JPWO2021155129A5 - - Google Patents
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- JPWO2021155129A5 JPWO2021155129A5 JP2022546426A JP2022546426A JPWO2021155129A5 JP WO2021155129 A5 JPWO2021155129 A5 JP WO2021155129A5 JP 2022546426 A JP2022546426 A JP 2022546426A JP 2022546426 A JP2022546426 A JP 2022546426A JP WO2021155129 A5 JPWO2021155129 A5 JP WO2021155129A5
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- 239000000611 antibody drug conjugate Substances 0.000 claims description 66
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- 150000003839 salts Chemical class 0.000 claims description 31
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- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 claims description 21
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 claims description 21
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 claims description 14
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 claims description 14
- 108010044540 auristatin Proteins 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
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- 238000011476 stem cell transplantation Methods 0.000 claims description 5
- MFRNYXJJRJQHNW-DEMKXPNLSA-N (2s)-2-[[(2r,3r)-3-methoxy-3-[(2s)-1-[(3r,4s,5s)-3-methoxy-5-methyl-4-[methyl-[(2s)-3-methyl-2-[[(2s)-3-methyl-2-(methylamino)butanoyl]amino]butanoyl]amino]heptanoyl]pyrrolidin-2-yl]-2-methylpropanoyl]amino]-3-phenylpropanoic acid Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFRNYXJJRJQHNW-DEMKXPNLSA-N 0.000 claims description 4
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- IEDXPSOJFSVCKU-HOKPPMCLSA-N [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrolidin-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl N-[(2S)-1-[[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-N-methylcarbamate Chemical compound CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN2C(=O)CCC2=O)C(C)C)cc1)C(C)C IEDXPSOJFSVCKU-HOKPPMCLSA-N 0.000 claims description 4
- 229960000106 biosimilars Drugs 0.000 claims description 4
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- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 claims description 2
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 2
- 108010062867 Lenograstim Proteins 0.000 claims description 2
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- 229960004177 filgrastim Drugs 0.000 claims description 2
- 210000001280 germinal center Anatomy 0.000 claims description 2
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- HQQSBEDKMRHYME-UHFFFAOYSA-N pefloxacin mesylate Chemical compound [H+].CS([O-])(=O)=O.C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(C)CC1 HQQSBEDKMRHYME-UHFFFAOYSA-N 0.000 claims description 2
- 108010044644 pegfilgrastim Proteins 0.000 claims description 2
