JP6837273B2 - 高い薬剤ロード量を有する抗体−薬剤コンジュゲート - Google Patents
高い薬剤ロード量を有する抗体−薬剤コンジュゲート Download PDFInfo
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- JP6837273B2 JP6837273B2 JP2015088055A JP2015088055A JP6837273B2 JP 6837273 B2 JP6837273 B2 JP 6837273B2 JP 2015088055 A JP2015088055 A JP 2015088055A JP 2015088055 A JP2015088055 A JP 2015088055A JP 6837273 B2 JP6837273 B2 JP 6837273B2
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Description
本出願は、いずれも参照により全体として本明細書中に組み込まれている、2014年4月25日に出願した米国仮出願第61/984,645号、2014年7月24日に出願した米国仮出願第62/028,731号、2015年1月15日に出願した米国仮出願第62/103,999号および2015年4月14日に出願した米国仮出願第62/147,293号の利益を請求する。
本出願は、EFS−Webを介した電子出願であり、電子的に提出された.txt形式の配列表を含む。.txtファイルは、2015年4月9日に作製された「PC7207805SEQLISTING_ST25.txt」と題する、9KBのサイズの配列表を含む。この.txtファイルに含まれる配列表は、明細書の一部であり、参照により全体として本明細書中に組み込まれている。
本明細書において別段の定義がない限り、本発明に関連して用いられる科学用語および技術用語は、当業者によって一般に理解されている意味を有する。さらに、文脈により別段の要求がない限り、単数形の用語は複数形を含み、複数形の用語は単数形を含む。全体として、本明細書において記載される細胞培養および組織培養、分子生物学、免疫学、微生物学、遺伝学、ならびにタンパク質化学および核酸化学、ならびにハイブリダイゼーションに関連して用いられる命名、およびその技術は、当技術分野において周知であり、一般的に用いられる。
本明細書中における抗体−薬剤コンジュゲートは、操作されたグルタミン含有タグ、内因性グルタミン(すなわち、操作されていない天然グルタミン、例えば、可変ドメイン、CDRなどにおけるグルタミン)および/または反応性の内因性グルタミンを介して、アミンドナー物質(例えば、アミンドナー単位によってリンカーに結合している低分子)に部位特異的にコンジュゲートしている抗体であって、薬剤−抗体比率(DAR)が少なくとも約5(例えば、抗体1つ当たり少なくとも5つの薬剤/ペイロード)である抗体を含む。内因性グルタミンは、抗体中の1つもしくは複数のアミノ酸の修飾(例えば、アミノ酸の欠失、挿入、置換、または突然変異)によって、酵素的脱グリコシル化によってまたは操作されたトランスグルタミナーゼとの反応によって、反応性(すなわち、アミンおよびトランスグルタミナーゼの存在下でアシルドナーとして共有結合を形成する能力)にされ得る。したがって、一態様において、式:抗体−(T−(X−Y−Za)b)c[式中、Tは、1)特異的部位で操作されたグルタミン含有タグ、2)内因性グルタミン、および/または3)抗体の操作もしくは操作されたトランスグルタミナーゼによって反応性にされた内因性グルタミンであり、Xはアミンドナー単位であり、Yはリンカーであり、Zは作用物質部分であり、X−Y−Zは、グルタミン含有タグ、内因性グルタミンおよび/または反応性の内因性グルタミンに部位特異的にコンジュゲートしているアミンドナー物質であり、aは1〜6の整数であり、bは1〜6の整数であり、cは1〜20の整数であり、a、bおよびcの積(薬剤−抗体比率)は少なくとも約5である]を含む抗体−薬剤コンジュゲート(ADC)が提供される。抗体上のグルタミン含有タグ、内因性グルタミンおよび/または反応性グルタミンと、本明細書中に記載するアミンドナー物質(X−Y−Z)はいずれも、トランスグルタミナーゼの基質であり、グルタミン含有タグおよび/または内因性/反応性グルタミンと、アミンドナー物質との間の連結は、式CH2−CH2−CO−NH−[式中、NH−は、リンカーおよび作用物質部分に連結されている]を有する。
