JP6691872B2 - 抗上皮増殖因子受容体(egfr)抗体 - Google Patents
抗上皮増殖因子受容体(egfr)抗体 Download PDFInfo
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Description
本出願は、その内容全体が参照により本明細書に援用される、2014年5月30日に出願された米国仮出願第62/005887号の優先権を主張する。
上皮増殖因子受容体(EGFR、ErbB−1及びHER1としても知られている)は、EGFR(ErbB−1)、HER2/c−neu(ErbB−2)、Her3(ErbB−3)及びHer4(ErbB−4)を含む、4つの密接に関連する受容体チロシンキナーゼのサブファミリーである、ErbBファミリーの受容体の細胞表面受容体である。EGFRのリガンド(例えば、上皮増殖因子(EGF)、トランスフォーミング増殖因子a(TGFα)、HB−EGF、アンフィレグリン、ベータセルリン/BTC、エピゲン/EPGN、又はその他)は、EGFRのC末端ドメインにおける幾つかのチロシン(Y)残基(Y992、Y1045、Y1068、Y1148、及びY1173)の受容体二量体化及び自己リン酸化を誘導する。この自己リン酸化は、MAPK、Akt、及びJNK経路を含む幾つかのシグナル伝達カスケードの下流での活性化を誘発し、細胞移動、接着及び細胞増殖を導く。
本発明により提供されるのは、(1)アミノ酸配列N/T/Q−YGVH(配列番号4)を含むCDR−H1;(2)アミノ酸配列Y−N/A/G/D−T/D/N−P/K/E−FTSRF(配列番号9)を含むCDR−H2;及び(3)アミノ酸配列T/D−Y/L−YDY−E/N−FAY(配列番号14)を含むCDR−H3を含む重鎖可変ドメイン配列;並びに(1)アミノ酸配列I−G/R/S−T/L/P−NIH(配列番号20)を含むCDR−L1;(2)アミノ酸配列KY−A/G−SE−S/T−I−S/R(配列番号24)を含むCDR−L2;及び(3)アミノ酸配列NWPT−T/L/S/A/Y(配列番号30)を含むCDR−L3を含む軽鎖可変ドメイン配列を含む抗上皮増殖因子受容体(EGFR)抗体又はその抗原結合断片である。
本発明は、新規な抗上皮増殖因子受容体(EGFR)抗体を提供する。出願人は驚くべきことに、本明細書に記載の抗EGFR抗体は、転移性結腸直腸がん及び頭頸部がんの治療のために使用されるFDA承認抗EGFR抗体であるERBITUX(登録商標)(セツキシマブ)と比較して増強された治療効果を示すことを見いだした。本明細書に記載の抗EGFR抗体はまた、ERBITUX(登録商標)よりも長い半減期を示す。
本明細書で使用する「治療」又は「治療する」は、臨床結果を含む有益な又は所望の結果を得るためのアプローチである。この発明の目的では、有益な又は所望の結果は、限定するものではないが、次のものの一又は複数を含む:疾患から生じる一又は複数の症状を軽減させること、疾患の程度を減少させること、疾患を安定化させること(例えば、疾患の悪化を防止又は遅延させる)、疾患の広がり(例えば、転移)を予防又は遅延させること、疾患の再発を予防又は遅延させること、疾患の進行を遅延又は緩慢にすること、疾患状態を寛解させること、疾患の寛解(部分的又は完全)を提供すること、疾患を治療するために必要とされる一又は複数の他の医薬の用量を減少させること、疾患の進行を遅延させること、生活の質を向上又は改善すること、体重増加を増やすこと、及び/又は生存を延長すること。また、「治療」に包含されるのは、がんの病理学的帰結(例えば、腫瘍体積など)の減少である。本明細書で提供される方法は、治療のこれらの態様の何れか一又は複数を企図する。
本発明は、上皮増殖因子受容体(EGFR)に結合する新規な抗体の同定に基づく。抗EGFR抗体は、様々な治療方法及び診断方法において使用することができる。例えば、頭頸部がん、咽喉がん、結腸直腸がん、肺がんなどを含む、異常なEGFR発現又は異常なEGFR活性を特徴とする疾患の治療において、抗EGFR抗体を単独で、又は他の薬剤と組み合わせて使用することができる。本明細書で提供される抗体は、抗EGFR抗体を患者に投与し、患者からの試料中において(例えば、インビボ又はエクスビボで)EGFRタンパク質に結合した抗EGFR抗体を検出することによって、又は患者からの試料と抗EGFR抗体とを接触させ、EGFRタンパク質に結合した抗EGFR抗体を定性的に又は定量的に検出することによって、患者又は患者試料中のEGFRタンパク質を検出するために使用することもできる。
配列番号32
EIVLTQSPATLSLSPGERATLSCRASQSIGTNIHWYQQKPGQAPRLLIKYASESISGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQNNNWPTSFGGGTKVEIKRT
配列番号33
EIVLTQSPATLSLSPGERATLSCRASQSIRTNIHWYQQKPGQAPRLLIKYGSESISGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQNNNWPTSFGGGTKVEIKRT
配列番号34
EIVLTQSPATLSLSPGERATLSCRASQSISTNIHWYQQKPGQAPRLLIKYGSESISGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQNNNWPTSFGGGTKVEIKRT
配列番号35
EIVLTQSPATLSLSPGERATLSCRASQSIGTNIHWYQQKPGQAPRLLIKYASESISGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQNNNWPTTFGGGTKVEIKRT
配列番号36
EVQLVESGGGLVQPGGSLRLSCAASGFSLTTYGVHWVRQAPGKGLEWLGVIWSGGNTDYGNEFTSRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARALDYYDYEFAYWGQGTMVTVSSA
配列番号37
EVQLVESGGGLVQPGGSLRLSCAASGFSLTNYGVHWVRQAPGKGLEWLGVIWSGGNTDYGNEFTSRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARALDYYDYEFAYWGQGTMVTVSSA
配列番号38
EVQLVESGGGLVQPGGSLRLSCAASGFSLTNYGVHWVRQAPGKGLEWLGVIWSGGNTDYATEFTSRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARALDYYDYEFAYWGQGTMVTVSSA
配列番号39
EVQLVESGGGLVQPGGSLRLSCAASGFSLTNYGVHWVRQAPGKGLEWLGVIWSGGNTDYNTPFTSRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARALTYYDYEFAYWGQGTMVTVSSA
モノクローナル抗体は、例えば、Kohler and Milstein、Nature、256:495(1975)に記載されているようなハイブリドーマ法を用いて調製することができ、又は組換えDNA法(米国特許第4816567号)若しくは以下の実施例において本明細書に記載の方法により作製することができる。ハイブリドーマ法においては、ハムスター、マウス、又は他の適切な宿主動物は、免疫剤に特異的に結合するであろう抗体を産生する、又は産生することができるリンパ球を誘発するために、免疫剤で典型的に免疫される。別法として、リンパ球をインビトロで免疫することもできる。
抗体は、ヒト化抗体又はヒト抗体であり得る。非ヒト(例えばマウス)抗体のヒト化型とは、キメラ免疫グロブリン、免疫グロブリン鎖、又はその断片(例えばFv、Fab、Fab’、F(ab’)2あるいは抗体の他の抗原結合サブ配列)であって、非ヒト免疫グロブリンに由来する最小配列を典型的に含むものである。ヒト化抗体はレシピエントのCDR由来の残基が、マウス、ラット又はウサギのような所望の特異性、親和性及び能力を有する非ヒト種(ドナー抗体)のCDR由来の残基によって置換されたヒト免疫グロブリン(レシピエント抗体)を含む。幾つかの例では、ヒト免疫グロブリンのFvフレームワーク残基は、対応する非ヒト残基によって置換されている。また、ヒト化抗体は、レシピエント抗体にも、移入されたCDRもしくはフレームワーク配列にも見出されない残基を含むことができる。一般に、ヒト化抗体は、全てあるいは殆ど全てのCDR領域が非ヒト免疫グロブリンのものに対応し、全てあるいは殆ど全てのFR領域がヒト免疫グロブリンコンセンサス配列のものである少なくとも一つ、典型的には二つの可変ドメインの実質的に全てを含むことができる。ヒト化抗体は、好ましくは、免疫グロブリン定常領域(Fc)の少なくとも一部、典型的にはヒト免疫グロブリンのそれも含むであろう。Jones et al. Nature, 321: 522-525 (1986); Riechmann et al., Nature, 332: 323-329 (1988); Presta, Curr. Op. Struct. Biol., 2:593-596 (1992)。