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- 210000000130 stem cell Anatomy 0.000 claims 1
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- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 1
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Description
ORRはITT解析セットを用いて治療群ごとにまとめられる。ORRの中間解析には、無作為化から6ヶ月以上のフォローアップを完了した被験者、または解析時点で試験を中止した被験者がすべて含まれる。ORRは、層別因子によって層別化されたCochran Mantel-Haenszel検定に基づいて検定される；ORRの差は対応する95％信頼区間とともに提示される。各群のORRも、Clopper-Pearson 法による正確な95%信頼区間とともに提示される。CR率についても同様の要約が提示される。
本開示は以下の実施形態を包含する。
[１] 被験者の非ホジキンリンパ腫を治療する方法であって、その方法が、レナリドミドまたはその塩もしくは溶媒和物、およびCD30に結合する抗体薬物複合体を被験者に投与することを含み、この抗体薬物複合体が、モノメチルアウリスタチンまたはその機能的アナログもしくは機能的誘導体とコンジュゲートした抗CD30抗体もしくはその抗原結合フラグメントを含んでいる、前記方法。
[２] 非ホジキンリンパ腫がびまん性大細胞型B細胞リンパ腫（DLBCL）である、請求項1に記載の方法。
[３] DLBCLが再発DLBCLである、請求項2に記載の方法。
[４] DLBCLが難治性DLBCLである、請求項2または3に記載の方法。
[５] DLBCLが胚中心B細胞様（GCB）である、請求項2～4のいずれか1つに記載の方法。
[６] DLBCLが非GCBである、請求項2～4のいずれか1つに記載の方法。
[７] 被験者が以前に、非ホジキンリンパ腫の治療のために同種幹細胞移植を受けたことがある、請求項1～6のいずれか1つに記載の方法。
[８] 被験者が以前に、非ホジキンリンパ腫の治療のために自家幹細胞移植を受けたことがある、請求項1～7のいずれか1つに記載の方法。
[９] 被験者が、幹細胞移植後に再発した、請求項7または8に記載の方法。
[１０] 被験者が以前に、CAR-T療法を受けたことがある、請求項1～9のいずれか1つに記載の方法。
[１１] 被験者が、CAR-T療法後に再発した、請求項10に記載の方法。
[１２] 被験者が以前に、レナリドミド、またはその塩もしくは溶媒和物による治療を受けたことがない、請求項1～11のいずれか1つに記載の方法。
[１３] 被験者が以前に、CD30に結合する抗体薬物複合体による治療を受けたことがない、請求項1～12のいずれか1つに記載の方法。
[１４] 非ホジキンリンパ腫が進行期の非ホジキンリンパ腫である、請求項1～13のいずれか1つに記載の方法。
[１５] 進行期の非ホジキンリンパ腫が病期III期またはIV期の非ホジキンリンパ腫である、請求項14に記載の方法。
[１６] 進行期の非ホジキンリンパ腫が転移性非ホジキンリンパ腫である、請求項14または15に記載の方法。
[１７] 非ホジキンリンパ腫が再発非ホジキンリンパ腫である、請求項1～16のいずれか1つに記載の方法。
[１８] 被験者の非ホジキンリンパ腫細胞の少なくとも1%がCD30を発現する、請求項1～17のいずれか1つに記載の方法。
[１９] 抗体薬物複合体の抗CD30抗体が重鎖可変領域および軽鎖可変領域を含み、その重鎖可変領域が：
(i) 配列番号1に記載のアミノ酸配列を含むCDR-H1；
(ii) 配列番号2に記載のアミノ酸配列を含むCDR-H2；および
(iii) 配列番号3に記載のアミノ酸配列を含むCDR-H3
を含んでいる；ならびに
その軽鎖可変領域が：
(i) 配列番号4に記載のアミノ酸配列を含むCDR-L1；
(ii) 配列番号5に記載のアミノ酸配列を含むCDR-L2；および
(iii) 配列番号6に記載のアミノ酸配列を含むCDR-L3
を含んでいる、請求項1～18のいずれか1つに記載の方法。
[２０] 抗体薬物複合体の抗CD30抗体が、配列番号7に記載のアミノ酸配列と少なくとも85%同一なアミノ酸配列を含む重鎖可変領域、および配列番号8に記載のアミノ酸配列と少なくとも85%同一なアミノ酸配列を含む軽鎖可変領域を含む、請求項1～19のいずれか1つに記載の方法。
[２１] 抗体薬物複合体の抗CD30抗体が、配列番号7に記載のアミノ酸配列と少なくとも90%同一なアミノ酸配列を含む重鎖可変領域、および配列番号8に記載のアミノ酸配列と少なくとも90%同一なアミノ酸配列を含む軽鎖可変領域を含む、請求項1～20のいずれか1つに記載の方法。
[２２] 抗体薬物複合体の抗CD30抗体が、配列番号7に記載のアミノ酸配列と少なくとも95%同一なアミノ酸配列を含む重鎖可変領域、および配列番号8に記載のアミノ酸配列と少なくとも95%同一なアミノ酸配列を含む軽鎖可変領域を含む、請求項1～21のいずれか1つに記載の方法。
[２３] 抗体薬物複合体の抗CD30抗体が、配列番号7に記載のアミノ酸配列を含む重鎖可変領域、および配列番号8に記載のアミノ酸配列を含む軽鎖可変領域を含む、請求項1～18のいずれか1つに記載の方法。
[２４] 抗CD30抗体がAC10である、請求項1～18のいずれか1つに記載の方法。
[２５] 抗CD30抗体がcAD10である、請求項1～18のいずれか1つに記載の方法。
[２６] 抗体薬物複合体が、抗CD30抗体もしくはその抗原結合部分と、モノメチルアウリスタチンとの間に、リンカーをさらに含む、請求項1～25のいずれか1つに記載の方法。
[２７] リンカーが切断可能なペプチドリンカーである、請求項26に記載の方法。
[２８] 切断可能なペプチドリンカーが式：-MC-vc-PAB-を有し、
式中
a) MCは：
[化１]
b) vcはジペプチド、バリン-シトルリンである；ならびに
c) PABは：
[化２]
[２９] モノメチルアウリスタチンがモノメチルアウリスタチンE（MMAE）である、請求項1～28のいずれか1つに記載の方法。
[３０] モノメチルアウリスタチンがモノメチルアウリスタチンF（MMAF）である、請求項1～28のいずれか1つに記載の方法。
