JP2017526682A - 抗体薬物複合体組成物の製剤化方法 - Google Patents
抗体薬物複合体組成物の製剤化方法 Download PDFInfo
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Abstract
Description
本出願は、2014年9月2日に出願された米国特許仮出願番号第62/044,592号の優先権及び利益を主張し、その内容全体を参照によって本願明細書に引用したものとする。
[薬物]=DAR×[抗体]。
USL(薬物)μg/mL=抗体濃度仕様の上限×DAR×薬物分子量×1000/抗体分子量
(e)以下のように算出された薬物仕様の下限(LSL(薬物))を決定すること:
LSL(薬物)μg/mL=抗体濃度仕様の下限×DAR×薬物分子量×1000/抗体分子量
(f)ステップ(d)で算出されたUSL(薬物)をステップ(c)で定義された薬物仕様の上限と比較し、2つの値のうちの低い方を薬物仕様の有効な上限として選択すること;(g)ステップ(e)で算出されたLSL(薬物)をステップ(c)で定義された薬物仕様の下限と比較し、2つの値のうちの高い方を薬物仕様の有効な下限として選択すること;及び(h)抗体薬物複合体組成物を、薬物仕様の有効な上限と薬物仕様の有効な下限の間の中間点である標的薬物濃度に製剤化することによって、組成物における効力変動性を低下させることを含む。一実施形態において、本方法は、薬物の仕様上限と下限の範囲を約±3〜9%に狭める。別の実施形態において、本方法は、薬物の仕様上限と下限の範囲を約±4%に狭める。一実施形態において、ステップ(b)における仕様が許す最大変動は、約±15%である。別の実施形態において、ステップ(b)における仕様が許す最大変動は、約±10、11、12、13、または14%未満である。一実施形態において、ステップ(c)における仕様が許す最大変動は、約±15%である。別の実施形態において、ステップ(c)における仕様が許す最大変動は、約±10、11、12、13、または14%未満である。種々の実施形態において、抗体は、非機能性抗体である。種々の実施形態において、DARは、DAR仕様の下限またはDAR仕様の上限である。種々の実施形態において、DAR仕様の下限は、2.3、2.4、または2.5である。種々の実施形態において、DAR仕様の上限は、2.9、3.0、または3.1である。
USL(薬物)μg/mL=抗体濃度仕様の上限×DAR×薬物分子量×1000/抗体分子量
(e)以下のように算出されたベンゾジアゼピン仕様の下限(LSL(薬物))を決定すること:
LSL(薬物)μg/mL=抗体濃度仕様の下限×DAR×薬物分子量×1000/抗体分子量
(f)ステップ(d)で算出されたUSL(薬物)をステップ(c)で定義されたベンゾジアゼピン仕様の上限と比較し、2つの値のうちの低い方をベンゾジアゼピン仕様の有効な上限として選択すること;(g)ステップ(e)で算出されたLSL(薬物)をステップ(c)で定義されたベンゾジアゼピン仕様の下限と比較し、2つの値のうちの高い方をベンゾジアゼピン仕様の有効な下限として選択すること;及び(h)抗体ベンゾジアゼピン複合体組成物を、ベンゾジアゼピン仕様の有効な上限とベンゾジアゼピン仕様の有効な下限の間の中間点である標的ベンゾジアゼピン濃度に製剤化することによって、組成物における効力変動性を低下させることを含む。
USL(薬物)μg/mL=抗体濃度仕様の上限×PAR×薬物分子量×1000/抗体分子量
LSL(薬物)μg/mL=抗体濃度仕様の下限×PAR×薬物分子量×1000/抗体分子量。
他に定義しない限り、本明細書で用いられる全ての技術的及び科学的用語は、本発明が属する分野において当業者によって通常理解される意味を有する。以下の参考文献は、当業者に本発明で使用する用語の多くの一般的な定義を提供する:Singletonら、Dictionary of Microbiology and Molecular Biology(2nd ed.1994);The Cambridge Dictionary of Science and Technology(Walker ed.、1988);The Glossary of Genetics、5th Ed.、R.Rieger et al.(eds.)、Springer Verlag(1991);及び Hale & Marham、The Harper Collins Dictionary of Biology(1991)。本明細書で用いられる場合、以下の用語は、別に指定のない限り、これらの文献で定義された意味となる。
理想体重(IBW)
1.IBW1(雄)=0.9H1−88
2.IBW1(雌)=0.9H1−92。
(1H=cm身長;W=kg体重)
IBW、LBW、及びADJは、Green and Duffull、British Journal of Clinical Pharmacology 58:119−133(2004)でより詳細に説明されており、その内容全体を参照によって本願明細書に引用したものとする。
用語、「または」は、包括的であると理解される。具体的に述べているかまたは内容から明らかでない限り、本明細書で用いられる場合、用語、「a」、「an」、及び「the」は、単数または複数であると理解される。
ADCがん治療薬は、抗体がん治療薬と同様に;すなわち、抗体タンパク質濃度に基づいて製剤化される。製剤ラベルは、投与のベースとなる「微量」または標的濃度の情報(例えば、mg/kgまたはmg/m2ベースで)を与えるが、抗体濃度の典型的な仕様は、標的±10〜20%である。ADCの効力は一般的に濃度に対して直線であるため、製剤の効力は±20%まで変動し得る。ADCは、抗体とは異なり、薬物対抗体比(DAR)により可変効力というさらなる可能性を有する。初期の臨床開発の典型的なDAR仕様は、標的±15%であり、これにより、連結した細胞毒性の量を所与の抗体濃度によって変動させることができる。ほとんどのADCでは、DARと、効力が投与された複合体薬物の濃度によって部分的または完全に指示されたことを示す効力との間には直線関係があることを実証することができる。
本発明は、細胞毒性剤(例えば、薬物またはプロドラッグ)に連結またはコンジュゲートされる本明細書に開示される、抗体(例えば、腫瘍抗原に結合する抗体)または抗体断片を含むADC、及びそれらの機能性等価物を製剤化するための改善された方法に関する。種々の抗体を本発明の方法で使用することができる。特定の実施形態において、抗体は、FOLR1(FRαとしても知られる)、CD33、CD123、CD19、MUC1、CA6、CD37、EGFRなどの抗原またはリガンド、及び上に挙げたポリペプチドのいずれかの断片に特異的に結合する。特定の実施形態において、本発明としては、以下の抗体:huMovl9、huMy9−6、huAnti−CD123、huB4、huDS6、huCD37−50、huCD37−3、及びhuEGFR−7Rのいずれかを含むADCが挙げられるが、これらに限定されない。