本明細書中に記載するADCを作製するための方法もまた、提供する。一態様において、本発明は、式:抗体−(T−(X−Y−Za)b)c[式中、Tは、1)特異的部位で操作されたグルタミン含有タグ、2)内因性グルタミン、および/または3)抗体の操作もしくは操作されたトランスグルタミナーゼによって反応性にされた内因性グルタミンであり、Xはアミンドナー単位であり、Yはリンカーであり、Zは作用物質部分であり、X−Y−Zは、グルタミン含有タグ、内因性グルタミンおよび/または反応性の内因性グルタミンに部位特異的にコンジュゲートしているアミンドナー物質であり、aは1〜6の整数であり、bは1〜6の整数であり、cは1〜20の整数であり、a、bおよびcの積(薬剤−抗体比率)は少なくとも約5である]を含むADCを作製するための方法であって、a)抗体およびグルタミン含有タグ;ならびに/または内因性グルタミンおよび/もしくは反応性の内因性グルタミンを有する抗体を含む抗体−T分子を提供するステップと、b)アミンドナー物質をトランスグルタミナーゼ(例えば、操作されたトランスグルタミナーゼまたは精製されたトランスグルタミナーゼ)の存在下において抗体−T分子と接触させるステップと、c)抗体−Tをアミンドナー物質に共有結合によって連結させて、抗体−薬剤コンジュゲートを形成するステップとを含む方法を提供する。いくつかの実施形態において、抗体−T分子は、CHO細胞において発現される。
本発明のADCは、限定はしないが、治療的処置法および診断的処置方法を含む様々な用途において有用である。
本発明はまた、本明細書中に記載するより高ロードのADCを、薬学的に許容できる賦形剤または担体中に含む医薬組成物を提供する。ADCは、単独で、または本発明の1種もしくは複数の他のADCと組み合わせて、または1種もしくは複数の他の薬剤と組み合わせて(またはその任意の組み合わせとして)投与することができる。例えば、本発明のADCは、従来のADC(例えば、DAR1〜4)または本明細書中に記載するトランスグルタミナーゼ−介在性コンジュゲーション技術を用いるDAR1〜4の部位特異的ADCと組み合わせて投与することができる。したがって、本発明の方法および使用はまた、以下に詳述されるように、他の活性物質との組み合わせ(同時投与)の実施形態を包含する。
本発明はまた、上記の障害の治療において用いるためのキット(または製品)を提供する。本発明のキットは、精製されたADCおよび疾患の治療にコンジュゲートを用いるための指示を含む、1つまたは複数の容器を含む。例えば、指示は、癌(例えば、固体癌または液性癌)などの疾患を治療するためのADCの投与についての記載を含む。キットはさらに、個体が疾患および疾患の段階を有しているかの同定に基づく、治療に適切な個体の選択についての記載を含み得る。
標的発現が高い細胞(BxPC3、Trop2+++)における、次第に高ロードにされた、部位特異的にコンジュゲートされた抗Trop−2−ADCの細胞傷害性
この実施例は、標的発現が高いBxPC3細胞における、より高ロードのADC(部位特異的ADCおよび従来のADC)のインビトロでの細胞傷害性を例示する。
a.トランスグルタミナーゼ介在性抗体−薬剤コンジュゲーション
キメラマウス抗Trop−2抗体を、様々なアミノ酸位置でグルタミン含有トランスグルタミナーゼ(「Q」)タグ(例えば、TG6、LCQ04、H7c、L11b;表1を参照されたい)で操作されたヒトIgG1サブタイプとして発現させ、様々なリンカーおよびペイロード(例えば、アミノカプロイル−vc−PABC−MMAD(アミノカプロイル−バリン−シトルリン−p−アミノベンジルオキシカルボニル−MMAD);アミノ−PEG6−C2−MMAD)とコンジュゲートさせた。一例において、トランスグルタミナーゼタグは、抗体の軽鎖および重鎖のC末端の両方で、ならびにヒトIgGの297位(EUナンバリングスキーム)で操作した(例えば、Trop−2抗体の297位において、野生型アミノ酸アスパラギン(N)を、グルタミンで置換した(N297Q))。抗体の軽鎖および重鎖の両方、または抗体の重鎖もしくは軽鎖内の複数の部位において操作されたタグの組み合わせは、抗体1つ当たり複数のコンジュゲーション部位を有していた(例えば、DAR4〜10)。次いで、ペイロード(例えば、MMAD)への抗Trop−2抗体のコンジュゲーションを、特異的部位(例えば、重鎖または軽鎖のカルボキシル末端および/もしくはアミノ末端、297位、ならびに/または抗体の別の部位)にグルタミン含有タグ(1つまたは複数)を有する抗Trop−2抗体と、ペイロード(例えば、MMAD)に連結されたアミン含有リンカーとの間の、微生物トランスグルタミナーゼによって触媒されるアミド基転移反応を介して行った。場合によっては、抗体の222位(EUナンバリングスキーム)の野生型アミノ酸リジンを、アミノ酸アルギニンに置き換えた(「K222R」)。例えば、K222R置換は、より均質な抗体およびペイロードコンジュゲート組成物、ならびに/または抗体軽鎖のC末端におけるグルタミンタグとの鎖間架橋の著しい減少をもたらすという驚くべき効果を有することが判明した。アミド基転移反応において、抗体上のグルタミンはアシルドナーとして作用し、アミン含有化合物はアシルアクセプター(アミンドナー)として作用した。33μMの濃度の精製抗Trop−2抗体を、150mMの塩化ナトリウムもしくは硫酸ナトリウム、および25mMのMES、HEPES[4−(2−ヒドロキシエチル)−1−ピペラジンエタンスルホン酸]またはTris HCl緩衝液(pH範囲6.2〜9.2)中、1〜3%(w/v)のストレプトベルティシリウム モバラエンス(Streptoverticillium mobaraense)トランスグルタミナーゼ(ACTIVA(商標)、味の素、日本)の存在下で、33〜3300μMの範囲の10〜100M過剰のアシルアクセプターと共にインキュベートした。