JP5547656B2 - Cd47によって媒介される食作用を操作するための方法 - Google Patents
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Description
細網内皮系(RES)は、免疫系の一部分である。RESは、細網性結合組織中に位置する食作用細胞、主として単球およびマクロファージからなる。RESは、1)循環血中の単球;2)肝臓、脾臓、リンパ節、胸腺、気道および消化管の粘膜下組織、骨髄、ならびに結合組織中の在住マクロファージ;ならびに3)リンパ節中の樹状細胞、皮膚中のランゲルハンス細胞、および中枢神経系中のミクログリア細胞を含むマクロファージ様細胞からなる。これらの細胞はリンパ節および脾臓中で蓄積する。RESは、病原体、血液循環中の粒子状物質、および老化または損傷した造血細胞をクリアランスする機能を果たす。
[本発明1001]
CD47を介したシグナル伝達を調整する作用物質を導入することによって、ヒト対象において造血細胞の食作用を操作する方法。
[本発明1002]
造血細胞が、循環血中の造血細胞である、本発明1001の方法。
[本発明1003]
造血細胞の集団とCD47模倣体とを含む組成物を対象に投与する段階を含む方法であって、該CD47模倣体がSIRPα受容体に結合し、かつ食作用を下方調節する、本発明1001の方法。
[本発明1004]
CD47模倣体が可溶性CD47である、本発明1003の方法。
[本発明1005]
CD47模倣体が、IgG1 Fcに融合された可溶性CD47を含む、本発明1003の方法。
[本発明1006]
前記細胞が造血幹細胞である、本発明1003の方法。
[本発明1007]
前記細胞が造血前駆細胞である、本発明1003の方法。
[本発明1008]
AML患者の血液細胞を、食作用を上方調節するCD47阻害物質と接触させる段階を含む、本発明1001の方法。
[本発明1009]
CD47阻害物質が、CD47に特異的に結合しかつSIRPα受容体とCD47との相互作用を阻害する抗体である、本発明1008の方法。
[本発明1010]
AMLSCをターゲティングするかまたは枯渇させるために、CD47に特異的に結合する抗体に、反応物血液細胞を接触させる段階を含む、AML癌幹細胞をターゲティングするかまたは枯渇させる方法。
[本発明1011]
前記抗体が細胞障害性物質に結合されている、本発明1010の方法。
[本発明1012]
細胞障害性物質が、放射性同位体、化学療法剤、および毒素からなる群より選択される、本発明1011の方法。
[本発明1013]
前記枯渇が、エクスビボの前記血液細胞において実施される、本発明1012の方法。
[本発明1014]
ヒト対象において固形腫瘍の癌細胞の食作用を増大させる方法であって、該癌細胞の食作用を上方調節するCD47阻害物質を含む組成物を該対象に投与する段階を含む、方法。
[本発明1015]
ヒト対象において固形腫瘍の癌細胞をターゲティングする方法であって、該癌細胞をターゲティングするために、CD47に特異的に結合する抗体を含む組成物を該対象に投与する段階を含む、方法。
[本発明1016]
CD47阻害物質が、CD47に特異的に結合しかつSIRPα受容体とCD47との相互作用を阻害する抗体である、本発明1015の方法。
[本発明1017]
前記抗体が細胞障害性物質に結合されている、本発明1015の方法。
[本発明1018]
前記抗体が二重特異性抗体である、本発明1015の方法。
循環血中の造血細胞を含む造血細胞を操作する方法が提供される。本発明のいくつかの態様において、造血幹細胞または造血前駆細胞は、マクロファージのような食作用細胞上のSIRPαと相互作用し、食作用を低減させるCD47模倣分子を宿主動物に提供することにより、循環血中の食作用から保護される。他の態様において、白血病細胞は、細胞表面のCD47をブロックすることによって食作用の標的とされる。他の態様において、固形腫瘍の細胞は、細胞表面のCD47をブロックすることによって食作用の標的とされる。別の態様において、AML癌幹細胞をターゲティングするかまたは枯渇させるための方法が提供され、この方法は、AMLSCをターゲティングするかまたは枯渇させるために、CD47に特異的に結合する抗体に反応物血液細胞を接触させる段階を含む。別の態様において、CD47に対する抗体を対象に投与することによって、ヒト対象において固形腫瘍の癌細胞をターゲティングするための方法が提供される。
CD47ポリペプチド。ヒトCD47の3種の転写変異体(変異体1、NM 001777;変異体2、NM 198793;および変異体3、NM 001025079)は、CD47ポリペプチドの3種のアイソフォームをコードする。3種のアイソフォームの内で最も長いCD47アイソフォーム1(NP 001768)は323アミノ酸長である。CD47アイソフォーム2(NP 942088)は、305アミノ酸長である。CD47アイソフォーム3は、312アミノ酸長である。これら3種のアイソフォームは、最初の303個のアミノ酸の配列が同一である。アミノ酸1〜8はシグナル配列を含み、アミノ酸9〜142は可溶性断片であるCD47免疫グロブリン様ドメインを含み、アミノ酸143〜300は膜貫通ドメインである。
