JP5726170B2 - 抗ceacam1抗体およびその使用方法 - Google Patents
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Description
5F4 mAb:胆汁糖タンパク質(CD66a)による、ヒト腸上皮内リンパ球の細胞溶解機能の制御[Morales VMら,J Immunol.(1999)163(3):1363−70]。
本発明は、そのいくつかの実施形態において、抗CEACAM1モノクローナル抗体およびそれを産生するハイブリドーマ細胞、ならびに免疫調節および癌治療における該抗体の使用方法に関する。
モノクローナル抗体の生成
MRG1モノクローナル抗体の生成
ナノモル濃度でCEACAM1同種相互作用をインビトロで効果的に遮断するモノクローナル抗体を生成した。簡潔には、マウスを、2週間間隔で3回、5μgの組換えヒトCEACAM1(タンパク質全体,R&D Systemsから市販されている)で免疫した。脾細胞を回収し、SP2/0細胞と融合させて、ハイブリドーマライブラリーを生成した。
Kat4c mAbおよびウサギポリクローナル抗CEACAMを、DAKO(Glostrup,デンマーク)から購入した。
抗CEACAM1 mAbの特異性
材料および実験手順
CEACAM発現細胞の生成
CEACAM陰性721.221ヒト細胞(親B細胞)に、エレクトロポレーションによってCEACAM1、CEACAM5、CEACAM6、またはCEACAM8を安定的にトランスフェクトし、G418で選択した。
CEACAM1結合活性について、ハイブリドーマをフローサイトメトリーによって以下のようにスクリーニングした。
(a)50,000個のトランスフェクトされたCEACAM細胞を、U字形をした96ウェルに入れた。
(b)細胞を、冷却したFACS用緩衝液(PBS、BSA0.5%、アジド0.05%)で洗浄した。
(c)細胞を染色用mAb(MRG1またはKat4c)とインキュベートした:100μlあたり0.1μgのmAb、氷上で30分間。
(d)細胞を遠心分離し、上清を除去し、細胞を1:200の希釈での100μlのFITC接合ヤギ抗マウス抗体(Jackson Immunoresearch)中に再懸濁した。
(e)インキュベーション(暗条件中、氷上)の30分後に、細胞を遠心分離し、洗浄し、FACS用緩衝液に再懸濁した。
(f)FACScaliburおよびCellQuestソフトウェアを用いて、細胞を分析した。
721.221親細胞はCEACAMタンパク質のいずれも発現しないため、これらの細胞にCEACAM1、CEACAM5、CEACAM6、またはCEACAM8を安定的にトランスフェクトし、CEACAM1モノクローナル抗体(mAb)の特異性を試験した。次いで、CEACAM1結合活性について、ハイブリドーマをフローサイトメトリーによってスクリーニングした。図1Aに示されているように、本教示に従って生成されたMRG1 mAbは、ヒトCEACAM1に特異的である。それは、CEACAM5とのごくわずかな交差反応があるが、CEACAM6またはCEACAM8とは結合しない。図1Bは、すべてのトランスフェクタントがCEACAM分子を発現し、CEACAM1が最も低かったことを示しており、MRG1の特異性パターンを強調している。
前記mAbはCEACAM1同種結合を阻害し得る
材料および実験手順
ELISAによる抗体スクリーニング
CEACAM1遮断活性をBW機能的システムを用いることによって試験した。BW機能的システムは、マウスζ鎖と融合させたヒトCEACAM1の細胞外ドメインを含むキメラ分子を安定的にトランスフェクトしたマウス細胞株(BW)(BW/CEACAM1−ζ、上記の実施例2を参照されたい)を含む。BW/CEACAM1−ζ細胞と他のCEACAM1陽性細胞との共インキュベーションによって、測定可能な濃度のマウスIL−2の分泌が生じた。
