JP2021518397A - 固形腫瘍を治療するためのチューブリン破壊剤を含む抗体薬物コンジュゲートの使用 - Google Patents
固形腫瘍を治療するためのチューブリン破壊剤を含む抗体薬物コンジュゲートの使用 Download PDFInfo
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Abstract
Description
本出願は、2018年3月23日出願の米国特許仮出願第62/647,346号および2018年4月16日出願の米国特許仮出願第62/658,276号(これらの全体が参照により本明細書中に組み入れられる)の優先権の利益を主張する。
本開示の分野
本開示は、一般的に、薬物-リンカー単位-抗体コンジュゲート療法(このとき、薬物はチューブリン破壊剤である)を投与するステップを含む、固形腫瘍の治療方法に関する。
定義
特に記載しない限り、本明細書中で用いられるすべての技術用語および科学用語は、本発明が属する技術分野の当業者により一般的に理解されるのと同じ意味を有する。以下の参考文献は、本発明で用いられる用語のうちの多数の一般的定義を当業者に提供する:Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY (2d 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);およびHale & Marham, THE HARPER COLLINS DICTIONARY OF BIOLOGY (1991)。
本開示の抗体は、好ましくはモノクローナルであり、多重特異的、ヒト、ヒト化またはキメラ型抗体、単鎖抗体、Fab断片、F(ab')断片、Fab発現ライブラリーにより生成される断片、および上記のうちのいずれかの抗原結合性断片であり得る。用語「抗体」とは、本明細書中で用いる場合、免疫グロブリン分子および免疫グロブリン分子の免疫学的活性部分、すなわち、CD30に免疫特異的に結合する抗原結合性部位を含む分子を意味する。本開示の免疫グロブリン分子は、いずれかのタイプ(例えば、IgG、IgE、IgM、IgD、IgAおよびIgY)、クラス(例えば、IgG1、IgG2、IgG3、IgG4、IgA1およびIgA2)またはサブクラスの免疫グロブリン分子のものであり得る。
固形腫瘍を治療するための、チューブリン破壊剤を含む薬物-リンカー単位-抗体コンジュゲート、または抗体薬物コンジュゲートの使用が、本明細書中で考慮される。
固形腫瘍を治療するために、チューブリン破壊剤を含む抗体-薬物コンジュゲートを投与するステップを含む、固形腫瘍を治療するための方法が、本明細書中に提供される。種々の実施形態では、本開示の方法が、微小管(mictrotubule)機能の破壊後にERストレス経路を誘導することにより、固形腫瘍を治療することが企図される。種々の実施形態では、チューブリン破壊剤を含む抗体薬物コンジュゲート剤は、固形腫瘍中でアポトーシスを誘導する。
種々の実施形態では、療法が、定期的に、例えば、週2回、週1回、2週間毎、3週間毎、月1回、2ヵ月に1回、またはより長い間隔で、施される。関連する実施形態では、例示的治療の中で、抗体薬物コンジュゲートが、0.1〜15mg/kgの用量範囲で投与される。
種々の送達システムを、薬物-リンカー単位-抗体コンジュゲート/抗体-薬物コンジュゲートを投与するために用いることができる。本開示の特定の実施形態では、抗体-薬物コンジュゲート化合物の投与は、静脈内点滴または皮下注入によるものである。一部の実施形態では、投与は、30分間、1時間または2時間の静脈内点滴による。
固形腫瘍細胞株に対するチューブリン破壊剤の効果を評価した。癌細胞を、MMAEを用いて処理し、その後の免疫原性細胞死(ICD)特性;ERストレス、ATP分泌および細胞外HMGB1レベルについて評価した。
腫瘍細胞が免疫細胞活性化を誘導する能力に対するチューブリン破壊剤の効果を決定するために、チューブリン破壊剤を用いて処理され、ERストレスおよび潜在的な細胞死を被る過程にある細胞を、抗原提示細胞に投入し、APC誘導に対する効果を測定した。
