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- JPWO2021087466A5 JPWO2021087466A5 JP2022525329A JP2022525329A JPWO2021087466A5 JP WO2021087466 A5 JPWO2021087466 A5 JP WO2021087466A5 JP 2022525329 A JP2022525329 A JP 2022525329A JP 2022525329 A JP2022525329 A JP 2022525329A JP WO2021087466 A5 JPWO2021087466 A5 JP WO2021087466A5
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- 210000000822 natural killer cell Anatomy 0.000 claims description 58
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- 239000002246 antineoplastic agent Substances 0.000 claims description 8
- 101150002659 CD38 gene Proteins 0.000 claims description 5
- 108090000623 proteins and genes Proteins 0.000 claims description 5
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 4
- 208000016778 CD4+/CD56+ hematodermic neoplasm Diseases 0.000 claims description 4
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- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 4
- 108020004459 Small interfering RNA Proteins 0.000 claims description 4
- 239000004037 angiogenesis inhibitor Substances 0.000 claims description 4
- 229940121369 angiogenesis inhibitor Drugs 0.000 claims description 4
- 229960002204 daratumumab Drugs 0.000 claims description 4
- 239000003862 glucocorticoid Substances 0.000 claims description 4
- 210000005134 plasmacytoid dendritic cell Anatomy 0.000 claims description 4
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 4
- 102000004169 proteins and genes Human genes 0.000 claims description 4
- 150000003384 small molecules Chemical class 0.000 claims description 4
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- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 claims description 3
- 238000010453 CRISPR/Cas method Methods 0.000 claims description 3
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- 230000000735 allogeneic effect Effects 0.000 claims description 2
- IMOZEMNVLZVGJZ-QGZVFWFLSA-N apremilast Chemical compound C1=C(OC)C(OCC)=CC([C@@H](CS(C)(=O)=O)N2C(C3=C(NC(C)=O)C=CC=C3C2=O)=O)=C1 IMOZEMNVLZVGJZ-QGZVFWFLSA-N 0.000 claims description 2
- 229960001164 apremilast Drugs 0.000 claims description 2
- 229960002537 betamethasone Drugs 0.000 claims description 2
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 claims description 2
- 229960003957 dexamethasone Drugs 0.000 claims description 2
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims description 2
- 238000004520 electroporation Methods 0.000 claims description 2
- SYWHXTATXSMDSB-GSLJADNHSA-N fludrocortisone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O SYWHXTATXSMDSB-GSLJADNHSA-N 0.000 claims description 2
- 229960003336 fluorocortisol acetate Drugs 0.000 claims description 2
- 238000009169 immunotherapy Methods 0.000 claims description 2
- 229960004942 lenalidomide Drugs 0.000 claims description 2