多重特異性抗体は、2つ以上の異なる抗原に対する結合特異性を有するモノクローナル、好ましくはヒト又はヒト化抗体である(例えば、二重特異性抗体は少なくとも2つの抗原に対する結合特異性を有する)。例えば、結合特異性の1つはa5−1タンパク質のためのものであり、他方は任意の他の抗原のためのものであり得る。1つの好ましい実施態様によれば、他の抗原は細胞表面タンパク質又は受容体又は受容体サブユニットである。例えば、細胞表面タンパク質は、ナチュラルキラー(NK)細胞受容体であり得る。従って、一実施態様によれば、本発明の二重特異性抗体は、EGFR及び例えば第2の細胞表面受容体の両方に結合することができる。
ヘテロコンジュゲート抗体は、2つの共有結合した抗体からなる。このような抗体は、例えば、免疫系細胞を不要な細胞に対してターゲティングさせるため[米国特許第4676980号]及びHIV感染の治療のために提案されている。国際公開第91/00360号;国際公開第92/200373号;EP03089。この抗体は、架橋剤を含むものを含む合成タンパク質化学における既知の方法を用いてインビトロで調製することができると考えられる。例えば、免疫毒素は、ジスルフィド交換反応を用いて、又はチオエーテル結合を形成することによって構築することができる。この目的に対して好適な試薬の例には、イミノチオレート及びメチル−4−メルカプトブチルイミダート、及び例えば米国特許第4676980号に開示されたものが含まれる。
例えばがんを治療する際の抗体の有効性を高めるために、エフェクター機能に関して本明細書で提供される抗体を改変することが望ましい場合がある。例えば、例えば、システイン残基をFc領域に導入することができ、それによってこの領域内に鎖間ジスルフィド結合を形成させることができる。このようにして生成されたホモ二量体抗体は、改善された内在化能力及び/又は補体媒介性細胞死滅並びに抗体依存性細胞傷害(ADCC)を有することができる。Caron et al., J. Exp. Med., 176: 1191-1195 (1992)及びShapes, J. Immunol.,148: 2918-2922 (1992)を参照。増強された抗腫瘍活性を有するホモ二量体抗体は、Wolff et a!., Cancer Research,53: 2560-2565 (1993)に記載されているようなヘテロ二官能性架橋剤を用いて調製することもできる。あるいは、二重のFc領域を有し、それによって亢進された補体溶解及びADCC能を有することができるように抗体を操作することができる。Stevenson et al., Anti-Cancer Drug Design3: 219-230 (1989)を参照。
本発明はまた、化学療法剤、毒素(例えば、細菌、真菌、植物又は動物起源の酵素的に活性な毒素、又はその断片)などの細胞傷害性剤、あるいは放射性同位体(すなわち、放射性コンジュゲート)にコンジュゲートした抗体を含むイムノコンジュゲートに関する。
抗EGFR抗体及びその断片の共有結合性修飾は、本発明の範囲内に含まれる。共有結合性修飾の1つのタイプは、ポリペプチドの標的化アミノ酸残基を、ポリペプチドの選択された側鎖又はN−又はC−末端残基と反応することができる有機誘導体化剤と反応させることを含む。二官能性薬剤による誘導体化は、例えば、抗体を精製するための方法における使用のためにポリペプチドを水不溶性支持マトリックス又は表面に架橋するのに有用であり、逆もまた同様である。一般に用いられる架橋剤は、例えば、1,1−ビス(ジアゾアセチル)−2−フェニルエタン、グルタルアルデヒド、N−ヒドロキシスクシンイミドエステル、例えば4−アジドサリチル酸とのエステル、3,3’−ジチオビス(スクシンイミジル−プロピオナート)のようなジスクシンイミジルエステルを含むホモ二官能性イミドエステル、ビス−N−マレイミド−1,8−オクタンのような二官能性マレイミド、及びメチル−3−[(p−アジドフェニル)−ジチオ]プロピオイミダートなどの薬剤が挙げられる。
本発明の抗EGFR抗体(又はその断片)は、別の異種ポリペプチド又はアミノ酸配列(例えば、イムノアドヘシン又はペプチボディ)に融合されたポリペプチドを含むキメラ分子を形成する方法において有利であれば修飾することもできる。
本明細書中に開示される抗体はまた、免疫リポソームとして処方され得る。抗体を含むリポソームは、Epstein et al., PNAS USA, 82: 3688 (1985); Hwang et al., PNAS USA,77: 4030 (1980);及び米国特許第4485045号及び同第4544545号に記載されるような当該分野で公知の方法によって調製される。循環時間が増したリポソームは米国特許第5013556号に開示されている。