[３１] 抗体薬物複合体が、ブレンツキシマブベドチンまたはそのバイオシミラーである、請求項1～18のいずれか1つに記載の方法。
[３２] 抗体薬物複合体が、ブレンツキシマブベドチンである、請求項1～18のいずれか1つに記載の方法。
[３３] レナリドミドまたはその塩もしくは溶媒和物が、1～30mgの用量で投与される、請求項1～32のいずれか1つに記載の方法。
[３４] レナリドミドまたはその塩もしくは溶媒和物が、20mgの用量で投与される、請求項33に記載の方法。
[３５] レナリドミドまたはその塩もしくは溶媒和物が経口投与される、請求項1～34のいずれか1つに記載の方法。
[３６] レナリドミドまたはその塩もしくは溶媒和物が、1日に約1回投与される、請求項1～35のいずれか1つに記載の方法。
[３７] レナリドミドまたはその塩もしくは溶媒和物が、1日1回投与される、請求項1～35のいずれか1つに記載の方法。
[３８] 抗体薬物複合体が、被験者の体重当たり0.6 mg/kg～2.3 mg/kgの用量で投与される、請求項1～37のいずれか1つに記載の方法。
[３９] 抗体薬物複合体が、被験者の体重当り約0.9 mg/kgの用量で投与される、請求項38に記載の方法。
[４０] 抗体薬物複合体が、被験者の体重当り0.9 mg/kgの用量で投与される、請求項38に記載の方法。
[４１] 抗体薬物複合体が、被験者の体重当り約1.2 mg/kgの用量で投与される、請求項38に記載の方法。
[４２] 抗体薬物複合体が、被験者の体重当り1.2 mg/kgの用量で投与される、請求項38に記載の方法。
[４３] 体重が100 kgを超える被験者に対して、その被験者が100 kgの体重を有するとして、抗体薬物複合体が投与される、請求項38に記載の方法。
[４４] 抗体薬物複合体が、約3週間に1回、被験者に投与される、請求項1～43のいずれか1つに記載の方法。
[４５] 抗体薬物複合体が、3週間に1回、被験者に投与される、請求項1～43のいずれか1つに記載の方法。
[４６] 抗体薬物複合体が、約21日投与サイクルのほぼ1日目に被験者に投与される、請求項1～45のいずれか1つに記載の方法。
[４７] 抗体薬物複合体が、21日投与サイクルの1日目に被験者に投与される、請求項1～45のいずれか1つに記載の方法。
[４８] 抗体薬物複合体が点滴静注で投与される、請求項1～47のいずれか1つに記載の方法。
[４９] 抗CD20抗体またはその抗原結合フラグメントを被験者に投与することをさらに含む、請求項1～48のいずれか1つに記載の方法。
[５０] 抗CD20抗体またはその抗原結合フラグメントが、配列番号17に記載の3つのCDRを含む重鎖可変領域、配列番号18に記載の3つのCDRを含む軽鎖可変領域を含み、これらの抗CD20抗体のCDRがKabatのナンバリングスキームによって定義される、請求項49に記載の方法。
[５１] 抗CD20抗体またはその抗原結合フラグメントが、配列番号17に記載のアミノ酸配列と少なくとも85%同一なアミノ酸配列を含む重鎖可変領域、および配列番号18に記載のアミノ酸配列と少なくとも85%同一なアミノ酸配列を含む軽鎖可変領域を含む、請求項49または50に記載の方法。
[５２] 抗CD20抗体またはその抗原結合フラグメントが、配列番号17に記載のアミノ酸配列を含む重鎖可変領域、および配列番号18に記載のアミノ酸配列を含む軽鎖可変領域を含む、請求項49に記載の方法。
[５３] 抗CD20抗体またはその抗原結合フラグメントが、リツキシマブまたはそのバイオシミラーである、請求項49に記載の方法。
[５４] 抗CD20抗体またはその抗原結合フラグメントがリツキシマブである、請求項49に記載の方法。
[５５] 抗CD20抗体またはその抗原結合フラグメントが、被験者の体表面積当り100 mg/m
2
～500 mg/m
2
の用量で投与される、請求項49～54のいずれか1つに記載の方法。
[５６] 抗CD20抗体またはその抗原結合フラグメントが、被験者の体表面積当り約375 mg/m
2
の用量で投与される、請求項55に記載の方法。
[５７] 抗CD20抗体またはその抗原結合フラグメントが、被験者の体表面積当り375 mg/m
2
の用量で投与される、請求項55に記載の方法。
[５８] 抗CD20抗体またはその抗原結合フラグメントが、500 mg～2000 mgの用量で投与される、請求項49～54のいずれか1つに記載の方法。
[５９] 抗CD20抗体またはその抗原結合フラグメントが、約1400 mgの用量で投与される、請求項58に記載の方法。
[６０] 抗CD20抗体またはその抗原結合フラグメントが、1400 mgの用量で投与される、請求項58に記載の方法。
[６１] 抗CD20抗体またはその抗原結合フラグメントが、約3週間に1回、被験者に投与される、請求項49～60のいずれか1つに記載の方法。
[６２] 抗CD20抗体またはその抗原結合フラグメントが、3週間に1回、被験者に投与される、請求項49～60のいずれか1つに記載の方法。
[６３] 抗CD20抗体またはその抗原結合フラグメントが、約21日投与サイクルのほぼ1日目に被験者に投与される、請求項49～62のいずれか1つに記載の方法。
[６４] 抗CD20抗体またはその抗原結合フラグメントが、21日投与サイクルの1日目に被験者に投与される、請求項49～62のいずれか1つに記載の方法。
[６５] 抗CD20抗体またはその抗原結合フラグメントが、点滴静注で投与される、請求項49～64のいずれか1つに記載の方法。
[６６] 抗CD20抗体またはその抗原結合フラグメントが、皮下注射で投与される、請求項49～64のいずれか1つに記載の方法。
[６７] 抗CD20抗体またはその抗原結合フラグメントが、被験者の体表面積当り約375 mg/m
2
の用量で、初回の21日投与サイクルのほぼ1日目に点滴静注により投与され、その後各回の21日投与サイクルのほぼ1日目に皮下注射により約1400 mgの用量で投与される、請求項63～66のいずれか1つに記載の方法。
[６８] 抗CD20抗体またはその抗原結合フラグメントが、被験者の体表面積当り375 mg/m
2
の用量で、初回の21日投与サイクルの1日目に点滴静注により投与され、その後各回の21日投与サイクルの1日目に皮下注射により1400 mgの用量で投与される、請求項63～66のいずれか1つに記載の方法。
