JP2020506949A - ピロロベンゾジアゼピン抗体複合体 - Google Patents
ピロロベンゾジアゼピン抗体複合体 Download PDFInfo
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- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
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Abstract
Description
本出願は、2017年2月8日出願のGB1702029.8及びGB1702031.4、ならびに2017年11月30日出願のGB1719906.8の優先権を主張する。
本発明は、抗体とのリンカーという形で易分解性保護基を有するピロロベンゾジアゼピン(PBD)に関する。
ピロロベンゾジアゼピン(PBD)の中には、DNAの特定配列を認識して結合する能力を有するものがあり、好適な配列はPuGPuである。最初のPBD抗腫瘍抗生物質であるアントラマイシンは、1965に発見された(Leimgruber, et al., J. AM. Chem. Soc., 87, 5793−5795(1965)、Leimgruber, et al., J. AM. Chem. Soc., 87, 5791−5793(1965))。それ以来、天然に存在するPBDがいくつか報告されており、多様な類似体を合成する10を超える合成経路が開発されている(Thurston, et al., Chem. Rev. 1994, 433−465(1994);Antonow, D. and Thurston, D.E., Chem. Rev. 2011 111(4), 2815−2864)。このファミリーに属するものとして、アベイマイシン(Hochlowski, et al., J. Antibiotics, 40, 145−148(1987))、チカマイシン(Konishi, et al., J. Antibiotics, 37, 200−206(1984)), DC−81(Japanese Patent 58−180 487;Thurston, et al., Chem.Brit., 26, 767−772(1990);Bose, et al., Tetrahedron, 48, 751−758(1992))、マゼトラマイシン(Kuminoto, et al., J. Antibiotics, 33, 665−667(1980))、ネオトラマイシンA及びB(Takeuchi, et al., J. Antibiotics, 29, 93−96(1976))、ポロトラマイシン(Tsunakawa, et al., J. Antibiotics, 41, 1366−1373(1988))、プロトラカルシン(Shimizu, et al, J. Antibiotics, 29, 2492−2503(1982)、Langley and Thurston, J. Org. Chem., 52, 91−97(1987))、シバノミシン(DC−102)(Hara, et al., J. Antibiotics, 41, 702−704(1988);Itoh, et al., J. Antibiotics, 41, 1281−1284(1988))、シビロマイシン(Leber, et al., J. AM. Chem. Soc., 110, 2992−2993(1988))、ならびにトママイシン(Arima, et al., J. Antibiotics, 25, 437−444(1972))が挙げられる。PBDは、以下の一般式のものである。