チューブリン破壊剤を用いる処理後の抗原提示の追加的分析
細胞培養グレードのプラスチックへとPBMCを接着させることにより、2名の健康なドナー由来のPBMCから、マクロファージを富化した。非接着細胞を24時間後に除去し、マクロファージに関して富化させた細胞集団を残した。
Claims (33)
- 式:薬物-リンカー単位-抗体(D-LU-Ab)を有し、式中、Dはチューブリン破壊剤である抗体薬物コンジュゲート剤を、固形腫瘍を治療するのに有効な量で、それを必要とする被験体に投与するステップを含む、固形腫瘍を治療するための方法。
- 式:薬物-リンカー単位-抗体(D-LU-Ab)を有し、式中、Dはチューブリン破壊剤である抗体薬物コンジュゲート剤を、固形腫瘍中でのアポトーシスを誘導するのに有効な量で投与するステップを含む、固形腫瘍中でのATP放出を調節するための方法。
- 式:薬物-リンカー単位-抗体(D-LU-Ab)を有し、式中、Dはチューブリン破壊剤である抗体薬物コンジュゲート剤を、固形腫瘍への免疫細胞浸潤を誘導するのに有効な量で、それを必要とする被験体に投与するステップを含む、固形腫瘍への免疫細胞移動を誘導する方法。
- 式:薬物-リンカー単位-抗体(D-LU-Ab)を有し、式中、Dはチューブリン破壊剤である抗体薬物コンジュゲート剤を、固形腫瘍中での免疫原性細胞死を誘導するのに有効な量で、それを必要とする被験体に投与するステップを含む、固形腫瘍中での免疫原性細胞死(ICD)を誘導するための方法。
- 前記抗体が、CD30、CD19、CD70、CD71、CD20、CD52、CD133、EGFR、HER2、VEGF、VEGFR2、PD-1、PDL1、RANKL、CTLA-4、IL-6、SLAMF7、CD3、TNF-α、PDGFR-α、CD38、GD2、cCLB8、p97、ネクチン-4、またはEpCAMに対して特異的である、請求項1〜4のいずれか1項に記載の方法。
- 前記チューブリン破壊剤が、ERストレスタンパク質経路を増大させ、ATP分泌を増加させ、かつ高移動度群ボックス1(HMGB1)タンパク質を増加させる、請求項1〜5のいずれか1項に記載の方法。
- 前記チューブリン破壊剤が、アウリスタチン、チューブリシン、コルヒチン、ビンカアルカロイド、タキサン、クリプトフィシン、メイタンシノイド、ヘミアステルリン、および他のチューブリン破壊剤からなる群より選択される、請求項1〜6のいずれか1項に記載の方法。
- 前記チューブリン破壊剤が、モノメチルアウリスタチンE(MMAE)、モノメチルアウリスタチンF(MMAF)、およびドラスタチン-10(dolostatin-10)からなる群より選択されるアウリスタチンである、請求項1〜7のいずれか1項に記載の方法。
- 前記チューブリン破壊剤が、チューブリシンD、チューブフェニルアラニン(tubuphenylalanine)およびチューブチロシン(tubutyrosine)からなる群より選択されるチューブリシンである、請求項1〜7のいずれか1項に記載の方法。
- 前記チューブリン破壊剤が、コルヒチンおよびCA-4からなる群より選択されるコルヒチンである、請求項1〜7のいずれか1項に記載の方法。
- 前記チューブリン破壊剤が、ビンブラスチン(VBL)、ビノレルビン(VRL)、ビンクリスチン(VCR)およびビンデシン(VDS)からなる群より選択されるビンカアルカロイドである、請求項1〜7のいずれか1項に記載の方法。
- 前記チューブリン破壊剤が、パクリタキセルおよびドセタキセルからなる群より選択されるタキサンである、請求項1〜7のいずれか1項に記載の方法。
- 前記チューブリン破壊剤が、クリプトフィシン-1およびクリプトフィシン-52からなる群より選択されるクリプトフィシンである、請求項1〜7のいずれか1項に記載の方法。
- 前記チューブリン破壊剤が、メイタンシン、メイタンシノール、メイタンシン類似体、DM1、DM3およびDM4、ならびにアンサマイトシン-2(ansamatocin-2)からなる群より選択されるメイタンシノイドである、請求項1〜7のいずれか1項に記載の方法。