[６９] 顆粒球コロニー刺激因子（G-CSF）を被験者に投与することをさらに含む、請求項1～68のいずれか1つに記載の方法。
[７０] G-CSFが、抗CD30抗体薬物複合体の投与の1～3日後に投与される、請求項69に記載の方法。
[７１] G-CSFが、フィルグラスチム、PEG-フィルグラスチム、レノグラスチム、およびtbo-フィルグラスチムからなる一群から選択される、請求項69または70に記載の方法。
[７２] レナリドミド、またはその塩もしくは溶媒和物、およびCD30に結合する抗体薬物複合体を被験者に投与することが、結果として、レナリドミド、またはその塩もしくは溶媒和物、および／またはCD30に結合する抗体薬物複合体を被験者に投与する前のがん細胞の量と比較して、少なくとも約5%、少なくとも約6%、少なくとも約7%、少なくとも約8%、少なくとも約9%、少なくとも約10%、少なくとも約15%、少なくとも約20%、少なくとも約25%、少なくとも約30%、少なくとも約35%、少なくとも約40%、少なくとも約45%、少なくとも約50%、少なくとも約60%、少なくとも約70%、少なくとも約80%、少なくとも約90%、少なくとも約95%、または約100%までの、がん細胞の枯渇をもたらす、請求項1～71のいずれか1つに記載の方法。
[７３] レナリドミド、またはその塩もしくは溶媒和物、およびCD30に結合する抗体薬物複合体の投与後に、被験者において1つもしくは複数の治療効果が、ベースラインと比較して改善する、請求項1～72のいずれか1つに記載の方法。
[７４] 1つもしくは複数の治療効果が、客観的奏効率、奏功期間、奏功までの時間、無増悪生存期間、および全生存期間からなる一群から選択される、請求項73に記載の方法。
[７５] 客観的奏効率が、少なくとも約20%、少なくとも約25%、少なくとも約30%、少なくとも約35%、少なくとも約40%、少なくとも約45%、少なくとも約50%、少なくとも約60%、少なくとも約70%、または少なくとも約80%である、請求項1～74のいずれか1つに記載の方法。
[７６] 被験者が、レナリドミド、またはその塩もしくは溶媒和物、および／またはCD30に結合する抗体薬物複合体の投与後、少なくとも約1月、少なくとも約2月、少なくとも約3月、少なくとも約4月、少なくとも約5月、少なくとも約6月、少なくとも約7月、少なくとも約8月、少なくとも約9月、少なくとも約10月、少なくとも約11月、少なくとも約12月、少なくとも約18月、少なくとも約2年、少なくとも約3年、少なくとも約4年、または少なくとも約5年の無増悪生存期間を示す、請求項1～75のいずれか1つに記載の方法。
[７７] 被験者が、レナリドミド、またはその塩もしくは溶媒和物、および／またはCD30に結合する抗体薬物複合体の投与後、少なくとも約1月、少なくとも約2月、少なくとも約3月、少なくとも約4月、少なくとも約5月、少なくとも約6月、少なくとも約7月、少なくとも約8月、少なくとも約9月、少なくとも約10月、少なくとも約11月、少なくとも約12月、少なくとも約18月、少なくとも約2年、少なくとも約3年、少なくとも約4年、または少なくとも約5年の全生存期間を示す、請求項1～76のいずれか1つに記載の方法。
[７８] レナリドミド、またはその塩もしくは溶媒和物、および／またはCD30に結合する抗体薬物複合体の奏功期間が、レナリドミド、またはその塩もしくは溶媒和物、および／またはCD30に結合する抗体薬物複合体の投与後、少なくとも約1月、少なくとも約2月、少なくとも約3月、少なくとも約4月、少なくとも約5月、少なくとも約6月、少なくとも約7月、少なくとも約8月、少なくとも約9月、少なくとも約10月、少なくとも約11月、少なくとも約12月、少なくとも約18月、少なくとも約2年、少なくとも約3年、少なくとも約4年、または少なくとも約5年である、請求項1～77のいずれか1つに記載の方法。
[７９] 被験者がヒトである、請求項1～78のいずれか1つに記載の方法。
[８０] 被験者において非ホジキンリンパ腫を治療するための医薬組成物であって、その組成物はレナリドミド、またはその塩もしくは溶媒和物、およびCD30に結合する抗体薬物複合体を含み、この抗体薬物複合体はモノメチルアウリスタチンまたはその機能的アナログもしくはその機能的誘導体とコンジュゲートした抗CD30抗体またはその抗原結合フラグメントを含むものであって、この組成物が請求項1～79のいずれか1つに記載の方法に使用するためのものである、前記医薬組成物。
[８１] 抗CD20抗体またはその抗原結合フラグメントをさらに含む、請求項80に記載の医薬組成物。
[８２] レナリドミド、またはその塩もしくは溶媒和物、およびCD30に結合する抗体薬物複合体を含むキットであって、該抗体薬物複合体はモノメチルアウリスタチンまたはその機能的アナログもしくはその機能的誘導体とコンジュゲートした抗CD30抗体またはその抗原結合フラグメントを含み、さらに、請求項1～79のいずれか1つに記載の方法でこのキットを使用するための使用説明書を含む、前記キット。
[８３] 抗CD20抗体またはその抗原結合フラグメントをさらに含む、請求項82に記載のキット。
ORR is summarized by treatment group using the ITT analysis set. The interim analysis of ORR will include all subjects who completed at least 6 months of follow-up from randomization or who discontinued the study at the time of analysis. ORR is tested based on the Cochran Mantel-Haenszel test stratified by stratification factors; ORR differences are presented with corresponding 95% confidence intervals. The ORR for each group is also presented with exact 95% confidence intervals using the Clopper-Pearson method. A similar summary is presented for CR rates.