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 claims description 2
- -1 methylprenisolone Chemical compound 0.000 claims description 2
- 229960000688 pomalidomide Drugs 0.000 claims description 2
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 claims description 2
- 229960005205 prednisolone Drugs 0.000 claims description 2
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 claims description 2
- 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 claims description 2
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- 108020004414 DNA Proteins 0.000 claims 1
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- 230000008685 targeting Effects 0.000 claims 1
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 5
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- 231100000135 cytotoxicity Toxicity 0.000 description 4
- WRFHGDPIDHPWIQ-UHFFFAOYSA-N 2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-2-(ethoxymethyl)phenyl]-n-(4,5-dimethyl-1,2-oxazol-3-yl)benzenesulfonamide Chemical compound O=C1N(CC=2C=C(COCC)C(=CC=2)C=2C(=CC=CC=2)S(=O)(=O)NC=2C(=C(C)ON=2)C)C(CCCC)=NC21CCCC2 WRFHGDPIDHPWIQ-UHFFFAOYSA-N 0.000 description 2
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- 230000001419 dependent effect Effects 0.000 description 1
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Description
ＭＭ細胞に対するＣＤ３８ＫＯＮＫ細胞の優れたイサツキシマブ媒介性ＡＤＣＣ．ＮＫ細胞のＤＡＲＡ誘発性枯渇は、標的細胞に対する細胞依存性細胞傷害を鈍化させる可能性があるため、ＣＤ３８ＫＯＮＫ細胞はまた、ＣＤ３８ＷＴＮＫ細胞よりも効率的に標的細胞を殺傷することができる。これがイサツキシマブにも適用されるかどうかを研究するために、高レベル、低レベル、または皆無のＣＤ３８発現を有する異なるＭＭ細胞株に対して、対のＣＤ３８ＷＴおよびＣＤ３８ＫＯＮＫ細胞の細胞傷害性を、イサツキシマブの存在下または不在下で試験することができる。各ＭＭ細胞株に対する直接的な細胞傷害性は、ＣＤ３８ＷＴとＣＤ３８ＫＯＮＫ細胞との間で同等であるが、イサツキシマブの存在下では、ＣＤ３８ＫＯＮＫ細胞は、ＣＤ３８＋標的細胞に対して有意に高い細胞傷害性を示し、ＣＤ３８ＫＯＮＫ細胞のより高いＡＤＣＣを示している。ＤＡＲＡ実験と同様に、ＣＤ３８ＷＴＮＫ細胞は、ＯＰＭ－２およびＫＭＳ－１１などの低レベルのＣＤ３８発現を有するＭＭ細胞に対して、わずかなまたは皆無のＡＤＣＣを示すが、ＣＤ３８ＫＯＮＫ細胞は、これらのＭＭ細胞株に対して、有意により強いＡＤＣＣを示す。細胞株を用いた結果と同様に、ＣＤ３８ＫＯＮＫ細胞は、初代ＭＭ試料に対して、より高いイサツキシマブ媒介性ＡＤＣＣ活性を示す。
本発明によれば、以下の態様を提供し得る。
[１]
対象におけるがんを治療する方法であって、前記対象に、ＣＤ３８遺伝子のノックアウトを含むように改変されているＮＫ細胞を投与することを含む、方法。
[２]
前記がんが、多発性骨髄腫、急性骨髄性白血病（ＡＭＬ）、Ｔ細胞性急性リンパ芽球性白血病（Ｔ－ＡＬＬ）、または芽球性形質細胞様樹状細胞腫瘍（ＢＰＤＣＮ）を含む、上記[１]に記載のがんを治療する方法。
[３]
前記対象に、ＣＤ３８を標的とする小分子、抗体、ペプチド、タンパク質、またはｓｉＲＮＡを含む抗がん剤を投与することをさらに含む、上記[１]または[２]に記載のがんを治療する方法。
[４]
前記抗がん剤が、ダラツムマブ、イサツキシマブ、ＴＡＫ－０７９、またはＭＯＲ２０２を含む、上記[３]に記載のがんを治療する方法。
[５]
前記対象に、血管新生阻害剤およびステロイドを投与することをさらに含む、上記[３]または[４]に記載のがんを治療する方法。
[６]
前記血管新生阻害剤が、ポマリドミド、レナリドミド、またはアプレミラストを含む、上記[５]に記載のがんを治療する方法。
[７]
前記ステロイドが、グルココルチコイドを含む、上記[５]に記載のがんを治療する方法。
[８]
前記グルココルチコイドが、デキサメタゾン、ベタメタゾン、プレドニゾロン、メソッドルプレニゾロン、トリアムシノロン、または酢酸フルドロコルチゾンを含む、上記[７]に記載のがんを治療する方法。
[９]
操作されたＮＫ細胞を、それを必要とする対象に養子移植する方法であって、
ａ）改変される標的ＮＫ細胞を得ることと、
ｂ）標的ＤＮＡ配列に特異的なｇＲＮＡを得ることと、
ｃ）エレクトロポレーションを介して、前記標的ＮＫ細胞に、前記標的ＮＫ細胞のゲノムＤＮＡ内の標的配列にハイブリダイズする対応するＣＲＩＳＰＲ／ＣａｓガイドＲＮＡと複合体化したクラス２ ＣＲＩＳＰＲ／Ｃａｓエンドヌクレアーゼ（Ｃａｓ９）を含むＲＮＰ複合体を導入して、操作されたＮＫ細胞を生成することと、
ｄ）前記操作されたＮＫ細胞を前記対象に移植することと、を含む、方法。
[１０]
前記対象が、がんを有する、上記[９]に記載の方法。
