JP7222104B2 - 抗ベータ1インテグリンヒト化抗体及びこれを含む癌治療用薬学組成物 - Google Patents
抗ベータ1インテグリンヒト化抗体及びこれを含む癌治療用薬学組成物 Download PDFInfo
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Description
本発明は、癌細胞の成長、分化、侵入及び転移に関連した生化学的信号を伝達するベータ1インテグリンに特異的に結合する抗体に関し、より詳細には、本発明の抗体は、ベータ1インテグリンの信号伝達機能を抑制させることによって、ベータ1インテグリンが過発現する様々な癌(例えば、非小細胞肺癌)の診断及び治療用途に用いることができる。
2018年度の世界癌発病は1,800万件であり、死亡は900万件と推算される。男性の5人に1人及び女性の6人に1人が生涯で癌にかかることがあり、男性の8人に1人と女性の11人に1人が癌で死亡すると知られている。全世界の癌診断後5年以内の生存者総数は4,380万人と推算される(Press ReleaseN゜263,WHO,Internal Agency for Research on Cancer,12 September 2018)。肺癌は、乳癌及び大腸癌とともに発病率が最も高い3大癌である。2018年世界的癌統計(Global cancer statistics)によれば、全世界の肺癌発生者は210万人、死亡者は180万人であり、全体癌死亡者の1/5である18.4%と予測される(World Health Organization Global Health Observatory Geneva 2018 who.int/gho/database/en/.Accessed June 21,2018)。
[発明が解決しようとする課題]
本発明者らは、ベータ1インテグリンに特異的に結合して癌細胞自滅能が極大化した新規抗体を発掘しようと鋭意努力した。その結果、P5抗体の一部のアミノ酸配列を他のアミノ酸配列に置換して最適化することによって抗癌活性を極大化できることを確認し、本発明を完成するに至った。
本発明の一態様によれば、本発明は、ベータ1インテグリン(beta 1 integrin)を抗原として認識してそれに特異的に結合する単一クローン抗体又はその断片を提供する。
(a)被検者から体外に分離されたサンプルを取得する段階;
(b)前記単一クローン抗体又はその断片を前記サンプルに処理する段階;及び
(c)前記被検者のサンプル中に含まれたLPA2の発現量が正常群サンプル中に含まれたベータ1インテグリンの発現量よりも高いか否か確認する段階。
本発明の特徴及び利点を要約すれば、次の通りである:
(i)本発明は、ベータ1インテグリンを抗原として認識してそれに特異的に結合する単一クローン抗体又はその断片を提供する。
[図1]本発明のGP5単クローン抗体の重鎖可変領域及び軽鎖可変領域のアミノ酸配列を示す。
以下、実施例を用いて本発明をより詳細に説明する。これらの実施例は単に本発明をより具体的に説明するためのもので、本発明の要旨によって本発明の範囲がこれらの実施例に制限されないということは、当業界における通常の知識を有する者にとって明らかであろう。
<実施例1>P5の癌細胞殺傷能改良及びヒト化
本発明者らは、P5(Kim MY et al.J Biomed Res,2016,30(3):217-24)に比べて癌細胞殺傷能の増加したヒト化抗体を開発するために次のような実験を行った。
1)具体的に、HFR1はIGHV7-4-1*03、HFR2はIGHV4-30-4*06、HFR3はIGHV1-69-2*01、HFR4はIGHJ6*01の配列を利用し、アミノ酸の物理化学的性質の類似性又は非類似性を考慮して親抗体と異なるアミノ酸を置換した。このような方法で置換されたアミノ酸は、IGHV7-4-1*03ではI20V、T25S、S30T;IGHV4-30-4*06ではR40H、H43K;IGHV1-69-2*01ではK66R、A67V、F69I、S75T、N76D、S79Y、Q81E、T83R、S87T;及びIGHJ6*01ではS108Tであった。このように置換された重鎖可変領域をさらにIGHV1-2*02を用いてアラインメントを行った後、最も性能に優れると予想される突然変異を選別した。