本明細書で提供される抗EGFR抗体(又はその断片)及び/又は組成物は、例えば、がん(頭頸部がん、咽喉がん、結腸直腸がん、肺がんなど)を含む異常なEGFR活性に関与する疾患及び障害を処置するために被験体(例えば、ヒトなどの哺乳動物)に投与することができる。ある実施態様において、本発明は、被験体におけるがん(例えば、頭頸部がん、肺がん又は結腸直腸がんなど)の処置のための医薬の製造における使用のための、本明細書に記載の抗EGFR抗体(又はその断片)を提供する。ある実施態様において、本発明は、被験体におけるがん(例えば、頭頸部がん、咽喉がん、結腸直腸がん、肺がんなど)の処置における使用のための、本明細書に記載の抗EGFR抗体(又はその断片)を提供する。ある実施態様において、本発明は、被験体におけるがん(例えば、頭頸部がん、咽喉がん、結腸直腸がん、肺がんなど)の処置における使用のための、本明細書において提供される抗EGFR抗体(又はその断片)を含む薬学的組成物を提供する。ある実施態様において、処置される被験体は哺乳動物(例えば、ヒト、非ヒト霊長類、ラット、マウス、ウシ、ウマ、ブタ、ヒツジ、ヤギ、イヌ、ネコなど)である。ある実施態様において、被験体はヒトである。ある実施態様において、被験体は、臨床患者、臨床試験ボランティア、実験動物などである。ある実施態様において、被験体は、がん(頭頸部がん、咽喉がん、結腸直腸がん、肺がんなど)を有するか、又は有するリスクがあると疑われているか、或いはがん又は異常なEGFR発現若しくは活性を有する他の疾患と診断されている。幾つかの実施態様において、本明細書に記載の抗EGFR抗体が投与される被験体は、KRASについて野生型である。ある実施態様において、本明細書に記載の抗EGFR抗体が投与される被験体は、KRASG13D変異を有する。幾つかの実施態様において、本明細書に記載の抗EGFR抗体が投与される被験体は、BRAFについて野生型である。ある実施態様において、本明細書に記載の抗EGFR抗体が投与される被験体は、BRAFV600E変異を有する。ある実施態様において、本明細書に記載の抗EGFR抗体を投与される被験体は、アービタックス又はそのバイオシミラーに耐性がある。ある実施態様において、本明細書に記載の抗EGFR抗体を投与される被験体は、アービタックス又はそのバイオシミラーで進行している。ある実施態様において、本明細書に記載の抗EGFR抗体を投与される被験体は、アービタックス又はそのバイオシミラーに対して難治性である。
抗EGFR抗体(又はその断片)は、それらが投与に適しているように、適切な担体又は賦形剤と共に製剤化することができる。抗体の適切な製剤は、所望の純度を有する抗体(又はその断片)を任意の薬学的に許容可能な担体、賦形剤又は安定剤(Remington's Pharmaceutical Sciences16th edition, Osol, A. Ed. (1980))と混合することによて凍結乾燥製剤又は水溶液の形態で得ることができる。許容可能な担体、賦形剤、又は安定化剤は、用いられる用量及び濃度でレシピエントに非毒性であり、リン酸、クエン酸、及び他の有機酸などの緩衝液;アスコルビン酸及びメチオニンを含む抗酸化剤;保存料(オクタデシルジメチルベンジルアンモニウムクロライド;ヘキサメトニウムクロライド;ベンズアルコニウムクロライド;ベンゼトニウムクロライド;フェノール;ブチル又はベンジルアルコール;メチル又はプロピルパラベン等のアルキルパラベン;カテコール;レゾルシノール;シクロヘキサノール;3−ペンタノール;及びm−クレゾールなど);低分子量(約10残基未満)ポリペプチド;血清アルブミン、ゼラチン、又は免疫グロブリン等のタンパク質;ポリビニルピロリドン等の親水性ポリマー;グリシン、グルタミン、アスパラギン、ヒスチジン、アルギニン、又はリジン等のアミノ酸;グルコース、マンノース、又はデキストリンを含む単糖類、二糖類、及び他の炭水化物;EDTA等のキレート剤;スクロース、マンニトール、トレハロース又はソルビトールなどの糖;ナトリウムなどの塩形成対イオン;金属錯体(例えば、Zn−タンパク質錯体)又はTWEENTM、PLURONICSTM又はポリエチレングリコール(PEG)等の非イオン性界面活性剤を含む。例示的な抗体製剤は、参照により本明細書に援用される国際公開第97/56418号に記載されている。皮下投与に適した凍結乾燥製剤は、国際公開第97/04801号に記載されている。そのような凍結乾燥製剤は、適切な希釈剤を用いて高タンパク質濃度まで再構成することができ、再構成製剤は、本明細書で治療される哺乳動物に皮下投与することができる。
EGFRポリペプチドに特異的に結合する、標識抗EGFR抗体、その断片、及びその誘導体及び類似体は、EGFRの発現、異常な発現及び/又は活性に関連する疾患及び/又は障害を検出、診断又はモニターする診断目的のために使用することができる。例えば、本明細書において提供される抗EGFR抗体(又はその断片)は、インサイツ、インビボ、エクスビボ、及びインビトロ診断アッセイ又は画像化アッセイにおいて使用され得る。(a)本発明の1つ以上の抗体を用いて個体の細胞(例えば、組織)又は体液中のポリペプチドの発現をアッセイすること及び(b)遺伝子発現のレベルを標準的な遺伝子発現レベルと比較することを含む、EGFRポリペプチドの発現を検出するための方法であって、それによって、標準的な発現レベルと比較してアッセイされた遺伝子発現レベルの増加又は減少が、異常な発現を示す、方法。
