JPWO2020081841A5 - - Google Patents
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- JPWO2020081841A5 JPWO2020081841A5 JP2021521098A JP2021521098A JPWO2020081841A5 JP WO2020081841 A5 JPWO2020081841 A5 JP WO2020081841A5 JP 2021521098 A JP2021521098 A JP 2021521098A JP 2021521098 A JP2021521098 A JP 2021521098A JP WO2020081841 A5 JPWO2020081841 A5 JP WO2020081841A5
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- JP
- Japan
- Prior art keywords
- cancer
- compound
- domain
- pharmaceutical composition
- antibody
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 108010024976 Asparaginase Proteins 0.000 claims description 6
- 102100026094 C-type lectin domain family 12 member A Human genes 0.000 claims description 6
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- 101000912622 Homo sapiens C-type lectin domain family 12 member A Proteins 0.000 claims description 6
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 6
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 6
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- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 claims description 3
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- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 3
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- 208000000453 Skin Neoplasms Diseases 0.000 claims description 3
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 claims description 3
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- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 claims description 3
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- 229960004528 vincristine Drugs 0.000 claims description 3
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims description 3
- 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 claims description 3
- 229960004355 vindesine Drugs 0.000 claims description 3
- 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 claims description 3
- 229960002066 vinorelbine Drugs 0.000 claims description 3
- 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 claims description 3
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 claims description 2
- 208000009565 Pharyngeal Neoplasms Diseases 0.000 claims description 2
- 206010034811 Pharyngeal cancer Diseases 0.000 claims description 2
- 210000004899 c-terminal region Anatomy 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000004936 stimulating effect Effects 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 10
- 230000001939 inductive effect Effects 0.000 claims 1
- 238000000034 method Methods 0.000 description 13
- 206010043515 Throat cancer Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
Description
いくつかの実施形態では、対象における癌を治療する方法を本明細書に提供し、本方法は、癌を治療するのに有効な量の本明細書に記載の化合物を対象に投与することを含む。いくつかの実施形態では、癌には、前立腺癌、肺癌、結腸癌、直腸癌、膀胱癌、黒色腫、腎臓癌、腎癌、口腔癌、咽頭癌、膵臓癌、子宮癌、甲状腺癌、皮膚癌、頭頸部癌、子宮頸癌、卵巣癌、または造血性癌が含まれる。いくつかの実施形態では、本明細書で提供される方法は、化学療法、腫瘍の外科的切除、または放射線療法の前、同時、または後に化合物を投与することをさらに含む。いくつかの実施形態では、化学療法は、アルトレタミン、アムサクリン、L-アスパラギナーゼ、コラスパーゼ(colaspase)、ブレオマイシン、ブスルファン、カペシタビン、カルボプラチン、カルムスチン、クロランブシル、シスプラチン、クラドリビン、シクロホスファミド、サイトホスファン(cytophosphane)、シタラビン、ダカルバジン、ダクチノマイシン、ダウノルビシン、ドセタキセル、ドキソルビシン、エピルビシン、エトポシド、フルオロウラシル、フルダラビン、フォテムスチン、ガンシクロビル、ゲムシタビン、ヒドロキシ尿素、イダルビシン、イフォスファマイド(ifosfamaide)、イリノテカン、ロムスチン、メルファラン、メルカプトプリン、メトトレキサート、ミトキサントロン、マイトマイシンC、ニムスチン、オキサリプラチン、パクリタキセル、ペメトレキセド、プロカルバジン、ラルチトレキセド、テモゾロミド、テニポシド、チオグアニン、チオテパ、トポテカン、ビンブラスチン、ビンクリスチン、ビンデシン、およびビノレルビンを含む。いくつかの実施形態では、造血性癌は、AMLである。
