * | 2011-12-13 | 2016-01-20 | 宁云山 | 免疫调节剂组合物及其药物组合物和应用 |
CA2858876A1 (en) * | 2011-12-15 | 2013-06-20 | The University Of Chicago | Methods and compositions for cancer therapy using mutant light molecules with increased affinity to receptors |
AR090263A1 (es) * | 2012-03-08 | 2014-10-29 | Hoffmann La Roche | Terapia combinada de anticuerpos contra el csf-1r humano y las utilizaciones de la misma |
CN103830211A (zh) * | 2012-11-27 | 2014-06-04 | 上海曼克尔瑞生物医药技术有限公司 | 一种β-catenin蛋白抑制剂-姜黄素在肝癌治疗方面的应用 |
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KR102363191B1 (ko) * | 2013-02-26 | 2022-02-17 | 메모리얼 슬로안 케터링 캔서 센터 | 면역치료용 조성물 및 방법 |
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JP2016527303A (ja) * | 2013-08-05 | 2016-09-08 | ケンブリッジ エンタープライズ リミテッド | がん免疫療法におけるcxcr4シグナル伝達の阻害 |
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