JP2023510209A - 抗クロ―ディン18.2の抗体及びその使用 - Google Patents
抗クロ―ディン18.2の抗体及びその使用 Download PDFInfo
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Abstract
Description
好ましくは、前記抗体または抗原結合フラグメントは、配列番号9もしくは10に示される配列を含む抗原性ペプチドを認識できる、または前記抗体または抗原結合フラグメントが、クラウディン18.2の配列番号9もしくは10に示される配列を含むエピトープを認識できる。
好ましくは、前記変異体が、アクセッション番号CCTCCNO.C202007またはCCTCCNO.C202008で寄託されたハイブリドーマ細胞株によって産生される抗体と少なくとも80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、または99%の相同性を有する。
好ましくは、前記抗体フラグメントが、scFv、Fabフラグメント、Fdフラグメント、Fvフラグメント、F(ab’)2フラグメント、または単一ドメイン抗体であり、
CCTCCNO.C202007ハイブリドーマ細胞株によって産生される抗体が抗体9であり、CCTCCNO.C202008ハイブリドーマ細胞株によって産生される抗体が抗体7である。
MAVTACQGLGFVVSLIGIAGIIAATCMDQWSTQDLYNNPVTAVFNYQGLWRSCVRESSGFTECRGYFTLLGLPAMLQAVRALMIVGIVLGAIGLLVSIFALKCIRIGSMEDSAKANMTLTSGIMFIVSGLCAIAGVSVFANMLVTNFWMSTANMYTGMGGMVQTVQTRYTFGAALFVGWVAGGLTLIGGVMMCIACRGLAPEETNYKAVSYHASGHSVAYKPGGFKASTGFGSNTKNKKIYDGGARTEDEVQSYPSKHDYV
に示される。
好ましくは、前記抗体または抗原結合フラグメントは、胃組織に特異的に結合するが、肺組織には結合しない。
好ましくは、前記検出可能な標識は、蛍光標識、発色標識、発光標識、発色団標識、放射性同位体標識、同位体標識、同量同位体標識(isobaric label)、酵素標識、粒子標識、または結合剤の使用によって検出された核酸もしくはタンパク質である。
検出されるサンプルを、上記本発明に記載の抗体もしくは抗原結合フラグメント、または本発明の上記のコンジュゲートに接触すること;前記抗体もしくは抗原結合フラグメント、または前記コンジュゲートとクローディン18.2によって形成される複合体の量を検出することを含むことを特徴とする。
(i)腫瘍細胞を含むサンプルを、上記本発明に記載の抗体もしくは抗原結合フラグメント、または上記本発明に記載のコンジュゲートに接触すること;
(ii)前記抗体もしくは抗原結合フラグメント、または前記コンジュゲートとクローディン18.2によって形成される複合体の量を検出することを含むことを特徴とし、
好ましくは、前記腫瘍細胞は、胃癌細胞、食道癌細胞、膵臓癌細胞、肺癌細胞、卵巣癌細胞、結腸癌細胞、肝臓癌細胞、頭頸部癌細胞、または胆道系腫瘍細胞であり、
より好ましくは、前記腫瘍細胞は、胃癌細胞、食道癌細胞、膵臓癌細胞、または胆道系腫瘍細胞である。
好ましくは、前記動物はネズミであり、
好ましくは、前記B細胞は脾細胞に由来する。
クロ―ディン18.2 C末端ポリペプチド(メチオニン191-バリン261、配列番号3を参照)は、免疫原としてインビトロで合成した。
MMCIACRGLAPEETNYKAVSYHASGHSVAYKPGGFKASTGFGSNTKNKKIYDGGARTEDEVQSYPSKHDYV
これら11の抗体から7つの抗体(抗体5、抗体6、抗体9、抗体11、抗体4、抗体8、抗体7)をスクリーニングし、ホルマリン固定パラフィン包埋組織(FFPE)における抗原への結合能力の組織特異性を免疫組織化学により評価した。