The present disclosure includes the following embodiments.
[1] A method of treating non-Hodgkin's lymphoma in a subject, the method comprising administering to the subject lenalidomide or a salt or solvate thereof, and an antibody-drug conjugate that binds to CD30, the antibody-drug conjugate The above method, wherein the conjugate comprises an anti-CD30 antibody or antigen-binding fragment thereof conjugated to monomethyl auristatin or a functional analog or derivative thereof.
[2] The method according to claim 1, wherein the non-Hodgkin's lymphoma is diffuse large B-cell lymphoma (DLBCL).
[3] The method according to claim 2, wherein the DLBCL is recurrent DLBCL.
[4] The method according to claim 2 or 3, wherein the DLBCL is refractory DLBCL.
[5] The method according to any one of claims 2 to 4, wherein the DLBCL is germinal center B cell-like (GCB).
[6] The method according to any one of claims 2 to 4, wherein the DLBCL is non-GCB.
[7] The method according to any one of claims 1 to 6, wherein the subject has previously undergone allogeneic stem cell transplantation for the treatment of non-Hodgkin's lymphoma.
[8] The method according to any one of claims 1 to 7, wherein the subject has previously undergone autologous stem cell transplantation for the treatment of non-Hodgkin's lymphoma.
[9] The method according to claim 7 or 8, wherein the subject has relapsed after stem cell transplantation.
[10] The method according to any one of claims 1 to 9, wherein the subject has previously received CAR-T therapy.
[11] The method of claim 10, wherein the subject has relapsed after CAR-T therapy.
[12] The method according to any one of claims 1 to 11, wherein the subject has not previously received treatment with lenalidomide, or a salt or solvate thereof.
[13] The method according to any one of claims 1 to 12, wherein the subject has not previously received treatment with an antibody-drug conjugate that binds to CD30.
[14] The method according to any one of claims 1 to 13, wherein the non-Hodgkin's lymphoma is advanced stage non-Hodgkin's lymphoma.
[15] The method according to claim 14, wherein the advanced stage non-Hodgkin's lymphoma is stage III or stage IV non-Hodgkin's lymphoma.
[16] The method according to claim 14 or 15, wherein the advanced stage non-Hodgkin's lymphoma is metastatic non-Hodgkin's lymphoma.
[17] The method according to any one of claims 1 to 16, wherein the non-Hodgkin's lymphoma is relapsed non-Hodgkin's lymphoma.
[18] The method according to any one of claims 1 to 17, wherein at least 1% of the subject's non-Hodgkin's lymphoma cells express CD30.
[19] The anti-CD30 antibody of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, and the heavy chain variable region:
(i) CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 1;
(ii) CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 2; and
(iii) CDR-H3 containing the amino acid sequence set forth in SEQ ID NO: 3
contains; and
Its light chain variable region is:
(i) CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 4;
(ii) CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 5; and
(iii) CDR-L3 containing the amino acid sequence set forth in SEQ ID NO: 6
19. The method according to any one of claims 1 to 18, comprising:
[20] The anti-CD30 antibody of the antibody-drug conjugate has a heavy chain variable region comprising an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 7, and at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 8. 20. The method according to any one of claims 1 to 19, comprising a light chain variable region comprising an amino acid sequence.
[21] The anti-CD30 antibody of the antibody-drug conjugate has a heavy chain variable region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 7, and at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 8. 21. The method according to any one of claims 1 to 20, comprising a light chain variable region comprising an amino acid sequence.