反応条件を、個別のアシルアクセプター誘導体に応じて調整し、最適な効率および特異性は、典型的には、150mMのNaCl、25mMのTris HCl(pH8.5)中、33μMの抗体、660μMの誘導体、および2%(w/v)のトランスグルタミナーゼで観察された。37℃で16〜20時間インキュベーション後、抗体を、当業者に知られている標準的なクロマトグラフィー方法、例えば、GE Healthcareからの市販のアフィニティークロマトグラフィーおよび疎水性相互作用クロマトグラフィーを用いて、MabSelect SuRe(商標)樹脂またはButyl Sepharose(商標)High Performance(GE Healthcare、Piscataway、NJ)で精製した。
平均薬剤ロード量が4(例えば、抗体1分子当たり4つのMMAD)である、従来のマレイミド連結を介してPEG6−C2−MMADとコンジュゲートされた抗体(例えば、キメラマウス抗Trop−2抗体(m7E6))を生成するために、最初に、5mg/mlの抗体を、25mMのTris(pH7.5)、150mMのNaClを含有する緩衝液中7.5モル当量のTCEP(トリス(2−カルボキシエチル)ホスフィン)で37℃において2時間還元した。還元された抗体に、室温(約22℃)において7.5モル過剰のマレイミド−PEG6−C2−MMADを加え、1時間インキュベートした。反応混合物を、4℃においてPBS(リン酸緩衝溶液)に対して透析し、0.2μmフィルターを通して滅菌濾過した。薬剤ロード量が8の、マレイミド−PEG6−C2−MMADを有するm7E6を生成するために、抗体を、50mMのEDTA(エチレンジアミン四酢酸)を含む前述のような反応緩衝液中、10モル過剰のTCEPで還元した。12モル過剰のマレイミド−PEG6−C2−MMADを、前述のように処理された、還元された抗体および材料に加えた。薬剤ロード量が6の、マレイミド−PEG6MMADとコンジュゲートされたm7E6を生成するために、抗体を、DAR8の還元に関しては、緩衝液中8倍モル過剰のTCEPで還元し、続いて8倍モル過剰のマレイミド−PEG6−C2−MMADを加えた。DAR6の種を精製するために、反応混合物を希釈して、0.75Mの硫酸アンモニウム、25mMのリン酸カリウム、pH7の緩衝液組成物(緩衝液A)を得た。材料を、直列に接続された2×1mlのButyl HP Hi Trap(GE Healthcare)に適用し、2CV(カラム容量)の緩衝液Aで洗浄し、20%イソプロパノールを含む25mMのリン酸カリウム(pH7)への20CV直線勾配で溶離させた。DAR6を含有するフラクションをプールし、PBSに対して透析し、10kDaのAmicon Ultra遠心式フィルターユニット(Millipore Corporation)を用いて濃縮した。
キメラ抗Trop2抗体、m7E6 H7cアミノ−PEG6−C2−MMAD(DAR1.96、部位特異的)、m7E6 L11bアミノ−PEG6−C2−MMAD(DAR1.96、部位特異的)、m7E6 TG6アミノ−PEG6−C2−MMAD(DAR1.99、部位特異的)、m7E6 LCQ04/K222RアミノPEG6−C2−MMAD(DAR1.97、部位特異的)、m7E6 N297Q/K222Rアミノ−PEG6−C2−MMAD(DAR3.83、部位特異的)、m7E6 N297Q/K222R/LCQ04アミノ−PEG6−C2−MMAD(DAR5.85、部位特異的)、m7E6 N297Q/K222R/LCQ04/TG6アミノ−PEG6−C2−MMAD(DAR7.71、部位特異的)、m7E6 N297Q/K222R/LCQ04/H7cアミノ−PEG6−C2−MMAD(DAR7.76、部位特異的)、m7E6 N297Q/K222R/LCQ04/L11bアミノ−PEG6−C2−MMAD(DAR7.80、部位特異的)およびm7E6マレイミド−PEG6−C2−MMAD(DAR7.20、従来)のインビトロ細胞傷害性の研究を、標的を発現するBxPC3細胞を用いて行った。この実施例および本明細書中に記載する他の実施例におけるDARの数は、抗体1分子当たりのペイロードの比率を指す。使用したリンカーはPEG6であり、使用したペイロードはMMADであった。BxPc3は、高い標的発現レベル(Trop−2+++)を有する癌細胞系である。細胞を、処理の24時間前に、壁が白く底が澄明なプレートに細胞2000個/ウェルで播種した。細胞を、4倍連続希釈された抗体−薬剤コンジュゲートで、3例ずつ処理した。細胞の生存率を、処理の96時間後に、CellTiter−Glo(登録商標)Luminescent Cell Viability Assay 96(Promega、Madison、WI)によって決定した。相対的な細胞生存率を、未処理対照に対するパーセンテージとして決定した。IC50、および50%の細胞死滅(すなわち、細胞傷害性)が起こるADC濃度を、GraphPad Prism 5ソフトウェアによって計算し、濃度(nM)として表し、試験したADCの最高濃度において観察された最大の細胞死滅を未処理対照に対するパーセンテージとして表した。細胞傷害アッセイの結果を図1に示し、表3に要約する。DAR7.71(m7E6 N297Q/K222R/LCQ04/TG6アミノ−PEG6−C2−MMAD)、DAR7.76(m7E6 N297Q/K222R/LCQ04/H7cアミノ−PEG6−C2−MMAD)およびDAR7.80(m7E6 N297Q/K222R/LCQ04/L11bアミノ−PEG6−C2−MMAD)の3つの部位特異的分子は、DAR7.20の従来の方法でコンジュゲートされたADC(m7E6マレイミド−PEG6−C2−MMAD)と同程度に強力であった。
