JP2020528069A - 高いインビボ忍容性を有するアントラサイクリン系の抗体薬物複合体 - Google Patents
高いインビボ忍容性を有するアントラサイクリン系の抗体薬物複合体 Download PDFInfo
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- JP2020528069A JP2020528069A JP2020506746A JP2020506746A JP2020528069A JP 2020528069 A JP2020528069 A JP 2020528069A JP 2020506746 A JP2020506746 A JP 2020506746A JP 2020506746 A JP2020506746 A JP 2020506746A JP 2020528069 A JP2020528069 A JP 2020528069A
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Abstract
Description
このような抗体薬物複合体を含む医薬組成物を提供することが別の目的である。
また、このような抗体薬物複合体の製造方法を提供することを目的とする。
別に定義しない限り、本明細書で使用される全ての技術及び科学用語は、本発明が関連する技術分野の通常の技術者により一般に理解されているものと同じ意味を有する。これに加えて、本発明の実施に際して読者を補助するために、以下の定義が提供される。
「非ヒト抗体」は、ヒト免疫グロブリン配列に対応する定常領域を含まない抗体を指す。
第1の態様によれば、本発明は
・ 少なくとも1つの軽鎖定常領域C末端を含む抗体、または標的結合特性を保持する抗体断片もしくは誘導体、および
・ アントラサイクリン系小分子(単数または複数)
を含む、抗体薬物複合体(ADC)に関し、アントラサイクリン分子は抗体、断片または誘導体の軽鎖定常領域C末端(単数または複数)のみに連結され、アントラサイクリン系小分子はペプチド配列を含むリンカーを介して、前記抗体、断片または誘導体に連結される。
「アントラサイクリン系小分子」は、本明細書では「アントラサイクリン分子」とも呼ばれる。
本発明によるADCの視覚的描写を図1に示す。
本発明の抗体は、IgA、IgD、IgE、IgG、またはIgMを含むがこれらに限定されない任意のアイソタイプのものであり得る。従って、例えば、抗体は、IgA1またはIgA2のような任意のIgA、またはIgG1、IgG2、IgG3、IgG4、または合成IgGのような任意のIgGであり得る。
抗体または断片または誘導体は、一価、二価または多価抗体である。
好ましい態様において、抗体はIgG抗体である。
本発明のADCは1つまたは2つのアントラサイクリン系小分子(「アントラサイクリン分子」)を含み、ここで、各々のアントラサイクリン分子は、ペプチド配列を含むリンカーを介して、軽鎖定常領域C末端で前記抗体または抗体誘導体に連結される。
一実施形態では、少なくとも1つのアントラサイクリン系小分子がドキソルビシンではない。
・ メイタンシンを含むメイタンシノイド、
・ モノメチルアウリスタチン MMAE、モノメチルアウリスタチン MMAFなどのアウリスタチン、
・ カリケアミシン、
・ ツブリシン
・ デュオカルマイシン
・ 放射性同位体
・ 毒性ペイロードを含むリポソーム
・ タンパク質毒素
・ タキサン、および/または
・ ピロロベンゾジアゼピン類。
本発明は、
・ 少なくとも1つの軽鎖定常領域C末端を含む抗体、または標的結合特性を保持する抗体断片もしくは誘導体、および
・ アントラサイクリン系小分子
を含み、アントラサイクリン分子(単数または複数)は抗体、断片または誘導体の軽鎖定常領域C末端(単数または複数)のみに連結され、アントラサイクリン系小分子はペプチド配列を含むリンカーを介して、前記抗体、断片または誘導体に連結される、抗体薬物複合体(ADC)に関する。
本発明のADCの一定の非限定的な実施形態の視覚的描写を図2に示す。
好ましい実施形態において、各軽鎖定常領域C末端に連結されたアントラサイクリン分子を有するように設計された本発明のADCは、≧1と≦2との間、好ましくは≧1.75と≦2との間、より好ましくは≧1.9と≦2との間の任意の値の抗体とペイロードとの間の化学量論比を有する。この比はまた、薬物対抗体比(「DAR」)と称され得る。DARを決定する方法は当業者に周知であり、逆相クロマトグラフィー、またはHPLC−MSを使用する方法を含む。ソルターゼ媒介ペプチド転移反応は、100%完全ではなく、記載されたDARを有するADCの調製をもたらすことが理解される。