1.重鎖可変領域:A9S、I20V、T25S、S30T、K66R、S75T、N76D、Q81E
2.軽鎖可変領域:V11L、F36Y、R39K
(抗体ドメインのアミノ酸残基番号は、当業界において通常用いられるカバットナンバリングシステム(Kabat EU numbering system,Kabat et al.,“Sequences of Proteins of Immunological Interest”,5th Ed.,U.S.Department of Health and Human Services,NIH Publication No.91-3242,1991では同一のEU指数番号に従う。)によってナンバリングした。)
ヒト化重鎖可変領域は、ヒトIgG1重鎖定常領域(CH1、CH2、CH3)と結合し、ヒト化軽鎖可変領域は、ヒト軽鎖定常領域(Ckappa)と結合して最終的にヒト化を完了した。
前記表で、太字はアミノ酸置換位置を表す(カバットナンバリングシステムに従うA9S、I20V、T25S、S30T、K66R、S75T、N76D、Q81E、V11L、F36Y、R39K)
<実施例2>GP5クローンの完全抗体転換及び発現/精製
実施例1で開発したGP5可変領域のDNAをscFv形態に合成し(Cosmogenetech、韓国)、PCR方法によって完全抗体(full IgG)に転換した。まず、scFvを含むpUCベクター(Cosmogenetech、韓国)から重鎖及び軽鎖の可変領域と定常領域の切片を、下記表2のVH、CH及びVL、CKプライマー組合せを用いてPCRで得た。得られた抗体の可変領域と定常領域を使用し、下記表2のHC及びLCプライマー組合せを用いてPCRを行ってGP5の重鎖及び軽鎖を確保した。重鎖は、EcoRIとNotI(New England Biolab、英国)酵素で処理し、同様に同一の制限酵素で処理された動物細胞発現用ベクターであるpCMVベクター(Thermo Fisher SCIENTIFIC、米国)にライゲーションした。また、軽鎖は、XbaI(New England Biolab、英国)酵素で処理し、同様に同一の制限酵素でpCMVベクターにライゲーションした。ライゲーションされたプラスミドは、DH5α大腸菌コンピテントセル(competent cell)(New England Biolab、英国)に熱衝撃を加えて形質転換し、コロニーを得た後、大量培養してプラスミドを得た。
完全抗体に転換させた重鎖と軽鎖のそれぞれのプラスミドを、PEI(Polyethylenimine)(Polysciences、米国)と150mM NaClを用いてHEK293F細胞(Invitrogen、米国)に形質感染(transfection)させ、フリースタイル293発現培地(Freestyle 293 expression medium)(Invitrogen、米国)で37℃の温度、8%CO2そして55%湿度の条件で7日間培養した。発現した細胞培養液を4,000rpm、10分間遠心分離した後、上澄液を取って0.22μmフィルターで濾過した。濾過された上澄液は4℃でプロテインA(GenScript、中国)レジン1mlに結合誘導した。結合したレジンは、10cv(column volume)のPBS溶液で洗浄後に、100mMグリシン-HCl(pH 2.7)溶液を溶出した後、1Mトリス-HCl(pH 9.0)で中和させた。pH 7.2~7.4のPBSにバッファ交換(buffer change)を行った後、SDS-PAGEにより、精製された抗体の軽鎖及び重鎖のサイズ及び純度を確認し、その結果を図2Aに示した。精製されたGP5単クローン抗体は、軽鎖及び重鎖の理論的計算値と一致する分子量及び高い純度が確認できた。また、SEC(Size Exclusion Chromatography)(GE Healthcare、米国)により、精製された抗体の均質性(homogeneity)を確認した結果、95%の均質性を示し、その結果を図2Bに示した。
