JPWO2019093383A1 - 抗pd−1抗体若しくは抗pd−l1抗体療法の奏効性を予測する方法、がんの悪性度を評価する方法、及び抗pd−1抗体若しくは抗pd−l1抗体療法の奏効性を上昇させる方法 - Google Patents
抗pd−1抗体若しくは抗pd−l1抗体療法の奏効性を予測する方法、がんの悪性度を評価する方法、及び抗pd−1抗体若しくは抗pd−l1抗体療法の奏効性を上昇させる方法 Download PDFInfo
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Abstract
Description
[1]被験者のがん組織から採取した試料のLAT1及びPD−L1の発現レベルを測定する工程と、上記LAT1及びPD−L1の発現レベルに基づいて、上記被験者に対する抗PD−1抗体又は抗PD−L1抗体療法の奏効性を予測する工程と、抗PD−1抗体又は抗PD−L1抗体療法が治療効果を示す可能性が高いと予測された上記被験者に抗PD−1抗体又は抗PD−L1抗体を投与する工程と、を備える、がんを治療する方法。
[2]抗PD−1抗体又は抗PD−L1抗体療法が治療効果を示す可能性が高いと予測された上記被験者に抗PD−1抗体又は抗PD−L1抗体を投与する工程において、抗PD−1抗体又は抗PD−L1抗体とLAT1阻害薬とを投与する、[1]に記載の方法。
[3]被験者のがん組織から採取した試料のLAT1の発現レベルを測定する工程と、上記LAT1の発現レベルに基づいて、上記被験者に対する抗PD−1抗体又は抗PD−L1抗体療法の奏効性を予測する工程と、抗PD−1抗体又は抗PD−L1抗体療法が治療効果を示す可能性が低いと予測された上記被験者に抗PD−1抗体又は抗PD−L1抗体とLAT1阻害薬とを投与する工程と、を備える、がんを治療する方法。
[4]上記抗PD−1抗体がニボルマブである、[1]〜[3]のいずれか一つに記載の方法。
[5]上記がんが肺がんである、[1]〜[4]のいずれか一つに記載の方法。
[6]上記肺がんが非小細胞肺がんである、[5]に記載の方法。
[7]上記非小細胞肺がんが肺腺がんである、[6]に記載の方法。
[8]上記発現レベルの測定を免疫組織化学により行う、[1]〜[7]のいずれか一つに記載の方法。
[9]上記LAT1の発現レベルの測定を免疫組織化学により行い、上記免疫組織化学は、上記試料から調製された単一切片を単染色することを含む、[1]〜[7]のいずれか一つに記載の方法。
[10]上記LAT1の発現レベルの測定と上記PD−L1の発現レベルの測定とを免疫組織化学により行い、上記免疫組織化学は、上記試料から調製された各連続切片を単染色することを含む、[1]に記載の方法。
[11]上記LAT1の発現レベルの測定と上記PD−L1の発現レベルの測定とを免疫組織化学により行い、上記免疫組織化学は、上記試料から調製された単一切片を二重染色することを含む、[1]に記載の方法。
[12]被験者に抗PD−1抗体又は抗PD−L1抗体とLAT1阻害薬とを投与する工程を備える、抗PD−1抗体又は抗PD−L1抗体療法の奏効性を上昇させる方法。
[13]上記被験者が、上記被験者のがん組織から採取した試料のLAT1及びPD−L1の発現レベルに基づいて、抗PD−1抗体又は抗PD−L1抗体療法が治療効果を示す可能性が高いと予測された被験者である、[12]に記載の方法。
[14]上記被験者が、上記被験者のがん組織から採取した試料のLAT1の発現レベルに基づいて、抗PD−1抗体又は抗PD−L1抗体療法が治療効果を示す可能性が低いと予測された被験者である、[12]に記載の方法。