がん、免疫不全、及び血管原性障害の患者の標的治療のための抗体療法が、確立されている(Carter, P.(2006) Nature Reviews Immunology 6:343−357)。がん治療における、細胞傷害剤または細胞分裂阻害剤、すなわち腫瘍細胞を殺傷または阻害する薬物を局所送達するための、抗体薬物複合体(ADC)、すなわち免疫複合体の使用は、薬物部分を腫瘍に送達し、腫瘍の細胞内に蓄積させることを目的とするが、こうした薬剤を複合体化させずに全身投与すると、許容不能なレベルの毒性を正常細胞にもたらす可能性がある(Xie et al(2006)Expert. Opin. Biol. Ther. 6(3):281−291;Kovtun et al(2006)Cancer Res. 66(6):3214−3121;Law et al(2006)Cancer Res. 66(4):2328−2337;Wu et al(2005)Nature Biotech. 23(9):1137−1145;Lambert J.(2005)Current Opin. in Pharmacol. 5:543−549;Hamann P.(2005)Expert Opin. Ther. Patents 15(9):1087−1103;Payne, G.(2003)Cancer Cell 3:207−212;Trail et al(2003)Cancer Immunol. Immunother. 52:328−337;Syrigos and Epenetos(1999)Anticancer Research 19:605−614)。
Ab−(DL)p (I)
式中:
Abは、AXLに結合する抗体であり;
DLは、以下
Xは、単結合、−CH2−、及び−C2H4−からなる群より選択され;
nは、1〜8であり;
mは、0または1であり;
R7は、メチルまたはフェニルいずれかであり;
C2とC3の間に二重結合がある場合、R2は、以下からなる群より選択され:
(ia)C5−10アリール基、この基は、以下からなる群より選択される1つまたは複数の置換基により任意選択で置換され:ハロ、ニトロ、シアノ、エーテル、カルボキシ、エステル、C1−7アルキル、C3−7ヘテロシクリル、及びビス−オキシ−C1−3アルキレン;
(ib)C1−5飽和脂肪族アルキル;
(ic)C3−6飽和シクロアルキル;
(id)
(ie)
(if)
C2とC3の間に単結合がある場合、R2は、以下
C2’とC3’の間に二重結合がある場合、R12は、以下からなる群より選択され:
(ia)C5−10アリール基、この基は以下からなる群より選択される1つまたは複数の置換基により任意選択で置換され:ハロ、ニトロ、シアノ、エーテル、カルボキシ、エステル、C1−7アルキル、C3−7ヘテロシクリル、及びビス−オキシ−C1−3アルキレン;
(ib)C1−5飽和脂肪族アルキル;
(ic)C3−6飽和シクロアルキル;
(id)
(ie)
(if)
C2’とC3’の間に単結合が存在する場合、R12は、以下
ならびにpは、1〜8である。
置換基
「任意選択で置換された」という用語は、本明細書中使用される場合、無置換の可能性も、置換されている可能性もある親基に関する。
飽和単環式炭化水素化合物:
シクロプロパン(C3)、シクロブタン(C4)、シクロペンタン(C5)、シクロヘキサン(C6)、シクロヘプタン(C7)、メチルシクロプロパン(C4)、ジメチルシクロプロパン(C5)、メチルシクロブタン(C5)、ジメチルシクロブタン(C6)、メチルシクロペンタン(C6)、ジメチルシクロペンタン(C7)、及びメチルシクロヘキサン(C7);
不飽和単環式炭化水素化合物:
シクロプロペン(C3)、シクロブテン(C4)、シクロペンテン(C5)、シクロヘキセン(C6)、メチルシクロプロペン(C4)、ジメチルシクロプロペン(C5)、メチルシクロブテン(C5)、ジメチルシクロブテン(C6)、メチルシクロペンテン(C6)、ジメチルシクロペンテン(C7)、及びメチルシクロヘキセン(C7);ならびに
飽和多環式炭化水素化合物:
ノルカラン(C7)、ノルピナン(C7)、ノルボルナン(C7)。