DM1は、以下の構造式によって表される:
米国特許公開第20130156796号も参照されたい。
DM4は、以下の構造式によって表される:
米国特許公開第20130156796号も参照されたい。
本発明は、本明細書に記載された1以上のADCを含む医薬組成物をさらに提供する。特定の実施形態において、医薬組成物は、薬学的に許容可能なビヒクルをさらに含む。これらの医薬組成物は、腫瘍増殖を阻害し、ヒト患者のがんを治療するための用途を見出す。
本発明は、本明細書に記載された方法を実施するために用いることができる抗体薬物複合体(ADC)を含むキットを提供する。特定の実施形態において、キットは、1以上の容器中にADCを含み、ADCの量は、薬物濃度に基づいており、ADCの量は、仕様から±10%程度まで変動する。開示されたADCが、当該技術分野において周知の確立されたキット形式の1つに容易に組み入れられ得ることを、当業者は容易に認識するであろう。所望の場合、キットは、患者を治療するためにADCを使用する説明書を含み得る。説明書は、容器(存在するとき)に直接、または容器に貼付したラベルとして、或いは容器内にまたは容器と共に供給される別個のシート、パンフレット、カード、またはホルダーとして印刷できる。
huMovl9−スルホ−SPDB−DM4の抗FOLR1モノクローナル抗体部分は、細胞表面抗原であるFOLR1(FRαとしても知られる)を標的にし、これと結合する。抗体と抗原が相互作用し、内在化した後、免疫複合体はDM4を放出し、DM4はチューブリンに結合し、微小管重合/分解動力学を乱すことによって、FOLR1発現腫瘍細胞の細胞分裂及び細胞増殖を阻害する。FOLR1、葉酸受容体ファミリーのメンバーは、種々の上皮由来がん細胞上で過剰発現される。
huMov19−スルホ−SPDB−DM4では、ADCレベルをできるたけ高く達成し、眼毒性閾値に接近せずに有効性を達成することが望ましい。図3に示すように、huMovl9−スルホ−SPDB−DM4 DARがおおよそ3.4であり、投与量が3.3〜7mg/kgの範囲である場合、32%の患者が眼毒性レベルを上回ることが分かった。huMovl9−スルホ−SPDB−DM4 DARが2.9であり、投与量が3.3〜7mg/kgの範囲である場合、13%の患者が眼毒性レベルを上回ることが予想される。huMovl9−スルホ−SPDB−DM4 DARが3.4であり、投与量が3.3〜7mg/kgの範囲である場合、32%の患者は、彼らが受けるDM4用量の減少に基づいて、眼毒性レベルを上回ることが予想される。huMov19−スルホ−SPDB−DM4DARが3.9であり、投与量が3.3〜7mg/kgの範囲である場合、48%の患者は、彼らが受けるDM4用量の増加に基づいて、眼毒性レベルを上回ることが予想される。
KB及びIGROV−1ネズミ異種移植モデル中のhuMovl9−スルホ−SPDB−DM4活性(図5)を分析するインビボ研究を実施した。KB細胞株は、腫瘍細胞のHeLa細胞汚染から確立した。KB細胞株は、再現性を有してヌードマウスで腫瘍を形成し、葉酸受容体を過剰発現するため、腫瘍モデルとして使用する。IGROV−1腫瘍モデルは、ヒト卵巣がんから得られる。
薬物抗体比がhuMovl9−スルホ−SPDB−DM4の最大耐用量(MTD)に与える影響を評価するためにインビボ試験を実施した(図6)。マウスは、huMov19−スルホ−SPDB−DM4を1400μg/kgの固定DM4用量で受けた。抗体用量は変動した。マウス体重は、毒性の尺度として監視した。投与したADCは、薬物対抗体比(例えば、DAR9.0対DAR3.6)を大きく変動させた。興味深いことに、同じDM4投与量を投与する限り、DARは、3.6〜9.0の範囲内で毒性に影響を及ぼさなかった。従って、毒性は、DARに無関係であった。
従来、抗体薬物複合体の治療用組成物は、抗体濃度に基づいて製剤化されている。図9Aは、仕様の許容可能な範囲内のままであっても、抗体濃度に基づいて、抗体薬物複合体を製剤化するのに固有の変動性を示す。特に、ADC製造プロセスの最後で、抗体の濃度を測定し、抗体を希釈して、huMov19−スルホ−SPDB DM4については5.0mg/mlである標的薬物濃度に到達する。図9Aでは、huMovl9−スルホ−SPDB−DM4に対する標的抗体濃度(5.0mg/ml)を枠で囲み、標的DAR(3.4)を丸で囲む。この標的抗体濃度で、DM4濃度は91.1μg/mlである。実際には、最終製剤の抗体濃度は、標的濃度からの変動を許される。最終製品の抗体濃度は、4.0mg/mlまで低下、または6.0mg/mlまで上昇することができた。従って、DM4濃度の枠で囲んだ領域で示したように、DARに応じて、最終製剤のDM4濃度は、62.1μg/mlまで低下、または125.4μg/mlまで上昇することができた。
huMovl9抗体、SPDBリンカー、及び細胞毒性薬であるDM4を含むADC huMovl9−スルホ−SPDB−DM4は、ADCの一例であり、インビトロ効力、インビボ有効性、及びインビボ毒性は、DARに無関係であり、投与されたDM4の濃度によって完全に引き起こされる。従って、huMov19−スルホ−SPDB−DM4は、huMov19濃度ではなくDM4濃度によって製剤化することが良好な候補である。これが製剤効力を狭めるという仮説を試験するために、一定範囲のDARを有する一連のhuMovl9−スルホ−SPDB−DM4複合体を製造した。複合体を塩基製剤緩衝剤(10mM酢酸ナトリウム、9%(w/v)ショ糖、pH5.0)に精製し、各試料のDM4及びhuMovl9抗体濃度を、それぞれ、252nm及び280nmの波長にて分光光度法で測定した。複合体を含むDM4及びhuMovl9抗体のモル濃度を以下のように算出した:
場合によっては、標的薬物濃度の変動により、非標的濃度(例えば、抗体濃度)の大きな変動よりも薬物及び抗体両方の濃度の小さな変動に到達させることが望ましいことがある。このような方法を用いてADC組成物を製剤化することは、抗体及び薬物の両方の濃度が特定のDAR値で重なる範囲の真ん中を標的化することによって仕様範囲を最大にする。実際には、薬物仕様は、抗体仕様よりも狭い(例えば、薬物の±10%対抗体の±15%)。従って、抗体及び薬物濃度の変動をより小さくさせることで、仕様には従わないが、完全に安全に使用されるバッチのリスクを最小限にしながら、(絶対標的よりも)強化された薬物濃度仕様を達成するためのさらなる制御戦略を提供する。
−これらの異常値は、>または<規則を用いて、LSL(34.0mg/mL)またはUSL(41.5mg/mL)のいずれかに設定することができる
−提案されるのは、製剤化の目的のため、DARを小数点第2位まで報告することである
前述の説明から、本明細書に記載されている本発明を、様々な使用及び条件に適用するために、改変及び修正できることは明らかであろう。このような実施態様もまた以下の特許請求の範囲の範囲内にある。