[15]抗PD−1抗体又は抗PD−L1抗体と組み合わせて投与されることを特徴とし、上記抗PD−1抗体又は抗PD−L1抗体と同時に又は別々に投与される、O−(5−アミノ−2−フェニルベンズオキサゾール−7−イル)メチル−3,5−ジクロロ−L−チロシン又はその薬理学的に許容される塩。
[16]抗PD−1抗体又は抗PD−L1抗体と、O−(5−アミノ−2−フェニルベンズオキサゾール−7−イル)メチル−3,5−ジクロロ−L−チロシン又はその薬理学的に許容される塩と、の組み合わせを含む、抗がん剤。
[17]抗PD−1抗体又は抗PD−L1抗体と、O−(5−アミノ−2−フェニルベンズオキサゾール−7−イル)メチル−3,5−ジクロロ−L−チロシン又はその薬理学的に許容される塩と、の組み合わせを含む、がんを治療するためのキット。
[18]抗PD−1抗体又は抗PD−L1抗体と、O−(5−アミノ−2−フェニルベンズオキサゾール−7−イル)メチル−3,5−ジクロロ−L−チロシン又はその薬理学的に許容される塩と、を含む、がんを治療するための医薬組成物。
[19]抗PD−1抗体又は抗PD−L1抗体と組み合わせて投与されることを特徴とし、上記抗PD−1抗体又は抗PD−L1抗体と同時に又は別々に投与される、がんの治療における使用のための、O−(5−アミノ−2−フェニルベンズオキサゾール−7−イル)メチル−3,5−ジクロロ−L−チロシン又はその薬理学的に許容される塩。
[20]抗PD−1抗体又は抗PD−L1抗体と組み合わせて投与されることを特徴とし、上記抗PD−1抗体又は抗PD−L1抗体と同時に又は別々に投与される医薬の製造のための、O−(5−アミノ−2−フェニルベンズオキサゾール−7−イル)メチル−3,5−ジクロロ−L−チロシン又はその薬理学的に許容される塩の使用。
がん患者3名からがん組織を採取し、単一切片を抗LAT1抗体及び抗PD−L1抗体を用いて二重染色した結果を図1〜図3に示した。
大腸がん患者からがん組織を採取し、単一切片をヘマトキシリン−エオジン(HE)及び抗体(抗LAT1、抗PD−1及び抗PD−L1)を用いて染色した。結果を図4に示した(倍率200倍)。HEは切片を紫色に染色し、抗体は切片を褐色に染める。上段左はHE染色像である。上段右は抗LAT1抗体による染色像である。下段左は抗PD−1抗体による染色像である。下段右は抗PD−L1抗体による染色像である。この大腸がん組織ではLAT1が強陽性であった。
トリプルネガティブ乳がん患者からがん組織を採取し、連続切片をHE及び抗体(抗LAT1、抗PD−1及び抗PD−L1)を用いて染色した。結果を図5に示した(倍率400倍)。上段左はHE染色像である。上段右は抗LAT1抗体による染色像である。下段左は抗PD−1抗体による染色像である。下段右は抗PD−L1抗体による染色像である。この乳がん組織ではPD−L1が陽性であった。
膵がん患者からがん組織を採取し、単一切片を抗LAT1抗体及び抗PD−L1抗体を用いて二重染色した。結果を図6に示した(倍率400倍)。上段左はLAT1を緑色の色素で染めたときの写真を表し、上段右はPD−L1を赤色の色素で染めたときの写真を表し、下段は両者を重ねた写真を表す。下段の写真に、PL−共存タイプのがん組織を示す黄色は認められなかった。
以下の試験例1〜3において、LAT1の発現レベル、又はLAT1の発現レベルとPD−L1の発現レベルとの組み合わせに基づいた、ニボルマブの奏効性の予測について検討した。本試験に組み込まれた、初回化学療法無効な再発進行非小細胞肺がんの患者21名(ステージIII/IV)からがん組織を採取し、抗LAT1抗体及び抗PD−L1抗体を用いた免疫組織化学によりLAT1及びPD−L1の発現を調べた。PD−L1及びLAT1発現の高発現及び低発現の判定基準を表3及び表4に示す。PD−L1及びLAT1ともに、腫瘍の細胞膜が染色されたときを陽性と判定して、10%以上のPD−L1陽性細胞を有する腫瘍をPD−L1高発現であると定義し、25%以上のLAT1陽性細胞を有する腫瘍をLAT1高発現であると定義した。
