JP5129122B2 - 癌治療のための抗体およびグルココルチコイドの組み合わせ - Google Patents
癌治療のための抗体およびグルココルチコイドの組み合わせ Download PDFInfo
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Description
1.サイトカインの上記放出を低減することにより、同じ投与量において、特異的な作用(すなわち、ターゲットとする抗原に対するもの)を概ね変化させなくとも、望ましくない副作用(上に列挙したような)は非常にわずかに生じるのみである。
図1は、EpCAM陽性癌細胞(濃度5×104細胞/ml)を用いて刺激を行った後、およびEpCAM陽性癌細胞(濃度5×104細胞/ml)を用いずに刺激を行った後における、末梢血単核球(PBMC)(濃度106細胞/ml)によるインターロイキン−6(IL−6)の放出を示すグラフである。
図4A〜図4Eの各例において、y軸には、活性マーカー(図4Aおよび4CではCD25、図4Bでおよび4DではCD69、図4EではHLA−DR)の発現したCD3/CD4陽性Tリンパ球(ヘルパーT細胞)またはCD3/CD8陽性Tリンパ球(キラーT細胞)の割合比をプロットしている。測定はFACS解析により行った。図4A〜Eにおける左側のバーは、ぞれぞれ、HCT8標的細胞(濃度5×104cells/ml)に接触しない刺激の結果を示しており、右側のバーは、ぞれぞれ、HCT8標的細胞に接触する場合の測定値を示している。三官能性二重特異性抗体の刺激がHCT8標的細胞への接触による場合、すなわち標的抗原の結合に特異的な刺激と一致する場合、図4A〜4Eにおいて変化することのない高い測定値が示すように、T細胞活性はデキサメタソンによる影響を受けない。
(i)図11〜16の実験的試験:抗EpCAM×抗CD3の特異性を有する三官能性二重特異性抗体による刺激;
(ii)図17〜18の実験的試験:単特異性モノクローナル抗体ハーセプチンによる刺激
上記両抗体は、それらの異なる作用機構にもかかわらず、さまざまなサイトカインの放出について、健康な披験者および腫瘍の患者の両方に対して、実質的に同様の効果を示したことに留意されたい。
(末梢血単核球(PBMC)の抽出)
フィコール(比重1.068g/cm3)上での遠心分離により、健康なボランティアの末梢血から単核球を抽出した。この目的のために、ヘパリン処理された静脈血を、フィコール上に層形成して、2000rpmで20分間の遠心分離を行った。遠心分離後、フィコール層の上にある単核球の層をピペットで回収し、PBSで洗浄した。
刺激を行うために、上記PBMCが1×106/ml濃度で用いられた。PBMCの上記刺激は、特異性が抗EpCAM×抗CD3で100μg/ml濃度の、または特異性が抗HER2/neu×抗CD3で1mg/ml濃度の、インタクトな三官能性二重特異性抗体(trifunctional bispecific antibody)を用いてなされた。上記刺激は、37℃で24時間行われた。上記刺激は、それぞれのサンプルについて、腫瘍細胞が存在しない状態、または1ml当たり5×104のHCT8腫瘍細胞(ATCC由来;EpCAM陽性)の存在下で行った。合成グルココルチコイドのデキサメサソン(Jenapharmより取得)について、グルココルチコイドなしでの刺激試験、ならびに、グルココルチコイドを0.01、0.1、1および10μg/ml用いた試験が行われた。
上記刺激後、上清中のサイトカインIL−6、IL−10、TNF−α、およびIFN−γ濃度の定量が、24穴プレート上においてELISA法によって各々測定された。各々に対して、測定を2回行った。ELISA法は、R&D System製造のスタンダードキットを用いて、取扱説明書通りに行った。
(IL−6の放出)
IL−6は、免疫反応が生じると直接的に免疫学的エフェクター細胞及び抗原提示細胞から分泌されるサイトカインである。血清中におけるサイトカインとしてのIL−6の臨床的意義は、炎症または免疫反応が生じた後、数時間分泌され、また、該免疫反応の程度と、その分泌量とには関連性がある。本実施例において、EpCAM陽性腫瘍細胞(HCT8)を接触させ、同時に0.01〜10μg/mlのデキサメサソンを添加した場合、図1Bに示すように、上清内に、5000pg/mlを上回る量のIL−6の放出が確認された。この放出は、EpCAM特異的抗体の免疫反応に関係するとともに、所望の免疫反応を示すものである。このようなIL−6の多量放出は、特異的な抗原抗体反応に直接的に寄与したわずかな免疫細胞によるものである。