1μg/mlのMRG1 mAbの存在下または非存在下で、腫瘍浸潤リンパ球による種々の黒色腫株の殺傷を試験する細胞毒性アッセイを行った。CEACAM1高526mel、624mel、およびCEACAM1弱09mel黒色腫細胞を標的細胞として用いた。10:1のE:T比で、TIL014細胞をエフェクター細胞として用いた。氷上でのMRG1 mAbとの1時間のインキュベーションの後、相互の細胞を添加し、37℃で5時間共インキュベートした。標的細胞を緑色蛍光色素(CFSE)であらかじめ標識し、特異的溶解をフローサイトメトリーにおけるヨウ化プロピジウム(PI)共染色によって測定した。自発的死を差し引いた。
精製MRG1 mAbのCEACAM1同種結合阻害能を検証した。図2に示されているように、精製MRG1 mAbは、CEACAM1同種結合の用量依存的阻害を示した。10ng/mlの濃度で、前記mAbはCEACAM1相互作用を効率的に減少させ、20ng/mlの濃度で、効果的にプラトーに達した。重要なことには、2つの実験的設定、すなわちエフェクター細胞BW/CEACAM1−ζへのまたは標的細胞221/CEACAM1へのMRG1 mAbの添加は、同様の結果(マウスIL−2の分泌が効果的に遮断された)を示した。
抗CEACAM1 mAbは癌細胞の移動および増殖を阻害する
材料および実験手順
浸潤アッセイ
抗体の遮断効果を浸潤アッセイで試験した。簡潔には、黒色腫細胞(08melまたは09mel)を、1μg/mlのMRG1 mAbの存在下または非存在下であらかじめインキュベートし、次いでマトリゲル浸潤アッセイによって試験した。24時間浸潤させ、浸潤細胞の量を標準化XTTで定量化した。
0日目に、CEACAM1高526mel細胞を48ウェルプレート中に播種した(1ウェルあたり2,500個の細胞)。播種の際に、MRG1を3つの異なる濃度(0.5、1、または3μg/ml)で添加し、あるいは全く添加しなかった。播種後2日目または5日目に、総生存細胞をカウントした。増殖を、標準化XTTを用いておよび細胞を直接カウントすることによって測定した。
図4に示されているように、MRG1は、CEACAM1陽性08mel細胞(CEACAM1発現レベルが中程度、すなわちCEACAM1発現の蛍光強度中央値が50)の浸潤を遮断し、かつCEACAM1dim09mel細胞(CEACAM1発現レベルが低い、すなわちCEACAM1発現の蛍光強度中央値が15)に対してほとんどまたは全く効果がなかった。
MRG1は動物実験モデルにおいて癌細胞の成長を阻害する
材料および実験手順
黒色腫異種移植モデル
5×106個のCEACAM1+ヒト黒色腫細胞を、7週齢のSCID−NODマウスの側腹部に皮下注射した。100%のマウスにおいて14〜17日以内に腫瘤が形成され、成長し続けた。腫瘍の寸法をカリパスを用いて週3回非侵襲的にモニタリングし、容積の近似値を(d1×d2×d3/2)として算出した。
上記で実証されている遮断機能と一致して、MRG1抗体の投与によって、腫瘍の成長が阻害された。この効果は、腫瘍細胞の接種の時に(図6A、「予防設定」)、または測定可能な腫瘤がすでに形成された後に(図6B、「治療設定」)、前記抗体を投与した場合に明らかであった。これらの効果は、非侵襲的モニタリングが続く8日以内の4回の注射の後に明らかであった(図6中の矢印を参照されたい)。SCID−NODマウスは免疫不全であるため、この効果はいかなる免疫調節効果とも無関係であったことに留意すべきである。
MRG1は以前に記載されている抗CEACAM1抗体よりも優れている
材料および実験手順
ELISAによる抗体スクリーニング
上文の実施例3で詳細に記載しているように、CEACAM1遮断活性をBW機能的システムを用いることによって試験した。
上文の実施例3に表記されているように、本発明者らは、15ng/mlのMRG1 mAbを用いることによって、CEACAM1活性のほぼ完全な遮断を実証した。対照的に、抗CEACAM1モノクローナル抗体のKat4cは、200倍高い濃度を試験した場合にのみわずかな遮断効果をもたらすことができ、ポリクローナルウサギ抗CEACAM抗体は、40倍高い濃度で同様の阻害効果をもたらした(それぞれ2600ng/mlおよび600ng/ml、図8)。