アカゲザルの胃と肺組織の抗体染色の結果を表1に示す。抗体4、抗体5、抗体6、抗体7、抗体8、抗体9、および抗体11は、アカゲザルの胃粘膜上皮細胞に対する染色の程度が異なり、染色強度は1+から3+まで変化し、個別の抗体は非特異的染色/バックグラウンド染色を生成する;アカゲザルの肺組織に対して陰性および陽性反応がある。抗体4、抗体5、抗体7、抗体8および抗体9は胃組織を特異的に染色したが、肺組織を染色しなかった。対照抗体43-14A2は肺組織を非特異的に染色したが、対照抗体EPR19202-244はプロトコルに推奨された0.37μg/mLの作業濃度では、胃組織に対する特異的染色強度が高く、肺組織に対しては染色はなかった。
0.2μg/mLの作業濃度の抗体9と0.37μg/mLの作業濃度の対照抗体EPR19202-244を使用し、正常者7例由来の正常臓器合計24種類、各種2~6例、各例1点の組織チップ(上海Xinchao、チップ番号:HorgN090PT02)をそれぞれ染色した。抗体9は胃粘膜上皮細胞でのみ陽性染色を示し、他の組織は陰性染色であったが、EPR19202-244は骨格筋および心臓筋組織に明らかなバックグラウンド染色を示した。6例の胃粘膜の胃粘膜上皮細胞では、抗体9とEPR19202-244はいずれも強い陽性染色を示した;EPR19202-244抗体は3例の心筋のうちの1例、及び7例の骨格筋のうちの1例でバックグラウンド染色を示したが、抗体9はすべて陰性染色であった。残りの甲状腺4例、舌3例、食道上皮4例、十二指腸粘膜2例、空腸粘膜6例、回腸粘膜3例、虫垂5例、結腸粘膜4例、直腸粘膜2例、肝臓2例、膵臓2例、気管3例、肺5例、皮膚3例、精嚢1例、前立腺3例、精巣7例、膀胱4例、延髄1例、終脳2例、小脳2例、脳幹1例、脾臓2例では、2つの抗体は陰性染色であった。
0.2μg/ mLの作業濃度の抗体7、抗体9、対照抗体43-14A2、及びプロトコルに推奨された0.37μg/mLの作業濃度の対照抗体Abcam EPR19202-244を使用して、ヒトの胃癌または肺癌組織サンプルを染色した。染色の主なステップとして、組織切片を脱パラフィンおよび抗原賦活化し、CLDN18A2抗体でインキュベートし、ブロッキング緩衝液でサンプルをインキュベートし、西洋ワサビペルオキシダーゼ(HRP)標識二次抗体とインキュベートし、最後に発色基質を加えて発色させた。
抗体9を選択して胃癌および傍癌性組織のチップ染色分析をした。それぞれ0.2μg/mLの作業濃度の抗体9および0.37μg/mLの推奨作業濃度のAbcam EPR19202-244を使用して、75例の胃癌および傍癌性組織チップ(上海Xinchao、チップ番号:HStm-Ade150CS4-01)を染色した。具体的なデータを表3に、染色結果の統計を表4に示す。
ELISA法:抗体7及び抗体9の、抗原の異なるペプチドセグメントへの結合を検出することにより、抗体が結合したエピトープを分析する。
Claims (23)
- 配列番号7(KNKKIYDGG)に示される配列を含む抗原性ペプチドを認識できる、またはクラウディン18.2の配列番号7に示される配列を含むエピトープを認識できる抗体または抗原結合フラグメントであって、
好ましくは、前記抗体または抗原結合フラグメントは、配列番号6(KNKKIYDGGART)に示される配列を含むペプチドを認識できる、または前記抗体または抗原結合フラグメントは、クラウディン18.2の配列番号6に示される配列を含むエピトープを認識できることを特徴とする、抗体または抗原結合フラグメント。 - 前記抗体または抗原結合フラグメントが、配列番号8(GFGSNTKNKKIYDGG)、9(SNTKNKKIYDGGART)もしくは10(KNKKIYDGGARTEDE)に示される配列を含む抗原性ペプチドを認識できる、または前記抗体または抗原結合フラグメントが、クラウディン18.2の配列番号8、9もしくは10に示される配列を含むエピトープを認識でき、