[１１]
前記ＮＫ細胞が、エクスビボで改変されており、かつ改変後に前記対象に移植される、初代ＮＫ細胞である、上記[９]に記載の方法。
[１２]
前記ＮＫ細胞が、自己ＮＫ細胞である、上記[９]に記載の方法。
[１３]
前記ＮＫ細胞が、同種ドナー源由来である、上記[９]に記載の方法。
[１４]
前記ＮＫ細胞を、前記対象に投与する前に、照射されたｍｂＩＬ－２１発現フィーダー細胞とともに増殖させる、上記[９]に記載の方法。
[１５]
前記対象への前記ＮＫ細胞の移植後に、前記ＮＫ細胞を、ＩＬ－２１または照射されたｍｂＩＬ－２１発現フィーダー細胞の投与を介して、前記対象において増殖させる、上記[９]に記載の方法。
[１６]
前記ＲＮＰ複合体が、前記ＣＤ３８遺伝子を標的とする、上記[９]に記載の方法。
[１７]
上記[９]～[１６]のいずれかに記載の方法によって作製された表面抗原分類３８（ＣＤ３８）をコードする遺伝子のノックアウトを含む、遺伝子改変ＮＫ細胞。
[１８]
対象におけるがんを治療する方法であって、前記対象に、上記[１７]に記載の遺伝子改変ＮＫ細胞を投与することを含む、方法。
[１９]
前記対象に、ＣＤ３８を標的とする小分子、抗体、ペプチド、タンパク質、またはｓｉＲＮＡを含む抗がん剤を投与することをさらに含む、上記[１８]に記載の方法。
[２０]
前記抗がん剤が、抗ＣＤ３８抗体を含む、上記[１９]に記載のがんを治療する方法。
[２１]
前記抗ＣＤ３８抗体が、ダラツムマブ、イサツキシマブ、ＴＡＫ－０７９、またはＭＯＲ２０２を含む、上記[２０]に記載のがんを治療する方法。
[２２]
前記がんが、多発性骨髄腫、急性骨髄性白血病（ＡＭＬ）、Ｔ細胞性急性リンパ芽球性白血病（Ｔ－ＡＬＬ）、または芽球性形質細胞様樹状細胞腫瘍（ＢＰＤＣＮ）を含む、上記[１８]～[２１]のいずれかに記載のがんを治療する方法。
[２３]
抗ＣＤ３８免疫療法を受ける対象においてＮＫ細胞のフラトリサイドを低減する方法であって、前記対象に、上記[１７]に記載の遺伝子改変ＮＫ細胞を投与することを含む、方法。
Superior isatuximab-mediated ADCC of CD38 KO NK cells against MM cells. CD38 KO NK cells may also kill target cells more efficiently than CD38 WT NK cells, as DARA-induced depletion of NK cells may blunt cell-dependent cytotoxicity against target cells. . To study whether this also applies to isatuximab, we measured the cytotoxicity of paired CD38 WT and CD38 KO NK cells against different MM cell lines with high, low, or no CD38 expression. , can be tested in the presence or absence of isatuximab. Direct cytotoxicity against each MM cell line is comparable between CD38 WT and CD38 KO NK cells, but in the presence of isatuximab, CD38 KO NK cells are significantly less potent against CD38 + target cells. Showing high cytotoxicity and higher ADCC of CD38 KO NK cells. Similar to DARA experiments, CD38 WT NK cells show little or no ADCC to MM cells with low levels of CD38 expression, such as OPM-2 and KMS-11, whereas CD38 KO NK cells Shows significantly stronger ADCC for these MM cell lines. Similar to the results with cell lines, CD38 KO NK cells exhibit higher isatuximab-mediated ADCC activity relative to primary MM samples.
According to the present invention, the following aspects can be provided.
[1]
A method of treating cancer in a subject, the method comprising administering to the subject NK cells that have been modified to include a knockout of the CD38 gene.
[2]
the cancer comprises multiple myeloma, acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (T-ALL), or blastic plasmacytoid dendritic cell tumor (BPDCN), The method for treating cancer described in [1] above.
[3]
Treating the cancer according to [1] or [2] above, further comprising administering to the subject an anticancer agent containing a small molecule, antibody, peptide, protein, or siRNA that targets CD38. Method.
[4]
The method for treating cancer according to [3] above, wherein the anticancer drug includes daratumumab, isatuximab, TAK-079, or MOR202.