循環血中の造血細胞の食作用を操作する方法が提供される。本発明のいくつかの態様において、循環血中の細胞は、特に、食作用からの保護が望ましい移植環境における、造血幹細胞または造血前駆細胞である。他の態様において、循環血中の細胞は、食作用の増大が望ましい白血病細胞、特に、急性骨髄性白血病(AML)である。
急性白血病は、造血細胞の悪性転換の結果として現れるクローンの芽細胞による正常骨髄の置換を特徴とする、急速に進行する白血病である。急性白血病には、急性リンパ芽球性白血病(ALL)および急性骨髄性白血病(AML)が含まれる。ALLはCNSにしばしば影響を与えるのに対し、急性単芽球性白血病は歯肉に影響を与え、AMLは任意の部位に局在した集団に影響を与える(顆粒球肉腫または緑色腫)。
本発明は、CD47遮断物質、例えば抗CD47抗体の導入を通して、食作用による癌細胞のクリアランスを増大させることによって癌細胞の増殖を低減させるための方法を提供する。一定の態様において、癌細胞はAML幹細胞でよい。他の態様において、癌細胞は、固形腫瘍、例えば、神経膠芽腫、黒色腫などの細胞でよい。CD47の活性をブロックすることによって、ある種の腫瘍細胞、例えばAML細胞で見出される食作用の下方調節が妨げられる。
CD47は骨髄性白血病のマーカーである
材料および方法
免疫組織化学。2重選別した(double sorted)骨髄系前駆細胞集団(CMP、GMP)、IL-3Rα高CD45 RA+細胞、およびCD14+c-kit+lin-細胞のサイトスピンをShandonサイトスピン装置を用いて実施した。H20で1/5希釈したギムザで10分間、サイトスピンを染色し、続いて、メイ・グリュンワルドで20分間染色した。Zeiss顕微鏡を用いてサイトスピンを解析した。
末梢血試料および骨髄試料は、骨髄増殖性障害患者および急性骨髄性白血病患者からインフォームドコンセントを得、StanfordのIRB規則およびHIPAA規則に従って、Stanford University Medical Centerにおいて得た。CD7、CD11b、およびCD14を除く以外は前記通りの系統カクテルで、末梢血単核細胞または骨髄単核細胞(細胞1〜5×106個)を染色した。続いて、CD14 PE(1/25)、CD47 FITC(1/25)、CD38 Bio(Bio)およびc-kit APC(1/25)またはCD34 APCもしくはFITC(1/50)で試料を45分間染色した後、洗浄し、ストレプトアビジン-テキサスレッド(1/25)で45分間染色し、最後にヨウ化プロピジウム中に再懸濁した。
本発明者らは本明細書において、CD47過剰発現が、AMLへのヒト骨髄増殖性障害の進行の特徴であることを示す(図1〜5Bを参照されたい)。CD47は、CD47発現のレベルに応じて、インテグリン機能だけでなく、マクロファージが細胞を貪食する能力も制御する。したがって、CD47発現が異常になると、宿主の先天性免疫および適応免疫の両方をLSCが回避することが可能になり得る。
ヒト白血病およびマウス白血病はCD47を上方調節して、マクロファージによる死滅化を回避する
CD47は生着(engraftment)を容易にし、食作用を阻害し、AML LSCにおいて、より高発現される。本発明者らは、ヒトAML LSCおよび正常HSCにおけるCD47発現をフローサイトメトリーによって測定した。正常な動員されたヒト末梢血の試料3つに由来するHSC(Lin-CD34+CD38-CD90+)およびヒトAMLの試料7つに由来するAML LSC(Lin-CD34+CD38-CD90-)を、CD47の表面発現に関して解析した(図6)。CD47は、正常HSCの表面では低レベルで発現された;しかしながら、AML LSCならびにバルク白血病芽球においては、CD47は平均で約5倍に高発現された。
マウス。以前に説明されているようにして、hMRP8bcrablトランスジェニックマウス、hMRP8bcl2トランスジェニックマウス、およびFaslpr/lprトランスジェニックマウスを作製し、交雑させて二重トランスジェニックを得た。ヘテロ接合体マウスを互いに交雑させることによって、hMRP8bcl2ホモ接合体を得た。本発明者らのコロニーに由来するC57Bl/6 Kaマウスを野生型細胞の供給源として使用した。移植実験のために、セシウム照射器(Phillips)からのγ線によって4Gyの放射線量を与えたC57Bl/6 RAG2-/-共通γ鎖(Gc)-/-マウスに細胞を移植した。初代マウス白血病(leukemias)を、9.5Gyの放射線量を与えたCD45.2 C57Bl6/Kaマウスに移植した。瀕死の場合、マウスを安楽死させた。
