JP2019522653A - 二重特異性抗体を用いた抗体薬物複合体プラットホーム - Google Patents
二重特異性抗体を用いた抗体薬物複合体プラットホーム Download PDFInfo
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Abstract
Description
本発明は、二重特異性抗体を用いた抗体薬物複合体及びその用途に関する。
[背景技術]
抗体薬物複合体(ADC)は、抗癌剤の新たな種類として抗原発現腫瘍細胞に細胞毒性製剤を選択的に伝達するために開発された。従来のADCは、高い適用性及び部位特異的な結合方法を使用するといった多くの長所がある。しかし、抗体に細胞毒性製剤を連結するためには多段階の結合法が必要となり、個々の抗体を最適化する過程が求められ、ADCの使用に困難がある。
[発明が解決しようとする課題]
本発明は、従来の抗体薬物複合体の短所を解消した新たな抗体薬物複合体プラットホームを提供することを目的とする。
[課題を解決するための手段]
本発明は、抗コチニン一本鎖可変切片 (scFv)を含む二重特異性抗体と、ペプチドと架橋結合した二価のコチニン及び薬物の接合体と、を含む抗体薬物複合体プラットホームを提供する。
[発明の効果]
本発明の抗体薬物複合体は、抗体が特異的に結合する標的に薬物を効果的に伝達することができ、体内薬物の半減期を増進させて治療効果を向上させることができる。特に、本発明の二重特異性セツキシマブ×抗コチニン抗体及びデュオカルマイシンと接合された二価のコチニン−ペプチドの複合体は、KRAS突然変異を有するEGFR陽性セツキシマブ難治性肺腺癌に著しい抗腫瘍活性を示す。
[図面の簡単な説明]
図1a〜図1dは、二重特異性(セツキシマブ×抗コチニン)抗体(ERC6)の生成及び特性を示す。図1aは、二重特異性抗体を用いた抗体薬物複合体(ADC)プラットホームの概略図である。二重特異性(セツキシマブ×抗コチニン)抗体(ERC6)は、ヒトEGFR及びコチニンペイロードへの結合特異性を共に有するように設計される。図1bは、SDS−ポリアクリルアミドゲル電気泳動法(SDS−PAGE)の結果を示す。精製されたERC6を4〜12%(w/v)SDS−PAGEに投入した。クマシーブリリアントブルーでゲルを染色することでバンドを視覚化した。一番または二番レーンは、各々還元剤があるか、またはないサンプルである。図1cは、サイズ排除クロマトグラフィ(SEC)である。高性能の液体クロマトグラフィーを用いたSEC(SEC−HPLC)によって精製されたERC6を分析した。図1dは、ERC6の薬物動態の分析結果を示す。200μgのERC6をBalb/cマウス(n=4)の静脈内に注射し、血液サンプルを眼窩内の静脈から収集した。ERC6の循環血清水準を酵素免疫測定法(ELISA)によって分析した。結果は、3回の実験から得た平均±SDで示した。
[発明を実施するための形態]
以下、添付された図面を参照して本発明の望ましい実施例を詳しく説明する。しかし、本発明による実施例は多くの他の形態に変形でき、本発明の範囲が後述する実施例に限定されると解釈されてはならない。本発明の実施例は当業界で通常の知識を有する者に本発明をより完全に説明するために提供されるものである。
A549(ヒト肺腺癌)細胞を韓国細胞株銀行から得て、5%のCO2及び湿った環境で37℃で10%熱非活性化したウシ胎児血清(GIBCO,Grand Island,NY,USA)、100U/mLペニシリン及び100μg/mLストレプトマイシンで補充したRPMI−1640培地(WELGENE,韓国)に培養した。HEK293F細胞(Invitrogen,Carlsbad,CA,USA)は、オービタルシェーキング培養基(Minitron,INFORS HT,Bottmingen,Switzerland)を用いて、135rpmで7%のCO2及び70%の湿度で37℃にてベントキャップ(vent cap)付きErlenmeyer組織培養フラスコ(Corning Inc.,NY,USA)で、100U/mLのペニシリン及び100μg/mLのストレプトマイシンを含むFreeStyleTM 293発現培地(GIBCO)で生長させた。