N1:アジリジン(C3)、アゼチジン(C4)、ピロリジン(テトラヒドロピロール)(C5)、ピロリン(例えば、3−ピロリン、2,5−ジヒドロピロール)(C5)、2H−ピロールまたは3H−ピロール(イソピロール、イソアゾール)(C5)、ピペリジン(C6)、ジヒドロピリジン(C6)、テトラヒドロピリジン(C6)、アゼピン(C7)、
O1:オキシラン(C3)、オキセタン(C4)、オキソラン(テトラヒドロフラン)(C5)、オキソール(ジヒドロフラン)(C5)、オキサン(テトラヒドロピラン)(C6)、ジヒドロピラン(C6)、ピラン(C6)、オキセピン(C7)、
S1:チイラン(C3)、チエタン(C4)、チオラン(テトラヒドロチオフェン)(C5)、チアン(テトラヒドロチオピラン)(C6)、チエパン(C7)、
O2:ジオキソラン(C5)、ジオキサン(C6)、及びジオキセパン(C7)、
O3:トリオキサン(C6)、
N2:イミダゾリジン(C5)、ピラゾリシン(ジアゾリジン)(C5)、イミダゾリン(C5)、ピラゾリン(ジヒドロピラゾール)(C5)、ピペラジン(C6)、
N1O1:テトラヒドロオキサゾール(C5)、ジヒドロオキサゾール(C5)、テトラヒドロイソオキサゾール(C5)、ジヒドロイソオキサゾール(C5)、モルホリン(C6)、テトラヒドロオキサジン(C6)、ジヒドロオキサジン(C6)、オキサジン(C6)、
N1S1:チアゾリン(C5)、チアゾリジン(C5)、チオモルホリン(C6)、
N2O1:オキサジアジン(C6)、
O1S1:オキサチオール(C5)及びオキサチアン(チオキサン)(C6)、ならびに、
N1O1S1:オキサチアジン(C6)。
カルボアリール基の例として、ベンゼン(すなわち、フェニル)(C6)、ナフタレン(C10)、アズレン(C10)、アントラセン(C14)、フェナントレン(C14)、ナフタセン(C18)、及びピレン(C16)に由来するものが挙げられるが、これらに限定されない。
N1:ピロール(アゾール)(C5)、ピリジン(アジン)(C6)、
O1:フラン(オキソール)(C5)、
S1:チオフェン(チオール)(C5)、
N1O1:オキサゾール(C5)、イソオキサゾール(C5)、イソオキサジン(C6)、
N2O1:オキサジアゾール(フラザン)(C5)、
N3O1:オキサトリアゾール(C5)、
N1S1:チアゾール(C5)、イソチアゾール(C5)、
N2:イミダゾール(1,3−ジアゾール)(C5)、ピラゾール(1,2−ジアゾール)(C5)、ピリダジン(1,2−ジアジン)(C6)、ピリミジン(1,3−ジアジン)(C6)(例えば、シトシン、チミン、ウラシル)、ピラジン(1,4−ジアジン)(C6)、
N3:トリアゾール(C5)、トリアジン(C6)、及び、
N4:テトラゾール(C5)。
C9(2つの縮合環を含む)として、ベンゾフラン(O1)、イソベンゾフラン(O1)、インドール(N1)、イソインドール(N1)、インドリジン(N1)、インドリン(N1)、イソインドリン(N1)、プリン(N4)(例えば、アデニン、グアニン)、ベンズイミダゾール(N2)、インダゾール(N2)、ベンゾオキサゾール(N1O1)、ベンゾイソオキサゾール(N1O1)、ベンゾジオキソール(O2)、ベンゾフラザン(N2O1)、ベンゾトリアゾール(N3)、ベンゾチオフラン(S1)、ベンゾチアゾール(N1S1)、ベンゾチアジアゾール(N2S)に由来するもの;
C10(2つの縮合環を含む)として、クロメン(O1)、イソクロメン(O1)、クロマン(O1)、イソクロマン(O1)、ベンゾジオキサン(O2)、キノリン(N1)、イソキノリン(N1)、キノリジン(N1)、ベンゾオキサジン(N1O1)、ベンゾジアジン(N2)、ピリドピリジン(N2)、キノキサリン(N2)、キナゾリン(N2)、シンノリン(N2)、フタラジン(N2)、ナフチリジン(N2)、プテリジン(N4)に由来するもの;
C11(2つの縮合環を含む)として、ベンゾジアゼピン(N2)に由来するもの;
C13(3つの縮合環を含む)として、カルバゾール(N1)、ジベンゾフラン(O1)、ジベンゾチオフェン(S1)、カルボリン(N2)、ペリミジン(N2)、ピリドインドール(N2)に由来するもの;ならびに
