JP6916741B2 - 抗cd19抗体およびブルトン型チロシンキナーゼ阻害剤の組み合わせ、およびその使用 - Google Patents
抗cd19抗体およびブルトン型チロシンキナーゼ阻害剤の組み合わせ、およびその使用 Download PDFInfo
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- JP6916741B2 JP6916741B2 JP2017560705A JP2017560705A JP6916741B2 JP 6916741 B2 JP6916741 B2 JP 6916741B2 JP 2017560705 A JP2017560705 A JP 2017560705A JP 2017560705 A JP2017560705 A JP 2017560705A JP 6916741 B2 JP6916741 B2 JP 6916741B2
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Description
すべてその全体を援用する国際公開第2012170976号パンフレット(米国特許出願第14/112,428号明細書)、国際公開第2013010380号パンフレット(米国特許出願第14/233,478号明細書)および国際公開第2014113932号パンフレット(米国特許出願第14/160,587号明細書)に記載されたACP−196(Acerta Pharma BV);
BGB−3111(BeiGene,Co.,Ltd.)およびCC−292 Evans et al.2013
が挙げられる。
>4G7 H1.52 Hybrid S239D/I332E
>4G7 L1.155
本開示の態様は、非ホジキンリンパ腫、慢性リンパ球性白血病および/または急性リンパ芽球性白血病の処置に使用される、CD19に特異的な抗体およびブルトン型チロシンキナーゼ(BTK)阻害剤を含む組み合わせである。実施形態において本組み合わせは相乗的である。
材料
試験対象の細胞株:MEC−1細胞(DSMZ# ACC497)。以下の細胞株を試験する:慢性B細胞白血病細胞株;JVM−2(ATCC(登録商標)CRL−3002)マントル細胞リンパ腫細胞株;Ramos細胞(ATCC番号CRL−1596)、ヒトバーキットリンパ腫細胞;HG−3(DSMZ#ACC765)およびCII(DSMZ#ACC773)は、慢性リンパ球性白血病細胞株であり;Su−DHL 6(DSMZ#ACC572)、U2932(DSMZ#ACC633)およびOCI−LY7(DSMZ#ACC688)は、びまん性大細胞型B細胞リンパ腫(DLBCL)細胞株であり;JVM−2(ATCC(登録商標)CRL−3002)は、マントル細胞リンパ腫細胞株であり;BALL−1(DSMZ#ACC742)は、急性リンパ芽球性白血病細胞株である。
MEC−1細胞株(CLL)を対象として、MOR00208およびイブルチニブ単独および組み合わせの細胞毒性を試験した。以下の標的細胞株:JVM−2、Ramos、HG−3、CII、Su−DHL 6、U2932、OCI−LY7、JVM−2およびBALL−1を対象として、MOR00208およびイブルチニブ単独および組み合わせの細胞毒性を試験する。
生データ(死細胞%)を以下の通り解析する。1)生データ(死細胞%)からバックグラウンド(対照)を差し引き、処理群ごとに特異的殺傷を得る;次いで2)特異的殺傷の値を、MOR00208+イブルチニブの組み合わせを1に設定することにより規格化する。
半数影響式は、阻害剤(薬剤など)の作用をFa/Fu=(D/D50)^mとしてモデル化する。式中、Dは用量であり、FaおよびFuは、用量Dにより影響を受けたまたは受けない系の割合であり(Fa+Fu=1);D50は、半数影響を発揮する用量(たとえば、IC50、ED50、LD50)である。定数mは、用量作用曲線の形状を決定する。
CI−isobol法は、薬剤間の協力作用の定量的評価を与える。併用係数(CI)は、単独および組み合わせた薬剤処理の用量作用データから推定する。CIが1未満であると協力作用を示し;CI=1であると相加作用を示し;CI>1であると拮抗作用を示す。薬剤相互作用(協力作用または拮抗作用)が顕著であるほど、CI値は1から離れる。
Chouインデックス曲線を図9〜11に示す。3つの実験(同じ濃度の)で得られたデータをマージして、イブルトニイブ濃度ごとに1つの曲線を作成した。