本明細書で提供される別の実施態様は、頭頸部がん、肺がん、又は結腸直腸がん(例えば、腫瘍)などのがんの治療に有用な物質を含有する製造品である。製造品は、容器と、容器上又は容器に付随したラベル又は添付文書を含むことができる。好適な容器は、例としてボトル、バイアル、シリンジ等を含む。容器はガラス又はプラスチックなどの様々な物質から形成されうる。容器は、ガラス又はプラスチックのような様々な材料から形成されてよい。一般に、容器は、症状の治療に有効である組成物を収容し、無菌のアクセスポートを有し得る(例えば、容器は皮下注射針により貫通可能なストッパーを有する静脈内溶液バッグ又はバイアルであってよい)。組成物中の少なくとも1つの活性剤は、本明細書で提供される抗EGFR抗体(又はその断片)である。ラベル又は添付文書は、組成物が特定の疾患の治療に用いられることを示す。ラベル又は添付文書は、抗体組成物を患者に投与するための説明書を更に含むであろう。また、本明細書中に記載の併用治療薬を含む製造品及びキットも考慮される。
生殖系列重鎖可変領域VH3.48及び生殖系列軽鎖可変領域VK3.11を用いて、ヒト化抗EGFR抗体348311を生成した。次いで、348311は、改良された結合性能を有するクローンを生成するために、インビトロファージディスプレイに基づく親和性成熟実験に使用された。最初に、CDR−L3/CDR−H3核酸ライブラリーをPCRにより生成し、ファージディスプレイベクターにクローニングし、大腸菌に形質転換してファージライブラリーを作製した。2ラウンドのパニングの後、284のFabクローンをELISAによってスクリーニングし、7つのクローン(すなわち、1−15,1−16,1−26,1−86,2−48,1−13及び3−66)が348311と同等又はそれ以上の結合性能を有することが判明した(図1)。更なるELISAを、以下の軽鎖/重鎖の組合せを含む全長IgGクローンを用いて行った:348311/348311(LC/HC)、1−15/348311(LC/HC)、1−26/348311(LC/HC)、1−86/348311(LC/HC)、2−48/348311(LC/HC)、348311/1−26(LC/HC)、1−15/1−26(LC/HC)、1−26/1−26(LC/HC)、1−86/1−26(LC/HC)、及び2−48/1−26(LC/HC)。HLX05(すなわち、社内で製造されたERBITUX(登録商標)バイオシミラー抗体)も試験した。1−26の重鎖を含むクローンは、348311の重鎖を含むクローンよりもEGFRに対するより良好な結合性能を示した。(図2を参照)。
生存率%=(試料の光学密度/対照の光学密度)×100
を用いて決定された。
ヒトFaDu下咽頭扁平上皮癌腫瘍異種移植片を保有するマウスを、本明細書に記載の抗EGFR抗体の治療有効性をアッセイするために使用した。簡潔には、ヒトFaDu下咽頭扁平上皮癌細胞(接種=2×106細胞)を雌のBALB/cヌードマウスに皮下移植した。マウスを7匹のマウスを各々含む4群に無作為に分けた。各群は、以下の表9に記載の投与計画の1つにより処置した:
DM1(N2’−デアセチル−N2’−(3−メルカプト−1−オキソプロピル)メイタンシン)は、有糸分裂停止を誘導することが示されている微小管集合の強力な阻害剤である(例えば、Chan (2008) Acc Chem Res 41, 98-107;Oroudjev et al. (2010) Mol Cancer Ther 9, 2700-2713;及びRemillard et al.(1975) Science 189, 1002-1005を参照)。HLX07−DM1コンジュゲートを調製し、抗がん剤としてのその有効性を下記のように評価した。
フコースを含まないHLX07(すなわち、HLX07−FF)の抗体依存性細胞媒介性細胞傷害活性を評価するために、エフェクター細胞として健康なヒトドナー由来のPBMC及び標的細胞としてKRASについて野生型であるヒト直腸癌細胞株であるDiFiを用いてADCCアッセイを行った。ヒトPBMCを、Histopaque(登録商標)−1077(Sigma−Aldrich)を用いて健康なドナーの全血から新たに調製し、5×106細胞/mLの密度でRPMI培地(L−グルタミン、25mMのHEPES、ペニシリン、ストレプトマイシン及び10%FBSを含むRPMI−1640)に懸濁した。DiFi標的細胞をRPMI培地に懸濁し、96ウェルU底マイクロタイタープレートに1×104細胞/ウェルで播種した。