- 前記チューブリン破壊剤が、ヘミアステルリンおよびHTI-286からなる群より選択されるヘミアステルリンである、請求項1〜7のいずれか1項に記載の方法。
- 前記チューブリン破壊剤が、タッカロノリドA、タッカロノリドB、タッカロノリドAF、タッカロノリドAJ、タッカロノリドAI-エポキシド、ジスコデルモリド、エポチロンA、エポチロンB、およびラウリマライドからなる群より選択される、請求項1〜7のいずれか1項に記載の方法。
- 前記固形腫瘍が、肺癌、乳癌、卵巣癌、子宮頸癌、消化管癌、頭頸部癌、黒色腫、肉腫、食道癌、膵臓癌、転移性膵臓癌、膵臓の転移性腺癌、膀胱癌、胃癌、線維性癌、神経膠腫、悪性神経膠腫、びまん性内在性橋膠腫、再発小児脳新生物、腎細胞癌、明細胞性転移性腎細胞癌、腎癌、前立腺癌、転移性去勢療法抵抗性前立腺癌、ステージIV前立腺癌、転移性黒色腫、黒色腫、悪性黒色腫、皮膚の再発黒色腫、黒色腫脳転移、ステージIIIA皮膚黒色腫;ステージIIIB皮膚黒色腫、ステージIIIC皮膚黒色腫;ステージIV皮膚黒色腫、頭頸部の悪性黒色腫、肺癌、非小細胞肺癌(NSCLC)、扁平上皮非小細胞肺癌、乳癌、再発転移性乳癌、肝細胞癌、リヒター症候群;ワルデンストレームマクログロブリン血症、成人膠芽腫;成人神経膠肉腫、再発膠芽腫、再発小児横紋筋肉腫、再発ユーイング肉腫/末梢性原始神経外胚葉腫瘍、再発神経芽腫;再発骨肉腫、結腸直腸癌、MSI陽性結腸直腸癌;MSI陰性結腸直腸癌、鼻咽頭非角化癌;再発鼻咽頭未分化癌、子宮頸部腺癌;子宮頸部腺扁平上皮癌;子宮頸部扁平上皮癌;再発子宮頸癌;ステージIVA子宮頸癌;ステージIVB子宮頸癌、肛門管扁平上皮癌;転移性肛門管癌;再発肛門管癌、再発頭頸部癌;頭頸部扁平上皮癌(HNSCC)、卵巣癌、結腸癌、胃癌、進行型GI癌、胃腺癌;胃食道接合部腺癌、骨新生物、軟組織肉腫;骨肉腫、胸腺癌、尿路上皮癌、再発メルケル細胞癌;ステージIIIメルケル細胞癌;ステージIVメルケル細胞癌、骨髄異形成症候群およびセザリー症候群からなる群より選択される、請求項1〜16のいずれか1項に記載の方法。
- 前記抗体薬物コンジュゲートが、プロテアーゼ切断可能リンカー、酸切断可能リンカーまたはジスルフィドリンカーを含む、請求項1〜17のいずれか1項に記載の方法。
- 前記プロテアーゼ切断可能リンカーが、チオール反応性スペーサーおよびジペプチドを含む、請求項18に記載の方法。
- 前記プロテアーゼ切断可能リンカーが、チオール反応性マレイミドカプロイルスペーサー、バリン-シトルリンジペプチド、およびp-アミノ-ベンジルオキシカルボニルスペーサーからなる、請求項18または19に記載の方法。
- 前記酸切断可能リンカーが、ヒドラジンリンカーまたは第4級アンモニウムリンカーである、請求項18に記載の方法。
- 化学療法レジメンを施すステップをさらに含む、請求項1〜21のいずれか1項に記載の方法。
- 前記化学療法レジメンが、本質的に、併用療法として、ドキソルビシン、ビンブラスチン、およびダカルバジン(AVD)からなる、請求項22に記載の方法。
- 前記化学療法レジメンが、本質的に、併用療法として、シクロホスファミド、ビンクリスチンおよびプレドニゾン(CHP)からなる、請求項22に記載の方法。
- 前記抗体薬物コンジュゲートの抗体がモノクローナル抗体である、請求項1〜24のいずれか1項に記載の方法。
- 前記抗体が抗CD30抗体であり、抗CD30抗体薬物コンジュゲートが、以下:
(i) 配列番号4で示される重鎖CDR1、配列番号6で示される重鎖CDR2、配列番号8で示される重鎖CDR3;および
(ii) 配列番号12で示される軽鎖CDR1、配列番号14で示される軽鎖CDR2、および配列番号16で示される軽鎖CDR13
を含む、請求項1〜25のいずれか1項に記載の方法。 - 前記抗体が抗CD30抗体であり、抗CD30抗体薬物コンジュゲートが、以下:
(i) 配列番号2で示される重鎖可変領域に対して少なくとも85%同一なアミノ酸配列、および
(ii) 配列番号10で示される軽鎖可変領域に対して少なくとも85%同一なアミノ酸配列
を含む、請求項1〜25のいずれか1項に記載の方法。 - 前記抗体が抗CD30抗体であり、前記抗体薬物コンジュゲートの該抗CD30抗体がキメラ型AC10抗体である、請求項1〜27のいずれか1項に記載の方法。
- 前記抗体薬物コンジュゲートが、モノメチルアウリスタチンEおよびプロテアーゼ切断可能リンカーを含む、請求項1〜28のいずれか1項に記載の方法。
- 前記プロテアーゼ切断可能リンカーが、チオール反応性スペーサーおよびジペプチドを含む、請求項29に記載の方法。
- 前記プロテアーゼ切断可能リンカーが、チオール反応性マレイミドカプロイルスペーサー、バリン-シトルリンジペプチド、およびp-アミノ-ベンジルオキシカルボニルスペーサーからなる、請求項29または30に記載の方法。
- 前記抗CD30抗体薬物コンジュゲートがブレンツキシマブ・ベドチンである、請求項1〜31のいずれか1項に記載の方法。
- 前記抗体薬物コンジュゲートが、腫瘍の部位への免疫細胞移動を誘導する、請求項1〜32のいずれか1項に記載の方法。
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- 2019-03-22 CN CN201980033040.7A patent/CN112189020A/zh active Pending
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- 2019-03-22 AU AU2019240403A patent/AU2019240403A1/en active Pending
- 2019-03-22 BR BR112020018948-0A patent/BR112020018948A2/pt not_active Application Discontinuation
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- 2019-03-22 JP JP2020550674A patent/JP2021518397A/ja active Pending
- 2019-03-22 WO PCT/US2019/023516 patent/WO2019183438A1/en active Application Filing
- 2019-03-22 EP EP19715720.9A patent/EP3768714A1/en active Pending
- 2019-03-22 US US16/362,125 patent/US20190290775A1/en not_active Abandoned
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EP3768714A1 (en) | 2021-01-27 |
MX2020009842A (es) | 2020-10-15 |
CA3093731A1 (en) | 2019-09-26 |
IL277338A (en) | 2020-10-29 |
AU2019240403A1 (en) | 2020-10-08 |
US20230110128A1 (en) | 2023-04-13 |
WO2019183438A1 (en) | 2019-09-26 |
KR20200135841A (ko) | 2020-12-03 |
MA52135A (fr) | 2021-01-27 |
SG11202009264WA (en) | 2020-10-29 |
CN112189020A (zh) | 2021-01-05 |
BR112020018948A2 (pt) | 2021-01-05 |
US20190290775A1 (en) | 2019-09-26 |
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