Claims (62)
- 抗体薬物複合体組成物における効力変動性の低下方法であって、
(a)固定抗体濃度及び固定薬物抗体比(DAR)で標的薬物濃度を決定すること;及び
(b)該標的薬物濃度を達成するように該抗体薬物複合体組成物を製剤化することによって、該組成物における効力変動性を低下させること
を含む、前記方法。 - 抗体薬物複合体を含む組成物における効力変動性の低下方法であって、
(a)標的抗体濃度及び固定薬物抗体比(DAR)で薬物濃度を決定すること;
(b)該抗体濃度の仕様範囲と該薬物濃度の仕様範囲が重なる範囲の中間点を同定する可変薬物濃度を標的化すること;
(c)該抗体薬物複合体組成物を該標的可変薬物濃度に製剤化することによって、該組成物における効力変動性を低下させること
を含む、前記方法。 - 前記薬物濃度の変動性が、約±10%である、請求項1または2に記載の方法。
- 前記抗体濃度の変動性が、約±10%である、請求項2に記載の方法。
- 前記変動性が、約±5、6、7、8、または9%未満である、請求項3または4に記載の方法。
- 抗体薬物複合体を含む組成物における効力変動性の低下方法であって、
(a)該抗体薬物複合体組成物のDARを測定すること;
(b)抗体仕様の上限と抗体仕様の下限を決定すること、該抗体仕様の上限は、該仕様は、標的抗体濃度+該仕様が許す最大変動であり、該抗体仕様の下限は、標的抗体濃度−該仕様が許す最大変動である;
(c)定義された薬物仕様の上限と定義された薬物仕様の下限を決定すること、該定義された薬物仕様の上限は、標的薬物濃度+該仕様が許す最大変動であり、該定義された薬物仕様の下限は、標的薬物濃度−該仕様が許す最大変動である;
(d)以下のように算出された薬物仕様の上限(USL(薬物))を決定すること:
USL(薬物)μg/mL=抗体濃度仕様の上限×DAR×薬物分子量×1000/抗体分子量
(e)以下のように算出された薬物仕様の下限(LSL(薬物))を決定すること:
LSL(薬物)μg/mL=抗体濃度仕様の下限×DAR×薬物分子量×1000/抗体分子量
(f)ステップ(d)で算出されたUSL(薬物)をステップ(c)で定義された薬物仕様の上限と比較し、該2つの値のうちの低い方を薬物仕様の有効な上限として選択すること;
(g)ステップ(e)で算出されたLSL(薬物)をステップ(c)で定義された薬物仕様の下限と比較し、該2つの値のうちの高い方を薬物仕様の有効な下限として選択すること;及び
(h)該抗体薬物複合体組成物を、該薬物仕様の有効な上限と該薬物仕様の有効な下限の間の中間点である標的薬物濃度に製剤化することによって、前記組成物における効力変動性を低下させること
を含む、前記方法。 - 前記方法が、前記薬物と前記抗体の仕様上限と下限の範囲を約±3〜9%に狭める、請求項6に記載の方法。
- 前記方法が、前記薬物の仕様上限と下限の範囲を約±4%に狭める、請求項6に記載の方法。
- ステップ(b)における前記仕様が許す前記最大変動が、約±15%である、請求項6に記載の方法。
- ステップ(b)における前記仕様が許す前記最大変動が、約±10、11、12、13、または14%未満である、請求項6に記載の方法。
- ステップ(c)における前記仕様が許す前記最大変動が、約±15%である、請求項6に記載の方法。
- ステップ(c)における前記仕様が許す前記最大変動が、約±10、11、12、13、または14%未満である、請求項6に記載の方法。
- 前記抗体が、非機能性抗体である、請求項1〜12のいずれか1項に記載の方法。
- 前記薬物濃度が、前記抗体仕様濃度内で変動する、請求項1〜13のいずれか1項に記載の方法。
- 前記抗体濃度及び前記薬物濃度が、変動を許される、請求項2〜14のいずれか1項に記載の方法。
- 抗体薬物複合体組成物の製剤化方法であって、
(a)固定抗体濃度及び固定薬物抗体比で標的薬物濃度を決定すること;及び
(b)ステップ(a)の該標的薬物濃度を達成するように該抗体薬物複合体組成物を製剤化すること
を含む、前記方法。 - 前記薬物が、チューブリン阻害剤、DNA損傷剤、DNA架橋剤、DNAアルキル化剤、または細胞周期かく乱物質である、請求項1〜16のいずれか1項に記載の方法。
- 前記薬物が、メイタンシノイドである、請求項1〜17のいずれか1項に記載の方法。
- 前記薬物が、ベンゾジアゼピン化合物である、請求項1〜17のいずれか1項に記載の方法。
- 前記ベンゾジアゼピン化合物が、ピロロベンゾジアゼピンまたはインドリノベンゾジアゼピンである、請求項19に記載の方法。
- 前記薬物が、オーリスタチンである、請求項1〜17のいずれか1項に記載の方法。
- 前記抗体が、非機能性抗体である、請求項13〜21のいずれか1項に記載の方法。
- 前記薬物が、ベンゾジアゼピン化合物であり、前記抗体が、非機能性抗体である、請求項1〜17、19、20、及び22のいずれか1項に記載の方法。
- 前記薬物が、メイタンシノイドであり、前記抗体が、非機能性抗体である、請求項1〜18、20、及び22のいずれか1項に記載の方法。
- 前記抗体が、機能性抗体である、請求項1〜12及び14〜21のいずれか1項に記載の方法。
- 抗体メイタンシノイド複合体を含む組成物における効力変動性の低下方法であって、
(a)固定抗体濃度及び固定メイタンシノイド対抗体比で標的メイタンシノイド濃度を決定すること;及び
(b)該標的メイタンシノイド濃度を達成するように該抗体メイタンシノイド複合体組成物を製剤化することによって、該組成物における効力変動性を低下させること
を含む、前記方法。 - 前記方法が、前記抗体薬物複合体または抗体メイタンシノイド複合体を製造する上でバッチ間の効力変動性を低下させる、請求項1〜26のいずれか1項に記載の方法。
- 前記組成物が、最終製剤である、請求項1〜26のいずれか1項に記載の方法。
- 抗体メイタンシノイド複合体組成物の製剤化方法であって、
(a)固定抗体濃度及び固定メイタンシノイド対抗体比で標的メイタンシノイド濃度を決定すること;及び
(b)該標的メイタンシノイド濃度を達成するように前記抗体メイタンシノイド複合体組成物を製剤化すること
を含む、前記方法。 - 抗体ベンゾジアゼピン複合体を含む組成物における効力変動性の低下方法であって、
(a)該抗体ベンゾジアゼピン複合体組成物のDARを測定すること;
(b)抗体仕様の上限と抗体仕様の下限を決定することであり、ここで該抗体仕様の上限は、標的抗体濃度+該仕様が許す最大変動であり、該抗体仕様の下限は、標的抗体濃度−該仕様が許す最大変動である;
(c)定義されたベンゾジアゼピン仕様の上限と定義されたベンゾジアゼピン仕様の下限を決定することであり、該定義されたベンゾジアゼピン仕様の上限は、標的ベンゾジアゼピン濃度+該仕様が許す最大変動であり、該定義されたベンゾジアゼピン仕様の下限は、標的ベンゾジアゼピン濃度−該仕様が許す最大変動である;
(d)以下のように算出されたベンゾジアゼピン仕様の上限(USL(薬物))を決定すること:
USL(薬物)μg/mL=抗体濃度仕様の上限×DAR×薬物分子量×1000/抗体分子量
(e)以下のように算出されたベンゾジアゼピン仕様の下限(LSL(薬物))を決定すること:
LSL(薬物)μg/mL=抗体濃度仕様の下限×DAR×薬物分子量×1000/抗体分子量
(f)ステップ(d)で算出されたUSL(薬物)をステップ(c)で定義されたベンゾジアゼピン仕様の上限と比較し、該2つの値のうちの低い方をベンゾジアゼピン仕様の有効な上限として選択すること;
(g)ステップ(e)で算出されたLSL(薬物)をステップ(c)で定義されたベンゾジアゼピン仕様の下限と比較し、該2つの値のうちの高い方をベンゾジアゼピン仕様の有効な下限として選択すること;及び
(h)該抗体ベンゾジアゼピン複合体組成物を、該ベンゾジアゼピン仕様の有効な上限と該ベンゾジアゼピン仕様の有効な下限の間の中間点である標的ベンゾジアゼピン濃度に製剤化することによって、前記組成物における効力変動性を低下させること
を含む、前記方法。 - 前記方法が、前記薬物と前記抗体の仕様上限と下限の範囲を約±3〜5%に狭める、請求項30に記載の方法。
- 前記方法が、前記仕様上限と下限の範囲を約±4%に狭める、請求項30に記載の方法。
- ステップ(b)における前記仕様が許す前記最大変動が、約±15%である、請求項30に記載の方法。
- ステップ(b)における前記仕様が許す前記最大変動が、約±10、11、12、13、または14%未満である、請求項30に記載の方法。
- ステップ(c)における前記仕様が許す前記最大変動が、約±15%である、請求項30に記載の方法。
- ステップ(c)における前記仕様が許す前記最大変動が、約±10、11、12、13、または14%未満である、請求項30に記載の方法。
- 前記抗体が、非機能性抗体である、請求項26〜36のいずれか1項に記載の方法。
- 前記DARが、DAR仕様の下限またはDAR仕様の上限である、請求項6〜15及び30〜37のいずれか1項に記載の方法。
- 前記DAR仕様の下限が、2.3、2.4、または2.5である、請求項38に記載の方法。
- 前記DAR仕様の上限が、2.9、3.0、または3.1である、請求項38に記載の方法。
- 前記組成物が、約10〜40%まで効力が変動する、請求項1〜40のいずれか1項に記載の方法。
- 前記組成物が、約10〜20%まで効力が変動する、請求項1〜40のいずれか1項に記載の方法。
- 前記組成物が、約20%まで効力が変動する、請求項1〜40のいずれか1項に記載の方法。
- 組成物効力の変動性が、前記抗体薬物複合体組成物を抗体濃度のみに基づいて製剤化する場合と比べて低下する、請求項1〜43のいずれか1項に記載の方法。
- 前記抗体濃度及び薬物濃度が、分光光度測定によって決定される、請求項1〜44のいずれか1項に記載の方法。
- 薬物対抗体比が、サイズ排除クロマトグラフィー(SEC)またはSEC−質量分析法(SEC−MS)によって決定される、請求項1〜44のいずれか1項に記載の方法。
- 前記抗体薬物複合体組成物が、注入用に製剤化される、請求項1〜44のいずれか1項に記載の方法。
- 前記抗体薬物複合体が、薬学的に許容可能な非経口ビヒクルと共に製剤化される、請求項1〜44のいずれか1項に記載の方法。
- 前記抗体薬物複合体が、単位投与量注入可能な形態で製剤化される、請求項1〜44のいずれか1項に記載の方法。
- 前記メイタンシノイドが、DM1、DM3、またはDM4である、請求項18〜49のいずれか1項に記載の方法。
- 前記抗体が、非機能性抗体である、請求項38〜50のいずれか1項に記載の方法。
- 前記非機能性抗体が、huMov19、huMy9−6、またはhuB4である、請求項51に記載の方法。
- 前記非機能性抗体が、huDS6である、請求項51に記載の方法。
- 前記抗体が、機能性抗体である、請求項26〜50のいずれか1項に記載の方法。
- 前記機能性抗体が、huEGFR−7RまたはhuCD37−3である、請求項54に記載の方法。
- 前記抗体薬物複合体が、開裂可能なリンカーまたは開裂不可能なリンカーを含む、請求項1〜55のいずれか1項に記載の方法。
- 前記開裂可能なリンカーが、N−スクシンイミジル3−(2−ピリジルジチオ)プロピオネート(SPDP)、N−スクシンイミジル4−(2−ピリジルジチオ)ブタノエート(SPDB)、N−スクシンイミジル4−(2−ピリジルジチオ)2−スルホブタノエート(スルホ−SPDB)、またはジスルフィドN−スクシンイミジル4−(2−ピリジルジチオ)ペンタノエート(SPP)である、請求項56に記載の方法。
- 前記開裂不可能なリンカーが、2−イミノチオラン、無水アセチルコハク酸、またはスクシンイミジル4−[N−マレイミドメチル]シクロヘキサン−1−カルボキシレート(SMCC)である、請求項57に記載の方法。
- 前記抗体薬物複合体が、huMovl9−スルホ−SPDB−DM4、huMovl9−スルホ−SPDB−Dl、huMovl9−D2、huMov19−スルホ−SPDB−D10、huMovl9−スルホ−SPDB−DGN462、huMy9−6−スルホ−SPDB−Dl、huMy9−6−D2、huMy9−6−スルホ−SPDB−D10、huMy9−6−スルホ−SPDB−DGN462、huAnti−CD123−スルホ−SPDB−Dl、huAnti−CD123−D2、huAnti−CD123−スルホ−SPDB−D10、huAnti−CD123−スルホ−SPDB−DGN462、huB4−SPDB−DM4、huDS6−SPDB−DM4、huCD37−3−SMCC−DMl、huCD37−50−SMCC−DM1、またはhuEGFR−7R−SMCC−DM1である、請求項1、2、6、16、26、29、または30のいずれか1項に記載の方法。
- 意図する狭い範囲内での対象への投与方法であって、
請求項1〜59のいずれか1項に記載の方法に従って製剤化された抗体薬物複合体組成物を前記対象に投与すること
を含む、前記方法。 - 請求項1〜18、22、24、26〜29、31〜52、56、及び57のいずれか1項に記載の方法に従って製剤化されたhuMovl9−スルホ−SPDB−DM4抗体薬物複合体を含む医薬組成物であって、
微量メイタンシノイド濃度は、ラベルで提供される、前記医薬組成物。 - 請求項2〜17、19、20、22、23、30〜49、51、52、56、及び57のいずれか1項に記載の方法に従って製剤化されたhuMy9−6−スルホ−SPDB−DGN462抗体薬物複合体を含む医薬組成物であって、