標的発現が中等度の細胞(Colo205、Trop2+)における、次第に高ロードにされた、部位特異的にコンジュゲートされた抗Trop−2−ADCの細胞傷害性
この実施例は、標的発現が中程度のColo205細胞における、より高ロードのADC(部位特異的ADCおよび従来のADC)のインビトロでの細胞傷害性を例示する。
標的発現が低い細胞(CF−PAC1、Trop2(+))における、次第に高ロードにされた、部位特異的にコンジュゲートされた抗Trop−2−ADCの細胞傷害性
この実施例は、標的発現が低いCF−PAC1細胞における、より高ロードの部位特異的ADCのインビトロ細胞傷害性を例示する。
標的発現がない細胞((SW620、Trop2−)における、次第に高ロードにされた、部位特異的にコンジュゲートされた抗Trop−2−ADCの細胞傷害性
この実施例は、標的発現がないSW620細胞における、より高ロードの部位特異的ADCのインビトロでの非特異的細胞傷害性を例示する。
標的発現が中等度の細胞(Colo205、Trop2+)における、次第に高ロードされた、部位特異的にコンジュゲートされた抗Trop−2−ADC対従来の方法でコンジュゲートされた抗Trop−2−ADC)の細胞傷害性の対照比較
この実施例は、標的発現が中程度のColo205細胞における、より高ロードの部位特異的ADCのインビトロでの増加した細胞傷害性および効力を例示する。
薬剤抗体比率が7.76の抗Trop−2 7E6部位特異的オーリスタチンコンジュゲートは、Colo205異種移植モデルにおいて長期腫瘍静止を誘発した
この実施例は、Colo205異種移植モデルにおけるより高ロードの部位特異的ADCの有効性を例示する。
薬剤抗体比率が5.86および7.77の抗Trop−2 7E6部位特異的オーリスタチンコンジュゲートは、Colo205異種移植モデルにおいて、対応する従来のコンジュゲートよりも有効であり、長期腫瘍静止を誘発した
この実施例もまた、Colo205異種移植モデルにおける、より高ロードの部位特異的ADCの有効性を例示する。
高い薬剤抗体比率を有する抗Trop−2 7E6部位特異的オーリスタチンコンジュゲートは、従来のADCと比較してより良好な薬物動態(PK)プロフィールを示す
この実施例は、マウスおよびラットの両方における、従来のより高ロードのADCと比較した、より高ロードの部位特異的ADCのPKプロフィールを例示する。
96ウェルマイクロタイタープレート(NUNC)の各ウェルに、1xPBS(Cell Gro)中1μg/mLのFc特異的なヤギ抗ヒトIgG抗体(Pierce、Rockford、IL)100μLをコーティングした。プレートを4〜8℃で終夜インキュベートした。全ての洗浄ステップを、1xPBS/0.05%Tweenを用いてBiotek ELx405プレートウォッシャーで行った。3回洗浄後、プレートを、アッセイ緩衝液(1xPBS/0.5%BSA/0.05% Polysorbate 20)200μLでブロックし、室温で穏やかに撹拌しながら1〜2時間インキュベートした。プレートを3回洗浄し、アッセイ緩衝液で1:100に希釈した標準物質、対照および試料100μLを、対応するウェルに加えた。室温で穏やかに撹拌しながら2時間インキュベート後、プレートを6回洗浄してから、アッセイ緩衝液で250ng/mLに希釈した検出抗体(Sigma(St Louis,MO)からのHRP標識された、Fc特異的抗ヒトIgG)100μLを分注した。プレートを、室温で穏やかに撹拌しながらさらに1時間インキュベートし、その後に6回洗浄した。次いで、TMB(3,3’,5,5’−テトラメチルベンジジン)(KPL、Gaithersburg、MD)100μLを各ウェルに加えた。約5分間発色させてから、1Mリン酸100μLで反応を停止させた。SpectraMax 340プレートリーダー(Molecular Devices)で、650nmを基準として、450nmで吸光度を測定した。SoftMax Pro 5.2ソフトウェアを用いて、標準曲線を4−パラメーター回帰に適合させ、試料濃度を計算した。