前記実施例2で製作したGP5単クローン抗体のべータ1インテグリンに対する結合力を直接ELISA(direct ELISA)で確認した。GP5単クローン抗体がヒト化抗体で、P5がマウス抗体であることから、直接の結合力比較のためにペロキシダーゼラベリングキットNH2(Peroxidase Labeling Kit-NH2)(Dojindo、日本)を用いて各抗体にHRPを標識した。直接ELISAは、50μlのPBSに1μg/mlで組換えヒトベータ1インテグリン(Sino biological、中国)及び組換えマウスベータ1インテグリン(MyBioSource、米国)を希釈して96ウェル免疫プレート(Corning、米国)に入れ、4℃で一晩保管して吸着させた。3%ウシ血清アルブミン(Milipore、米国)が含まれた緩衝溶液で37℃で1時間反応させた後、逐次濃度(0.01、0.03、0.1、0.3、1、3、100、300、1000nM)に希釈したそれぞれのHRPが標識された抗体を、ウェル当たり50μlずつ処理した。抗原に抗体が結合し得るように37℃で2時間反応させた後、0.5%ツイン20(Amresco、米国)が含まれた緩衝溶液で3回洗浄した後、3,3’,5,5’-テトラメチルベンジジン(TMB)(Life technologies、米国)を50μlずつ各ウェルに分注して30分間発色させた。分光光度計(Biotek、米国)を用いて450nmで吸光度を測定し、その結果を図3A及び図3Bに示した。
本発明者らは、非小細胞肺癌を含む様々な癌細胞株においてべータ1インテグリンの発現を確認するために下記のように実験を行った。
本発明者らは、P5と本発明のGP5単クローン抗体が、べータ1インテグリンが発現している非小細胞肺癌を含む様々な癌細胞株において細胞自滅死を誘発できるかどうかを調べるために下記のように実験を行った。
本発明者らは、P5と本発明のGP5単クローン抗体が、非小細胞肺癌を含む様々な癌細胞株においてべータ1インテグリンの内在化を誘導する効果を確認するために、下記のような実験を行った。0.05%トリプシン-EDTA(Gibco、米国)を処理してT75フラスコ(SPL、韓国)からはがした非小細胞肺癌細胞株A549、乳癌細胞株MDA-MB-231及び大腸癌細胞株HCT116を5×105個ずつEPチューブに入れて3500rpmで5分間遠心分離後に、PBSで洗浄した。その後、PBSを用いてP5又はGP5単クローン抗体を10μg/mlとなるように希釈した後、100μlを処理した。4℃で1時間反応させた後、37℃で非小細胞肺癌細胞株A549は0、40、60、80、90、120及び150分ずつそれぞれ反応を持続し、乳癌細胞株MDA-MB-231及び大腸癌細胞株HCT116は、120分間反応を持続した。反応が終わった後、PBSで洗浄し、P5が処理されたEPチューブには、FITCが標識され抗マウス抗体(Sigma、米国)を1:100の比率にPBSで希釈して100μl処理し、GP5単クローン抗体が処理されたEPチューブには、FITCが標識された抗ヒト抗体(Life technologies、米国)を1:200の比率にPBSで希釈して100ulを処理した。30分間遮光して4℃で反応後に、PBSで洗浄し、流細胞分析装備であるAttune NxT(ThermoFisher Scientific、米国)で流細胞分析を行い、その結果を図6に示した。図6Aは、37℃で非小細胞肺癌細胞株A549、乳癌細胞株MDA-MB-231及び大腸癌細胞株HCT116を120分反応させた結果であり、図6Bは、非小細胞肺癌細胞株A549を37℃で反応させた時間帯別結果をグラフで示したものである。その結果、P5が処理されたA549、MDA-MB-231及びHCT116細胞に比べて、GP5単クローン抗体が処理されたA549、MDA-MB-231及びHCT116細胞の表面においてべータ1インテグリンが大きく減少した(図6)。