C14(3つの縮合環を含む)として、アクリジン(N1)、キサンテン(O1)、チオキサンテン(S1)、オキサントレン(O2)、フェノキサチイン(O1S1)、フェナジン(N2)、フェノキサジン(N1O1)、フェノチアジン(N1S1)、チアントレン(S2)、フェナントリジン(N1)、フェナントロリン(N2)、フェナジン(N2)に由来するもの。
1つの態様において、抗体は、AXLに結合する抗体である。
実施形態によっては、抗体は、配列番号7のアミノ酸配列を持つVH CDR3を有するVHドメインを含む。実施形態によっては、VHドメインは、さらに、配列番号6のアミノ酸配列を持つVH CDR2、及び/または配列番号5のアミノ酸配列を持つVH CDR1を含む。実施形態によっては、抗体は、配列番号5のアミノ酸配列を持つVH CDR1、配列番号6のアミノ酸配列を持つVH CDR2、及び配列番号7のアミノ酸配列を持つVH CDR3を有するVHドメインを含む。好適な実施形態において、抗体は、配列番号1に記載の配列を有するVHドメインを含む。
実施形態によっては、抗体は、配列番号15のアミノ酸配列を持つVH CDR3を有するVHドメインを含む。実施形態によっては、VHドメインは、さらに、配列番号14のアミノ酸配列を持つVH CDR2、及び/または配列番号13のアミノ酸配列を持つVH CDR1を含む。実施形態によっては、抗体は、配列番号13のアミノ酸配列を持つVH CDR1、配列番号14のアミノ酸配列を持つVH CDR2、及び配列番号15のアミノ酸配列を持つVH CDR3を有するVHドメインを含む。
「抗体」という用語は、本明細書中、最も広義の意味で用いられ、具体的には、モノクローナル抗体、ポリクローナル抗体、二量体、多量体、多重特異性抗体(例えば、二重特異性抗体)、無傷抗体、及び抗体断片を包含するが、ただし、それらが所望の生物活性を示す、例えば、AXLに結合する能力を持つ限りにおいてである。抗体は、マウス抗体、ヒト抗体、ヒト化抗体、キメラ抗体、または他の種由来抗体が可能である。抗体とは、免疫系により産生される、特定の抗原を認識してそれに結合することができるタンパク質である。(Janeway, C., Travers, P., Walport, M., Shlomchik(2001)Immuno Biology, 5th Ed., Garland Publishing, New York)。標的抗原は、一般に、複数の抗体のCDRで認識される多数の結合部位(エピトープとも呼ばれる)を有する。異なるエピトープに特異的に結合する抗体は、それぞれ異なる構造を有する。すなわち、1つの抗原は、1つより多い対応する抗体を有する可能性がある。抗体として、全長免疫グロブリン分子または全長免疫グロブリン分子の免疫学的活性部分、すなわち、関心対象の標的の抗原に免疫特異的に結合する抗原結合部位またはその一部分を有する分子が挙げられ、そのような標的として、がん細胞または自己免疫疾患に関連した自己免疫抗体を産生する細胞が挙げられるが、これらに限定されない。免疫グロブリンは、任意の型(例えば、IgG、IgE、IgM、IgD、及びIgA)、クラス(例えば、IgG1、IgG2、IgG3、IgG4、IgA1、及びIgA2)、またはサブクラス、あるいはアロタイプ(例えば、ヒトG1m1、G1m2、G1m3、非G1m1[これは、G1m1以外の任意のアロタイプである]、G1m17、G2m23、G3m21、G3m28、G3m11、G3m5、G3m13、G3m14、G3m10、G3m15、G3m16、G3m6、G3m24、G3m26、G3m27、A2m1、A2m2、Km1、Km2、及びKm3)の免疫グロブリン分子が可能である。免疫グロブリンは、任意の種由来のものが可能であり、ヒト、マウス、またはウサギ起原が挙げられる。