PD−L1の発現レベルのみに基づいてニボルマブの奏効性を予測することの可能性について検討した。2つのがんマーカーを指標にした、上記21人の患者のがん組織試料におけるニボルマブの奏効性を表す結果を、図13及び図14に示す。図13上はPD−L1高発現群の奏効性を、図13下はPD−L1低発現群の奏効性を表す。PD−L1高発現群は8例であり、そのうち4例が奏効であり、1例が増悪であり、3例が安定であった。他方、PD−L1低発現群は13例であり、そのうち3例が奏効であり、7例が増悪、3例が安定であった。
PD−L1及びLAT1の発現レベルに基づいてニボルマブの奏効性を予測することの可能性について検討した。上記21症例の非小細胞性肺がん患者でのニボルマブの奏効と増悪の結果を図15にまとめた。図15上は奏効群を、図15下は増悪群を表す。奏効群7例のうち、LAT1高発現群は1例であり、LAT1低発現群は6例であり、統計学的有意差が認められた(p=0.029)。また、増悪群7例のうちLAT1高発現群は5例であり、LAT1低発現群は2例であり、統計学的有意差は認められなかった。
既に図3及び図10で示したような、上記2つのがんマーカーが同一細胞に存在する、PL−共存タイプのがん組織を有する患者の予後を表6に例示した。PL−共存タイプにおいては、同一細胞に2つのがんマーカーが発現しているので、PL−共存タイプは、各マーカーに対する分子標的に特異的な治療薬に対して抵抗性を発揮すると考えられる。PL−共存タイプ組織の検出には、単一切片を用いた二重染色を施す必要があるので、高い技術が必要とされる。標的がん細胞に対する新規の治療法の開発が、この治療抵抗性を克服できるものと思われる。
siRNAを使ってPD−L1又はLAT1のmRNA発現の転写レベルでの抑制を試みた。WiDr細胞(ヒト結腸腺がん由来)、SKN細胞(ヒト子宮平滑筋肉腫細胞由来)、及びH520細胞(ヒト肺扁平上皮がん細胞由来)を培養皿に播種した。PD−L1のmRNA発現を抑制するsiRNA、LAT1のmRNA発現を抑制するsiRNA、又はコントロールsiRNAを細胞に導入した。siRNAとしては、サーモフィッシャーサイエンティフィック株式会社のAmbion(登録商標)シリーズのSilencer(登録商標) Select siRNAsを用いた。具体的には、PD−L1のmRNA発現を抑制するsiRNAとしては、配列番号1及び2で示されるsiPD−L1#2(siRNA ID:s26548)を、LAT1のmRNA発現を抑制するsiRNAとしては、配列番号3及び4で示されるsiLAT1#3(siRNA ID:s15653)を、コントロールsiRNAとしては、Silencer Select Negative control #2(Cat#:390847)を用いた。発現抑制の効果が顕著に表れやすい48時間後に細胞を回収し、定量PCR法にて、細胞当たりのLAT1及びPD−L1のmRNA発現量を解析した。結果を表7に示す。
siRNAを用いた遺伝子抑制のかわりに、阻害薬JPH203を用いたLAT1活性の抑制を行い、試験例5と同様の結果が得られるかを調べた。JPH203はO−(5−アミノ−2−フェニルベンズオキサゾール−7−イル)メチル−3,5−ジクロロ−L−チロシンである。HuccT1細胞(ヒト胆管がん由来)及びOST細胞(ヒト骨線維肉腫由来)を培養皿に播種した。30μMのJPH203(LAT1選択的阻害薬)で24時間処理した後、細胞を回収し、定量PCR法にてPD−L1のmRNA発現量を解析した。結果を表8に示す。
Claims (17)
