JP2020533406A - 癌を治療するための治療用の組み合わせおよび方法 - Google Patents
癌を治療するための治療用の組み合わせおよび方法 Download PDFInfo
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Abstract
Description
本出願は2017年9月18日に出願された米国仮特許出願第62/559728号の利益を主張し、その全体が参照により本明細書に組み込まれる。
本開示は治療用の組み合わせに関し、より詳細には、癌またはウイルス感染の治療のための1つ以上の免疫治療剤と組み合わせて、CXCR4に選択的に結合するペプチドを使用する。
化学療法、放射線療法、および外科手術に加えて、免疫療法は、癌治療の第4の柱として認識されている。既存の癌免疫治療剤は主に、T細胞チェックポイントレセプターとそれらの同族リガンドとの間のタンパク質−タンパク質相互作用を遮断するモノクローナル抗体(mAb)である。臨床的に承認されたmAbは、T細胞チェックポイント阻害抗体イピリムマブ(Bristol−Myers SquibbによるYervoy(登録商標))、ペムブロリズマブ(MerckによるKeytruda(登録商標))、ニボルマブ(Bristol−Myers SquibbによるOpdivo(登録商標))、アテゾリズマブ(Roche/GenetechによるTecentriq(登録商標))、アベルマブ(EMD SeronoによるBavencio(登録商標))、およびデュルバルマブ(AstraZenecaによるImfinzi(登録商標))を含む。
本開示の目的は、有効な抗腫瘍免疫応答を促進する免疫療法を増強させる補助剤を提供することである。
添付の図面は、本発明の1つ以上の実施形態を示し、記述された説明とともに、本発明の原理を説明する。可能な限り、実施形態の同じまたは類似の要素を指すために、図面全体を通して同じ参照番号が使用される。
以下、本発明の種々の例示的な実施形態を示す添付の図面を参照して、本発明をより完全に説明する。しかし、本発明は、多くの異なる形態で具現化されてもよく、本明細書に記載された実施形態に限定されるものとして解釈されるべきではない。むしろ、これらの実施形態は、本開示が詳細かつ完全となり、本開示の範囲が当業者に完全に伝わるように提供される。全体を通して、同様の参照番号は、同様の要素を指す。
MC38ヒト大腸癌細胞を、30匹の7〜9週齢のC57BL/6雌マウスに接種し、マウスにおける腫瘍の平均体積が、約80〜120mm3(すなわち、100mm3周辺)に達したときに治療を開始した。マウスを無作為に3つのグループ(すなわち、1グループあたり10匹のマウス)に分けた。グループ1には、リン酸緩衝生理食塩水(PBS)を、週2回、計5回、腹腔内投与した。グループ2には、PBS中10mg/kgの抗PD−1抗体を、週2回、計5回、腹腔内投与した。グループ3には、PBS中10mg/kgの抗PD−1抗体を、週2回、計5回、および25mg/kgのPTX−9908を、5日間の投薬期間−2日間の休薬期間というスケジュールで、計13回、腹腔内投与した。グループIの平均腫瘍体積が2,000mm3に達した時点で、研究を終了した。
V=(L×W×W)/2
式中、Vは平均腫瘍体積、Lは平均腫瘍長(すなわち、最も長い腫瘍寸法)、およびWは平均腫瘍幅(すなわち、Lに垂直な最も長い腫瘍寸法)を意味する。グループ間の平均腫瘍体積の差の統計分析を、収集したデータを用いた、独立サンプルT検定によって行った。P値は小数点以下3桁に四捨五入したが、0.001未満の未処理のP値はP<0.001とした。全ての検定は両側検定であった。
腫瘍体積阻害の平均%=(平均(C)−平均(T))/平均(C)×100%
式中、Tは現行のグループ平均値、およびCは対照グループ平均値を意味する。図2Bに示すように、グループ3はまた、グループ2よりも有意に大きな腫瘍体積阻害を示した。
腫瘍増殖阻害の平均%=(平均(C)−平均(T))/平均(C)×100%
式中、Tは現行のグループ平均値、およびCは対照グループ平均値を意味する。図3Bに示すように、グループ3はまた、グループ2よりも有意に大きいTGIを示した。