二重特異性セツキシマブ×抗コチニン抗体(ERC6)発現ベクターを製造するために、セツキシマブ軽鎖及びセツキシマブ重鎖−リンカー(Gly−Gly−Gly−Gly−Ser)3−抗コチニンscFvをコーディングする遺伝子を化学的に合成した(Genscript,Picataway,NJ,USA)。制限部位、AgeI及びXbaIを、セツキシマブの軽鎖をコーディングする遺伝子の5’及び3’末端に各々挿入した。追加的な制限部位、NheI及びBsiWIを、セツキシマブの重鎖をコーディングする遺伝子の5’末端及び抗コチニンscFvの遺伝子の3’末端に各々挿入した。[Park S, Lee DH,Park JG,Lee YT,Chung J.A sensitive enzyme immunoassay for measuring cotinine in passive smokers.Clin Chim Acta 2010;411(17−18):1238−42]に開示の方法のように、軽鎖及び重鎖−リンカー−抗コチニンscFvを、再組合タンパク質の分泌のために設計された哺乳動物発現ベクターでサブクローンした。
精製されたERC6を製造者の指示に従ってNuPage4〜12%のBis−Trisゲル(Invitrogen)を用いてソジウムドデシルサルフェート−ポリアクリルアミドゲル電気泳動(SDS−PAGE)で分析した。前記ゲルは、クマシーブリリアントブルーR−250(Amresco,Colon,OH,USA)で染色した。
300Åの気孔を含む3μm粒子で包装されたBio SEC−3 カラム(7.8×300mm)が装着されたAgilent 1260 Infinity高圧液体クロマトグラフィー(HPLC)システム(Agilent Technologies,Santa Clara,CA,USA)を用いて、精製されたERC6を、SEC−HPLCによって分析した。移動相は、pH7.0の50mMソジウムホスフェート及び150mMソジウムクロライドを含む。20μLのERC6(1mg/ml)を注入し、30分間1mL/分の流速でイソクラティック溶出した。カラム流出物を280nmにて紫外線検出器でモニターし、mAUで示した。単量体、凝集体及び切片の百分率をピーク面積を基準にして定量化した。
本実験に用いられた全てのペプチドは、Fmocペプチド固相合成(Peptron、韓国)を用いて合成した。二つのトランス−4’−コチニンカルボックシル酸(Sigma−Aldrich,St Louis,MO,USA)を、GGGGSKGGGGSK及びGSKGSKGSKGSKKペプチドのN末端及びC末端に自由アミン基で架橋結合した。トリフェニルホスフィン(tetrakis)パラジウムでペプチドの中間でリシン上のアリルオキシカルボニル(alloc)基を除去した後、dPEG6(Peptide international Inc.,Louisville,KY,USA)を、GGGGSKGGGGSKペプチドの自由アミン基に結合した。その後、ビオチンをdPEG6結合したペプチド(Peptron社、韓国)上の自由アミンに架橋結合した。単純化のために、ビオチンと架橋結合した二価のコチニン接合したペプチド(コチニン−GGGGSK[(dPEG6)−ビオチン]GGGGSK−コチニン)を、コチニン−ビオチンとして略称する。
ERC6とコチニン接合したペイロードの複合体を生成するために、コチニンペイロード及びERC6をピペッティング(pipetting)アップ及びダウンによって1:1のモル比で混合した。その後、混合物を室温で30分間培養した。その後、複合体を追加的な変更なくインビトロ(in vitro)またはインビボ(in vivo)で使用した。
96ウェルマイクロタイタープレートのウェル(Corning社)を、コーティングバッファー(蒸留水内に0.1M重炭酸ナトリウム、pH8.6)内のヒトEGFR(Sigma)またはBSA結合したコチニンで4℃で一晩中コーティングし、37℃で1時間の間PBS内の3%[w/v]ウシ胎児血清(BSA)で遮断した。50μL遮断バッファー内の1μg/mL濃度の抗体を各ウェルに添加し、37℃で2時間培養した。PBS内の0.05%[v/v]Tween20(PBST)で洗浄した後、遮断バッファー内に希釈されたHRP結合の抗ヒトIgG(Fab特異的)抗体(Sigma)を37℃で1時間培養した。その後、プレートを0.05%PBSTでさらに洗浄し、50μLの3,3’,5,5’−テトラメチルベンジジン基質溶液(TMB)(GenDEPOT,Barker,TX,USA)を各ウェルに添加し、吸光度をMultiskan Ascentマイクロプレートリーダー(Labsystems,Helsinki,Finland)を用いて650nmで測定した。