組み合わせて使用するときの単剤の作用を計算し比較するための別のアプローチは、1963年に最初にWebb J.L.により“Enzymes and metabolic inhibitors”に記載された分画産物の概念である。この解析方法では、いくつかの薬剤の作用は、作用が非競合である限り、同じ細胞分画に向かい得ると考えられており、これはMOR00208およびイブルチニブに当てはまり、したがって、測定された組み合わせ作用は単独作用の理論的合計より小さくなる。分画産物の概念によると、2つの薬剤が標的細胞分画の50%を殺傷するときは常に、組み合わせの作用が75%(適用した式:1−(1−0.5)×(1−0.5)=0.75)に過ぎず、期待される100%ではない。依然として生存しており、2つの薬剤の1つに感受性を示すのは標的細胞の50%のみであるためである。
拮抗的(AB)/C<(A/C)×(B/C)
相加的(AB)/C=(A/C)×(B/C)
相乗的(AB)/C>(A/C)×(B/C)
AはMOR00208を単独で用いた処理であり;Bはイブルチニブを単独で用いた処理であり;Cは対照DMSO+RefMab33に対する反応であり;ABは処理AおよびBの組み合わせである。
各濃度での実験1〜3から、Clarke et al.の方法を用いてMOR00208+イブルチニブの組み合わせの明らかな相乗作用が示される。しかしながら、Clarke et al.の方法からは、少数ながらイブルチニブ活性が対照のそれより低かった実験にもかかわらず、協力作用が示される。
Claims (19)
- 非ホジキンリンパ腫、慢性リンパ球性白血病、または急性リンパ芽球性白血病の治療であって、CD19に特異的な抗体がイブルチニブと組み合わせて用いられる治療のための医薬の製造における、CD19に特異的な抗体の使用であって、
前記CD19に特異的な抗体は、配列SYVMH(配列番号1)のHCDR1領域、配列NPYNDG(配列番号2)のHCDR2領域、配列GTYYYGTRVFDY(配列番号3)のHCDR3領域、配列RSSKSLQNVNGNTYLY(配列番号4)のLCDR1領域、配列RMSNLNS(配列番号5)のLCDR2領域、および配列MQHLEYPIT(配列番号6)のLCDR3領域を含むことを特徴とする使用。 - 請求項1乃至5の何れか1項に記載の使用において、前記CD19に特異的な抗体およびイブルチニブは、別々に投与されることを特徴とする使用。
- 請求項1乃至5の何れか1項に記載の使用において、イブルチニブは、前記CD19に特異的な抗体の投与前に投与されることを特徴とする使用。
- 請求項1乃至5の何れか1項に記載の使用において、前記CD19に特異的な抗体およびイブルチニブは、同時に投与されることを特徴とする使用。
- 請求項1乃至5の何れか1項に記載の使用において、前記CD19に特異的な抗体およびイブルチニブは、患者において両方の薬剤が同時に有効であるときに投与されることを特徴とする使用。
- 請求項1乃至9の何れか1項に記載の使用において、慢性リンパ球性白血病の治療のための医薬の製造における使用であることを特徴とする使用。
- 請求項1乃至9の何れか1項に記載の使用において、急性リンパ芽球性白血病の治療のための医薬の製造における使用であることを特徴とする使用。
- 請求項1乃至9の何れか1項に記載の使用において、非ホジキンリンパ腫の治療のための医薬の製造における使用であることを特徴とする使用。
- 請求項12に記載の使用において、前記非ホジキンリンパ腫は、濾胞性リンパ腫であることを特徴とする使用。
- 請求項12に記載の使用において、前記非ホジキンリンパ腫は、小リンパ球性リンパ腫であることを特徴とする使用。
- 請求項12に記載の使用において、前記非ホジキンリンパ腫は、粘膜関連リンパ組織であることを特徴とする使用。
- 請求項12に記載の使用において、前記非ホジキンリンパ腫は、びまん性大細胞型B細胞リンパ腫であることを特徴とする使用。
- 請求項12に記載の使用において、前記非ホジキンリンパ腫は、バーキットリンパ腫であることを特徴とする使用。
- 請求項12に記載の使用において、前記非ホジキンリンパ腫は、マントル細胞リンパ腫であることを特徴とする使用。
- 請求項12に記載の使用において、前記非ホジキンリンパ腫は、辺縁帯リンパ腫であることを特徴とする使用。
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