ADCが追加の非アントラサイクリン毒素を含む実施形態では、DARは≧1〜≦4の間の任意の値であり得る。
一実施形態では本発明が
・ 少なくとも1つの軽鎖定常領域C末端を含む抗体、または標的結合特性を保持する抗体断片もしくは誘導体、および
・ アントラサイクリン系小分子
を含み、アントラサイクリン分子(単数または複数)は抗体、断片、または誘導体の軽鎖定常領域C末端(単数または複数)のみに連結され、アントラサイクリン系小分子はペプチド配列を含むリンカーを介して、前記抗体、断片、または誘導体に連結された抗体薬物複合体(ADC)に関連し、前記ADCは好ましくは同じ数および種類のアントラサイクリン分子を有するが、アントラサイクリン分子(単数または複数)が重鎖定常領域C末端または重鎖および軽鎖定常領域C末端の両方の混合物に連結された同等なADCと比較して、インビボで改善された忍容性を示す、抗体薬物複合体(ADC)に関連する。
・ 少なくとも1つの軽鎖定常領域C末端を含む抗体、または標的結合特性を保持する抗体断片もしくは誘導体、および
・ アントラサイクリン系小分子
を含み、アントラサイクリン分子(単数または複数)は抗体、断片、または誘導体の軽鎖定常領域C末端(単数または複数)のみに連結され、アントラサイクリン系小分はペプチド配列を含むリンカーを介して、前記抗体、断片または誘導体に連結され、前記ADCは同じ数および種類のアントラサイクリン分子を有するが、アントラサイクリン分子が重鎖定常領域C末端または重鎖定常領域C末端と軽鎖定常領域C末端の両方の混合物に連結された同等なADCと比較して、インビボでより大きな治療指数を示す、抗体薬物複合体(ADC)に関する。治療指数は、治療作用を引き起こす治療剤の量と、毒性を引き起こす量との対比である。意外にも、同じ投与量で重鎖C末端と比較して軽鎖C末端に結合した同じ量の毒素が、インビボでより高い効力を生じることを示した(図9を参照のこと)。
・ 少なくとも1つの軽鎖定常領域C末端を含む抗体、または標的結合特性を保持する抗体断片もしくは誘導体、および
・ アントラサイクリン系小分子
を含み、アントラサイクリン分子(単数または複数)は抗体、断片、または誘導体の軽鎖定常領域C末端(単数または複数)のみに連結され、アントラサイクリン系小分子はペプチド配列を含むリンカーを介して、前記抗体、断片、または誘導体に連結され、同じ治療効果のために、前記ADCは好ましくは同じ数および種類のアントラサイクリン分子を有するが、アントラサイクリン分子が重鎖定常領域C末端または重鎖定常領域C末端と軽鎖定常領域C末端の両方の混合物に連結された同等なADCと比較して、低減された投薬頻度および/またはより低い投薬量をインビボで必要とする、抗体薬物複合体(ADC)に関する。
・ 少なくとも1つの軽鎖定常領域C末端を含む抗体、または標的結合特性を保持する抗体断片もしくは誘導体、および
・ アントラサイクリン系小分子
を含み、アントラサイクリン分子(単数または複数)は抗体、断片または誘導体の軽鎖定常領域C末端(単数または複数)のみに連結され、アントラサイクリン系小分子はペプチド配列を含むリンカーを介して、前記抗体、断片または誘導体に連結され、前記ADCは好ましくは同じ数および種類のアントラサイクリン分子を有するが、アントラサイクリン分子が重鎖定常領域C末端または重鎖および軽鎖定常領域C末端の両方の混合物に連結された同等なADCと比較して、減少した疎水性を示す、抗体薬物複合体(ADC)に関する。そのような疎水性の減少は、ADCの取扱いおよび製剤を改善することができる。
いくつかの関連する態様において、本明細書中に記載される抗体薬物複合体の治療的に有効な量および薬学的に許容される担体を含む薬学的組成物を提供する。
第1の態様によれば、本発明は、
・ 少なくとも1つの軽鎖定常領域C末端を含む抗体、または標的結合特性を保持する抗体断片もしくは誘導体、および
・ アントラサイクリン系小分子
を含み、ここで、アントラサイクリン分子(単数または複数)は抗体、断片または誘導体の軽鎖定常領域C末端(単数または複数)のみに連結され、