本実験に用いられた全ての実験動物は、韓国国立癌センター研究所の動物実験倫理委員会によって検討され承認された(許可番号:NCC−15−267)。動物は、AAALAC国際動物保護政策によって国立癌センターの動物施設で管理した。
各サンプル当り4×105細胞の最終濃度でA549細胞をv−bottom96−ウェルプレート(Corning社)にシードした(seeded)。30分間37℃で流動細胞分析バッファー(PBS内に1%[w/v]BSAを含む0.1%[w/v]アジ化ナトリウム)内に希釈されたERC6及びコチニン−ビオチンの0または100nMで細胞を処理した。対照群の実験として、ERC6の代わりにパリビズマブ(palivizumab)(Synagis,Boehringer Ingelheim Pharma,Biberach an der Riss,Germany)、抗コチニンIgGまたはセツキシマブ(Erbitux,Merck K GaA,Darmstadt,Germany)を用いた。流動細胞分析バッファーで洗浄した後、暗い所で37℃で1時間の間、ピコエリスリン(PE)結合したストレプトアビジン(BD Biosciences Pharminogen,San Diego,CA,USA)及びFITC結合した抗ヒトIgG(Fc特異的)抗体(Thermo Fisher Scientific Pierce)と共に細胞を培養した。同じバッファーで追加洗浄をした後、細胞を200μLのPBSに再懸濁し、488nmのレーザーが装着されたFACS Canto II instrument(BD Bioscience,San Jose,CA,USA)を用いて流動細胞分析を行った。測定当り1万個の細胞が検出されており、FlowJo ソフトウェア(TreeStar,Ashland,OR,USA)を用いてデータを分析した。
腫瘍細胞生存力に対するERC6及びコチニン−デュオカルマイシンの影響をCell Titer−Glo試薬(Promega Corp.,Madison,WI,USA)を用いて評価した。A549細胞を黒色壁の96−ウェルプレート(ウェル当り4,000個の細胞)においてRPMI−1640培地50μLにシードし、5%のCO2及び湿った環境で37℃で一晩中接着した。その後、ERC6及びコチニン−デュオカルマイシンの複合体を新鮮な培養培地で10倍系列希釈した(0.02nM〜2000nM)。対照群の実験において、ERC6の代わりにパリビズマブ(Boehringer Ingelheim Pharma)、またはセツキシマブ(Merck K GaA)を用いた。50μLの培地内のコチニン−デュオカルマイシン及び抗体希釈物を各ウェルに添加し、72時間培養した。各ウェルにCell Titer−Glo試薬(Promega Corp.)を添加した後、製造者の指示に従ってマイクロプレート発光測定器(microplate luminometer)(PerkinElmer,Waltham,MA,USA)を用いて発光信号を測定した。全ての実験は、3倍数で行った。相対的な細胞生存力は、対照群の発光信号で割ることで計算した[%生存力=(実験(Test)−背景(Background))/(対照群(Control)−背景)×100]。