Claims (18)
- ATCC登録番号PTA−9974の下で寄託されている、ハイブリドーマ細胞。
- 請求項1に記載のハイブリドーマ細胞から産生される抗体のCDR配列および配向性を有する抗原認識ドメインを含む、単離した抗体または抗体フラグメント。
- 細胞毒性部分に接着している、請求項2に記載の単離した抗体または抗体フラグメント。
- 前記細胞毒性部分には、細胞毒素、ケモカイン、化学療法剤、アポトーシス促進性因子、インターフェロン、放射性部分、またはそれらの組み合わせが含まれる、請求項3に記載の単離した抗体または抗体フラグメント。
- 同定可能な部分に接着している、請求項2に記載の単離した抗体または抗体フラグメント。
- CEACAM1発現リンパ球を請求項2に記載の抗体または抗体フラグメントと接触させる工程を含む免疫調節の方法において使用するための、請求項2に記載の単離した抗体または抗体フラグメント。
- CEACAM1発現腫瘍細胞の移動または増殖を阻害する方法であって、該CEACAM1発現腫瘍細胞を請求項2に記載の抗体または抗体フラグメントと接触させ、それによって、CEACAM1発現腫瘍細胞の移動または増殖を阻害する方法において使用するための、請求項2に記載の単離した抗体または抗体フラグメント。
- 必要としている対象における癌を診断するための方法であって、該対象由来の生物学的サンプルを請求項2または5に記載の抗体または抗体フラグメントと接触させる工程を含み、既定の閾値を超えた複合体形成が該対象における該癌を示す方法において使用するための、請求項2または5に記載の単離した抗体または抗体フラグメント。
- 前記癌の細胞が、罹患していない細胞と比較してCEACAM1の過剰発現を特徴とする、請求項8に記載の単離した抗体または抗体フラグメント。
- 癌を治療する方法であって、それを必要としている対象に治療上有効な量の請求項2に記載の抗体または抗体フラグメントを投与し、それによって、該対象における該癌を治療する工程を含む方法において使用するための、請求項2に記載の単離した抗体または抗体フラグメント。
- 前記方法が、前記対象のリンパ球に投与する工程をさらに含む、請求項10に記載の単離した抗体または抗体フラグメント。
- 前記リンパ球にはT細胞またはNK細胞が含まれる、請求項11に記載の単離した抗体または抗体フラグメント。
- CEACAM1同型または異型タンパク質−タンパク質相互作用を阻害する方法であって、CEACAM1発現リンパ球を請求項2に記載の抗体または抗体フラグメントと接触させ、それによって、CEACAM1同型または異型タンパク質−タンパク質相互作用を阻害する工程を含む方法において使用するための、請求項2に記載の単離した抗体または抗体フラグメント。
- 前記CEACAM1発現リンパ球が腫瘍浸潤リンパ球またはNK細胞である、請求項6または13に記載の単離した抗体または抗体フラグメント。
- 前記CEACAM1発現リンパ球が細胞毒性T細胞である、請求項6または13に記載の単離した抗体または抗体フラグメント。
- 前記腫瘍細胞には黒色腫腫瘍細胞が含まれる、請求項7に記載の単離した抗体または抗体フラグメント。
- 前記癌が黒色腫である、請求項8または10に記載の単離した抗体または抗体フラグメント。
- 活性成分として請求項2または3に記載の抗体または抗体フラグメントを含む、医薬組成物。
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KR20180011725A (ko) * | 2016-07-25 | 2018-02-02 | 시즈오카켄 | 간외 담관암, 간내 담관암, 또는 담낭암의 진단용 바이오 마커 |
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