[5]
The method for treating cancer according to [3] or [4] above, further comprising administering an angiogenesis inhibitor and a steroid to the subject.
[6]
The method for treating cancer according to [5] above, wherein the angiogenesis inhibitor includes pomalidomide, lenalidomide, or apremilast.
[7]
The method for treating cancer according to [5] above, wherein the steroid includes a glucocorticoid.
[8]
The method for treating cancer according to [7] above, wherein the glucocorticoid includes dexamethasone, betamethasone, prednisolone, method luprenisolone, triamcinolone, or fludrocortisone acetate.
[9]
A method for adoptively transferring engineered NK cells to a subject in need thereof, the method comprising:
a) obtaining target NK cells to be modified;
b) obtaining gRNA specific for the target DNA sequence;
c) delivering to said target NK cells via electroporation a class 2 CRISPR/Cas endonuclease ( introducing an RNP complex containing Cas9) to generate engineered NK cells;
d) transplanting the engineered NK cells into the subject.
[10]
The method according to [9] above, wherein the subject has cancer.
[11]
The method according to [9] above, wherein the NK cells are primary NK cells that have been modified ex vivo and are transplanted into the subject after modification.
[12]
The method according to [9] above, wherein the NK cells are autologous NK cells.
[13]
The method according to [9] above, wherein the NK cells are derived from an allogeneic donor source.
[14]
The method according to [9] above, wherein the NK cells are grown together with irradiated mbIL-21-expressing feeder cells before being administered to the subject.
[15]
The method according to [9] above, wherein after transplantation of the NK cells into the subject, the NK cells are expanded in the subject via administration of IL-21 or irradiated mbIL-21-expressing feeder cells.
[16]
The method according to [9] above, wherein the RNP complex targets the CD38 gene.
[17]
A genetically modified NK cell comprising a knockout of the gene encoding surface antigen classification 38 (CD38) produced by the method according to any one of [9] to [16] above.
[18]
A method for treating cancer in a subject, the method comprising administering to the subject the genetically modified NK cells described in [17] above.
[19]
The method according to [18] above, further comprising administering to the subject an anticancer agent containing a small molecule, antibody, peptide, protein, or siRNA that targets CD38.
[20]
The method for treating cancer according to [19] above, wherein the anti-cancer agent comprises an anti-CD38 antibody.
[21]
The method for treating cancer according to [20] above, wherein the anti-CD38 antibody comprises daratumumab, isatuximab, TAK-079, or MOR202.
[22]
the cancer comprises multiple myeloma, acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (T-ALL), or blastic plasmacytoid dendritic cell tumor (BPDCN), The method for treating cancer according to any one of [18] to [21] above.
[23]
A method for reducing NK cell fratricide in a subject receiving anti-CD38 immunotherapy, the method comprising administering to the subject the genetically modified NK cells described in [17] above.
Claims (17)
ａ）改変される標的ＮＫ細胞を得ることと、 a) obtaining target NK cells to be modified;
ｂ）標的ＤＮＡ配列に特異的なｇＲＮＡを得ることと、 b) obtaining gRNA specific for the target DNA sequence;
ｃ）エレクトロポレーションを介して、前記標的ＮＫ細胞に、前記標的ＮＫ細胞のゲノムＤＮＡ内の標的配列にハイブリダイズする対応するＣＲＩＳＰＲ／ＣａｓガイドＲＮＡと複合体化したクラス２ ＣＲＩＳＰＲ／Ｃａｓエンドヌクレアーゼを含むＲＮＰ複合体を導入して、操作されたＮＫ細胞を生成することであって、前記ＲＮＰ複合体がＣＤ３８遺伝子を標的とすることと、を含む方法によってエクスビボで改変される、遺伝子改変ＮＫ細胞。 c) applying to said target NK cells via electroporation a class 2 CRISPR/Cas endonuclease complexed with a corresponding CRISPR/Cas guide RNA that hybridizes to a target sequence within the genomic DNA of said target NK cells; Genetically modified NK cells are modified ex vivo by a method comprising: introducing an RNP complex comprising an RNP complex to produce an engineered NK cell, the RNP complex targeting the CD38 gene; .