6週齢の雌Balb/cヌードマウスの左側及び右側のわき腹の皮下にA549(1×107細胞)を注射した。腫瘍の体積が約150mm3に到達するとき、全ての動物を三つのグループにランダムで分けて(n=4/グループ) 5週間処理した。初めの2週間は、一週に二回、適切な対照群をマウスの腹腔に注射した:グループIは、パリビズマブ(2.15mg/kg)及びコチニン−デュオカルマイシン(95μg/kg)を投与;グループIIは、ERC6(3mg/kg)及びジメチルスルホキシド(DMSO)を投与;グループIIIは、ERC6(3mg/kg)及びコチニン−デュオカルマイシン(95μg/kg)の複合体を投与。その後、前記薬物の3倍の投与量を、以後の3週間、週3回注射した。パリビズマブは、二重特異性抗体の同型(isotype)対照群として用いられた。DMSOは、コチニン−デュオカルマイシンのビヒクル対照群として用いられた。腫瘍の体積は、注射してから32日後、一週間に二回、デジタルキャリパを用いて測定した。腫瘍の体積は、長さ×(幅)2×0.5で計算し、前記長さは最も長い軸であり、幅は前記長さに垂直な距離である。全身毒性は、週二回、体重を測定して評価した。注射してから35日目にマウスを犠牲させ、腫瘍を切開して重さを測定した。
A549(1×107細胞)をBalb/cヌードマウスの左側及び右側わき腹の皮下に注射した。平均腫瘍体積が500mm3に到達したとき、腫瘍を有するマウスに、下記の単一腹腔内(i.p.)注射を投与した:グループIは、144μgのパリビズマブ及び1.85μgのコチニン−ビオチンを投与;グループIIは、200μgのERC6及びビヒクル(蒸留水)を投与;グループIIIは、ERC6(200μg)及びコチニン−ビオチン(1.85μg)の複合体を投与。注射してから24時間後にマウスをイソフルランで麻酔し、PBS内の4%[w/v]パラホルムアルデヒド10mlで経心腔的潅流(transcardial perfusion)で安楽死した。解剖された腫瘍を4℃で24時間の間、PBS中に30%[w/v]スクロースを含む凍結保存溶液中に平衡化し、最適切断温度(OCT)を有する内装培地(Sakura Finetek,Torrance,CA,USA)に入れて凍結し、切開するまで−80℃で保存した。免疫蛍光染色のために、4μmの厚さで凍結切片(cryosections)を準備し、PBS内の4%パラホルムアルデヒドで10分間室温で固定した。PBSで洗浄した後、前記切片(sections)を室温で1時間の間、IHC−Tek 抗体希釈液(pH7.4)(IHC WORLD,Woodstock,MD, USA)内の10%[v/v]正常ヤギ血清(normal goat serum)(CST,Danvers,MA,USA)で遮断した。前記組織切片をAlexa Fluor 488結合したストレプトアビジン(Molecular Probes Inc.,Eugene,OR,USA)と共に8時間培養し、Alexa Fluor 594結合した抗ヒトIgG抗体(Molecular Probes Inc.)で4℃の暗くて湿ったチャンバで16時間染色した。PBSで洗浄した後、製造者の指示に従って4’,6−ジアミジノ−2−フェニルインドル(DAPI;Pierce,Rockford,IL,USA)で核を染色した。前記切片を蛍光固定培地(DAKO,Glostrup,Denmark)と共にスライド上に固定し、FV1000レーザースキャニング顕微鏡(Olympus,Tokyo,Japan)を用いてFV10 ASWソフトウェアで40倍の拡大イメージを得た。放出及び励起フィルターは同時に3色イメージ化するように配列した。
実験に使用された統計は、GraphPad Prism version 5.0ソフトウェア(GraphPad Software Inc.,San Diego,CA,USA)を用いて行った。結果は、表示された独立的な測定回数に対する±標準偏差(SD)の平均値で示した。統計的有意性は、2標本スチューデントt検定(two tailed unpaired Student’s t−test)を用いて決定し、0.05未満のp値は統計的に重要なものとして看做した。P値は、図面及びその凡例で示した。
重鎖のCH3ドメインに二つの一本鎖抗体(scFvs)を融合することでIgGに基づく4価のフォーマットで二重特異性抗体を設計した(図1a)。柔軟性のために、グリシン及びセリンの豊富なペプチドリンカー[(Gly−Gly−Gly−Gly−Ser)3]をCH3ドメインとscFvとの間に挿入した。これによって、二重特異性抗体の二つのFabアーム及び重鎖のC末端上における二つのsvFvを含む4価の抗体が生成され、各々上皮成長因子受容体(EGFR)とコチニンとを同時に標的化した。二重特異的セツキシマブ×抗コチニンscFv抗体(ERC6)を開発するために、セツキシマブIgG、リンカー及び抗コチニンscFvをコーディングする遺伝子構造を真核発現ベクターにクローニングした。ER6は、タンパク質A親和性カラムクロマトグラフィーを用いて一時的に形質導入された(transfected)HEK393F培養上澄液から精製した。