96ウェルマイクロタイタープレート(NUNC)の各ウェルに、1xPBS(Cell Gro)中2μg/mLのヤギ抗ヒトIgG抗体100μLをコーティングした。プレートを4〜8℃で終夜インキュベートした。全ての洗浄ステップを、1xPBS/0.05%Tweenを用いてBiotek ELx405プレートウォッシャーで行った。3回洗浄後、プレートを、アッセイ緩衝液(1xPBS/0.5%BSA/0.05%Polysorbate 20)200μL/ウェルでブロックし、室温で穏やかに撹拌しながら1〜2時間インキュベートした。プレートを3回洗浄し、アッセイ緩衝液で1:100に希釈した標準物質、対照および試料100μLを、対応するウェルに2例ずつ加えた。室温で穏やかに撹拌しながら2時間インキュベート後、プレートを6回洗浄してから、アッセイ緩衝液で4μg/mLに希釈した検出抗体(ビオチン化抗MMADモノクローナル抗体)100μLを分注した。プレートを、室温で穏やかに撹拌しながら1.5時間インキュベートし、その後に6回洗浄した。アビジン−HRP(Vector Labs、Burlingame、CA)をアッセイ緩衝液で0.5μg/mLに希釈し、100μLを各ウェルに分注した。プレートをさらに1時間インキュベートし、その後、6回洗浄した。次いで、TMB(KPL、Gaithersburg、MD)100μLを各ウェルに加えた。約5分間発色させてから、1Mリン酸100μLで反応を停止させた。SpectraMax 340プレートリーダー(Molecular Devices、Downingtown、PA)で、650nmを基準として、450nmで吸光度を測定した。SoftMax Pro 5.2ソフトウェアを用いて、標準曲線を4−パラメーター回帰に適合させ、試料濃度を計算した。
LC/MS分析の前に、ADC(部位特異的DAR6およびDAR8ならびに従来のDAR8)を、37℃において非変性条件下でPNGase F(New England Biolabs Inc.、Ipswich,、MA)によって終夜脱グリコシル化させた。ADC(1μg)を、ポリマー材料(Michrom−Bruker、Fremont、CA)を充填した逆相カラムに装填した。LC/MS分析を、エレクトロスプレーイオン源を有するOrbitrap Velos Pro(Thermo Fisher Scientific、Somerset、NJ)質量分析計に連結された、バイナリーHPLCポンプ、脱ガス装置、温度制御自動サンプラー、カラムヒーターおよびダイオードアレイ検出器(DAD)を含むAgilent 1100シリーズHPLCシステムを用いて行った。移動相は、溶媒A(水 0.1%ギ酸)および溶媒B(アセトニトリル 0.1%ギ酸)から構成された。HPLCを、イソクラチック流からなる30分間のラン(溶媒B3%に10分間、続いて1分間にわたる溶媒B97%までの勾配、溶媒B97%に2分間保持、最後に溶媒B3%に17分間の平衡化ステップからなる)での、次第に増加する溶媒Bの勾配を用いて行った。得られた質量スペクトルを、ProMassソフトウェア(Thermo Fisher Scientific、Somerset、NJ)を用いてデコンヴォルーション(deconvolute)した。部位特異的ADCに関しては、DARは、ADCのインタクト質量(intact mass)を用いて計算した。従来のADCは分子間ジスルフィド結合がなくかつ鎖が逆相条件下で分離するので、従来のADCに関しては、DARは、重鎖および軽鎖のデコンヴォルーションされたスペクトルから計算した。DARの計算は、観察されたDAR種の相対強度に基づく。
マウスにおいて、全てのADCの単回用量(6mg/kg)を、Colo205異種移植モデルで試験した。これらの条件下において、(1)m7E6 N297Q/K222R/LCQ04アミノ−PEG6−C2−MMAD(DAR5.85、部位特異的)および2)m7E6 N297Q/K222R/LCQ04/H7cアミノ−PEG6−C2−MMAD(DAR7.76、部位特異的)として、PEG6MMADにコンジュゲートしている抗体m7E6は、コンジュゲートしてない野生型抗体m7E6と同様な薬物動態プロフィールを示した。総mAbおよびADCのシグナルの比較により、より高ロードのADC(mAbまたはADC m7E6 N297Q/K222R/LCQ04アミノ−PEG6−C2−MMAD(DAR5.85、部位特異的);またはmAbもしくはADC m7E6 N297Q/K222R/LCQ04/H7cアミノ−PEG6−C2−MMAD(DAR7.76、部位特異的)は、2週間の期間にわたってペイロードの損失をほとんど示さないことが明らかになった。図8Cおよび8Dを参照されたい。このデータは、アミノ−PEG6−C2−MMADのトランスグルタミナーゼ介在性連結が安定なコンジュゲートをもたらすことを示している。対照的に、従来の方法を用いてマレイミド−PEG6−C2−MMADにコンジュゲートさせた抗体m7E6(m7E6マレイミド−PEG6−C2−MMAD(DAR7.8))は、総mAbおよびコンジュゲートしていない抗体の両方と比較して、より低いADC曝露量を示し、これはペイロードの損失を示唆した。図8Bを参照されたい。マレイミドをベースとするコンジュゲートからのペイロードの損失については既に記載されており(例えば、Alleyら、Bioconj.Chem.19(3):759〜765(2008)、およびShenら、Nat.Biotechnol.30(2):184〜189(2012)を参照されたい)、逆マイケル付加メカニズムによって起こると考えられている。DAR8の従来のコンジュゲートと本発明のADCコンジュゲートの間のADC曝露量の差が、インビボにおいて従来のADCコンジュゲートの活性が劣る原因である可能性が高い。