HLX07−FF、HLX07、及び対照抗体(抗CD20)の連続希釈物を、1.5pg/mlから3.3ng/mLの様々な濃度で個々のウェルに添加した。次に、PBMCをウェルに添加してエフェクター細胞:標的細胞比25:1を達成し、プレートを37℃で5時間インキュベートした。次いで、プレートを遠心分離し、上清を乳酸デヒドロゲナーゼ活性についてアッセイした。490nmでの上清の吸光度を記録し、CytoscanTM−LDH細胞毒性アッセイキット(G−Bioscience)を用いて乳酸脱水素酵素の放出を測定した。EC50値は、試験した細胞株においてADCCの50%誘導を示す濃度として算出した。図15Aに示すように、HLX07−FFは1.69ng/mlで50%誘導を示し、50%誘導を示すのに必要なHLX07の濃度(すなわち4.388ng/ml)より60%低い濃度であった。
2匹のカニクイザル(1匹の雄及び1匹の雌)に24mg/kgの抗体(すなわち、33/34−#1、33/34−#2、3/67−#3、及び3/67−#4)を静脈内を経由して注射した。抗EGFR抗体の血清濃度を、注入後の様々な時点でELISA法によって測定した。この実験をカニクイザルの第2セットで繰り返した。図16Aの血清濃度−時間プロファイルに示されるように、抗体3/67は、抗体34/33より約100倍長い間、カニクイザルの血清中で検出することができる。図16Bは、カニクイザルにおけるHLX05(1−3)及びERBITUX(登録商標)(すなわち、4−6)の血清濃度−時間プロファイルを示す。
HLX07 1−26/3−67のトップサブクローンは、確立されたDASGIPバイオリアクタープラットホームに組み込むことによってスクリーニングされた。流加給餌スケジュールにより、酪酸塩を添加し、pH7での制御を伴うより低温のインキュベーション条件により、サブクローン1−26/3−67−45−9は17日目に4.9g/Lに達した。図17を参照。
5mg/ml、10mg/ml、15mg/ml、20mg/ml及び25mg/mlを含むHLX07抗体製剤が最大4週間まで加速保存条件(すなわち37℃)に供される安定性試験が実施された。0週間、1週間、2週間、及び4週間の時点で各製剤から試料を採取し、サイズ排除クロマトグラフィー(SEC)及び陽イオン交換クロマトグラフィー(CEX)によって分析した。SECは、抗体凝集体(すなわち、高分子量種、又はHMWS)、単量体及び断片(すなわち、低分子量種、又はLMWS)を検出するために広く使用されている。陽イオン交換クロマトグラフィー(CEX)は、脱アミド化又は酸化などのタンパク質分解事象を検出するためのよく知られて広く使用されているツールである(Moorhouse et al. (1997) J. Pharm. Biomed. Anal. 16, 593-603)。分解生成物は、典型的には、主要種と比較して酸性又は塩基性種と称される。酸性種は、より低い見かけのpIを有する変異体であり、塩基性種は、より高い見かけのpIを有する変異体である。酸性種は、CEXの主ピークよりも早く溶出する変異体であるが、塩基性種はCEXの主ピークより後に溶出する変異体である。加速条件下で保存された製剤から採取した試料のSEC及びCEX分析の結果を以下の表13に示す。
本発明によって提供される実施態様には、限定するものではないが、以下が含まれる。
Claims (28)
- (a)(1)アミノ酸配列NYGVH(配列番号1)を含むCDR−H1;(2)アミノ酸配列YGNEFTSRF(配列番号8)を含むCDR−H2;及び(3)アミノ酸配列DYYDYEFAY(配列番号11)を含むCDR−H3を含む重鎖可変ドメイン配列;並びに(1)アミノ酸配列IGTNIH(配列番号15)を含むCDR−L1;(2)アミノ酸配列KYASESIS(配列番号21)を含むCDR−L2;及び(3)アミノ酸配列NWPTS(配列番号27)を含むCDR−L3を含む軽鎖可変ドメイン配列;
(b)(1)アミノ酸配列NYGVH(配列番号1)を含むCDR−H1;(2)アミノ酸配列YATEFTSRF(配列番号7)を含むCDR−H2;及び(3)アミノ酸配列DYYDYEFAY(配列番号11)を含むCDR−H3を含む重鎖可変ドメイン配列;並びに(1)アミノ酸配列IGTNIH(配列番号15)を含むCDR−L1;(2)アミノ酸配列KYASESIS(配列番号21)を含むCDR−L2;及び(3)アミノ酸配列NWPTS(配列番号27)を含むCDR−L3を含む軽鎖可変ドメイン配列;
(c)(1)アミノ酸配列TYGVH(配列番号3)を含むCDR−H1;(2)アミノ酸配列YGNEFTSRF(配列番号8)を含むCDR−H2;及び(3)アミノ酸配列DYYDYEFAY(配列番号11)を含むCDR−H3を含む重鎖可変ドメイン配列;並びに(1)アミノ酸配列IRTNIH(配列番号16)を含むCDR−L1;(2)アミノ酸配列KYGSESIS(配列番号22)を含むCDR−L2;及び(3)アミノ酸配列NWPTS(配列番号27)を含むCDR−L3を含む軽鎖可変ドメイン配列;又は