・ アントラサイクリン系小分子はペプチド配列を含むリンカーを介して、前記抗体、断片または誘導体に連結される、
抗体薬物複合体(ADC)に関する。
a)軽鎖C末端にソルターゼ酵素認識モチーフを有する抗体または断片または誘導体、および
b)各々オリゴグリシンタグを有する1つ以上のアントラサイクリン系小分子の部位特異的ソルターゼ酵素媒介結合
によって得ることができる。
a)軽鎖C末端(単数または複数)にソルターゼ酵素認識モチーフを有する抗体または抗体誘導体を提供する工程、
b)各々オリゴグリシンタグを有する1つ以上のアントラサイクリン系小分子を提供する工程、および
c)抗体または抗体誘導体および1つ以上のアントラサイクリン系小分子を、前記ソルターゼ酵素認識モチーフを認識するソルターゼ酵素を使用するソルターゼ媒介結合によって結合する工程。
好ましくは本明細書中で議論される全ての実施形態において、ソルターゼ酵素認識モチーフは軽鎖C末端(単数または複数)のみに提供される。
本発明はさらに、腫瘍性疾患に罹患しているか、発症する危険性があるか、および/または腫瘍性疾患と診断された対象の治療における使用のための、本明細書中に記載されるようなADCに関する。
一実施形態では、ADCは単剤療法として投与される。代替の実施形態では、ADCがさらなる治療薬と一緒にまたは並行して投与される。
特に、ADCは、約0.1〜20mg/kgの用量で投与され得る。
「対象」という用語はヒトおよび非ヒト動物(特に非ヒト哺乳動物)を指し、好ましくはヒト動物を指す。
発現ベクター:ヒトCS1に結合するために上記で決定されたFab配列を、ヒト発現のためにコドン最適化した;可変ドメインを、GenScript(Piscataway,USA)によってDNAとして合成し、適切な制限部位および適切な定常ドメインを含む発現ベクター内に含めた(HEK293T細胞における発現についてはWaldmeierら、2016年、およびCHO細胞における発現についてはBeerliら、2015年)。
発現ベクターを、Lipofectamine(登録商標)LTX試薬(Thermo Fisher Scientific, Reinach,Switzerland,15388100)を用いたLipofectamine(登録商標)LTX試薬(Thermo Fisher Scientific,Reinach,Switzerland,15388100)を用いてHEK293T細胞にトランスフェクトした;1日のインキュベーション(37℃、5%CO2、増殖培地:10%(v/v)ウシ胎仔血清(FCS)、100IU/mLのPen−Strep−Fungizoneおよび2mMのL−グルタミン(すべてBioconcept,Allschwil,Switzerland)を含むL−グルタミンを含むダルベッコ改変イーグル培地(DMEM)高グルコース(4.5g/L))後、細胞を選択条件下で増殖させた。細胞を分割し、さらに増殖させた(37℃、5%CO2);コンフルエントに達したら、組織培養皿を20μg/mlのポリ−L−リシン(Sigma−Aldrich,P1524)で、37℃で2時間コーティングし、PBSで2回洗浄した。次に、細胞をトリプシン処理し、ポリ−L−リシンでコーティングしたプレート上に1:3に分けた。コンフルエントに達した後、細胞をPBSで洗浄し、続いて、1μg/mLのピューロマイシン(Sigma、P8833)、100IU/mLのPen−Strep−Fungizone(Bioconcept)、161μg/mLのN−アセチル−L−システイン(Sigma−Aldrich、A8199)および10μg/mLのL−グルタチオン還元物(Sigma−Aldrich、G6529)を補充した生成培地(DMEM/F−12、Gibco/Thermo Fisher Scientific、31330−03)に培地を置き換えた。上清を隔週で回収し、濾過する(0.22μm)ことにより細胞を除去して、精製まで4℃で保存した。
全ての忍容性評価は、オーリゴン(Aurigon)で行った。表5のADC(PBS中に製剤化された)を、5匹のCD−1雌マウス(5〜6週齢;Charles River,Sulzfeld,Germanyから)のグループに、示された用量で14日間にわたって2回(1日目および8日目に、ボーラスによる静脈内投与によって)投与した。マウスをケージ当たり5匹の動物のグループで飼育し、水およびペレットを自由に与えた。研究全体を通して1日2回モニターしたパラメーターは、死亡率およびケージサイドでの臨床観察を含んだ。