微量DGN462濃度は、ラベルで提供される、前記医薬組成物。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2021510694A (ja) * | 2018-01-12 | 2021-04-30 | イミュノジェン, インコーポレイテッド | 抗体薬物のコンジュゲーション、精製、及び製剤のための方法 |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HUE036172T2 (hu) | 2011-04-01 | 2018-06-28 | Immunogen Inc | Eljárások a hatékonyság növelésére a FOLR1 rákkezelésénél |
KR102585409B1 (ko) | 2013-08-30 | 2023-10-05 | 이뮤노젠 아이엔씨 | 엽산 수용체 1의 검출을 위한 항체 및 분석 |
KR102626976B1 (ko) | 2014-09-02 | 2024-01-18 | 이뮤노젠 아이엔씨 | 항체 약물 컨쥬게이트 조성물의 제형화 방법 |
LT3313845T (lt) | 2015-06-29 | 2020-12-10 | Immunogen, Inc. | Cisteino inžinerijos antikūnų konjugatai |
EP3463477A4 (en) | 2016-06-07 | 2020-03-04 | NanoPharmaceuticals LLC | NON-CLeavable POLYMER CONJUGATED WITH THYROID ANTAGONISTS OF avß3 INTEGRIN |
WO2018085359A1 (en) * | 2016-11-02 | 2018-05-11 | Immunogen, Inc. | Combination treatment with antibody-drug conjugates and parp inhibitors |
TWI755450B (zh) | 2016-11-23 | 2022-02-21 | 美商伊繆諾金公司 | 苯二氮平衍生物之選擇性磺化 |
US10328043B1 (en) | 2018-04-11 | 2019-06-25 | Nanopharmaceuticals, Llc. | Composition and method for dual targeting in treatment of neuroendocrine tumors |
US11351137B2 (en) | 2018-04-11 | 2022-06-07 | Nanopharmaceuticals Llc | Composition and method for dual targeting in treatment of neuroendocrine tumors |
JP7232925B2 (ja) | 2019-02-15 | 2023-03-03 | ウーシー バイオロジクス アイルランド リミテッド | 改善された均一性を有する抗体薬物コンジュゲートの調製するプロセス |
SG11202111109UA (en) | 2019-04-29 | 2021-11-29 | Immunogen Inc | Biparatopic fr-alpha antibodies and immunoconjugates |
US10961204B1 (en) | 2020-04-29 | 2021-03-30 | Nanopharmaceuticals Llc | Composition of scalable thyrointegrin antagonists with improved blood brain barrier penetration and retention into brain tumors |
US11723888B2 (en) | 2021-12-09 | 2023-08-15 | Nanopharmaceuticals Llc | Polymer conjugated thyrointegrin antagonists |
Family Cites Families (85)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4307016A (en) | 1978-03-24 | 1981-12-22 | Takeda Chemical Industries, Ltd. | Demethyl maytansinoids |
US4256746A (en) | 1978-11-14 | 1981-03-17 | Takeda Chemical Industries | Dechloromaytansinoids, their pharmaceutical compositions and method of use |
JPS55102583A (en) | 1979-01-31 | 1980-08-05 | Takeda Chem Ind Ltd | 20-acyloxy-20-demethylmaytansinoid compound |
JPS55162791A (en) | 1979-06-05 | 1980-12-18 | Takeda Chem Ind Ltd | Antibiotic c-15003pnd and its preparation |
JPS5645483A (en) | 1979-09-19 | 1981-04-25 | Takeda Chem Ind Ltd | C-15003phm and its preparation |
JPS5645485A (en) | 1979-09-21 | 1981-04-25 | Takeda Chem Ind Ltd | Production of c-15003pnd |
EP0028683A1 (en) | 1979-09-21 | 1981-05-20 | Takeda Chemical Industries, Ltd. | Antibiotic C-15003 PHO and production thereof |
US4444887A (en) | 1979-12-10 | 1984-04-24 | Sloan-Kettering Institute | Process for making human antibody producing B-lymphocytes |
WO1982001188A1 (en) | 1980-10-08 | 1982-04-15 | Takeda Chemical Industries Ltd | 4,5-deoxymaytansinoide compounds and process for preparing same |
US4450254A (en) | 1980-11-03 | 1984-05-22 | Standard Oil Company | Impact improvement of high nitrile resins |
US4315929A (en) | 1981-01-27 | 1982-02-16 | The United States Of America As Represented By The Secretary Of Agriculture | Method of controlling the European corn borer with trewiasine |