好ましくは、前記抗体または抗原結合フラグメントが、配列番号9もしくは10に示される配列を含む抗原性ペプチドを認識できる、または前記抗体または抗原結合フラグメントが、クラウディン18.2の配列番号9もしくは10に示される配列を含むエピトープを認識できることを特徴とする、請求項1に記載の抗体または抗原結合フラグメント。 - 前記抗体が、アクセッション番号CCTCCNO.C202007またはCCTCCNO.C202008で寄託されたハイブリドーマ細胞株によって産生される抗体であり、CCTCCNO.C202007ハイブリドーマ細胞株によって産生される抗体が抗体9であり、CCTCCNO.C202008ハイブリドーマ細胞株によって産生される抗体が抗体7であることを特徴とする、請求項1または2に記載の抗体または抗原結合フラグメント。
- 前記抗体または抗原結合フラグメントが、ネズミ抗体、キメラ抗体、ヒト化抗体、または完全ヒト抗体であることを特徴とする、請求項1または2に記載の抗体または抗原結合フラグメント。
- 前記抗体または抗原結合フラグメントが、アクセッション番号CCTCCNO.C202007(抗体9)またはCCTCCNO.C202008(抗体7)で寄託されたハイブリドーマ細胞株によって産生されるヒト化抗体またはキメラ抗体であることを特徴とする、請求項1または2に記載の抗体または抗原結合フラグメント。
- 前記抗体または抗原結合フラグメントが、アクセッション番号CCTCCNO.C202007またはCCTCCNO.C202008で寄託されたハイブリドーマ細胞株によって産生される抗体の変異体であり、CCTCCNO.C202007ハイブリドーマ細胞株によって産生される抗体が抗体9であり、CCTCCNO.C202008ハイブリドーマ細胞株によって産生される抗体が抗体7であり、
好ましくは、前記変異体が、アクセッション番号CCTCCNO.C202007またはCCTCCNO.C202008で寄託されたハイブリドーマ細胞株によって産生される抗体と少なくとも80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、または99%の相同性を有することを特徴とする、請求項1または2に記載の抗体または抗原結合フラグメント。 - 前記抗体フラグメントが、アクセッション番号CCTCCNO.C202007またはCCTCCNO.C202008で寄託されたハイブリドーマ細胞株によって産生される抗体の抗体フラグメントであり、
好ましくは、前記抗体フラグメントが、scFv、Fabフラグメント、Fdフラグメント、Fvフラグメント、F(ab’)2フラグメント、または単一ドメイン抗体であり、
CCTCCNO.C202007ハイブリドーマ細胞株によって産生される抗体が抗体9であり、CCTCCNO.C202008ハイブリドーマ細胞株によって産生される抗体が抗体7であることを特徴とする、請求項1または2に記載の抗体または抗原結合フラグメント。 - 前記抗体または抗原結合フラグメントが、クロ―ディン18.2を発現する細胞に結合し、
好ましくは、前記クロ―ディン18.2のアミノ酸配列は、配列番号2
MAVTACQGLGFVVSLIGIAGIIAATCMDQWSTQDLYNNPVTAVFNYQGLWRSCVRESSGFTECRGYFTLLGLPAMLQAVRALMIVGIVLGAIGLLVSIFALKCIRIGSMEDSAKANMTLTSGIMFIVSGLCAIAGVSVFANMLVTNFWMSTANMYTGMGGMVQTVQTRYTFGAALFVGWVAGGLTLIGGVMMCIACRGLAPEETNYKAVSYHASGHSVAYKPGGFKASTGFGSNTKNKKIYDGGARTEDEVQSYPSKHDYV
に示されることを特徴とする、請求項1~7のいずれか一項に記載の抗体または抗原結合フラグメント。 - 前記抗体または抗原結合フラグメントが胃組織に特異的に結合し、
好ましくは、前記抗体または抗原結合フラグメントは、胃組織に特異的に結合するが、肺組織には結合しないことを特徴とする、請求項8に記載の抗体または抗原結合フラグメント。 - 請求項1~9のいずれか一項に記載の抗体または抗原結合フラグメント、及び少なくとも1つの検出可能な標識を含むコンジュゲートであって、
好ましくは、前記検出可能な標識は、蛍光標識、発色標識、発光標識、発色団標識、放射性同位体標識、同位体標識、同量同位体標識(isobaric label)、酵素標識、粒子標識、または結合剤の使用によって検出された核酸もしくはタンパク質であることを特徴とする、コンジュゲート。 - 請求項1~9のいずれか一項に記載の抗体を産生することができるハイブリドーマ。