であり、β-アクチンの場合は
であり、CD47の場合は
であった。
造血幹細胞および造血前駆細胞はCD47を上方調節して、造血組織への動員およびホーミングを促進する
発明者らは本明細書において、CD47欠損(IAP-/-)マウスに由来する造血幹細胞(HSC)が野生型レシピエントに生着できないことを示す。予想されるように、これらの細胞は宿主マクロファージによって迅速にクリアランスされるのに対し、IAP+/+HSCはそうではない。シクロホスファミド/G-CSFまたはリポ多糖を用いて幹細胞および前駆細胞を強制的に分離して血液循環中に移行させた場合、CD47がこれらの細胞において急速に上方調節される。本発明者らは、造血および動員によってストレスが提供される間に幹細胞中のCD47のレベルが高くなることにより、細網内皮系の活性化マクロファージによる食作用からの保護が追加されたことを提唱する。この仮説の裏付けとして、本発明者らは、野生型レシピエントに移植されたIAP+/-細胞が時間と共に生着しなくなるのに対し、野生型ドナー細胞はそうならないことを示す。本発明者らは、食作用は造血前駆細胞を経時的にクリアランスする重要な生理学的メカニズムであり、食作用クリアランスを防止するにはCD47の過剰発現が必要とされると結論付ける。
マウス。C57Bl/6 CD45.1マウスおよびC57Bl/6 CD45.2(野生型)マウスを本発明者らのコロニーにおいて維持した。IAP-/-マウスは、EricBrown(University of California, San Francisco)から得た。これらはC57Bl6/J背景で飼育されており、本発明者らの野生型コロニーと交雑させた。
CD47は、ヒト急性骨髄性白血病細胞上の独立した予後因子および治療的抗体標的である
急性骨髄性白血病(AML)は、自己複製する白血病幹細胞(LSC)のサブセットによって開始され維持される細胞階層として組織化される。本発明者らは、AML LSCにおけるCD47発現増大は、CD47と食細胞上の阻害性受容体との相互作用を介して食作用を阻害することによって病理発生をもたらすと仮説を立てた。本発明者らは、AML LSCの方がそれらの正常な対応物よりもCD47を高発現すること、およびAML成人患者の独立した3つのコホートにおいて全生存が悪化することがCD47発現の増大から予測されることを発見した。さらに、CD47に対するモノクローナル遮断抗体は、インビトロで、マクロファージによるAML LSCの食作用を優先的に可能にし、インビボでのそれらの生着を阻害した。最後に、ヒトAMLを移植したマウスを抗CD47抗体で治療すると、インビボでAMLが除去された。要約すれば、CD47発現の増大は、LSCの食作用を刺激することができるモノクローナル抗体を用いてヒトAML幹細胞上でターゲティングすることができる、独立した予後不良因子である。
CD47は、AML LSCにおいての方が、それらの正常な対応物においてよりも高発現され、FLT3-ITD変異に関連している。本発明者らは、骨髄性白血病のいくつかのマウスモデルを研究して、正常な骨髄と比べてマウス白血病細胞上ではCD47発現が増大していることを確認した。これがきっかけとなって、ヒトAML LSCおよびその正常な対応物におけるCD47発現の調査が始まった。フローサイトメトリーを用いると、CD47は、正常骨髄のHSCおよびMPPよりも、複数のAML LSC標本において高発現されていた(図6)。この発現増大はバルク白血病細胞に拡大し、これらの細胞は、LSC濃縮画分と同様にCD47を発現した。
診断時の臨床的特徴および分子的特徴を表にした。WBCは白血球数を示す;FABは、フランス人-アメリカ人-イギリス人を示す;FLT3-ITDは、FLT3遺伝子の遺伝子内縦列重複を示す(FLT3-ITD状態が存在しない10症例では、遺伝子発現に基づいて予測されるFLT3-ITD状態をBullinger et al., 2008の方法を用いて代入した);FLT3-TKDは、FLT3遺伝子のチロシンキナーゼドメイン変異を示す;NPM1は、NPM1遺伝子の変異を示す;MLL-PTDは、MLL遺伝子の部分的な縦列重複を示す;CEBPAは、CEBPA遺伝子の変異を示す。CRは完全寛解を示す。CRは、ICE(idarubicin, etoposide, cytarabine)(イダルビシン、エトポシド、シタラビン)またはA-HAM (all-trans retinoic acid and high-dose cytarabine plus mitoxantrone)(オールトランスレチノイン酸ならびに高用量のシタラビンおよびミトキサントロン)を含む1回目の導入治療プログラム後および2回目の導入治療プログラム後の両方に評価した。自家HSCTは、自家移植を示す;同種異系HSCTは、同種異系間移植を示す。†P値は、CD47 mRNA発現値が低い患者とCD47 mRNA発現値が高い患者の診断時の分子的特徴および臨床的特徴の差を比較する。CD47発現は、補足的方法で説明するように、公開された独立的マイクロアレイデータセット(Valk et al, 2004)に基づいて本発明者らが特定した、全生存階層化のために最適なカットポイントに基づいて二種類に分けた。