(d)(1)アミノ酸配列TYGVH(配列番号3)を含むCDR−H1;(2)アミノ酸配列YGNEFTSRF(配列番号8)を含むCDR−H2;及び(3)アミノ酸配列DYYDYEFAY(配列番号11)を含むCDR−H3を含む重鎖可変ドメイン配列;並びに(1)アミノ酸配列ISTNIH(配列番号19)を含むCDR−L1;(2)アミノ酸配列KYGSESIS(配列番号22)を含むCDR−L2;及び(3)アミノ酸配列NWPTS(配列番号27)を含むCDR−L3を含む軽鎖可変ドメイン配列;
を含む、抗EGFR抗体又はその抗原結合断片。 - (1)アミノ酸配列NYGVH(配列番号1)を含むCDR−H1;(2)アミノ酸配列YGNEFTSRF(配列番号8)を含むCDR−H2;及び(3)アミノ酸配列DYYDYEFAY(配列番号11)を含むCDR−H3を含む重鎖可変ドメイン配列;並びに(1)アミノ酸配列IGTNIH(配列番号15)を含むCDR−L1;(2)アミノ酸配列KYASESIS(配列番号21)を含むCDR−L2;及び(3)アミノ酸配列NWPTS(配列番号27)を含むCDR−L3を含む軽鎖可変ドメイン配列を含む、請求項1に記載の抗EGFR抗体又はその抗原結合断片。
- (1)アミノ酸配列NYGVH(配列番号1)を含むCDR−H1;(2)アミノ酸配列YATEFTSRF(配列番号7)を含むCDR−H2;及び(3)アミノ酸配列DYYDYEFAY(配列番号11)を含むCDR−H3を含む重鎖可変ドメイン配列;並びに(1)アミノ酸配列IGTNIH(配列番号15)を含むCDR−L1;(2)アミノ酸配列KYASESIS(配列番号21)を含むCDR−L2;及び(3)アミノ酸配列NWPTS(配列番号27)を含むCDR−L3を含む軽鎖可変ドメイン配列を含む、請求項1に記載の抗EGFR抗体又はその抗原結合断片。
- (1)アミノ酸配列TYGVH(配列番号3)を含むCDR−H1;(2)アミノ酸配列YGNEFTSRF(配列番号8)を含むCDR−H2;及び(3)アミノ酸配列DYYDYEFAY(配列番号11)を含むCDR−H3を含む重鎖可変ドメイン配列;並びに(1)アミノ酸配列IRTNIH(配列番号16)を含むCDR−L1;(2)アミノ酸配列KYGSESIS(配列番号22)を含むCDR−L2;及び(3)アミノ酸配列NWPTS(配列番号27)を含むCDR−L3を含む軽鎖可変ドメイン配列を含む、請求項1に記載の抗EGFR抗体又はその抗原結合断片。
- (1)アミノ酸配列TYGVH(配列番号3)を含むCDR−H1;(2)アミノ酸配列YGNEFTSRF(配列番号8)を含むCDR−H2;及び(3)アミノ酸配列DYYDYEFAY(配列番号11)を含むCDR−H3を含む重鎖可変ドメイン配列;並びに(1)アミノ酸配列ISTNIH(配列番号19)を含むCDR−L1;(2)アミノ酸配列KYGSESIS(配列番号22)を含むCDR−L2;及び(3)アミノ酸配列NWPTS(配列番号27)を含むCDR−L3を含む軽鎖可変ドメイン配列を含む、請求項1に記載の抗EGFR抗体又はその抗原結合断片。
- a)配列番号32に記載のアミノ酸配列を含む軽鎖可変ドメイン、及び配列番号37に記載のアミノ酸配列を含む重鎖可変ドメイン;
b)配列番号32に記載のアミノ酸配列を含む軽鎖可変ドメイン、及び配列番号38に記載のアミノ酸配列を含む重鎖可変ドメイン;
c)配列番号33に記載のアミノ酸配列を含む軽鎖可変ドメイン、及び配列番号36に記載のアミノ酸配列を含む重鎖可変ドメイン、又は
d)配列番号34に記載のアミノ酸配列を含む軽鎖可変ドメイン、及び配列番号36に記載のアミノ酸配列を含む重鎖可変ドメイン
を含む、請求項1に記載の抗EGFR抗体又はその抗原結合断片。 - 配列番号32に記載のアミノ酸配列を含む軽鎖可変ドメイン、及び配列番号37に記載のアミノ酸配列を含む重鎖可変ドメイン
を含む、請求項1に記載の抗EGFR抗体又はその抗原結合断片。 - 配列番号32に記載のアミノ酸配列を含む軽鎖可変ドメイン、及び配列番号38に記載のアミノ酸配列を含む重鎖可変ドメイン
を含む、請求項1に記載の抗EGFR抗体又はその抗原結合断片。 - 配列番号33に記載のアミノ酸配列を含む軽鎖可変ドメイン、及び配列番号36に記載のアミノ酸配列を含む重鎖可変ドメイン
を含む、請求項1に記載の抗EGFR抗体又はその抗原結合断片。 - 配列番号34に記載のアミノ酸配列を含む軽鎖可変ドメイン、及び配列番号36に記載のアミノ酸配列を含む重鎖可変ドメイン
を含む、請求項1に記載の抗EGFR抗体又はその抗原結合断片。 - 抗体がヒトIgGのFc配列を含む、請求項1−10の何れか一項に記載の抗EGFR抗体又はその抗原結合断片。