ラットにおいて、野生型薬物動態プロフィールを個別に示すADCコンジュゲーション部位を組み合わせると、曝露量が減少し得る
この実施例は、ラットにおいて、コンジュゲーション部位の種々の組み合わせを有する、より高ロードの部位特異的ADCのPKプロフィールを例示する。
マウスにおける、従来のADCと比較した、部位特異的にコンジュゲートされた抗Trop−2 7E6オーリスタチンの安全性および耐容性
この実施例は、C57B1/6マウスにおけるより高ロードの部位特異的ADCの安全性および耐容性を例示する。
標的を高発現する細胞(BxPC3、Trop2+++)における、次第に高ロードにされた、部位特異的にコンジュゲートされた抗Trop−2−ADCの細胞傷害性
この実施例は、標的発現が高いBxPC3細胞における、より高ロードのADC(例えば、DAR5.95〜9.4(部位特異的コンジュゲーション))のインビトロでの細胞傷害性を例示する。
標的発現が中等度の細胞(Colo205、Trop2+)における、次第に高ロードにされた、部位特異的にコンジュゲートされた抗Trop−2−ADCの細胞傷害性
この実施例は、標的発現が中程度のColo205細胞における、より高ロードのADC(例えば、DAR5.95〜9.4(部位特異的コンジュゲーション))のインビトロでの細胞傷害性を例示する。
標的発現が低い細胞(CF−PAC1、Trop2(+))における、次第に高ロードにされた、部位特異的にコンジュゲートされた抗Trop−2−ADCの細胞傷害性
この実施例は、標的発現が低いCF−PAC1細胞における、より高ロードのADC(例えば、DAR5.95〜9.4(部位特異的コンジュゲーション))のインビトロでの細胞傷害性を例示する。
標的発現がない細胞(SW620、Trop2−)における、次第に高ロードにされた、部位特異的にコンジュゲートされた抗Trop−2−ADCの細胞傷害性
この実施例は、標的発現がないSW620細胞における、より高ロードのADC(例えば、DAR5.95〜9.4(部位特異的コンジュゲーション))のインビトロでの細胞傷害性を例示する。
標的BCMAの発現が低い細胞および中程度の細胞における、次第に高ロードにされた、部位特異的にコンジュゲートされた抗BCMA ADCの細胞傷害性
この実施例は、標的発現がそれぞれ低いおよび中程度のL363細胞およびMM1.S細胞における、より高ロードのADC(例えば、DAR5.95(部位特異的コンジュゲーション))のインビトロ細胞傷害性を例示する。
Claims (26)
- 式
抗体−(T−(X−Y−Za)b)c
[式中、
Tは、特異的部位で操作されたグルタミン含有タグであり、
Xはアミンドナー単位であり、Yはリンカーであり、Zは作用物質部分であり、
X−Y−Zは、グルタミン含有タグに部位特異的にコンジュゲートしているアミンドナー物質であり、
aは1〜6の整数であり、
bは1〜6の整数であり、
cは1〜20の整数であり、
a、bおよびcの積(薬剤−抗体比率)は少なくとも5であり、
抗体が、297位(EUナンバリングスキーム)においてアスパラギン(N)からグルタミン(Q)への置換を有し、222位(EUナンバリングスキーム)においてリジン(K)からアルギニン(R)への置換を有し、かつ、グルタミン含有タグがGGLLQGA(配列番号23)を含む]
を含む抗体−薬剤コンジュゲート。 - 抗体が、モノクローナル抗体、ポリクローナル抗体、ヒト抗体、ヒト化抗体、キメラ抗体、二重特異性抗体、ミニボディ、ダイアボディまたは抗体断片である、請求項1に記載のコンジュゲート。
- アミンドナー物質が、1)軽鎖、重鎖または軽鎖および重鎖の両方のいずれかのカルボキシル末端、2)軽鎖、重鎖または軽鎖および重鎖の両方のいずれかのアミノ末端、ならびに3)S60〜R61、R108、T135、S160、S168、S190〜S192、P189〜S192、G200〜S202、K222〜T225、K222〜T223、T223、L251〜S254、M252〜I253、E294〜N297、E293〜N297、N297、および/またはG385からなる群から選択される抗体の少なくとも1つまたは複数の位置でグルタミン含有タグに部位特異的にコンジュゲートしており、グルタミン含有タグが、抗体に挿入されているか、または抗体中の1つもしくは複数の内因性アミノ酸と置き換わっている、請求項1または2に記載のコンジュゲート。
- a)アミンドナー物質が、295位の内因性グルタミンおよび297位の置換グルタミンに部位特異的にコンジュゲートしているアミノ酸置換と、
b)1つまたは複数のグルタミン含有タグであって、アミンドナー物質が、抗体軽鎖のカルボキシル末端のグルタミン含有タグ(1つまたは複数)に部位特異的にコンジュゲートしているグルタミン含有タグと