表6のADC(PBS中に製剤化された)を、3匹のCD−1雌マウス(4〜6週齢;Charles River,Sulzfeld,Germanyから)のグループに、1日目に示された用量で(ボーラスによる静脈内投与によって)投与し、14日間(2.5および5mg/kg用量について)または28日間(10、15および20mg/kg用量について)観察した。マウスをケージ当たり3匹の動物のグループで飼育し、水およびペレットを自由に与えた。研究全体を通して1日2回モニターしたパラメーターは、死亡率およびケージサイドでの臨床観察を含んだ。
表7のHER2標的化ADCの細胞毒性を、HER2陽性ヒトSKBR3細胞株を用いて調べた。HER2陰性ヒト細胞株Karpas−299を対照として使用した。このために、ウェル当たり5000個のSKBR3および5000個のKarpas−299細胞を、それぞれ、10体積%を補充した75μLのDMEMまたはRPMI中の96ウェルプレート(水を含有する端のウェルを除く)上にプレートした。FCS、100IU/mL Pen−Strep−Fungizoneおよび2mM L−Glutamineを、1ウェルあたり6.66×104cellsの密度で、5%CO2雰囲気の加湿インキュベーター中で、37℃で増殖させた。1日間インキュベーションした後、それぞれのADCを、増殖培地中の25μLの3.5倍連続希釈液(80μg/mLの開始ADC濃度、20μg/mL〜0.89ng/mLの範囲の最終ADC濃度を与えた)をそれぞれのウェルに添加した。さらに4日後、プレートをインキュベーターから取り出し、室温に平衡化した。約30分後、50μLのCellTiter−GloOB2.0発光溶液(Promega,G9243)を各ウェルに添加した。プレートを750rpmで5分間振盪し、続いて振盪せずに10分間インキュベートした後、Spark 10Mプレートリーダー上で、ウェル当たり1秒の積分時間で発光を測定した。発光対ADC濃度(ng/mL)の曲線を、Graphpad Prism Softwareに適合させた。プリズムソフトウェアの組み込み「log(阻害剤)vs応答−可変勾配(4つのパラメータ)」IC50決定機能を使用して決定されたIC50値を表7に報告する。
表8のHER2標的化ADCの細胞毒性を、HER2陽性ヒトSKOV3細胞株を用いて調べた。同等のCD30標的ADCをアイソタイプ対照として使用した。このために、実施例4のプロトコルに従ったが、ウェルあたり2,000 SKOV3細胞を、10体積%FCS、100IU/mL Pen−Strep−Fungizoneおよび2mM L−Glutamineを補充した75μLのDMEMの96ウェルプレート(水を含有する端のウェルを除く)上に、ウェルあたり2.66×104細胞の濃度でプレーティングした。
表9のADC(PBS中に製剤化された)を、3匹または6匹のCD−1雌マウス(4〜6週齢;Charles River,Sulzfeld,Germanyから)のグループに、1日目に示された用量で(ボーラスによる静脈内投与によって)投与し、7〜10日間観察した。マウスをケージ当たり3匹の動物のグループで飼育し、水およびペレットを自由に与えた。研究全体を通して1日2回モニターしたパラメーターは、死亡率およびケージサイドでの臨床観察を含んだ。
表10のADC(PBS中に製剤化)を、15匹のスイスの雌異系交配CD1マウスのグループ(体重21〜26g;フランス、Saint BerthevinのJanvierから;単純なランダム割り当てによりグループに割り当てた)に1mg/kg(ボーラスによる単回静脈内投与により)で投与した。マウスをケージ当たり3匹の動物のグループで飼育し、水およびペレットを自由に与えた。処置グループあたり3匹のマウスのグループを、ADC投与から1時間、24時間、3日、7日および14日目に深麻酔後の末端出血によって安楽死させた。所与のグループからの血清および時点を、ELISAによる分析のために収集した。