[本発明1001]
NK結合ドメインと、
前記NK結合ドメインに作動可能に連結されたNK活性化ドメインと、
標的細胞に選択的に結合する標的指向ドメインであって、前記NK活性化ドメインおよび前記NK結合ドメインに作動可能に連結された、前記標的指向ドメインと
を含む、化合物であって、
前記標的指向ドメインが、CLEC12Aに選択的に結合する、
前記化合物。
[本発明1002]
前記NK結合ドメインが、CD16に選択的に結合する部分を含む、本発明1001の化合物。
[本発明1003]
前記NK結合ドメイン部分が、抗体またはその結合フラグメント、あるいはナノボディを含む、本発明1001の化合物。
[本発明1004]
前記抗体結合フラグメントが、scFv、F(ab)2、またはFabを含む、本発明1003の化合物。
[本発明1005]
前記抗体またはその結合フラグメントあるいは前記ナノボディが、ヒトのものであるかまたはヒト化されている、本発明1003の化合物。
[本発明1006]
前記抗体またはその結合フラグメントあるいは前記ナノボディが、ラクダ科動物のものである、本発明1003の化合物。
[本発明1007]
前記NK活性化ドメインが、IL-15またはその機能的フラグメントを含む、本発明1001の化合物。
[本発明1008]
前記IL-15が、配列番号9のアミノ酸配列またはその機能的変異体を含む、本発明1007の化合物。
[本発明1009]
前記標的指向ドメイン部分が、抗体またはその結合フラグメント、あるいはナノボディを含む、本発明1001の化合物。
[本発明1010]
前記抗体結合フラグメントが、scFv、F(ab)2、またはFabを含む、本発明1009の化合物。
[本発明1011]
前記NK結合ドメインが、CD16に選択的に結合する部分を含み、前記NK活性化ドメインが、IL-15を含み、かつ前記標的指向ドメインが、CLEC12Aに選択的に結合する、本発明1001の化合物。
[本発明1012]
前記ドメインのうちの2つを連結する少なくとも1つの隣接配列を含む、本発明1001の化合物。
[本発明1013]
前記2つの連結されたドメインを第3のドメインと連結する第2の隣接配列をさらに含む、本発明1012の化合物。
[本発明1014]
前記隣接配列が、前記NK活性化ドメインに隣接している、本発明1013の化合物。
[本発明1015]
第1の隣接配列が、前記NK結合ドメインのC末端側であり、かつ第2の隣接配列が、前記抗CLEC12A標的指向ドメインのN末端側である、本発明1014の化合物。
[本発明1016]
配列番号1を含む、単離されたアミノ酸配列。
[本発明1017]
配列番号1のアミノ酸配列をコードする、単離されたDNA配列。
[本発明1018]
配列番号2を含む、単離されたアミノ酸配列。
[本発明1019]
配列番号2のアミノ酸配列をコードする、単離されたDNA配列。
[本発明1020]
前記CLEC12Aドメインが、配列番号4に記載されている、本発明1001の化合物。
[本発明1021]
本発明1001の化合物と、
薬学的に許容される担体と
を含む、組成物。
[本発明1022]
標的細胞のNK媒介性殺傷を誘導するのに有効な量の本発明1001の化合物を対象に投与することを含む、方法。
[本発明1023]
前記標的細胞が、癌細胞である、本発明1022の方法。
[本発明1024]
インビボでNK細胞の増殖を刺激するための方法であって、
対象におけるNK細胞の増殖を刺激するのに有効な量の本発明1001の化合物を前記対象に投与すること
を含む、前記方法。
[本発明1025]
対象の癌を治療する方法であって、
前記癌を治療するのに有効な量の本発明1001の化合物を前記対象に投与すること
を含む、前記方法。
[本発明1026]
前記癌が、前立腺癌、肺癌、結腸癌、直腸癌、膀胱癌、黒色腫、腎臓癌、腎癌、口腔癌、咽頭癌、膵臓癌、子宮癌、甲状腺癌、皮膚癌、頭頸部癌、子宮頸癌、卵巣癌、または造血性癌を含む、本発明1025の方法。
[本発明1027]
化学療法、腫瘍の外科的切除、または放射線療法の前、同時、または後に前記化合物を投与することをさらに含む、本発明1026の方法。
[本発明1028]
前記化学療法が、アルトレタミン、アムサクリン、L-アスパラギナーゼ、コラスパーゼ(colaspase)、ブレオマイシン、ブスルファン、カペシタビン、カルボプラチン、カルムスチン、クロランブシル、シスプラチン、クラドリビン、シクロホスファミド、サイトホスファン(cytophosphane)、シタラビン、ダカルバジン、ダクチノマイシン、ダウノルビシン、ドセタキセル、ドキソルビシン、エピルビシン、エトポシド、フルオロウラシル、フルダラビン、フォテムスチン、ガンシクロビル、ゲムシタビン、ヒドロキシ尿素、イダルビシン、イフォスファマイド(ifosfamaide)、イリノテカン、ロムスチン、メルファラン、メルカプトプリン、メトトレキサート、ミトキサントロン、マイトマイシンC、ニムスチン、オキサリプラチン、パクリタキセル、ペメトレキセド、プロカルバジン、ラルチトレキセド、テモゾロミド、テニポシド、チオグアニン、チオテパ、トポテカン、ビンブラスチン、ビンクリスチン、ビンデシン、およびビノレルビンを含む、本発明1027の方法。
[本発明1029]
前記造血性癌が、AMLである、本発明1026の方法。
In some embodiments, provided herein are methods of treating cancer in a subject, the methods comprising administering to the subject an amount of a compound described herein effective to treat cancer. include. In some embodiments, cancer includes prostate cancer, lung cancer, colon cancer, rectal cancer, bladder cancer, melanoma, kidney cancer, renal cancer, oral cancer, throat cancer, pancreatic cancer, uterine cancer, thyroid cancer, skin cancer. Included are cancer, head and neck cancer, cervical cancer, ovarian cancer, or hematopoietic cancer. In some embodiments, the methods provided herein further comprise administering a compound prior to, concurrently with, or after chemotherapy, surgical resection of the tumor, or radiation therapy. In