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201962928524P | 2019-10-31 | 2019-10-31 | |
| US62/928,524 | 2019-10-31 | ||
| PCT/US2020/058565 WO2021087466A1 (en) | 2019-10-31 | 2020-11-02 | Generation of cd38 knock-out primary and expanded human nk cells |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2022554284A JP2022554284A (en) | 2022-12-28 |
| JPWO2021087466A5 true JPWO2021087466A5 (en) | 2024-03-14 |
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| Application Number | Title | Priority Date | Filing Date |
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| JP2022525329A Pending JP2022554284A (en) | 2019-10-31 | 2020-11-02 | Generation of CD38 knockout primary and expanded human NK cells |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US20220401482A1 (en) |
| EP (1) | EP4051297A4 (en) |
| JP (1) | JP2022554284A (en) |
| KR (1) | KR20220093337A (en) |
| CN (1) | CN114867485A (en) |
| AU (1) | AU2020375053A1 (en) |
| BR (1) | BR112022008215A2 (en) |
| CA (1) | CA3156509A1 (en) |
| IL (1) | IL292584A (en) |
| MX (1) | MX2022005051A (en) |
| WO (1) | WO2021087466A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11661459B2 (en) | 2020-12-03 | 2023-05-30 | Century Therapeutics, Inc. | Artificial cell death polypeptide for chimeric antigen receptor and uses thereof |
| TW202241935A (en) | 2020-12-18 | 2022-11-01 | 美商世紀治療股份有限公司 | Chimeric antigen receptor system with adaptable receptor specificity |
| EP4362957A1 (en) | 2021-07-01 | 2024-05-08 | Indapta Therapeutics, Inc. | Engineered natural killer (nk) cells and related methods |
| CN118369110A (en) * | 2021-11-03 | 2024-07-19 | 英特利亚治疗股份有限公司 | CD38 compositions and methods for immunotherapy |
| WO2023080210A1 (en) * | 2021-11-05 | 2023-05-11 | 学校法人東海大学 | Identification of treatment target in aggressive nk leukemia |
| WO2023172917A1 (en) | 2022-03-07 | 2023-09-14 | Sanofi-Aventis U.S. Llc | Use of isatuximab in combination with other agents for the treatment of multiple myeloma |
| CN114921416B (en) * | 2022-05-12 | 2023-05-23 | 广东普罗凯融生物医药科技有限公司 | NK cell and preparation method thereof |
| WO2024007020A1 (en) | 2022-06-30 | 2024-01-04 | Indapta Therapeutics, Inc. | Combination of engineered natural killer (nk) cells and antibody therapy and related methods |
| WO2024124242A2 (en) * | 2022-12-09 | 2024-06-13 | Research Institute At Nationwide Children's Hospital | Combination cd38ko/car ki nk cell immunotherapy for dual targeting with cd38 monoclonal antibodies |
| WO2024124244A1 (en) * | 2022-12-09 | 2024-06-13 | Research Institute At Nationwide Children's Hospital | Cd38 as integration site for enhanced function of gene-modified immune cells |
| WO2024155711A1 (en) * | 2023-01-17 | 2024-07-25 | Research Institute At Nationwide Children's Hospital | Methods of targeting glycogen synthase kinase 3 beta in nk cells |
| CN116679065B (en) * | 2023-07-31 | 2023-11-14 | 北京大学人民医院 | Application of detection reagent, method for predicting prognosis of multiple myeloma treatment and product |
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| CA2986314C (en) * | 2015-06-30 | 2024-04-23 | Cellectis | Methods for improving functionality in nk cell by gene inactivation using specific endonuclease |
| MA42895A (en) * | 2015-07-15 | 2018-05-23 | Juno Therapeutics Inc | MODIFIED CELLS FOR ADOPTIVE CELL THERAPY |
| WO2017127755A1 (en) * | 2016-01-20 | 2017-07-27 | Fate Therapeutics, Inc. | Compositions and methods for immune cell modulation in adoptive immunotherapies |
| ES2746856T3 (en) * | 2016-12-09 | 2020-03-09 | Onk Therapeutics Ltd | Manipulated natural killer cells and their uses |
| BR112020023232A2 (en) * | 2018-05-16 | 2021-02-23 | Research Institute At Nationwide Children's Hospital | generation of expanded and primary knock-out human nk cells using cas9 ribonucleoproteins |
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