マウスEMT−6乳癌細胞を、10%(v/v)ウシ胎仔血清(FCS)、100IU/mLのPen−Strep−Fungizoneおよび2mM L−グルタミン(全て、Bioconcept,Allschwil,Switzerland)を含むL−グルタミンを含むDMEM完全(ダルベッコ改変イーグル培地(DMEM)高グルコース(4.5g/L))中、37℃および5% CO2で培養した。細胞を移植によりROR1を過剰表現するように設計し、セルを遠心分離(6min,1200rpm,4℃)し、RPMI−1640メディア(5x106 cells/ml)で再懸濁した。400μLの細胞懸濁液を、13.3μgのトランスポータブルベクターpPB−PGK−Puro−ROR1(完全長ROR1(NP_005003.2)とピューロマイシン耐性遺伝子の同時発現を指令する)および6.6μgのトランスポザーゼ含有ベクターpCDNA3.1_hy_mPBを含有する400μLのRPMIに添加した。DNA/EMT−6細胞混合物をエレクトロポレーションキュベット(0.4cm−ギャップ、165−2088、BioRad、Cressier、スイス)に移し、300Vおよび950μFでキャパシタンスエクステンダーを有するBiorad Gene Pulser IIを使用してエレクトロポレーションした。次に、細胞を室温で5〜10分間インキュベートした。インキュベーション後、細胞を1200rpmで6分間遠心分離し、1回洗浄し、続いてDMEMに完全に再懸濁した後、5%CO2雰囲気の加湿インキュベーター中で、37℃でインキュベーションした。エレクトロポレーションの1日後、ヒトROR1を安定に発現する細胞プールを、3μg/mLのピューロマイシン(Sigma−Aldrich,P8833)を添加することによって選択した。ROR1を発現する単一細胞クローンは、抗生物質選択EMT−6−ROR1細胞に由来した。次いで、細胞を抗ROR1抗体2A2と共に30分間インキュベートし(4℃、最終濃度2μg/mL)、続いて遠心分離および洗浄した。次いで、細胞を前述のように再懸濁し、暗所(30分、4℃)で1:250希釈した抗ヒトIgG抗体(Fcγ特異的)PE(eBioscience,Vienna,Austria,12−4998−82)とインキュベートし、緩衝液中で1回洗浄し、FACSAriaII機器(BD Biocsiences,San Jose,USA)を用いたFACSによる抗原発現細胞の単一選別まで氷上に保持した。以下の実験で使用したクローン14上のROR1の発現を、FACSによって決定した(図7)。
表11のCS1標的化およびROR1標的化ADCの細胞毒性を、実施例8のROR1過剰発現EMT6クローン14細胞およびCS1陽性L363細胞株を用いて調べた。このために、実施例4のプロトコルに従ったが、1ウェルあたり1000個のEMT6クローン14および10000個のL363細胞を、10体積%FCS、100IU/mL Pen−Strep−Fungizoneおよび2mM L−Glutamineを補充した75μLのDMEM中にそれぞれウェルあたり1.3×104細胞および1.3×105の濃度でプレーティングした。
以下の研究をProQinaseで行った。0日目に、100μlのPBS中の1x106 EMT−6−ROR1クローン14腫瘍細胞(実施例8から)を、5〜6週齢の雌BALB/cマウスの乳房脂肪パッドに同所的に移植した。3日目に約30〜80mm3(カリパスによる)の平均腫瘍体積に達したら、マウスを、腫瘍の大きさに従ってそれぞれ6匹の動物のグループにブロックランダム化した。表12のADC(PBS中に製剤化)を、3日目に示された用量で投与した(ボーラスによる静脈内投与による)。マウスに水およびペレットを自由に与えた。カリパスによって週2回評価した腫瘍体積の進展(グループあたりの平均および平均の標準誤差に対応するエラーバー)を図9に示す。
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下記の配列は、本出願の開示の一部を形成する。WIPO ST 25互換性のある電子化配列表もまた、この出願と共に提供される。疑義を避けるため、以下の表中の配列と電子化配列表中の配列との間に齟齬が存在する場合、この表中の配列は正しいものとみなされるものとする。
Claims (19)
- ・ 少なくとも1つの軽鎖定常領域C末端を含む抗体、もしくは標的結合特性を保持する抗体断片または誘導体、および
・ アントラサイクリン系小分子
を含み、アントラサイクリン分子(単数または複数)は、前記抗体、断片または誘導体の軽鎖定常領域C末端(単数または複数)のみに連結され、
アントラサイクリン系小分子はペプチド配列を含むリンカーを介して、前記抗体、断片または誘導体に連結される、抗体薬物複合体(ADC)。 - 前記抗体または断片または誘導体が、