US4313946A (en) | 1981-01-27 | 1982-02-02 | The United States Of America As Represented By The Secretary Of Agriculture | Chemotherapeutically active maytansinoids from Trewia nudiflora |
US4563304A (en) | 1981-02-27 | 1986-01-07 | Pharmacia Fine Chemicals Ab | Pyridine compounds modifying proteins, polypeptides or polysaccharides |
JPS57192389A (en) | 1981-05-20 | 1982-11-26 | Takeda Chem Ind Ltd | Novel maytansinoid |
US4716111A (en) | 1982-08-11 | 1987-12-29 | Trustees Of Boston University | Process for producing human antibodies |
GB8607679D0 (en) | 1986-03-27 | 1986-04-30 | Winter G P | Recombinant dna product |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5208020A (en) | 1989-10-25 | 1993-05-04 | Immunogen Inc. | Cytotoxic agents comprising maytansinoids and their therapeutic use |
GB8928874D0 (en) | 1989-12-21 | 1990-02-28 | Celltech Ltd | Humanised antibodies |
DE69120146T2 (de) | 1990-01-12 | 1996-12-12 | Cell Genesys Inc | Erzeugung xenogener antikörper |
US5545806A (en) | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
US5814318A (en) | 1990-08-29 | 1998-09-29 | Genpharm International Inc. | Transgenic non-human animals for producing heterologous antibodies |
EP0519596B1 (en) | 1991-05-17 | 2005-02-23 | Merck & Co. Inc. | A method for reducing the immunogenicity of antibody variable domains |
ES2136092T3 (es) | 1991-09-23 | 1999-11-16 | Medical Res Council | Procedimientos para la produccion de anticuerpos humanizados. |
ES2149768T3 (es) | 1992-03-25 | 2000-11-16 | Immunogen Inc | Conjugados de agentes enlazantes de celulas derivados de cc-1065. |
US5639641A (en) | 1992-09-09 | 1997-06-17 | Immunogen Inc. | Resurfacing of rodent antibodies |
ES2304786T3 (es) | 1995-04-27 | 2008-10-16 | Amgen Fremont Inc. | Anticuerpos anti-il-8 humanos, derivados a partir de xenoratones inmunizados. |
EP0823941A4 (en) | 1995-04-28 | 2001-09-19 | Abgenix Inc | HUMAN ANTIBODIES DERIVED FROM IMMUNIZED XENO MOUSES |
US5916771A (en) | 1996-10-11 | 1999-06-29 | Abgenix, Inc. | Production of a multimeric protein by cell fusion method |
DK1500329T3 (da) | 1996-12-03 | 2012-07-09 | Amgen Fremont Inc | Humane antistoffer, der specifikt binder TNF-alfa |
WO1998046645A2 (en) | 1997-04-14 | 1998-10-22 | Micromet Gesellschaft Für Biomedizinische Forschung Mbh | Method for the production of antihuman antigen receptors and uses thereof |
US6235883B1 (en) | 1997-05-05 | 2001-05-22 | Abgenix, Inc. | Human monoclonal antibodies to epidermal growth factor receptor |
US6995145B1 (en) * | 1999-06-04 | 2006-02-07 | Au Jessie L-S | Methods and compositions for modulating drug activity through telomere damage |
US6333410B1 (en) | 2000-08-18 | 2001-12-25 | Immunogen, Inc. | Process for the preparation and purification of thiol-containing maytansinoids |
US6441163B1 (en) | 2001-05-31 | 2002-08-27 | Immunogen, Inc. | Methods for preparation of cytotoxic conjugates of maytansinoids and cell binding agents |