some embodiments, the chemotherapy is altretamine, amsacrine, L-asparaginase, colaspase, bleomycin, busulfan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, cyclophosphamide, cytophosphane ), cytarabine, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, etoposide, fluorouracil, fludarabine, fotemustine, ganciclovir, gemcitabine, hydroxyurea, idarubicin, ifosfamaide, irinotecan, lomustine, melphalan, Mercaptopurine, methotrexate, mitoxantrone, mitomycin C, nimustine, oxaliplatin, paclitaxel, pemetrexed, procarbazine, raltitrexed, temozolomide, teniposide, thioguanine, thiotepa, topotecan, vinblastine, vincristine, vindesine, and vinorelbine. In some embodiments, the hematopoietic cancer is AML.
[Invention 1001]
an NK binding domain;
an NK activation domain operably linked to the NK binding domain;
a targeting domain that selectively binds to a target cell, said targeting domain being operably linked to said NK activation domain and said NK binding domain;
A compound comprising
said targeting domain selectively binds to CLEC12A;
said compound.
[Invention 1002]
1001. The compound of the invention 1001, wherein said NK binding domain comprises a portion that selectively binds to CD16.
[Invention 1003]
1001. The compound of the invention 1001, wherein said NK binding domain portion comprises an antibody or binding fragment thereof, or a Nanobody.
[Invention 1004]
1003. The compound of the invention 1003, wherein said antibody binding fragment comprises scFv, F(ab)2, or Fab.
[Invention 1005]
1003. The compound of the invention 1003, wherein said antibody or binding fragment thereof or said Nanobody is human or humanized.
[Invention 1006]
1003. The compound of the invention 1003, wherein said antibody or binding fragment thereof or said Nanobody is camelid.
[Invention 1007]
1001. The compound of the invention 1001, wherein said NK activation domain comprises IL-15 or a functional fragment thereof.
[Invention 1008]
1007. The compound of the invention 1007, wherein said IL-15 comprises the amino acid sequence of SEQ ID NO:9 or a functional variant thereof.
[Invention 1009]
1001. The compound of the invention 1001, wherein said targeting domain portion comprises an antibody or binding fragment thereof, or a Nanobody.
[Invention 1010]
1009. The compound of the invention 1009, wherein said antibody binding fragment comprises scFv, F(ab)2, or Fab.
[Invention 1011]
1001. The compound of the invention 1001, wherein said NK binding domain comprises a moiety that selectively binds to CD16, said NK activation domain comprises IL-15, and said targeting domain selectively binds to CLEC12A. .
[Invention 1012]
1001. A compound of the invention 1001 comprising at least one flanking sequence linking two of said domains.
[Invention 1013]
1012. The compound of the invention 1012 further comprising a second flanking sequence linking said two linked domains with a third domain.
[Invention 1014]
1013. The compound of the invention 1013, wherein said flanking sequences flank said NK activation domain.
[Invention 1015]
1014. The compound of the invention 1014, wherein a first flanking sequence is C-terminal to said NK binding domain and a second flanking sequence is N-terminal to said anti-CLEC12A targeting domain.