精製されたERC6の純度及び分子量を分析するために、ERC6をクマシーブリリアントブルーで染色されたソジウムドデシルサルフェート(SDS)ポリアクリルアミドゲルで視覚化した。206kDaの分子量を有する主要バンドは、非還元条件で観察されており、78kDa及び25kDaの二つの主要バンドが還元条件で観察された(図1b)。206kDaの分子量を有する再組合タンパク質は、ProtParamツール(ExPASy)によって予測された、完全に組み立てられたERC6に相応する。25kDaの非変形の軽鎖及び75kDaのCH3ドメイン上における一つのscFvと融合した重鎖は、二硫化結合の減少によって視覚化した。したがって、データは、二重特異性抗体が純粋で損傷なく製造されたことを立証した。
EGFR及びコチニンに対してERC6の反応性を実験するために、酵素免疫測定による分析を適用した(図2a)。EGFRに対するERC6の結合活性が確認されることで、EGFRに対する反応性が追加的scFvとは関係ないことが立証された。また、コチニンに対する抗コチニンscFvモジュールの親和度が維持されたことが確認された(図2a)。
A549は、セツキシマブのようなEGFR標的治療に対する一次抵抗性を示すKRAS突然変異と共に野生型EGFRを発現する肺腺癌細胞株である。したがって、野生型のEGFR及びKRAS突然変異を有する癌細胞にERC6結合したコチニン細胞毒性剤の効能をテストするために前記細胞株を使用した。
また、追加実験によってERC6とコチニン−エムタンシン(Cot−DM1)とが組み合わされた抗体薬物複合体の細胞毒性効果を実験した。このような抗体薬物複合体も、前記コチニン−デュオカルマイシンが組み合わせられた複合体と同様に、A549細胞株に対して著しく高い細胞毒性効果を示した(図6b)。
ERC6複合のコチニン−デュオカルマイシンのインビボ(in vivo)効能を評価するために、セツキシマブ−難治性(refractory)A549細胞をマウス(n=4/グループ)に移植した。腫瘍の体積が150mm3に至ったとき、パリビズマブ及びコチニン−デュオカルマイシン、ERC6及びビヒクルまたはERC6複合のデュオカルマイシンを5週間腹腔内に注射した。マウスに薬物を2週間は週2回、その後、3週間は週3回投与した。
薬物動態分析は、ERC6複合されたペイロードの循環半減期がERC6に結合することで延長されることを立証した。抗原発現腫瘍組織へのコチニンペイロードの特異的伝達を調査するために、A549異種移植マウスモデルにおいて免疫蛍光分析を行った。A549細胞を、各Balb/cヌードマウスの左側わき腹の皮下に注射した。腫瘍が500mm3に至ったとき、腫瘍保有マウスにパリビズマブ及びコチニン−ビオチン、セツキシマブ及びビヒクルまたはERC6複合のコチニン−ビオチンを腹腔内に注射した。注射してから24時間後に動物を犠牲させ、解剖した腫瘍組織をエクスビボ(ex vivo)イメージ化した。腫瘍組織上のコチニンペイロード及び抗体を蛍光標識された二次抗体を通じて検出した。抗体は、Alexa 594標識された抗ヒトFc(赤色)によって検出され、コチニン−ビオチンは、Alexa 488標識されたストレプトアビジン(緑色)によって検出された。参照までに、核はDAPI(青色)で染色し、イメージ倍率は×40であった。共焦点顕微鏡によってERC6複合コチニン−ビオチンの組織分布を観察した。
Claims (15)
- 抗コチニン一本鎖可変切片を含む二重特異性抗体と、
ペプチドと架橋結合した二価のコチニン及び薬物の接合体と、を含むことを特徴とする抗体薬物複合体。 - 前記抗コチニン一本鎖可変切片が、前記二価のコチニンと結合したことを特徴とする請求項1に記載の抗体薬物複合体。
- 前記二価のコチニンは、二つのコチニンが各々6〜18merペプチドのN末端及びC末端に架橋結合したことを特徴とする請求項1に記載の抗体薬物複合体。