US6716821B2 (en) | 2001-12-21 | 2004-04-06 | Immunogen Inc. | Cytotoxic agents bearing a reactive polyethylene glycol moiety, cytotoxic conjugates comprising polyethylene glycol linking groups, and methods of making and using the same |
GB0202319D0 (en) | 2002-02-01 | 2002-03-20 | Calex Electronics Ltd | Apparatus |
IL163668A0 (en) * | 2002-02-22 | 2005-12-18 | New River Pharmaceuticals Inc | Use of peptide-drug conjugation to reduce inter-subject variability ofdrug serum levels |
US20090068178A1 (en) * | 2002-05-08 | 2009-03-12 | Genentech, Inc. | Compositions and Methods for the Treatment of Tumor of Hematopoietic Origin |
MXPA05004712A (es) | 2002-11-07 | 2005-11-23 | Immunogen Inc | Anticuerpos anti-cd33 y metodo para tratamiento de leucemia mieloide aguda utilizando los mismos. |
US8088387B2 (en) | 2003-10-10 | 2012-01-03 | Immunogen Inc. | Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates |
KR101424624B1 (ko) * | 2003-05-14 | 2014-07-31 | 이뮤노젠 아이엔씨 | 약물 콘쥬게이트 조성물 |
CA2525130C (en) | 2003-05-20 | 2014-04-15 | Immunogen, Inc. | Improved cytotoxic agents comprising new maytansinoids |
US7276497B2 (en) | 2003-05-20 | 2007-10-02 | Immunogen Inc. | Cytotoxic agents comprising new maytansinoids |
US7834155B2 (en) | 2003-07-21 | 2010-11-16 | Immunogen Inc. | CA6 antigen-specific cytotoxic conjugate and methods of using the same |
AU2004258955C1 (en) | 2003-07-21 | 2012-07-26 | Immunogen, Inc. | A CA6 antigen-specific cytotoxic conjugate and methods of using the same |
NZ551180A (en) | 2004-06-01 | 2009-10-30 | Genentech Inc | Antibody drug conjugates and methods |
HUE025449T2 (en) * | 2004-12-09 | 2016-04-28 | Janssen Biotech Inc | Immunoconjugates against Integrin, a method for their preparation and use |
US20110166319A1 (en) * | 2005-02-11 | 2011-07-07 | Immunogen, Inc. | Process for preparing purified drug conjugates |
US8156876B2 (en) | 2005-06-23 | 2012-04-17 | Georgia Tech Research Corporation | Systems and methods for integrated plasma processing of waste |
EP1917034A4 (en) | 2005-08-22 | 2009-04-29 | Immunogen Inc | CA6 ANTIGEN-SPECIFIC CYTOTOXIC CONJUGATE AND METHOD OF ITS APPLICATION |
AU2006283726C1 (en) * | 2005-08-24 | 2015-05-07 | Immunogen, Inc. | Process for preparing maytansinoid antibody conjugates |
SI1813614T1 (sl) * | 2006-01-25 | 2012-01-31 | Sanofi 174 | Citotoksična sredstva, ki obsegajo nove tomajmicinske derivate |
AU2007212147A1 (en) * | 2006-02-03 | 2007-08-16 | Medimmune, Llc | Protein formulations |
AR060978A1 (es) * | 2006-05-30 | 2008-07-23 | Genentech Inc | Anticuerpos e inmunoconjugados y sus usos |
EP2626372B1 (en) | 2007-03-29 | 2018-03-21 | Genmab A/S | Bispecific antibodies and methods for production thereof |
US20090163698A1 (en) * | 2007-05-11 | 2009-06-25 | John Joseph Grigsby | Method for Preparing Antibody Conjugates |
US7576505B2 (en) * | 2007-06-21 | 2009-08-18 | Jack Chen | Device for finding a home position for a moveable member |
US20090208979A1 (en) * | 2008-02-14 | 2009-08-20 | Technion Research And Development Foundation Ltd. | Method for identifying antipsychotic drug candidates |