を含み、薬剤−抗体比率が少なくとも5である、請求項1から3のいずれか1項に記載のコンジュゲート。 - アミンドナー物質が、S60〜R61、R108、T135、S160、S168、S190〜S192、P189〜S192、G200〜S202、K222〜T225、K222〜T223、T223、L251〜S254、M252〜I253、E294〜N297、E293〜N297、N297およびG385からなる群から選択される1つまたは複数の位置でグルタミン含有タグに部位特異的にさらにコンジュゲートしており、グルタミン含有タグが、抗体に挿入されているか、または抗体中の1つもしくは複数の内因性アミノ酸と置き換わっており、薬剤−抗体比率が少なくとも6である、請求項4に記載のコンジュゲート。
- アミンドナー物質が、抗体重鎖のカルボキシル末端のグルタミン含有タグに部位特異的にさらにコンジュゲートしており、薬剤−抗体比率が6〜9である、請求項4または5に記載のコンジュゲート。
- アミンドナー物質が、抗体重鎖中のアミノ酸位置T135の後に挿入されたグルタミン含有タグに部位特異的にさらにコンジュゲートしており、薬剤−抗体比率が6〜9である、請求項4から6のいずれか1項に記載のコンジュゲート。
- アミンドナー物質が、抗体軽鎖のアミノ酸位置G200〜S202でグルタミン含有タグに部位特異的にさらにコンジュゲートしており、内因性アミノ酸残基がグルタミン含有タグに置き換えられており、薬剤−抗体比率が6〜11である、請求項4または7に記載のコンジュゲート。
- a)抗体軽鎖のカルボキシル末端で、
b)抗体重鎖のアミノ酸位置T135の後で、および
c)抗体軽鎖のアミノ酸位置G200〜S202で
グルタミン含有タグに部位特異的にコンジュゲートしているアミンドナー物質を含み、内因性アミノ酸残基がグルタミン含有タグに置き換えられており、薬剤−抗体比率が5〜7である、請求項1から8のいずれか1項に記載のコンジュゲート。 - グルタミン含有タグが、Q、LQG、LLQGG(配列番号1)、LLQG(配列番号2)、LSLSQG(配列番号3)、GGGLLQGG(配列番号4)、GLLQG(配列番号5)、LLQ、GSPLAQSHGG(配列番号6)、GLLQGGG(配列番号7)、GLLQGG(配列番号8)、GLLQ(配列番号9)、LLQLLQGA(配列番号10)、LLQGA(配列番号11)、LLQYQGA(配列番号12)、LLQGSG(配列番号13)、LLQYQG(配列番号14)、LLQLLQG(配列番号15)、SLLQG(配列番号16)、LLQLQ(配列番号17)、LLQLLQ(配列番号18)、LLQGR(配列番号19)、LLQGPP(配列番号20)、LLQGPA(配列番号21)、GGLLQGPP(配列番号22)、GGLLQGA(配列番号23)、LLQGPGK(配列番号25)、LLQGPG(配列番号26)、LLQGP(配列番号27)、LLQP(配列番号28)、LLQPGK(配列番号29)、LLQAPGK(配列番号30)、LLQGAPG(配列番号31)、LLQGAP(配列番号32)、およびLLQLQG(配列番号36)からなる群から選択されるアミノ酸配列を含む、請求項4から9のいずれか1項に記載のコンジュゲート。
- グルタミン含有タグが、LLQGA(配列番号11)、LQG、GGLLQGA(配列番号23)、LLQGPA(配列番号21)、LLQGPP(配列番号20)、GGLLQGPP(配列番号22)、LLQGSG(配列番号13)、LLQG(配列番号2)、LLQYQG(配列番号14)、LLQLLQG(配列番号15)、LLQLQG(配列番号36)、LLQLLQ(配列番号18)、LLQLQ(配列番号17)、LLQGR(配列番号19)、LLQYQGA(配列番号12)、SLLQG(配列番号16)、またはLLQLLQGA(配列番号10)である、請求項10に記載のコンジュゲート。
- アミンドナー単位−リンカー(X−Y)が、直鎖状または分岐鎖状である、請求項1から11のいずれか一項に記載のコンジュゲート。
- アミンドナー単位−リンカー(X−Y)が、Ac−Lys−Gly(アセチル−リジン−グリシン)、アミノカプロン酸、Ac−Lys−β−Ala(アセチル−リジン−β−アラニン)、アミノ−PEG2(ポリエチレングリコール)−C2、アミノ−PEG3−C2、アミノ−PEG6−C2、Ac−Lys−Val−Cit−PABC(アセチル−リジン−バリン−シトルリン−p−アミノベンジルオキシカルボニル)、アミノ−PEG6−C2−Val−Cit−PABC、アミノ−PEG3−C2−Val−Cit−PABC、アミノカプロイル−Val−Cit−PABC、[(3R,5R)−1−{3−[2−(2−アミノエトキシ)エトキシ]プロパノイル}ピペリジン−3,5−ジイル]ビス−Val−Cit−PABC、[(3S,5S)−1−{3−[2−(2−アミノエトキシ)エトキシ]プロパノイル}ピペリジン−3,5−ジイル]ビス−Val−Cit−PABC、プトレシンおよびAc−Lys−プトレシンからなる群から選択される、請求項12に記載のコンジュゲート。
- 作用物質部分が、細胞傷害物質である、請求項1から13のいずれか一項に記載のコンジュゲート。
- 細胞傷害物質が、アントラサイクリン、オーリスタチン、カンプトセシン、コンブレタスタチン、ドラスタチン、デュオカルマイシン、エンジイン、ゲルダナマイシン、インドリノ−ベンゾジアゼピン二量体、マイタンシン、ピューロマイシン、ピロロベンゾジアゼピン二量体、タキサン、ビンカアルカロイド、ツブリシン、ヘミアステリン、スプリセオスタチン、プラジエノライド、またはそれらの立体異性体、アイソスター、類似体もしくは誘導体から選択される、請求項14に記載のコンジュゲート。
