JP6560682B2 - 小細胞肺癌に対する標的療法 - Google Patents
小細胞肺癌に対する標的療法 Download PDFInfo
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Description
抗体および特異的リガンドなどの標的療法は、癌と闘うのに、とりわけ従来の療法が奏功しない症例において有効であることが分かっている。さらにより有望であることは、癌に対する抗体は、一般的に、伝統的な化学療法または放射線療法とは別個のメカニズムで作動し、それゆえそれらを伝統的療法と組み合わせて、相加的または相乗的な効果をしばしば生み出し得るということである。
[本発明1001]
患者における肺癌の治療のための方法であって、CD24、CD166、CD56、CD326、CD298、CD29、CD63、CD9、CD164、CD99、CD46、CD59、CD57、CD165、およびEpCAMを含めた1種または複数種の細胞表面抗原に特異的に結合する標的化された治療用作用物質の有効用量を患者に投与する工程を含む、方法。
[本発明1002]
SIRPαへのCD47の結合を選択的に遮断する第二の標的化された剤を投与する工程をさらに含む、本発明1001の方法。
[本発明1003]
第二の標的化された作用物質が、可溶性SIRPαポリペプチドを含む、本発明1002の方法。
[本発明1004]
第一の作用物質が、細胞表面マーカーに選択的な抗体である、本発明1003の方法。
[本発明1005]
肺癌が小細胞肺癌である、本発明1001の方法。
[本発明1006]
マーカーが、CD56、CD99、CD44、およびEpCamより選択される、本発明1005の方法。
[本発明1007]
第一および第二の作用物質を、CD47および第二の癌関連細胞マーカーに選択的な二重特異性抗体の状態で含む、本発明1002の方法。
治療用作用物質、例えば肺癌のマーカーに標的化された抗体、例えば、CD24、CD166、CD56、CD326、CD298、CD29、CD63、CD9、CD164、CD99、CD46、CD59、CD57、CD165、EpCAMなどを含めた1種または複数種の細胞表面抗原に標的化された抗体による、肺癌の治療のための方法および組成物が提供される。いくつかの態様において、作用物質の組み合わせ、例えば相乗的組み合わせが提供され、一方の作用物質は抗CD47遮断作用物質であり、第二の作用物質は、肺癌マーカー、例えばCD24、CD166、CD56、CD326、CD298、CD29、CD63、CD9、CD164、CD99、CD46、CD59、CD57、CD165、EpCAMなどに標的化されている。
相乗的組み合わせ。相乗的組み合わせは、単独療法、すなわち組み合わせの個々の構成要素の有効性に匹敵する治療効果を提供し得、一方で有害な副作用、例えば非標的組織へのダメージ、免疫状態、および他の臨床兆候を低下させる。あるいは、相乗的組み合わせは、単独療法、すなわち組み合わせの個々の構成要素の有効性と比較した場合に向上した有効性を提供し得、その効果は、総腫瘍細胞数;再発までの時間の長さ;および患者の健康状態の他の兆候によって測定され得る。
肺癌腫は、世界的に癌関連死の主因である。約85%の症例は、喫煙に関連付けされる。症状には、咳、胸部の不快感または痛み、体重減少、およびそれほど多くはないものの喀血が含まれ得る;しかしながら、多くの患者は、いかなる臨床症状もなしに転移性疾患を呈示する。診断は、典型的には、胸部X線またはCTによって行われ、生検によって確認される。疾患の病期に応じて、治療には、外科手術、化学療法、放射線療法、または併用が含まれる。過去数十年間、肺癌患者、特にIV期(転移性)疾患を有する患者の予後は不良である。
本発明は、CD24、CD166、CD56、CD326、CD298、CD29、CD63、CD9、CD164、CD99、CD46、CD59、CD57、CD165、EpCAMなどを含むがそれらに限定されない肺癌細胞表面マーカーに向けられた標的化された治療用作用物質の有効用量の導入により、肺癌細胞の成長を低下させるための方法を提供する。いくつかの態様において、マーカーは、CD56、CD44、CD99、およびEpCamのうちの1つである。好ましい態様において、標的化された治療用作用物質と、CD47遮断作用物質、例えば可溶性SIRPα単量体または多量体、抗CD47抗体、小分子などとを組み合わせる。ある特定の態様において、癌はSCLCである。CD47の活性を遮断することによって、ある特定の腫瘍細胞に関して見出される、食作用の下方調節が阻止される。
高アフィニティーSIRPα変種は、小細胞肺癌のマクロファージによる破壊を増強する
CD47は、マクロファージ上の阻害性受容体であるSIRPαを介したシグナル伝達によって、癌細胞が免疫系を回避することを可能にする。本発明者らは、最近、SIRPαのN末免疫グロブリンドメインを操作することによって、次世代CD47アンタゴニストを開発した。これらの「高アフィニティーSIRPα変種」は、野生型SIRPαと比べておよそ50,000倍向上した、11.1pMという、ヒトCD47に対する低いアフィニティー(KD)を有する。腫瘍特異的抗体と組み合わせた場合、高アフィニティーSIRPα変種は、免疫療法用アジュバントとして作用して、癌細胞のマクロファージによる破壊を最大限に高める。
CD47遮断療法は、小細胞肺癌のマクロファージによる破壊を刺激する