べータ1インテグリンが様々な癌において細胞毒性化学療法(cytotoxic chemtherapy)に対する耐性の原因になると知られているので(Park CC et al.Cancer Res,2006,66(3):1526-35)、本発明者らは、細胞毒性化学療法に使用されるゲフィチニブに対する耐性が現れた非小細胞肺癌細胞株においてGP5単クローン抗体の単独又はゲフィチニブとの併用使用時に細胞自滅死誘導の程度を確認するために下記のように実験を行った。
本発明者らは、P5と本発明のGP5単クローン抗体が、非小細胞肺癌細胞株の移植されたヌードマウスにおいて抗癌活性を示すか否かを調べるために下記のように実験を行った。
免疫組織化学染色はロクウォンバイオ融合研究財団で行い、組織病理学的分析はエスジーメディカル(株)で行った。実験終了時点(Day 60)に全てのマウスは組織処理及び免疫組織化学染色、組織学的分析のために犧牲死させた。実験動物を深く麻酔させた状態で改服して心臓から採血した後、組織を摘出し、摘出した組織は4%ホルムアルデヒド溶液に固定した後、パラフィンで包埋した。組織切片は、腫瘍の最も大きい部分で4μm厚に薄切りし、パラフィンを除去した後、再水和した。免疫ペロキシダーゼ標識のために細胞内のペロキシダーゼを0.3% H2O2に15分間露出して抑制した。その後、抗原復旧のために抗原復旧液(antigen retrieval solution;TE pH 9.0)(Sigma、米国)に入れ、圧力クッカー(pressure cooker)(Bio SB、米国)で30分間加熱した。非特異性免疫反応排除のためにブロッキング溶液に20分間露出させた。
Claims (11)
- ベータ1インテグリン(beta1integrin)を抗原として認識してそれに特異的に結合する単一クローン抗体又はその抗原結合断片であって、該単一クローン抗体又はその抗原結合断片は、配列番号3の重鎖可変領域及び配列番号4の軽鎖可変領域を含み、該単一クローン抗体又はその抗原結合断片は、カバットナンバリングシステム(Kabat EU numbering system)による下記のアミノ酸置換を含むことを特徴とする単一クローン抗体又はその抗原結合断片:
a)配列番号1の重鎖可変領域(heavy chain variable region,VH)においてA9S、I20V、T25S、S30T、K66R、S75T、N76D及びQ81Eのアミノ酸置換;及び
b)配列番号2の軽鎖可変領域(light chain variable region,VL)においてV11L、F36Y及びR39Kのアミノ酸置換。 - 前記単一クローン抗体又はその抗原結合断片は、単一鎖抗体(single-chain variable fragment,scFv)であることを特徴とする、請求項1に記載の単一クローン抗体又はその抗原結合断片。
- 請求項1の単一クローン抗体又はその抗原結合断片を含む多重特異抗体(multispecific antibody)又は抗体-薬物接合体(Antibody-drug conjugate,ADC)。
- 請求項1の単一クローン抗体又はその抗原結合断片をコードする核酸分子。
- 請求項4の核酸分子を含むベクター。
- 請求項5のベクターを含む宿主細胞。
- 請求項1の単一クローン抗体又はその抗原結合断片、請求項4の核酸分子又は請求項5のベクターを含む、癌の予防又は治療用薬剤学的組成物。
- 前記癌は、細胞毒性化学療法(cytotoxic chemtherapy)に耐性ができたことを特徴とする、請求項7に記載の薬剤学的組成物。
- 前記癌は、肺癌、乳癌又は大腸癌であることを特徴とする、請求項7に記載の薬剤学的組成物。
- 請求項1の単一クローン抗体又はその抗原結合断片を処理する段階を含む、サンプル中に含まれたベータ1インテグリン(beta1integrin)の定量方法。
- 請求項1の単一クローン抗体又はその抗原結合断片を含むベータ1インテグリン(beta 1 integrin)定量キット。
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