ヒト試料。正常ヒト骨髄単核細胞をAllCells Inc. (Emeryville, CA)から購入した。IRBに承認されたプロトコール(Stanford IRB番号76935および6453)に従って、Stanford University Medical Centerの患者からインフォームドコンセントを得て、ヒト急性骨髄性白血病試料(図1A)を得た。磁性ビーズ(Miltenyi Biotech)を用いてヒトCD34-陽性細胞を濃縮した。
およびリバースプライマー12R
、ならびに10〜50ngのゲノムDNAを含む50μlの体積で実施した。FLT3遺伝子を増幅するためのPCR条件は、変性(95℃で30秒)、アニーリング(62℃で30秒)、および伸長(72℃で30秒)を40サイクルであった。
CD47は予後因子であり、固形腫瘍癌幹細胞上の治療的抗体標的である
本発明者らは、CD47発現の増大が、びまん性大型B細胞リンパ腫(DLBCL)および卵巣癌の臨床転帰の悪化に関連していることを発見した(図24)。さらに、本発明者らはここで、抗CD47抗体が、インビトロにおいて膀胱癌、卵巣癌、および髄芽細胞腫に由来する癌幹細胞のヒトマクロファージによる食作用を可能にすることを発見した(図25)。
Claims (7)
- ヒト対象において固形腫瘍細胞に対する食作用を増大させることにより固形腫瘍を治療するための、
第1の細胞上のCD47の第2の細胞上のSIRPα受容体への結合を妨げ、それにより食作用について第1の細胞をターゲティングする、抗体を含む薬学的組成物。 - 前記抗体が細胞障害性物質に結合されている、請求項1記載の薬学的組成物。
- 細胞障害性物質が、放射性同位体、化学療法剤、および毒素からなる群より選択される、請求項2記載の薬学的組成物。
- 抗体が第1および第2の癌細胞マーカーを認識する二重特異性抗体であり、第1の癌細胞マーカーがCD47である、請求項1記載の薬学的組成物。
- 固形腫瘍細胞が癌腫細胞である、請求項1記載の薬学的組成物。
- 癌腫細胞が卵巣癌または膀胱癌細胞である、請求項5記載の薬学的組成物。
- 固形腫瘍細胞が神経膠芽腫細胞である、請求項1記載の薬学的組成物。
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2014148521A (ja) * | 2008-01-15 | 2014-08-21 | Board Of Trustees Of The Leland Stanford Junior Univ | Cd47によって媒介される食作用を操作するための方法 |
US11773165B2 (en) | 2008-01-15 | 2023-10-03 | The Board Of Trustees Of The Leland Stanford Junior University | Markers of acute myeloid leukemia stem cells |
JP2013534409A (ja) * | 2010-05-14 | 2013-09-05 | ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティ | Cd47に対するヒト化及びキメラモノクローナル抗体 |
JP2017039709A (ja) * | 2010-05-14 | 2017-02-23 | ザ ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティー | Cd47に対するヒト化及びキメラモノクローナル抗体 |
US11014985B2 (en) | 2010-05-14 | 2021-05-25 | The Board Of Trustees Of The Leland Stanford Junior University | Humanized and chimeric monoclonal antibodies to CD47 |
US11807684B2 (en) | 2010-05-14 | 2023-11-07 | The Board Of Trustees Of The Leland Stanford Junior University | Humanized and chimeric monoclonal antibodies to CD47 |
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