- 抗原結合断片が、Fab、Fab’、F(ab)’2、一本鎖Fv(scFv)、Fv断片、ダイアボディ、及び線状抗体からなる群から選択される、請求項1−11の何れか一項に記載の抗EGFR抗体の抗原結合断片。
- 抗体が多重特異性抗体である、請求項1−11の何れか一項に記載の抗EGFR抗体。
- 抗体がアフコシル化抗体である、請求項1−13の何れか一項に記載の抗EGFR抗体。
- 治療剤にコンジュゲートした、請求項1−14の何れか一項に記載の抗EGFR抗体又はその抗原結合断片。
- 標識にコンジュゲートした、請求項1−14の何れか一項に記載の抗EGFR抗体又はその抗原結合断片。
- 標識が放射性同位体、蛍光色素、及び酵素からなる群から選択される、請求項16に記載の抗EGFR抗体。
- 請求項1−14の何れか一項に記載の抗EGFR抗体又はその抗原結合断片をコードする単離された核酸分子。
- 請求項18の核酸分子をコードする発現ベクター。
- 請求項19の発現ベクターを含む細胞。
- 請求項20の細胞を培養すること及び細胞培養物から抗体を回収することを含む、抗体を産生する方法。
- 請求項1−15の何れか一項に記載の抗EGFR抗体又はその抗原結合断片及び薬学的に許容可能な担体を含む、組成物。
- 請求項1−10の何れか一項に記載の抗EGFR抗体又はその抗原結合断片を試料に接触させること、及びEGFRタンパク質に結合した抗EGFR抗体を検出することにより、患者からの試料中のEGFRタンパク質を検出する方法。
- 抗EGFR抗体又はその抗原結合断片が免疫組織化学アッセイ(IHC)又はELISAアッセイで使用される、請求項23に記載の方法。
- 請求項1−15の何れか一項に記載の抗EGFR抗体又はその抗原結合断片、又は請求項22に記載の組成物を含む、被験体におけるがんを治療することに使用するための組成物。
- がんが、咽喉がん、結腸直腸がん、肺がん、及び頭頸部がんから選択される、請求項25に記載の使用のための組成物。
- 抗腫瘍剤、化学療法剤、増殖阻害剤、及び細胞傷害性剤からなる群から選択される更なる治療剤との共投与のために製剤化される、請求項25に記載の使用のための組成物。
- 放射線療法と組み合わせて投与するために製剤化される、請求項25に記載の使用のための組成物。
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HRP20192038T1 (hr) | 2020-02-07 |
EP3148581A2 (en) | 2017-04-05 |
EP3148581B1 (en) | 2019-10-09 |
EP3148581A4 (en) | 2017-11-01 |
SG11201609959UA (en) | 2016-12-29 |
AU2015266664A1 (en) | 2016-12-08 |
PT3148581T (pt) | 2020-01-06 |
EP3613433B1 (en) | 2022-01-05 |
US20200223929A1 (en) | 2020-07-16 |
WO2015184403A2 (en) | 2015-12-03 |
WO2015184403A3 (en) | 2016-01-21 |
AU2015266664B2 (en) | 2020-04-30 |
PL3148581T3 (pl) | 2020-05-18 |
SI3148581T1 (sl) | 2020-02-28 |
DK3148581T3 (da) | 2020-01-13 |
US20170218073A1 (en) | 2017-08-03 |
US10584171B2 (en) | 2020-03-10 |
CN106714830A (zh) | 2017-05-24 |
EP3613433A1 (en) | 2020-02-26 |
HUE047113T2 (hu) | 2020-04-28 |
ES2761675T3 (es) | 2020-05-20 |
TW201613971A (en) | 2016-04-16 |
ES2905777T3 (es) | 2022-04-12 |
JP2017521054A (ja) | 2017-08-03 |
TWI689520B (zh) | 2020-04-01 |
US11261255B2 (en) | 2022-03-01 |
CY1122436T1 (el) | 2021-01-27 |
CN106714830B (zh) | 2020-08-25 |
KR102366644B1 (ko) | 2022-02-22 |
KR20170010855A (ko) | 2017-02-01 |
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