JP2021510702A - 相乗的がん治療 - Google Patents
相乗的がん治療 Download PDFInfo
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- JP2021510702A JP2021510702A JP2020538844A JP2020538844A JP2021510702A JP 2021510702 A JP2021510702 A JP 2021510702A JP 2020538844 A JP2020538844 A JP 2020538844A JP 2020538844 A JP2020538844 A JP 2020538844A JP 2021510702 A JP2021510702 A JP 2021510702A
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- Prior art keywords
- inhibitor
- topoisomerase
- ddr
- subject
- conjugate
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Abstract
Description
この出願は、2018年1月12日出願の米国仮出願第62/617,095号、2018年5月21日出願の米国仮出願第62/674,483号、2018年7月27日出願の米国仮出願62/711,421号、2018年8月9日出願の米国仮出願第62/716,788号、2018年8月9日出願の米国仮出願第62/716,796号、2018年7月18日出願の米国仮出願第62/700,147号、および2018年7月27日出願の米国仮出願第62/711,423号からの優先権を主張するものであり、これらの開示内容はその全体が参照により本明細書に組み込まれる。
本発明は、がんを治療するための、β脱離(beta elimination)を受ける結合(linkage)を介して高分子に連結されたトポイソメラーゼI阻害剤の使用に関する。より具体的には、本発明は、薬物動態が適切に制御される場合のトポイソメラーゼI阻害剤によるがん担持対象者の治療に関し、該対象者にはDNA損傷応答(DNA damage response:DDR)の遺伝的欠陥があり、かつ/または前記治療は、トポイソメラーゼI阻害剤を、DDRの阻害剤と組み合わせて、または細胞周期チェックポイント阻害剤と組み合わせて、投与することを含む。ある実施形態では、本発明は、DDRに必要な遺伝子の欠陥により、別の遺伝子が細胞生存に不可欠となる場合の、がん細胞における合成致死的相互作用(synthetic lethal interactions)の利用を必然的に伴う。
先に引用した文献から明らかなように、トポイソメラーゼIは、DNA複製に不可欠であって、細胞増殖および複製にとって必須であることが知られている。トポイソメラーゼIの阻害剤、例えば、イリノテカンおよびその活性代謝産物であるSN-38は、良好なDNA複製を阻害することによってがんを治療するために使用されてきた。
式中、
PEGは、直鎖状または分枝鎖状、qが2〜8である場合はマルチアーム状の、ポリエチレングリコールである;
Xは、(CH2)mであり、ここでm=1〜6;
Lは、(CH2CH2O)p(CH2)rであり、ここでr=1〜10およびp=0〜10;
R1は、CNまたはSO2NR2 2であり、ここで各R2は、独立して、アルキル、アリール、ヘテロアリール、アルキルアルケニル、アルキルアリール、またはアルキルヘテロアリールであるか、2個のR2は一緒になって環を形成できる;
Yは、COR3またはSO2R3であり、ここでR3=OH、アルコキシ、またはNR4 2、ここで各R4は、独立して、アルキル、置換アルキルであるか、2個のR4は一緒になって環を形成できる;および
qは、1〜8である。
PLX038AとPARP阻害剤タラゾパリブ(Talazoparib;別名BMN673またはTLZ)の相乗効果
マウスMX-1異種移植片の準備:
MX-1細胞株をCharles River Labs(Frederick, メリーランド州)から入手した1。細胞をRPMI-1640、10%FBS、および1%2mM L-グルタミン中37℃で95%空気/5%CO2の雰囲気にて培養した。