SG189817A1 (en) | 2008-04-30 | 2013-05-31 | Immunogen Inc | Potent conjugates and hydrophilic linkers |
US8236319B2 (en) | 2008-04-30 | 2012-08-07 | Immunogen, Inc. | Cross-linkers and their uses |
NZ596807A (en) * | 2009-05-06 | 2013-09-27 | Biotest Ag | Uses of immunoconjugates targeting cd138 |
AR078470A1 (es) * | 2009-10-02 | 2011-11-09 | Sanofi Aventis | Anticuerpos que se unen especificamente al receptor epha2 |
TW202348631A (zh) * | 2010-02-24 | 2023-12-16 | 美商免疫遺傳股份有限公司 | 葉酸受體1抗體類和免疫共軛物類及彼等之用途 |
CN102971012B (zh) | 2010-03-12 | 2016-05-04 | 伊缪诺金公司 | Cd37结合分子及其免疫缀合物 |
US9150663B2 (en) | 2010-04-20 | 2015-10-06 | Genmab A/S | Heterodimeric antibody Fc-containing proteins and methods for production thereof |
CN103298489A (zh) | 2010-10-29 | 2013-09-11 | 伊缪诺金公司 | 新型egfr结合分子及其免疫偶联物 |
MX346635B (es) * | 2011-02-15 | 2017-03-27 | Immunogen Inc | Derivados citotoxicos de la benzodiazepina. |
HUE036172T2 (hu) | 2011-04-01 | 2018-06-28 | Immunogen Inc | Eljárások a hatékonyság növelésére a FOLR1 rákkezelésénél |
CN103596590A (zh) * | 2011-04-01 | 2014-02-19 | 伊缪诺金公司 | Cd37结合分子及其免疫缀合物 |
US20120282282A1 (en) | 2011-04-04 | 2012-11-08 | Immunogen, Inc. | Methods for Decreasing Ocular Toxicity of Antibody Drug Conjugates |
WO2012177837A2 (en) | 2011-06-21 | 2012-12-27 | Immunogen, Inc. | Novel maytansinoid derivatives with peptide linker and conjugates thereof |
EP2550975A1 (en) * | 2011-07-29 | 2013-01-30 | Sanofi | Combination therapy for the treatment of CD19+ B-cell malignancies symptoms comprising an anti-CD19 maytansinoid immunoconjugate and rituximab |
MX353958B (es) | 2011-09-22 | 2018-02-07 | Amgen Inc | Proteinas de union al antigeno cd27l. |
KR20140105765A (ko) | 2011-11-21 | 2014-09-02 | 이뮤노젠 아이엔씨 | EGfr 항체 세포독성제 접합체에 의한 EGfr 치료에 내성을 나타내는 종양의 치료 방법 |
NZ707091A (en) * | 2012-10-04 | 2018-12-21 | Immunogen Inc | Use of a pvdf membrane to purify cell-binding agent cytotoxic agent conjugates |
WO2014079886A1 (en) * | 2012-11-20 | 2014-05-30 | Sanofi | Anti-ceacam5 antibodies and uses thereof |
MX2015010682A (es) * | 2013-02-22 | 2016-05-31 | Stemcentrx Inc | Nuevos conjugados de anticuerpos y usos de los mismos. |
CN105592861A (zh) * | 2013-08-02 | 2016-05-18 | 赛诺菲 | 抗Muc1类美登素免疫偶联抗体用于治疗实体瘤的用途 |
KR102626976B1 (ko) | 2014-09-02 | 2024-01-18 | 이뮤노젠 아이엔씨 | 항체 약물 컨쥬게이트 조성물의 제형화 방법 |
US10988531B2 (en) * | 2014-09-03 | 2021-04-27 | Immunogen, Inc. | Conjugates comprising cell-binding agents and cytotoxic agents |
ES2815353T3 (es) * | 2014-09-03 | 2021-03-29 | Immunogen Inc | Derivados de benzodiazepina citotóxicos |
JP2017527562A (ja) * | 2014-09-03 | 2017-09-21 | イミュノジェン・インコーポレーテッド | 細胞毒性ベンゾジアゼピン誘導体 |
JP2016052860A (ja) | 2014-09-04 | 2016-04-14 | 株式会社東海理化電機製作所 | タイヤ位置登録システム |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2021510694A (ja) * | 2018-01-12 | 2021-04-30 | イミュノジェン, インコーポレイテッド | 抗体薬物のコンジュゲーション、精製、及び製剤のための方法 |
JP7474195B2 (ja) | 2018-01-12 | 2024-04-24 | イミュノジェン, インコーポレイテッド | 抗体薬物のコンジュゲーション、精製、及び製剤のための方法 |
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