TNF−αは、標的細胞(ここではHCT8腫瘍細胞)の免疫的破壊が起きた場合に免疫学的エフェクター細胞(ここではPBMC)によって分泌されるTH1サイトカインである。腫瘍細胞を用いない場合の非特異的刺激と比較すれば、本実施例の場合は、特定の抗原(EpCAM)を有した腫瘍細胞の存在下において三官能性二重特異性抗体によって刺激した後に測定したところ、TNF−α量がおおよそ3倍増加した(図2A及び図2B)。TNF−α濃度における上記した明確な増加は、腫瘍細胞の免疫的破壊の過程における、PBMCによる、腫瘍細胞依存性の放出に起因している。仮に、本発明に沿って、三官能性二重特異性抗体がグルココルチコイド(本実施例ではデキサメサソン)と組み合わされたら、非特異的な影響によるTNF−α放出を低減させることができ、もし、グルココルチコイド濃度が比較的高ければ、TNF−α放出を完全に抑制することができる。このように、本発明によれば、グルココルチコイドを用いることにより、TNF−αの非特異的放出に起因する臨床的な副作用を大幅に抑制もしくは完全に無くすことが可能となる。サイトカインの非特異的放出と比較すれば、デキサメサソンを添加することによって、抗原依存の、標的細胞特異的なTNF−αの放出は、完全が維持することが可能となる。
IFN−γもまた、TH1サイトカインである。更には、IFN−γは、抗原に対しての刺激後の活性化された特異的Tリンパ球によって分泌されるものであり、T細胞介在型の抗原特異的な標的細胞破壊のためのマーカーとして用いられる。従って、IFN−γは、HCT8標的細胞の非存在下での三官能性二重特異性抗体を用いたPBMCの刺激後に分泌されるわけではない。なぜなら、この場合は非特異的な刺激のみが起こり、抗原に対して直接的なものではないからである(図3A)。HCT8細胞の存在下での刺激の過程では、抗体による、EpCAMに対する刺激によって、IFN−γの有意な放出がみられた。本実施例では、グルココルチコイド濃度が1μg/mlを下回っている場合は、この標的細胞に特異的なIFN−γ放出が、実質的に維持される。
抗EpCAM×抗CD3の三官能性二重特異性抗体を用いて刺激を行うT細胞活性化におけるグルココルチコイドの影響を調べるために、実施例1で説明した刺激実験を行った。そして、T細胞特異的活性マーカーCD25、CD69、HLA−DRをそれぞれ、CD3+/CD4+、CD3+/CD8+、Tリンパ球の場合に用いて測定した。
FACS解析は、Becton Dickinson製のFACSCaliburを用いることによって行った。必須特異性であるFITC−、PE−、APC−標識化抗体によって適切に刺激されたPBMCは、標識化される。
図4A〜図4Eからわかるように、二重特異性の三官能性抗体による刺激の場合は、グルココルチコイドであるデキサメサソンによる、T細胞の活性化への影響は無いと言える。
次に、T細胞毒性に関するグルココルチコイドの影響について、細胞傷害性試験を用いて調べた。PBMC抽出物およびそれらの刺激されたものを用いて、実施例1で説明した試験が行われた。
CECF−AM色素を使用した蛍光テストによって、細胞傷害性を調べた。テストは、Kolber et al. (1988) J.Immunol.Meth. 108:255-264に記載の2時間リリース術を用いて行った。
図5A及び図5Bからわかるように、三官能性二重特異性抗体によって生じる、刺激されたPBMCの細胞傷害性に関するデキサメサソンの影響は、以下のようにまとめることができる。デキサメサソンが0.01mg/mlである場合は、促進PBMCの細胞傷害性に関して、デキサメサソンの影響は無いといえる。刺激中にHCT8腫瘍細胞が有るか無いかに関わらず、濃度0.1μg/mlから細胞傷害性の顕著な低下がみられた。HCT8存在下での刺激の場合は、効果細胞と標的細胞とが40:1で、デキサメサソンの濃度が0.1μg/ml〜10μg/mlであると、細胞毒性の割合は、高いレベルで一定に維持される。PBMCの刺激中に標的細胞が存在しない場合は、デキサメサソンの濃度に応じて、細胞傷害性の割合は更に減少する。
胃癌(腹膜癌症;pT3 pN2 M1)の患者(46歳男性)に対して、抗EpCAM×抗CD3の三官能性二重特異性抗体と、グルココルチコイドとを用いた本発明の免疫治療を施した。治療は、西暦2000年の胃切除術後、腫瘍に対して行われた数々の効果の無い化学治療の後に行われた。患者は、腹水の症状を示していた。腹水内の腫瘍細胞の検査を行った結果、強いEpCAM発現(EpCAM+++)が得られた。抗体は腹腔内(i.p.)に投与され、毎回、6時間から10時間かけて投与された。