- 前記ハイブリドーマは、受託アクセッション番号がCCTCCNO.C202007またはCCTCCNO.C202008である、請求項11に記載のハイブリドーマ。
- 検出されるサンプル中のクローディン18.2の発現を検出するための方法であって、前記検出されるサンプルを、請求項1~9のいずれか一項に記載の抗体もしくは抗原結合フラグメント、または請求項10に記載のコンジュゲートに接触させること;前記抗体もしくは抗原結合フラグメント、または前記コンジュゲートとクローディン18.2によって形成される複合体の状況を検出することを含むことを特徴とする、方法。
- がんを診断、検出または監視するための方法であって、
検出されるサンプルを、請求項1~9のいずれか一項に記載の抗体もしくは抗原結合フラグメント、または請求項10に記載のコンジュゲートに接触させること;前記抗体もしくは抗原結合フラグメント、または前記コンジュゲートとクローディン18.2によって形成される複合体の量を検出することを含むことを特徴とする、方法。 - クロ―ディン18.2を標的とする腫瘍療法によって腫瘍を治療できるかどうかを分析するための方法であって、前記方法は、
(i)腫瘍細胞を含むサンプルを、請求項1~9のいずれか一項に記載の抗体もしくは抗原結合フラグメント、または請求項10に記載のコンジュゲートに接触させること;
(ii)前記抗体もしくは抗原結合フラグメント、または前記コンジュゲートとクローディン18.2によって形成される複合体の量を検出することを含み、
好ましくは、前記腫瘍細胞は、胃癌細胞、食道癌細胞、膵臓癌細胞、肺癌細胞、卵巣癌細胞、結腸癌細胞、肝臓癌細胞、頭頸部癌細胞、または胆道系腫瘍であり、
より好ましくは、前記腫瘍細胞は、胃癌細胞、食道癌細胞、膵臓癌細胞、または胆道系腫瘍であることを特徴とする、方法。 - 請求項1~9のいずれか一項に記載の抗体もしくは抗原結合フラグメント、または請求項10に記載のコンジュゲートを含む検出キット。
- 前記クローディン18.2が、配列表の配列番号2のアミノ酸配列またはその変異体を含む、請求項13~15のいずれか一項に記載の方法。
- クロ―ディン18.2を標的とするモノクローナル抗体を産生する方法であって、前記方法は、配列番号6、7、8、9もしくは10に示される配列を含むポリペプチドを免疫原として使用し、または配列番号6、7、8、9もしくは10に示される配列と少なくとも80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、または99%の相同性を有するポリペプチドを免疫原として使用し、動物を免疫した後、動物のB細胞を骨髄腫細胞と融合させてハイブリドーマ細胞を得てモノクローナル抗体を産生することを含み、
好ましくは、前記動物はネズミであり、
好ましくは、前記B細胞は脾細胞に由来することを特徴とする、方法。 - 前記ハイブリドーマ細胞から前記モノクローナル抗体を単離することをさらに含むことを特徴とする、請求項18に記載の方法。
- 配列番号3(MMCIACRGLAPEETNYKAVSYHASGHSVAYKPGGFKASTGFGSNTKNKKIYDGGARTEDEVQSYPSKHDYV)に示されるポリペプチドを免疫原として使用することを特徴とする、請求項18に記載の方法。
- 前記モノクローナル抗体が前記抗原に特異的に結合することを特徴とする、請求項18に記載の方法。
- 前記抗原への特異的結合を保持する前記モノクローナル抗体の修飾形態を産生することをさらに含むことを特徴とする、請求項19に記載の方法。
- 前記モノクローナル抗体の修飾形態がヒト化抗体であることを特徴とする、請求項20に記載の方法。
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WO2021136550A1 (zh) | 2021-07-08 |
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