[22] The anti-CD30 antibody of the antibody-drug conjugate has a heavy chain variable region comprising an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 7, and at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 8. 22. The method according to any one of claims 1 to 21, comprising a light chain variable region comprising an amino acid sequence.
[23] Claims 1 to 2, wherein the anti-CD30 antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 8. The method described in any one of 18.
[24] The method according to any one of claims 1 to 18, wherein the anti-CD30 antibody is AC10.
[25] The method according to any one of claims 1 to 18, wherein the anti-CD30 antibody is cAD10.
[26] The method according to any one of claims 1 to 25, wherein the antibody-drug conjugate further comprises a linker between the anti-CD30 antibody or antigen-binding portion thereof and monomethyl auristatin.
[27] The method according to claim 26, wherein the linker is a cleavable peptide linker.
[28] the cleavable peptide linker has the formula: -MC-vc-PAB-,
During the ceremony
a) The MC is:
[Case 1]
b) vc is a dipeptide, valine-citrulline; and
c) PAB is:
[Case 2]
[29] The method according to any one of claims 1 to 28, wherein the monomethyl auristatin is monomethyl auristatin E (MMAE).
[30] The method according to any one of claims 1 to 28, wherein the monomethyl auristatin is monomethyl auristatin F (MMAF).
[31] The method according to any one of claims 1 to 18, wherein the antibody-drug conjugate is brentuximab vedotin or a biosimilar thereof.
[32] The method according to any one of claims 1 to 18, wherein the antibody-drug conjugate is brentuximab vedotin.
[33] The method according to any one of claims 1 to 32, wherein lenalidomide or a salt or solvate thereof is administered at a dose of 1 to 30 mg.
[34] The method of claim 33, wherein lenalidomide or a salt or solvate thereof is administered at a dose of 20 mg.
[35] The method according to any one of claims 1 to 34, wherein lenalidomide or a salt or solvate thereof is administered orally.
[36] The method of any one of claims 1 to 35, wherein lenalidomide or a salt or solvate thereof is administered about once a day.
[37] The method according to any one of claims 1 to 35, wherein lenalidomide or a salt or solvate thereof is administered once a day.
[38] The method of any one of claims 1-37, wherein the antibody-drug conjugate is administered at a dose of 0.6 mg/kg to 2.3 mg/kg body weight of the subject.
[39] The method of claim 38, wherein the antibody-drug conjugate is administered at a dose of about 0.9 mg/kg body weight of the subject.
[40] The method of claim 38, wherein the antibody-drug conjugate is administered at a dose of 0.9 mg/kg body weight of the subject.
[41] The method of claim 38, wherein the antibody drug conjugate is administered at a dose of about 1.2 mg/kg body weight of the subject.
[42] The method of claim 38, wherein the antibody drug conjugate is administered at a dose of 1.2 mg/kg body weight of the subject.
[43] The method of claim 38, wherein the antibody-drug conjugate is administered to a subject who weighs more than 100 kg, assuming that the subject has a body weight of 100 kg.
[44] The method of any one of claims 1-43, wherein the antibody-drug conjugate is administered to the subject about once every three weeks.
[45] The method according to any one of claims 1 to 43, wherein the antibody-drug conjugate is administered to the subject once every three weeks.
[46] The method of any one of claims 1-45, wherein the antibody drug conjugate is administered to the subject on approximately day 1 of an approximately 21 day dosing cycle.
[47] The method of any one of claims 1-45, wherein the antibody-drug conjugate is administered to the subject on day 1 of a 21-day dosing cycle.
[48] The method according to any one of claims 1 to 47, wherein the antibody-drug conjugate is administered by intravenous infusion.
[49] The method according to any one of claims 1 to 48, further comprising administering to the subject an anti-CD20 antibody or antigen-binding fragment thereof.
[50] An anti-CD20 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region comprising three CDRs set forth in SEQ ID NO: 17 and a light chain variable region comprising three CDRs set forth in SEQ ID NO: 18, 50. The method of claim 49, wherein the CDRs of the CD20 antibody are defined by the Kabat numbering scheme.
[51] The anti-CD20 antibody or antigen-binding fragment thereof has a heavy chain variable region comprising an amino acid sequence at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 17, and at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 18. 51. The method of claim 49 or 50, comprising a light chain variable region comprising an amino acid sequence.
[52] Claim 49, wherein the anti-CD20 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 17, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 18. Method described.
[53] The method according to claim 49, wherein the anti-CD20 antibody or antigen-binding fragment thereof is rituximab or a biosimilar thereof.
[54] The method according to claim 49, wherein the anti-CD20 antibody or antigen-binding fragment thereof is rituximab.
[55] The method according to any one of claims 49 to 54, wherein the anti-CD20 antibody or antigen-binding fragment thereof is administered at a dose of 100 mg/m 2 to 500 mg/m 2 per body surface area of the subject. .
[56] The method of claim 55, wherein the anti-CD20 antibody or antigen-binding fragment thereof is administered at a dose of about 375 mg/ m2 per body surface area of the subject.