次に、腺癌(シグマpT3 pN2 M1)で、汎発性の肝転移(diffuse hepatic metastasis)である女性患者(68歳)に対して、抗EpCAM×抗CD3の三官能性二重特異性抗体と、グルココルチコイドのデキサメサソンとを用いた免疫治療を施した。肝転移細胞の80%がEpCAM陽性であった。本発明の治療の過程で、抗体の投与は、組織(本実施例の場合は肝臓内)へ選択的に投与することができたり、または(肝臓への散布の後)全身に投与できる一例である肝動脈(A. hepatica dextra)を経由した選択的なカテーテルを経由して行われた。デキサメサソンの投与は、免疫促進抗体の投与に先駆けて、前投与として行われた。
Claims (11)
- 抗EpCAM×抗CD3の特異性を有する免疫刺激性の三官能性の二重特異性抗体(trAB)を用いた癌性の疾患および腫瘍性の疾患からなる群より選択される疾患の治療における非特異的なサイトカインの放出を低減させるための薬剤を製造するための、デキサメタゾンの使用。
- 上記癌性の疾患が胃癌、腺癌、悪性黒色腫、結腸癌、膵癌、卵巣癌、子宮癌、肝細胞癌、全組織型の気管支癌、リンパ腫、肉腫、芽細胞腫、および消化器間質腫瘍(GIST)からなる群より選択されることを特徴とする請求項1に記載の使用。
- 上記抗体が、モノクローナル抗体、キメラ抗体、および/またはヒト化抗体であることを特徴とする請求項1または2に記載の使用。
- 上記抗体および/または上記デキサメタゾンが、腹腔内、静脈内、動脈内、筋肉内、皮内、皮下、腫瘍内、または所定の組織に選択的に投与されることを特徴とする請求項1〜3の何れか一項に記載の使用。
- 上記所定の組織への選択的な投与が、組織の供給血管へのカテーテルを介して行われることを特徴とする請求項4に記載の使用。
- 肝臓への上記投与が、肝動脈へのカテーテルを介して行われることを特徴とする請求項5に記載の使用。
- 上記デキサメタゾンおよび上記抗体が同時に投与されることを特徴とする請求項1〜6の何れか一項に記載の使用。
- 抗EpCAM×抗CD3の特異性を有する免疫刺激性の三官能性の二重特異性抗体と、
デキサメタゾンとを含んでいる、癌性の疾患および腫瘍性の疾患からなる群より選択される疾患の治療用組成物。 - 一またはそれ以上の薬学的に適合可能な担体をさらに含んでいる、請求項8に記載の癌性の疾患および腫瘍性の疾患からなる群より選択される疾患の治療用組成物。
- 上記抗体が、モノクローナル抗体、キメラ抗体、および/またはヒト化抗体であることを特徴とする請求項8または9に記載の癌性の疾患および腫瘍性の疾患からなる群より選択される疾患の治療用組成物。
- 上記癌性の疾患が胃癌、腺癌、悪性黒色腫、結腸癌、膵癌、卵巣癌、子宮癌、肝細胞癌、全組織型の気管支癌、リンパ腫、肉腫、芽細胞腫、および消化器間質腫瘍(GIST)からなる群より選択されることを特徴とする請求項8〜10の何れか一項に記載の癌性の疾患および腫瘍性の疾患からなる群より選択される疾患の治療用組成物。
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WO2006114115A1 (de) | 2006-11-02 |
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US8709421B2 (en) | 2014-04-29 |
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US20150086550A1 (en) | 2015-03-26 |
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CA2606081C (en) | 2013-09-17 |
PL1874821T3 (pl) | 2013-09-30 |
US20090191201A1 (en) | 2009-07-30 |
JP2008539177A (ja) | 2008-11-13 |
US20180236067A1 (en) | 2018-08-23 |
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