本明細書中開示される抗体は、修飾可能である。例えば、ヒト対象に対するそれらの免疫原性を低下させるためである。修飾は、当業者によく知られた多数の技法のいずれかを用いて達成可能である。そのような技法のいくつかを、以下でより詳細に説明する。
非ヒト抗体または抗体断片のin vivo免疫原性を低下させる技法として、「ヒト化」と呼ばれるものが挙げられる。
この技法では、ヒト化抗体は、ヒト免疫グロブリン(レシピエント抗体)の相補性決定領域(CDR)由来の残基が、所望の性質を有する、マウス、ラット、ラクダ、ウシ、ヤギ、またはウサギなどの非ヒト種(ドナー抗体)のCDR由来の残基で置換されているヒト免疫グロブリン(レシピエント抗体)である(実際には、非ヒトCDRが、ヒトフレームワークに「移植」されている)。場合によっては、ヒト免疫グロブリンのフレームワーク領域(FR)残基が、相当する非ヒト残基で置換されている(これは、例えば、特定のFR残基が抗原結合に対して大きな効果を有する場合などにそうなる可能性がある)。
この方法は、特定のエピトープに対して特異的な所定の非ヒト抗体のVHまたはVLドメインをヒトVHまたはVLライブラリーと組み合わせることからなり、特異的ヒトVドメインは、関心対象の抗原に対して選択される。次いで、この選択されたヒトVHを、VLライブラリーと組み合わせて、完全なヒトVH×VLの組み合わせを作成する。この方法は、Nature Biotechnology (N.Y.) 12,(1994)899−903に記載されている。
この方法では、ヒト抗体由来のアミノ酸配列の2つ以上のセグメントを、最終抗体分子内にひとまとめにする。最終抗体分子は、複数のヒトVH及びVL配列セグメントを、ヒトT細胞エピトープを制限または回避する組み合わせで、最終複合抗体V領域内にひとまとめにすることにより、構築される。必要な場合は、T細胞エピトープに寄与するまたはこれをコードするV領域セグメントを、T細胞エピトープを回避する代替セグメントに交換することにより、T細胞エピトープを制限または回避する。この方法は、US2008/0206239A1に記載される。
この方法は、ヒト(または他の二次種)T細胞エピトープを、治療用抗体(または他の分子)のV領域から除去することを含む。治療用抗体V領域配列を、例えば、MHC結合モチーフのデータベース(www.wehi.edu.auがホストである「モチーフ」データベースなど)と比較することで、MHCクラスII結合モチーフの存在について分析する。あるいは、MHCクラスII結合モチーフは、Altuviaらにより記載される方法(J. Mol. Biol. 249 244−250(1995))などのコンピューターによるスレッド化法を用いて同定することができる。これらの方法では、V領域配列由来の連続重複ペプチドを、それらのMHCクラスIIタンパク質との結合エネルギーについて試験する。次いで、このデータを、連続して存在するペプチドと関連する他の配列特性についての情報(両親媒性、ロスバードモチーフ(Rothbard motif)、ならびにカテプシンB及び他のプロセシング酵素による切断部位など)とまとめることができる。
この方法は、以下を含む:
(a)非ヒト(例えば、齧歯類)抗体(またはその断片)の可変領域の三次元モデルを構築することにより、非ヒト抗体可変領域の高次立体構造を決定する;
(b)十分な数の非ヒト及びヒト抗体の可変領域重鎖及び軽鎖でのX線結晶構造解析に基づく構造から、相対的到達性分布を用いて、配列アラインメントを作成して、アラインメント位置が、十分な数の非ヒト抗体重鎖及び軽鎖の98%において同一である、重鎖及び軽鎖のフレームワーク位置の組を得る;
(c)工程(b)で作成したフレームワーク位置の組を用いて、ヒト化しようとする非ヒト抗体について、重鎖及び軽鎖の表面露出アミノ酸残基の組を定義する;
(d)ヒト抗体アミノ酸配列から、工程(c)で定義した表面露出アミノ酸残基の組との相同性が最も高い重鎖及び軽鎖の表面露出アミノ酸残基の組を同定するが、このヒト抗体由来の重鎖及び軽鎖は、天然に対形成するかどうかは問わない;