- アミンドナー物質が、Alexa 488カダベリン、5−FITCカダベリン、Alexa 647カダベリン、Alexa 350カダベリン、5−TAMRAカダベリン、5−FAMカダベリン、SR101カダベリン、5,6−TAMRAカダベリン、5−FAMリジン、Ac−LysGly−MMAD、アミノ−PEG3−C2−MMAD、アミノ−PEG6−C2−MMAD、アミノ−PEG3−C2−アミノ−ノナノイル−MMAD、アミノカプロイル−Val−Cit−PABC−MMAD、アミノ−PEG3−C2−Val−Cit−PABC−MMAD、アミノ−PEG6−C2−Val−Cit−PABC−MMAD、Ac−Lys−Val−Cit−PABC−MMAD、アミノカプロイル−MMAD、Ac−Lys−β−Ala−MMAD、アミノ−PEG2−C2−MMAE、アミノカプロイル−MMAE、アミノ−PEG3−C2−MMAE、アミノカプロイル−MMAF、アミノカプロイル−Val−Cit−PABC−MMAE、アミノ−PEG−6−C2−Val−Cit−PABC−MMAE、Ac−Lys−Val−Cit−PABC−MMAE、アミノカプロイル−Val−Cit−PABC−MMAF、アミノ−PEG−6−C2−Val−Cit−PABC−MMAF、Ac−Lys−Val−Cit−PABC−MMAF、アミノ−PEG6−C2−Val−Cit−PABC−0101、Ac−Lys−Val−Cit−PABC−0101、プトレシニル−ゲルダナマイシン、Ac−Lys−プトレシニル−ゲルダナマイシン、アミノカプロイル−3377、アミノ−PEG6−C2−3377、アミノカプロイル−0131、アミノ−PEG6−C2−0131、アミノカプロイル−0121、アミノ−PEG6−C2−0121、[(3R,5R)−1−{3−[2−(2−アミノエトキシ)エトキシ]プロパノイル}ピペリジン−3,5−ジイル]ビス−Val−Cit−PABC−MMAD、[(3R,5R)−1−{3−[2−(2−アミノエトキシ)エトキシ]プロパノイル}ピペリジン−3,5−ジイル]ビス−Val−Cit−PABC−MMAE、2−アミノエトキシ−PEG6−NODAGA、およびN2アセチル−L−リシル−L−バリル−N5−カルバモイル−N−[4−({[(2−{[(3R,5S,7R,8R)−8−ヒドロキシ−7−{(1E,3E)−5−[(2S,3S,5R,6R)−5−{[(2Z,4S)−4−ヒドロキシペンタ−2−エノイル]アミノ}−3,6−ジメチルテトラヒドロ−2H−ピラン−2−イル]−3−メチルペンタ−1,3−ジエン−1−イル}−1,6−ジオキサスピロ[2.5]オクタ−5−イル]アセチル}ヒドラジニル)カルボニル]オキシ}メチル)フェニル]−L−オルニチンアミドからなる群から選択される、請求項1から15のいずれか1項に記載のコンジュゲート。
- 請求項1から16のいずれか1項に記載のコンジュゲートと、薬学的に許容できる賦形剤とを含む医薬組成物。
- 請求項1から16のいずれか1項に記載の複数のコンジュゲートを含む医薬組成物であって、平均薬剤−抗体比率が少なくとも5.0である、医薬組成物。
- 複数の抗体−薬剤コンジュゲートを含む医薬組成物であって、少なくとも1種の抗体−薬剤コンジュゲートが、請求項1から16のいずれか1項に記載のコンジュゲートであり、平均薬剤−抗体比率が少なくとも4.1である、医薬組成物。
- 癌の治療のための、請求項17から19のいずれか1項に記載の医薬組成物。
- 腫瘍の成長または進行を阻害するための、請求項17から19のいずれか1項に記載の医薬組成物。
- a)癌を患っている疑いのある対象の試料を、請求項1から16のいずれか1項に記載のコンジュゲートと、コンジュゲートと癌関連タンパク質との結合をもたらす条件下で接触させるステップと、b)癌関連タンパク質へのコンジュゲートの結合を測定するステップとを含む、癌関連タンパク質量を測定する方法。
- 請求項1から16のいずれか1項に記載のコンジュゲートを調製するための方法であって、
a)抗体およびグルタミン含有タグ;ならびに/または内因性グルタミンおよび/もしくは反応性の内因性グルタミンを有する抗体を含む抗体−T分子を提供するステップと、
b)アミンドナー物質をトランスグルタミナーゼの存在下において抗体−T分子と接触させるステップと、
c)抗体−Tをアミンドナー物質に共有結合によって連結させて、抗体−薬剤コンジュゲートを形成するステップと
を含む、方法。 - コンジュゲートが、少なくとも51%のコンジュゲーション効率を有する、請求項23に記載の方法。
- トランスグルタミナーゼが、微生物トランスグルタミナーゼ、精製トランスグルタミナーゼまたは操作されたトランスグルタミナーゼである、請求項23または24に記載の方法。
- 精製ステップをさらに含み、コンジュゲートがクロマトグラフィーステップによって精製される、請求項23から25のいずれか一項に記載の方法。
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