[57] The method of claim 55, wherein the anti-CD20 antibody or antigen-binding fragment thereof is administered at a dose of 375 mg/ m2 per body surface area of the subject.
[58] The method of any one of claims 49-54, wherein the anti-CD20 antibody or antigen-binding fragment thereof is administered at a dose of 500 mg to 2000 mg.
[59] The method of claim 58, wherein the anti-CD20 antibody or antigen-binding fragment thereof is administered at a dose of about 1400 mg.
[60] The method of claim 58, wherein the anti-CD20 antibody or antigen-binding fragment thereof is administered at a dose of 1400 mg.
[61] The method of any one of claims 49 to 60, wherein the anti-CD20 antibody or antigen-binding fragment thereof is administered to the subject about once every three weeks.
[62] The method according to any one of claims 49 to 60, wherein the anti-CD20 antibody or antigen-binding fragment thereof is administered to the subject once every three weeks.
[63] The method of any one of claims 49-62, wherein the anti-CD20 antibody or antigen-binding fragment thereof is administered to the subject on about day 1 of an about 21 day administration cycle.
[64] The method of any one of claims 49-62, wherein the anti-CD20 antibody or antigen-binding fragment thereof is administered to the subject on day 1 of a 21-day administration cycle.
[65] The method according to any one of claims 49 to 64, wherein the anti-CD20 antibody or antigen-binding fragment thereof is administered by intravenous infusion.
[66] The method of any one of claims 49-64, wherein the anti-CD20 antibody or antigen-binding fragment thereof is administered by subcutaneous injection.
[67] Anti-CD20 antibodies or antigen-binding fragments thereof were administered by intravenous infusion at a dose of approximately 375 mg/m 2 of the subject's body surface area on approximately day 1 of an initial 21-day dosing cycle, followed by each subsequent 67. The method of any one of claims 63-66, wherein the method is administered at a dose of about 1400 mg by subcutaneous injection on approximately day 1 of a 21-day dosing cycle.
[68] Anti-CD20 antibodies or antigen-binding fragments thereof were administered by intravenous infusion at a dose of 375 mg/m2 per subject's body surface area on day 1 of the first 21-day dosing cycle, and then on each subsequent 21-day dosing cycle. 67. The method of any one of claims 63-66, wherein the dose is 1400 mg administered by subcutaneous injection on day 1 of the administration cycle.
[69] The method according to any one of claims 1 to 68, further comprising administering granulocyte colony stimulating factor (G-CSF) to the subject.
[70] The method of claim 69, wherein G-CSF is administered 1 to 3 days after administration of the anti-CD30 antibody drug conjugate.
[71] The method of claim 69 or 70, wherein the G-CSF is selected from the group consisting of filgrastim, PEG-filgrastim, lenograstim, and tbo-filgrastim.
[72] Administering to a subject an antibody-drug conjugate that binds to lenalidomide, or a salt or solvate thereof, and CD30 results in lenalidomide, or a salt or solvate thereof, and/or binding to CD30 at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10% compared to the amount of cancer cells before administering the antibody drug conjugate to the subject. , at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70% 72. The method of any one of claims 1-71, wherein the method results in depletion of cancer cells by at least about 80%, at least about 90%, at least about 95%, or up to about 100%.
[73] Claims 1-1, wherein one or more therapeutic effects are improved in a subject after administration of lenalidomide, or a salt or solvate thereof, and an antibody-drug conjugate that binds to CD30 as compared to baseline. The method described in any one of 72.
[74] The method of claim 73, wherein the one or more therapeutic effects are selected from the group consisting of objective response rate, duration of response, time to response, progression-free survival, and overall survival.
[75] The objective response rate is at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least 75. The method of any one of claims 1 to 74, which is about 70%, or at least about 80%.
[76] At least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months after administration of lenalidomide, or a salt or solvate thereof, and/or an antibody-drug conjugate that binds to CD30. , at least about May, at least about June, at least about July, at least about August, at least about September, at least about October, at least about November, at least about December, at least about 18 months, at least about 2 years 76. The method of any one of claims 1-75, wherein the method exhibits a progression free survival of at least about 3 years, at least about 4 years, or at least about 5 years.
[77] At least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months after administration of lenalidomide, or a salt or solvate thereof, and/or an antibody-drug conjugate that binds to CD30. , at least about May, at least about June, at least about July, at least about August, at least about September, at least about October, at least about November, at least about December, at least about 18 months, at least about 2 years 77. The method of any one of claims 1-76, wherein the method exhibits an overall survival of at least about 3 years, at least about 4 years, or at least about 5 years.
[78] The duration of response of lenalidomide, or a salt or solvate thereof, and/or an antibody-drug conjugate that binds to CD30 is longer than that of lenalidomide, or a salt or solvate thereof, and/or an antibody-drug conjugate that binds to CD30. at least about one month, at least about two months, at least about March, at least about April, at least about May, at least about June, at least about July, at least about August, at least about September, at least about any of claims 1-77, which is about October, at least about November, at least about December, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years. The method described in one.