EMT−6ヒト乳癌細胞を、30匹の7〜9週齢のBALB/C雌マウスに接種し、マウスにおける腫瘍の平均体積が、約80〜120mm3(すなわち、約100mm3周辺)に達したときに治療を開始した。マウスを無作為に3つのグループに分けた。グループ1には、リン酸緩衝生理食塩水(PBS)を週2回、計6回、腹腔内投与した。グループ2には、PBS中10mg/kgの抗PD−1抗体を、週2回、計6回、腹腔内投与した。グループ3には、PBS中10mg/kgの抗PD−1抗体を、週2回、計6回、および25mg/kgのPTX−9908を、5日間の投薬期間−2日間の休薬期間というスケジュールで、計15回、腹腔内投与した。グループIの平均腫瘍体積が2,000mm3に達した時点で、研究を終了した。
V=(L×W×W)/2
式中、Vは平均腫瘍体積、Lは平均腫瘍長(すなわち、最も長い腫瘍寸法)、およびWは平均腫瘍幅(すなわち、Lに垂直な最も長い腫瘍寸法)を意味する。グループ間の平均腫瘍体積の差の統計分析を、収集したデータを用いた、独立サンプルT検定によって行った。P値は小数点以下3桁に四捨五入したが、0.001未満の未処理のP値はP<0.001とした。全ての検定は両側検定であった。
腫瘍体積阻害の平均%=(平均(C)−平均(T))/平均(C)×100%
式中、Tは現行のグループ平均値、およびCは対照グループ平均値を意味する。図6Bに示すように、グループ3はまた、グループ2よりも有意に大きな腫瘍体積阻害を示した。
腫瘍増殖阻害の平均%=(平均(C)−平均(T))/平均(C)×100%
式中、Tは現行のグループ平均値、およびCは対照グループ平均値を意味する。図7Bに示すように、グループ3はまた、グループ2よりも有意に大きいTGIを示した。
LL/2ヒト肺癌細胞を、30匹の7〜9週齢のC57BL/6雌マウスに接種し、マウスにおける腫瘍の平均体積が約80〜120mm3(すなわち、約100mm3周辺)に達したときに治療を開始した。マウスを無作為に3つのグループに分けた。グループ1には、リン酸緩衝生理食塩水(PBS)を、週2回、計5回、腹腔内投与した。グループ2には、PBS中10mg/kgの抗PD−1抗体を、週2回、計5回、腹腔内投与した。グループ3には、PBS中10mg/kgの抗PD−1抗体を、週2回、計5回、および25mg/kgのPTX−9908を、5日間の投薬期間−2日間の休薬期間というスケジュールで、計13回、腹腔内投与した。グループIの平均腫瘍体積が2,000mm3に達した時点で、研究を終了した。
V=(L×W×W)/2
式中、Vは平均腫瘍体積、Lは平均腫瘍長(すなわち、最も長い腫瘍寸法)、およびWは平均腫瘍幅(すなわち、Lに垂直な最も長い腫瘍寸法)を意味する。グループ間の平均腫瘍体積の差の統計分析を、収集したデータを用いた、独立サンプルT検定によって行った。P値は小数点以下3桁に四捨五入したが、0.001未満の未処理のP値はP<0.001とした。全ての検定は両側検定であった。
腫瘍体積阻害の平均%=(平均(C)−平均(T))/平均(C)×100%
式中、Tは現行のグループ平均値、およびCは対照グループ平均値を意味する。図10Bに示すように、グループ3はまた、グループ2よりも大きな腫瘍体積阻害を示した。
Claims (17)
- 配列番号1〜3のうち1つを含み、CXCケモカインレセプター4(CXCR4)に選択的に結合することができるペプチド、および
癌を治療するための免疫治療剤
を含む、腫瘍を有する対象における癌を治療するための、治療用の組み合わせ。 - 前記免疫治療剤は、CTLA−4、PD−1、PD−L1、TIM−3、LAG−3、B7−1、B7−H3、NKG2A、KIR、BTLA、VISTA/PD−1H、TIGIT、CD96、OX40、CD28、ICOS、HVEM、41BB、CD40L、CD137、GITR、CD27、CD30、DNAM−1、CD28Hまたはこれらのコレセプターを選択的に標的とする、請求項1に記載の治療用の組み合わせ。