・ 二重可変ドメイン免疫グロブリン(DVD−Ig)フォーマットとして、または
・ IgA、IgD、IgE、IgGまたはIgMとの一本鎖可変断片(scFv)融合体として
提供される、請求項1に記載の抗体薬物複合体。 - 前記抗体または断片または誘導体が、
・ 腫瘍特異的であるか、または
・ 健康な組織上よりも腫瘍組織上でより高い割合で発現される抗原に結合する、
上記請求項の何れかに記載の抗体薬物複合体。 - 前記抗体または断片または誘導体がヒトおよび/またはマウスCS1に結合しない、上記請求項の何れかに記載の抗体薬物複合体。
- 前記抗体または断片または誘導体がhu4−2−17のCDR(カバット番号付けに基づく)
・ HC CDR1 (SYYMS)
・ HC CDR2 (AIGISGNAYYASWAKS)
・ HC CDR3 (DHPTYGMDL)
・ LC CDR1 (EGNNIGSKAVH)
・ LC CDR2 (DDDERPS),および
・ LC CDR3 (QVWDSSAYV)
を含み、CDRは抗体の標的に結合することができるように、適切なタンパク質フレームワークに含まれる、上記請求項の何れかに記載の抗体薬物複合体。 - 前記抗体または断片または誘導体がhuERCS−409のCDR(カバット番号付けに基づく)
・ HC CDR1 (SYGVI)
・ HC CDR2 (IIGSSGNTYYASSVKG)
・ HC CDR3 (YYGDSGFDS)
・ LC CDR1 (RASQSIGSWLS)
・ LC CDR2 (GASNLAS)、および
・ LC CDR3 (LGASPNGWA)
を含み、CDRは抗体の標的に結合することができるように、適切なタンパク質フレームワークに含まれる、上記請求項の何れかに記載の抗体薬物複合体。 - 前記抗体または断片または誘導体が、以下からなるリストのうちの少なくとも1つを含む、上記請求項の何れかに記載の抗体薬物複合体:
・ トラスツズマブの可変ドメイン(配列番号1/2の可変ドメイン)、
・ hu4−2−17の可変ドメイン(配列番号4/5の可変ドメイン)、および/または
・ huERCS−409の可変ドメイン(配列番号7/8の可変ドメイン)。 - 少なくとも1つのアントラサイクリン系小分子がドキソルビシンではない、上記請求項の何れかに記載の抗体薬物複合体。
- アントラサイクリン系小分子が、式(i)の構造を含む、PNU−159682またはその誘導体から選択される、上記請求項の何れかに記載の抗体薬物複合体:
- 前記リンカーのペプチド配列が、ソーターゼ酵素認識モチーフの特異的切断から生じるペプチドモチーフを含むか、またはそれからなる、上記請求項の何れかに記載の抗体薬物複合体。
- 前記リンカーの前記ペプチド配列がGnまたはGlyn(nが1〜21であり、好ましくはnが1、2、3、4または5である)と表示されるオリゴグリシン配列(「タグ」)を含むか、またはそれからなる、請求項10に記載の抗体薬物複合体。
- 前記リンカーが、NH2−(CH2)m−NH2(式中、m≧1および≦11、好ましくはm=2)のアルキルジアミノ基をさらに含む、請求項9〜10のいずれかに記載の抗体薬物複合体。
- 前記リンカーが少なくとも1つのさらなる切断可能または非切断可能リンカーをさらに含み、リンカーが好ましくは、ヒドラジンリンカー、チオ尿素リンカー、自己免疫リンカー、スクシンイミジルトランス−4−(マレイミジルメチル)シクロヘキサン−1−カルボキシレート(SMCC)リンカー、ジスルフィドリンカー、セレノエーテルリンカー、アミドリンカー、チオエーテルリンカー、および/またはマレイミドリンカーからなる群から選択される、上記請求項の何れかに記載である抗体薬物複合体。
- (i)抗体、断片または誘導体と、(ii)アントラサイクリン系小分子との間の、≧1〜≦2の間の任意の値の化学量論比を有する、上記請求項の何れかに記載の抗体薬物複合体。
- 治療有効量の上記請求項の何れかに記載の抗体薬物複合体と、薬学的に許容される担体とを含む、医薬組成物。
- a)軽鎖C末端(単数または複数)にソルターゼ酵素認識モチーフを有する抗体または断片または誘導体、および
b)各々オリゴグリシンタグを有する1つ以上のアントラサイクリン系小分子
の部位特異的ソルターゼ酵素媒介結合によって得ることができる抗体薬物複合体。 - 上記請求項の何れかに記載の抗体薬物複合体を製造する方法であって、以下の工程を含む、方法:
d)軽鎖C末端(単数または複数)にソルターゼ酵素認識モチーフを有する抗体または断片または誘導体を提供する工程、
e)各オリゴグリシンタグを有する1つ以上のアントラサイクリン系小分子を提供する工程、
f)前記ソルターゼ酵素認識モチーフを認識するソルターゼ酵素を使用するソルターゼ媒介結合の手段によって、抗体または断片または誘導体および1つ以上のアントラサイクリン系小分子を結合させる工程。 - 腫瘍性疾患に罹患しているか、発症する危険性があるか、および/または腫瘍性疾患と診断された対象の治療に使用するための上記請求項の何れかに記載の抗体薬物複合体。
- 請求項1〜14のいずれか1項に記載の抗体薬物複合体を治療有効量または用量で投与することを含む、腫瘍性疾患に罹患しているか、発症する危険性があるか、および/または腫瘍性疾患と診断されている患者を治療するための方法。
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EP3665193A1 (en) * | 2017-08-07 | 2020-06-17 | NBE Therapeutics AG | Anthracycline-based antibody drug conjugates having high in vivo tolerability |
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WO2016102679A1 (en) * | 2014-12-23 | 2016-06-30 | Nbe-Therapeutics Ag | Binding protein drug conjugates comprising anthracycline derivatives |
WO2017127664A1 (en) * | 2016-01-20 | 2017-07-27 | The Scripps Research Institute | Ror1 antibody compositions and related methods |
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RU2020103344A (ru) | 2021-07-27 |
CN111133002A (zh) | 2020-05-08 |
CN111133002B (zh) | 2024-05-24 |
CA3071212C (en) | 2023-12-12 |
AU2018315127A1 (en) | 2020-02-20 |
KR102486090B1 (ko) | 2023-01-10 |
WO2019030240A1 (en) | 2019-02-14 |
US10758556B2 (en) | 2020-09-01 |
KR20200033306A (ko) | 2020-03-27 |
WO2019030223A1 (en) | 2019-02-14 |
NZ761287A (en) | 2023-08-25 |
RU2020103344A3 (ja) | 2021-07-27 |
CA3071212A1 (en) | 2019-02-14 |
JP2021063098A (ja) | 2021-04-22 |
AU2018315127B2 (en) | 2021-12-23 |
KR20230008269A (ko) | 2023-01-13 |
US20210023103A1 (en) | 2021-01-28 |
RU2764031C2 (ru) | 2022-01-12 |
SG11202000846WA (en) | 2020-02-27 |
MX2020001212A (es) | 2020-03-20 |
JP7133611B2 (ja) | 2022-09-08 |
IL272534A (en) | 2020-03-31 |
JP6817492B2 (ja) | 2021-01-20 |
US20190381079A1 (en) | 2019-12-19 |
EP3665193A1 (en) | 2020-06-17 |
ZA202000480B (en) | 2020-11-25 |
BR112020002368A2 (pt) | 2020-09-01 |
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