[79] The method according to any one of claims 1 to 78, wherein the subject is a human.
[80] A pharmaceutical composition for treating non-Hodgkin's lymphoma in a subject, the composition comprising lenalidomide, or a salt or solvate thereof, and an antibody-drug conjugate that binds to CD30, the composition comprising: the composition comprising an anti-CD30 antibody or antigen-binding fragment thereof conjugated to monomethyl auristatin or a functional analog or derivative thereof, the composition according to any one of claims 1 to 79 The above pharmaceutical composition for use in the method of.
[81] The pharmaceutical composition according to claim 80, further comprising an anti-CD20 antibody or an antigen-binding fragment thereof.
[82] A kit comprising lenalidomide, or a salt or solvate thereof, and an antibody drug conjugate that binds to CD30, the antibody drug conjugate being conjugated with monomethyl auristatin or a functional analog thereof or a functional derivative thereof. 80. A kit comprising a gated anti-CD30 antibody or antigen binding fragment thereof and further comprising instructions for using this kit in the method of any one of claims 1 to 79.
[83] The kit according to claim 82, further comprising an anti-CD20 antibody or an antigen-binding fragment thereof.
Claims (47)
(i) 配列番号1に記載のアミノ酸配列を含むCDR-H1；
(ii) 配列番号2に記載のアミノ酸配列を含むCDR-H2；および
(iii) 配列番号3に記載のアミノ酸配列を含むCDR-H3
を含んでいる；ならびに
その軽鎖可変領域が：
(i) 配列番号4に記載のアミノ酸配列を含むCDR-L1；
(ii) 配列番号5に記載のアミノ酸配列を含むCDR-L2；および
(iii) 配列番号6に記載のアミノ酸配列を含むCDR-L3
を含んでいる、請求項１～１３のいずれか1つに記載の組成物。 The anti-CD30 antibody of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, and the heavy chain variable region:
(i) CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 1;
(ii) CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 2; and
(iii) CDR-H3 containing the amino acid sequence set forth in SEQ ID NO: 3
as well as its light chain variable region:
(i) CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 4;
(ii) CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 5; and
(iii) CDR-L3 containing the amino acid sequence set forth in SEQ ID NO: 6
The composition according to any one of claims 1 to 13 , comprising:
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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| US4714681A (en) | 1981-07-01 | 1987-12-22 | The Board Of Reagents, The University Of Texas System Cancer Center | Quadroma cells and trioma cells and methods for the production of same |
| US4474893A (en) | 1981-07-01 | 1984-10-02 | The University of Texas System Cancer Center | Recombinant monoclonal antibodies |
| US4925648A (en) | 1988-07-29 | 1990-05-15 | Immunomedics, Inc. | Detection and treatment of infectious and inflammatory lesions |
| US5601819A (en) | 1988-08-11 | 1997-02-11 | The General Hospital Corporation | Bispecific antibodies for selective immune regulation and for selective immune cell binding |
| ES2096590T3 (en) | 1989-06-29 | 1997-03-16 | Medarex Inc | BI-SPECIFIC REAGENTS FOR AIDS THERAPY. |
| WO1992005793A1 (en) | 1990-10-05 | 1992-04-16 | Medarex, Inc. | Targeted immunostimulation with bispecific reagents |
| EP0557300B1 (en) | 1990-10-29 | 1997-11-19 | Chiron Corporation | Bispecific antibodies, method of production, and uses thereof |
| AU665758B2 (en) | 1991-04-26 | 1996-01-18 | Surface Active Limited | Novel antibodies, and methods for their use |
| US6407213B1 (en) | 1991-06-14 | 2002-06-18 | Genentech, Inc. | Method for making humanized antibodies |
| GB9203459D0 (en) | 1992-02-19 | 1992-04-08 | Scotgen Ltd | Antibodies with germ-line variable regions |
| PT627940E (en) | 1992-03-05 | 2003-07-31 | Univ Texas | USE OF IMMUNOCONJUGATES FOR THE DIAGNOSIS AND / OR THERAPY OF VASCULARIZED TUMORS |
| US5736137A (en) | 1992-11-13 | 1998-04-07 | Idec Pharmaceuticals Corporation | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
| DK0669836T3 (en) | 1992-11-13 | 1996-10-14 | Idec Pharma Corp | Therapeutic use of chimeric and radiolabeled antibodies and human B lymphocyte restricted differentiation antigen for the treatment of B cell lymphoma |
| US7090843B1 (en) | 2000-11-28 | 2006-08-15 | Seattle Genetics, Inc. | Recombinant anti-CD30 antibodies and uses thereof |
| WO2010081004A1 (en) | 2009-01-09 | 2010-07-15 | Seattle Genetics, Inc. | Weekly dosing regimens for anti-cd30 vc-pab-mmae antibody drug-conjugates |
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