[Invention 1016]
An isolated amino acid sequence, including SEQ ID NO:1.
[Invention 1017]
An isolated DNA sequence encoding the amino acid sequence of SEQ ID NO:1.
[Invention 1018]
An isolated amino acid sequence, including SEQ ID NO:2.
[Invention 1019]
An isolated DNA sequence encoding the amino acid sequence of SEQ ID NO:2.
[Invention 1020]
1001. The compound of the invention 1001, wherein said CLEC12A domain is set forth in SEQ ID NO:4.
[Invention 1021]
a compound of the present invention 1001;
a pharmaceutically acceptable carrier and
A composition comprising:
[Invention 1022]
A method comprising administering to a subject an amount of a compound of invention 1001 effective to induce NK-mediated killing of a target cell.
[Invention 1023]
1023. The method of invention 1022, wherein said target cell is a cancer cell.
[Invention 1024]
A method for stimulating NK cell proliferation in vivo comprising:
administering to said subject an amount of a compound of the present invention 1001 effective to stimulate proliferation of NK cells in said subject
The above method, comprising
[Invention 1025]
A method of treating cancer in a subject, comprising:
administering to said subject an amount of a compound of the invention 1001 effective to treat said cancer
The above method, comprising
[Invention 1026]
The cancer is prostate cancer, lung cancer, colon cancer, rectal cancer, bladder cancer, melanoma, kidney cancer, renal cancer, mouth cancer, pharyngeal cancer, pancreatic cancer, uterine cancer, thyroid cancer, skin cancer, head and neck cancer, child cancer The method of the invention 1025, comprising cervical cancer, ovarian cancer, or hematopoietic cancer.
[Invention 1027]
The method of invention 1026, further comprising administering said compound prior to, concurrently with, or after chemotherapy, surgical resection of the tumor, or radiation therapy.
[Invention 1028]
said chemotherapy is altretamine, amsacrine, L-asparaginase, colaspase, bleomycin, busulfan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, cyclophosphamide, cytophosphane, cytarabine, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, etoposide, fluorouracil, fludarabine, fotemustine, ganciclovir, gemcitabine, hydroxyurea, idarubicin, ifosfamaide, irinotecan, lomustine, melphalan, mercaptopurine, methotrexate, mitoki 1027. The method of the present invention, comprising santron, mitomycin C, nimustine, oxaliplatin, paclitaxel, pemetrexed, procarbazine, raltitrexed, temozolomide, teniposide, thioguanine, thiotepa, topotecan, vinblastine, vincristine, vindesine, and vinorelbine.
[Invention 1029]
1026. The method of the invention 1026, wherein said hematopoietic cancer is AML.
Claims (29)
前記NK結合ドメインに作動可能に連結されたNK活性化ドメインと、
標的細胞に選択的に結合する標的指向ドメインであって、前記NK活性化ドメインおよび前記NK結合ドメインに作動可能に連結された、前記標的指向ドメインと
を含む、化合物であって、
前記標的指向ドメインが、CLEC12Aに選択的に結合する、
前記化合物。 an NK binding domain;
an NK activation domain operably linked to the NK binding domain;
a targeting domain that selectively binds to a target cell, said targeting domain operably linked to said NK activation domain and said NK binding domain, said compound comprising:
said targeting domain selectively binds to CLEC12A;
said compound.
薬学的に許容される担体と
を含む、組成物。 a compound of claim 1;
and a pharmaceutically acceptable carrier.
対象におけるNK細胞の増殖を刺激するのに有効な量の請求項1に記載の化合物を含む、前記医薬組成物。 A pharmaceutical composition for stimulating NK cell proliferation in a subject , comprising:
11. The pharmaceutical composition comprising an amount of the compound of claim 1 effective to stimulate NK cell proliferation in a subject.
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US62/747,983 | 2018-10-19 | ||
PCT/US2019/056777 WO2020081841A1 (en) | 2018-10-19 | 2019-10-17 | Nk engager molecules and methods of use thereof |
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EP (1) | EP3867278A4 (en) |
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KR (1) | KR20210081346A (en) |
CN (1) | CN112912400A (en) |
AU (1) | AU2019361096A1 (en) |
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JP6471095B2 (en) * | 2012-09-27 | 2019-02-20 | メルス ナムローゼ フェンノートシャップ | Bispecific IgG antibody as a T cell engager |
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