小細胞肺癌(SCLC)は、不良な予後を有する非常に侵襲性の強い肺癌の亜型である。該疾患に対して、臨床上認可された抗体、標的療法、または免疫療法は存在しない。本発明者らは、SCLCサンプルが、癌細胞が免疫系を回避することを可能にする細胞表面分子である高レベルのCD47を発現することを見出した。特に、CD47は、マクロファージ上の阻害性受容体であるSIRPαを介したシグナル伝達によって、免疫回避を促進する。本発明者らは、CD47遮断療法がSCLCの治療に適用され得るという仮説を立てた。本発明者らは、CD47遮断療法が、インビトロにおいてSCLCサンプルのマクロファージ食作用を誘導し得ることを見出した。また、CD47遮断療法は、SCLC腫瘍を担持するマウスの腫瘍成長を阻害しかつ生存を有意に延長させた。さらに、包括的抗体アレイを用いて、本発明者らは、SCLC細胞の表面にあるいくつかの新しいおよび確立された治療標的を同定した。これらの標的に対する抗体は、マクロファージ食作用を誘発し得、CD47遮断療法と組み合わせた場合に増強された。これらの知見は、CD47-SIRPaの系を妨害する療法が、特に腫瘍特異的抗体と組み合わせた場合に、SCLCを有する患者に利益をもたらし得ることを示唆する。
CD47はSCLCの表面に発現している。CD47遮断療法がSCLCに適用され得るかどうかを評価するために、本発明者らは、最初に、SCLC細胞の表面上でのCD47の発現を調べた。本発明者らは、6種のSCLC細胞株を入手し、それらをフローサイトメトリーに供して、細胞表面上でのCD47発現を評価した。6種すべての細胞株は、高いCD47発現を呈した(図5A)。本発明者らは、原発性SCLC患者サンプルから得られたSCLC患者由来異種移植片上でのCD47表面発現も評価した。細胞株と同様に、H29患者サンプルもその表面上に高レベルのCD47を発現した(図5B)。これらの知見は、CD47が、SCLC上の免疫療法標的であることを示唆した。
細胞株および培養:NCI-H82、NCI-524、NCI-H69、およびNCI-1688をATCCから入手した。細胞を、10%ウシ胎仔血清(Hyclone)、1×Glutamax(Invitrogen)、ならびに100U/mLペニシリンおよび100ug/mLストレプトマイシン(Invitrogen)を補充したRPMI-1640中で培養した。細胞株を浮遊状態で成長させ(NCI-H82、NCI-524、NCI-H69)、穏やかなピペッティングまたは1×TrypLE(Invitrogen)との短時間のインキュベーションによって解離した。NCI-1688細胞を接着性単層状態で成長させ、1×TrypLEとの短時間のインキュベーションによって取り出した。細胞株を、5%二酸化炭素を含む加湿インキュベーター内で37℃にて培養した。
Claims (9)
- 小細胞肺癌を有する個体を治療するための医薬の製造における組み合わせの使用であって、該組み合わせが、肺癌細胞の枯渇を増加させるために有効な量の、(i) SIRPαへのCD47の結合を選択的に遮断する物質、および(ii) 肺癌細胞上の1種または複数種の細胞表面抗原に特異的に結合する標的化された治療物質の組み合わせであり、
該SIRPαへのCD47の結合を選択的に遮断する物質が、
(a) CD47に特異的に結合する抗体、
(b) SIRPαに特異的に結合する抗体、または
(c) 可溶性SIRPαポリペプチド
であり;
該肺癌細胞上の1種または複数種の細胞表面抗原に特異的に結合する標的化された治療物質が、抗体であり;かつ
該肺癌細胞上の1種または複数種の細胞表面抗原が、CD24、CD56、CD166、CD326、CD298、CD29、CD63、CD9、CD164、CD99、CD46、CD59、CD57、およびCD165から選択される、
前記使用。 - 前記SIRPαへのCD47の結合を選択的に遮断する物質が、抗体である、請求項1に記載の使用。
- 前記抗体が、CD47に特異的に結合する、請求項2に記載の使用。
- 前記抗体が、SIRPαに特異的に結合する、請求項2に記載の使用。
- 前記SIRPαへのCD47の結合を選択的に遮断する物質が、可溶性SIRPαポリペプチドである、請求項1に記載の使用。
- 前記物質の組み合わせが、同時に投与される、請求項1に記載の使用。
- 前記物質の組み合わせが、逐次的に投与される、請求項1に記載の使用。
- 前記物質の組み合わせが、重複した投薬レジメンで投与される、請求項1に記載の使用。
- 前記個体がヒトである、請求項1に記載の使用。
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EP3092006A2 (en) | 2016-11-16 |
EP3553087A1 (en) | 2019-10-16 |
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CN106456748A (zh) | 2017-02-22 |
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WO2015105995A3 (en) | 2015-11-12 |
JP2019196383A (ja) | 2019-11-14 |
SG11201605585SA (en) | 2016-08-30 |
ES2728668T3 (es) | 2019-10-28 |
EP3092006B1 (en) | 2019-03-20 |
JP2017502048A (ja) | 2017-01-19 |
CA2935774C (en) | 2023-06-27 |
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