- 前記免疫治療剤は、抗体、ワクチン、サイトカイン、タンパク質、ペプチド、前記タンパク質もしくは前記ペプチドをコードする発現ベクター、小分子、RNAi、またはアプタマーである、請求項2に記載の治療用の組み合わせ。
- 前記免疫治療剤は、自己免疫細胞、腫瘍特異的自己T細胞、T細胞レセプター(TCR)操作T細胞、またはキメラ抗原レセプターT(CAR−T)細胞である、請求項1に記載の治療用の組み合わせ。
- 前記ペプチドがCXCR4に結合すると、前記腫瘍の免疫微小環境が調節される、請求項1に記載の治療用の組み合わせ。
- 前記ペプチドがCXCR4に結合すると、前記腫瘍に対する免疫細胞の接近性が調整される、請求項1に記載の治療用の組み合わせ。
- 前記免疫細胞は、CD45+細胞、CD3+T細胞、CD4+CD8−T細胞、CD4−CD8+T細胞、T−reg細胞、NK細胞、NKT細胞、マクロファージ、顆粒球、または単球である、請求項6に記載の治療用の組み合わせ。
- 前記癌は、乳癌、結腸癌、肺癌、膵臓癌、前立腺癌、腎臓癌、肝臓癌、リンパ腫または黒色腫である、請求項1に記載の治療用の組み合わせ。
- 配列番号1〜3のうち1つを含み、CXCケモカインレセプター4(CXCR4)に選択的に結合することができるペプチド、および
癌を治療するための免疫治療剤
を含む治療用の組み合わせを、対象に投与する工程を含む、腫瘍を有する対象における癌を治療するための方法。 - 前記ペプチドは、対象に、静脈内投与、皮下投与、または腹腔内投与される、請求項9に記載の方法。
- 前記免疫治療剤は、CTLA−4、PD−1、PD−L1、TIM−3、LAG−3、B7−1、B7−H3、NKG2A、KIR、BTLA、VISTA/PD−1H、TIGIT、CD96、OX40、CD28、ICOS、HVEM、41BB、CD40L、CD137、GITR、CD27、CD30、DNAM−1、CD28Hまたはこれらのコレセプターを選択的に標的とする、請求項9に記載の方法。
- 前記免疫治療剤は、抗体、ワクチン、サイトカイン、タンパク質、ペプチド、前記タンパク質もしくは前記ペプチドをコードする発現ベクター、小分子、RNAi、またはアプタマーである、請求項11に記載の方法。
- 免疫治療剤は、自己免疫細胞、腫瘍特異的自己T細胞、T細胞レセプター(TCR)操作T細胞、またはキメラ抗原レセプターT(CAR−T)細胞である、請求項9に記載の方法。
- 前記ペプチドがCXCR4に結合すると、前記腫瘍の免疫微小環境が調節される、請求項9に記載の方法。
- 前記ペプチドがCXCR4に結合すると、前記腫瘍に対する免疫細胞の接近性が調整される、請求項9に記載の方法。
- 前記免疫細胞は、CD45+細胞、CD3+T細胞、CD4+CD8−T細胞、CD4−CD8+T細胞、T−reg細胞、NK細胞、NKT細胞、マクロファージ、顆粒球、または単球である、請求項15に記載の方法。
- 前記癌は、乳癌、結腸癌、肺癌、膵臓癌、前立腺癌、腎臓癌、肝臓癌、リンパ腫または黒色腫である、請求項9に記載の方法。
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EP2384115A4 (en) * | 2009-01-30 | 2012-11-07 | Genzyme Corp | METHODS AND COMPOSITIONS FOR TREATING HEMATOLOGICAL MALIGNANT TUMORS |
US9267934B2 (en) * | 2010-10-26 | 2016-02-23 | University Of South Alabama | Methods and compositions for ameliorating pancreatic cancer |
CN105163749B (zh) * | 2013-03-24 | 2018-03-27 | 拜欧肯治疗有限公司 | 治疗骨髓性白血病的方法 |
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US20190233524A1 (en) | 2019-08-01 |
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