- 被験者に対する抗PD−1抗体又は抗PD−L1抗体療法の奏効性を予測する方法であって、
前記被験者のがん組織から採取した試料のLAT1の発現レベルを測定する工程と、
前記LAT1の発現レベルに基づいて、前記被験者に対する抗PD−1抗体又は抗PD−L1抗体療法の奏効性を予測する工程と、
を備える方法。 - 前記被験者のがん組織から採取した試料のPD−L1の発現レベルを測定する工程をさらに備え、
前記被験者に対する前記抗PD−1抗体又は抗PD−L1抗体療法の奏効性を予測する工程において、前記LAT1及びPD−L1の発現レベルに基づいて予測を行う、
請求項1記載の方法。 - 前記抗PD−1抗体がニボルマブである、請求項1又は2に記載の方法。
- 前記がんが肺がんである、請求項1〜3のいずれか一項に記載の方法。
- 前記肺がんが非小細胞肺がんである、請求項4に記載の方法。
- 前記非小細胞肺がんが肺腺がんである、請求項5に記載の方法。
- 前記発現レベルの測定を免疫組織化学により行う、請求項1〜6のいずれか一項に記載の方法。
- 前記LAT1の発現レベルの測定を免疫組織化学により行い、前記免疫組織化学は、前記試料から調製された単一切片を単染色することを含む、請求項1〜6のいずれか一項に記載の方法。
- 前記LAT1の発現レベルの測定と前記PD−L1の発現レベルの測定とを免疫組織化学により行い、前記免疫組織化学は、前記試料から調製された各連続切片を単染色することを含む、請求項2〜6のいずれか一項に記載の方法。
- 前記LAT1の発現レベルの測定と前記PD−L1の発現レベルの測定とを免疫組織化学により行い、前記免疫組織化学は、前記試料から調製された単一切片を二重染色することを含む、請求項2〜6のいずれか一項に記載の方法。
- 被験者のがんの悪性度を評価する方法であって、
前記被験者のがん組織から採取した試料を抗LAT1抗体及び抗PD−L1抗体で染色する工程と、
LAT1陽性かつPD−L1陽性の部位の有無に基づいて、前記被験者のがんの悪性度を評価する工程と、
を備える方法。 - 前記がんが肺がん、大腸がん、膵がん又は胆道がんである、請求項11に記載の方法。
- 前記染色工程が、前記試料から調製された各連続切片を単染色することを含む、請求項11又は12に記載の方法。
- 前記染色工程が、前記試料から調製された単一切片を二重染色することを含む、請求項11又は12に記載の方法。
- 抗PD−1抗体又は抗PD−L1抗体と組み合わせて投与されることを特徴とし、
前記抗PD−1抗体又は抗PD−L1抗体と同時に又は別々に投与される、O−(5−アミノ−2−フェニルベンズオキサゾール−7−イル)メチル−3,5−ジクロロ−L−チロシン又はその薬理学的に許容される塩。 - 抗PD−1抗体又は抗PD−L1抗体と、O−(5−アミノ−2−フェニルベンズオキサゾール−7−イル)メチル−3,5−ジクロロ−L−チロシン又はその薬理学的に許容される塩と、の組み合わせを含む、抗がん剤。
- 抗PD−1抗体又は抗PD−L1抗体と、O−(5−アミノ−2−フェニルベンズオキサゾール−7−イル)メチル−3,5−ジクロロ−L−チロシン又はその薬理学的に許容される塩と、を含む、がんを治療するための医薬組成物。
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KR20200003418A (ko) | 2020-01-09 |
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JP2022025113A (ja) | 2022-02-09 |
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