- 前記薬物が、二価のコチニンと架橋結合した6〜18merペプチドにおいてリシン残基と接合したことを特徴とする請求項1に記載の抗体薬物複合体。
- 前記二重特異性抗体が、CH3ドメインと抗コチニン一本鎖可変切片との間にペプチドリンカー(Gly−Gly−Gly−Gly−Ser)3が挿入されたことを特徴とする請求項1に記載の抗体薬物複合体。
- 前記薬物が、デュオカルマイシン、アウリスタチン、コルヒチン、アントラサイクリン、カリケアマイシン、メイタンシノイド、ピロロベンゾジアゼピン、ドラスタチン、ツブリシン、メイタンシノイド、ドキソルビシン、クリプトフィシン、エポチロン、サフラニン、デアセチルコルヒチン、メイタンシノール、ベドチン、マホドチン、エムタンシン、メルタンシン、ラブタンシン、ソラブタンシン、タリリン、テシリン、インドリノベンゾジアゼピン、イリノテカンプロドラッグ、エキサテカン誘導体及びツブリン阻害剤からなる群より選択されたいずれか一種、または
癌を発生させる遺伝子の発現を抑制するsiRNAであることを特徴とする請求項1に記載の抗体薬物複合体。 - 前記二重特異性抗体が、セツキシマブ、トラスツズマブ、オレゴボマブ、エドレコロマブ、アレムツズマブ、ラベツズマブ、ベバシズマブ、イブリツモマブ、オファツムマブ、パニツムマブ、リツキシマブ、トシツモマブ、イピリムマブ、ゲムツズマブ、ブレンツキシマブ、バダスツキシマブ、グレムバツムマブ、デパツキシズマブ、ポラツズマブ、デニンツズマブ、エンフォーツマブ、テリソツズマブ、チソツマブ、ピナツズマブ、リファスツズマブ、インデュサツマブ、バンドルツズマブ、ソフィツズマブ、ボルセツズマブ、トラスツズマブ、ミルベツキシマブ、コルツキシマブ、ナラツキシマブ、インダツキシマブ、アネツマブ、ロルボツズマブ、カンツズマブ、ラプリツキシマブ、ビバツズマブ、バダスツキシマブ、ロバルピツズマブ、イノツズマブ、サシツズマブ、ラベツズマブ、ミラツズマブ、ルパルツマブ及びアプルツマブからなる群より選択されたいずれか一つを含むことを特徴とする請求項1に記載の抗体薬物複合体。
- 請求項1に記載の抗体薬物複合体を含むことを特徴とする癌治療用の薬学的組成物。
- 前記癌が、KRAS突然変異を有する肺腺癌であることを特徴とする請求項8に記載の癌治療用の薬学的組成物。
- (s1)抗コチニン一本鎖可変切片を含む二重特異性抗体を製造する段階と、
(s2)ペプチドと架橋結合した二価のコチニン及び薬物の接合体を製造する段階と、
(s3)(s1)段階で生成した二重特異性抗体と(s2)段階で生成した接合体とを混合する段階と、を含むことを特徴とする抗体薬物複合体の製造方法。 - 前記(s3)段階は、抗コチニン一本鎖可変切片と二価のコチニンとが特異的に結合することを特徴とする請求項10に記載の抗体薬物複合体の製造方法。
- 前記二価のコチニンは、二つのコチニンが6〜18merペプチドのN末端及びC末端に架橋結合したことを特徴とする請求項10に記載の抗体薬物複合体の製造方法。
- 前記薬物が、二価のコチニンと架橋結合した6〜18merペプチドにおいてリシン残基と接合したことを特徴とする請求項10に記載の抗体薬物複合体の製造方法。
- 請求項1に記載の抗体薬物複合体の有効量を、癌を有する動物に処理する段階を含む癌治療方法。
- 請求項1に記載の抗体薬物複合体を用いて薬物の半減期を増進させる方法。
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US11167037B2 (en) | 2021-11-09 |
KR20190023084A (ko) | 2019-03-07 |
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US20190328894A1 (en) | 2019-10-31 |
JP7130243B2 (ja) | 2022-09-05 |
EP3473274A1 (en) | 2019-04-24 |
EP3473274A4 (en) | 2020-03-11 |
KR102529267B1 (ko) | 2023-05-04 |
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