1 Ovejera AA et al. Chemotherapy of human tumor xenografts in genetically athymic mice. Ann Clin Lab Sci 8: 50-6, 1978.
2 Morton CL, Houghton PJ. Establishment of human tumor xenografts in immunodeficient mice. Nat Protoc. 2007;2(2):247-50.
PLX038A(1.02mM SN38;0.26mM PLX038Aコンジュゲート)の溶液をpH5の等張酢酸中に調製し、使用前に滅菌ろ過(0.2μm)した。BMN673(52μM)の溶液を10%ジメチルアセトアミド/5%Solutol HS15/85%1X PBS中に調製し、使用前に滅菌ろ過(0.2μm)した。
PLX038Aと腫瘍細胞欠陥の相乗作用
MX-1細胞はBRCA 1欠損であり、CAPAN-1細胞はBRCA 2欠損(-/-)または欠損なし(+/+)として供給される。これらの細胞株の腫瘍を担持するマウスを用いて、実施例1の一般的なプロトコルを行った。MX-1腫瘍があるマウスの場合、投与量は、137μg/kgのイリノテカンまたは4、40もしくは120μg/kgのPLX038Aの単回の腹腔内注入であった。CAPAN-1異種移植片を持つマウスの場合、投与量は、137μg/kgのイリノテカンまたは15、40もしくは120μg/kgのPLX038Aの単回の腹腔内注入であった。図4A〜4Cは、週2回測定された腫瘍体積に対するこれらの投与量の結果を示す。
Claims (17)
- がんの治療が必要な対象者におけるがんの治療方法であって、該対象者は、DNA損傷応答(DDR)に1つまたは複数の欠陥があると診断されており、該対象者に、有効量の、β脱離機構による切断を受け得るリンカーを介して高分子に結合されたトポイソメラーゼI阻害剤のコンジュゲートを投与することを含む方法。
- 前記対象者に、前記コンジュゲートと組み合わせて、有効量のDDRの阻害剤を投与することを含む、請求項1に記載の方法。
- 前記対象者に、前記コンジュゲートと組み合わせて、有効量の細胞周期チェックポイント阻害剤を投与することを含む、請求項1に記載の方法。
- 前記欠陥があるかないかについて前記対象者を診断することをさらに含む、請求項1に記載の方法。
- 前記トポイソメラーゼI阻害剤がSN-38である、請求項1に記載の方法。
- 前記高分子がポリエチレングリコール(PEG)である、請求項5に記載の方法。
- 前記コンジュゲートがPLX038である、請求項5に記載の方法。
- 前記対象者におけるDDRの欠陥が相同的組換え修復(HRR)の欠陥または一本鎖切断修復の欠陥であるか、該欠陥が腫瘍抑制遺伝子にある、請求項1〜7のいずれか1つに記載の方法。
- 前記DDRの阻害剤が、HRR修復の阻害剤または一本鎖切断修復の阻害剤である、請求項2に記載の方法。
- 前記細胞周期チェックポイント阻害剤が、CHK1、CHK2またはWee1キナーゼの阻害剤である、請求項3に記載の方法。
- がんの治療が必要な対象者におけるがんの治療方法であって、該対象者に、有効量の、β脱離機構による切断を受け得るリンカーを介して高分子に結合されたトポイソメラーゼI阻害剤のコンジュゲートを、有効量のDDRの阻害剤と組み合わせて投与することを含む方法。
- 前記阻害剤がHRR修復または一本鎖切断修復の阻害剤である、請求項11に記載の方法。
- がんの治療が必要な対象者におけるがんの治療方法であって、該対象者に、有効量の、β脱離機構による切断を受け得るリンカーを介して高分子に結合されたトポイソメラーゼI阻害剤のコンジュゲートを、有効量の細胞周期チェックポイント阻害剤と組み合わせて投与することを含む方法。
- 前記細胞周期チェックポイント阻害剤が、CHK1、CHK2またはWee1キナーゼの阻害剤である、請求項13に記載の方法。
- 前記トポイソメラーゼI阻害剤がSN-38である、請求項11〜14のいずれか1つに記載の方法。
- 前記高分子がポリエチレングリコール(PEG)である、請求項15に記載の方法。
- 前記コンジュゲートがPLX038である、請求項15に記載の方法。
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CN111587126A (zh) | 2020-08-25 |
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WO2019140271A2 (en) | 2019-07-18 |
JP2021510701A (ja) | 2021-04-30 |
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MX2020007306A (es) | 2020-09-25 |
EP3737416A1 (en) | 2020-11-18 |
CA3087967A1 (en) | 2019-07-18 |
EP3737416A4 (en) | 2022-03-30 |
RU2020126853A3 (ja) | 2022-02-14 |
US20240082436A1 (en) | 2024-03-14 |
MX2023005786A (es) | 2023-05-29 |
MX2020007442A (es) | 2020-09-14 |
US20200360545A1 (en) | 2020-11-19 |
WO2019140271A3 (en) | 2019-08-22 |
AU2019208024A1 (en) | 2020-08-13 |
KR20200109345A (ko) | 2020-09-22 |
RU2020126774A (ru) | 2022-02-14 |
US20200397778A1 (en) | 2020-12-24 |
JP2024012442A (ja) | 2024-01-30 |
KR20200110377A (ko) | 2020-09-23 |
WO2019140266A1 (en) | 2019-07-18 |
CA3087628A1 (en) | 2019-07-18 |
RU2020126853A (ru) | 2022-02-14 |
US11730836B2 (en) | 2023-08-22 |
US20230321286A1 (en) | 2023-10-12 |
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