(e)ヒト化しようとする非ヒト抗体のアミノ酸配列において、工程(c)で定義した重鎖及び軽鎖の表面露出アミノ酸残基の組を、工程(d)で同定した重鎖及び軽鎖の表面露出アミノ酸残基の組と置換する;
(f)工程(e)で指定される置換から得られる非ヒト抗体の可変領域の三次元モデルを構築する;
(g)工程(a)及び工程(f)で構築した三次元モデルを比較することにより、ヒト化しようとする非ヒト抗体の相補性決定領域のいずれかの残基のいずれかの原子から5オングストローム内にあるいずれかのアミノ酸残基を、工程(c)または工程(d)で同定した組から同定する;ならびに
(h)工程(g)で同定したいずれかの残基を、ヒトアミノ酸残基から元々の非ヒトアミノ酸残基に交換し、それにより、表面露出アミノ酸残基の非ヒト抗体ヒト化の組を確定させる;ただし、工程(a)は、必ずしも最初に行う必要はないが、工程(g)の前に行わなければならない。
この方法は、非ヒト配列を、機能的ヒト生殖系列遺伝子レパートリーと比較する。これらのヒト遺伝子の中から、非ヒト配列と同一または密接に関連する標準構造をコードするものを選択する。選択したこれらのヒト遺伝子の中から、CDR内で最も高い相同性を持つものをFRドナーとして選択する。最後に、非ヒトCDRをこれらのヒトFRに移植する。この方法は、WO2005/079479A2に記載されている。
この方法は、非ヒト(例えば、マウス)配列を、ヒト生殖系列遺伝子のレパートリーと比較し、差異を、ヒトストリング含有量(HSC)として点数付けする。HSCは、潜在的MHC/T細胞エピトープのレベルで配列を定量する。次いで、標的配列を、全体的な相同性尺度を用いるのではなく、標的配列のHSCを最大にするようにヒト化することで、複数の多様なヒト化変異型を作成する(Molecular Immunology, 44,(2007)1986−1998に記載されている)。
非ヒト抗体のCDRを、全てが既知の重鎖及び軽鎖ヒト生殖系列遺伝子フレームワークを包含するcDNAプールと、インフレームで融合させる。次いで、ヒト化抗体を、例えば、ファージ提示型抗体ライブラリーをパニングすることで選択する。この方法は、Methods 36, 43−60(2005)に記載されている。
薬物リンカーと複合体形成させるための抗体は、3工程プロセスで調製することができる:
1)コアN−グリカンを有する抗体(Ab)を、適切な発現系(例えば、CHO細胞株)で発現させる。コアN−グリカンは、典型的には、Kabat命名体系に従って重鎖のAsn−297で複合体形成する;
2)全てのグリカンアイソフォーム(複合型、ハイブリッド型、高マンノース型)を、エンドグリコシダーゼでトリミングして、核GlcNAcを残す;及び
3)核GlcNAcに、薬物リンカーと複合体形成させるためのアジド基を抱えたN−アセチルガラクトース残基を、酵素で転移させる。
X
実施形態によっては、Xは、単結合である。
他の実施形態において、Xは、−CH2−である。
さらなる実施形態において、Xは、−C2H4−である。
これらの実施形態の他のものにおいて、nは、2である。
これらの実施形態のさらなるものにおいて、nは、4である。
1つの実施形態において、R7は、メチルである。
別の実施形態において、R7は、フェニルである。
C2とC3の間に二重結合がある場合、R2は、以下からなる群より選択される:
(a)C5−10アリール基、この基は、以下からなる群より選択される1つまたは複数の置換基により任意選択で置換される:ハロ、ニトロ、シアノ、エーテル、C1−7アルキル、C3−7ヘテロシクリル、及びビス−オキシ−C1−3アルキレン;
(b)C1−5飽和脂肪族アルキル;
(c)C3−6飽和シクロアルキル;
(d)
(e)
(f)
R2がC5−10アリール基の場合のR2置換基がハロである場合、これは、好ましくは、FまたはClであり、より好ましくはClである。
R2は、
R2に関する上記の優先事項は、R12にも等しく当てはまる。
薬物担持数は、抗体、例えば抗体あたりのPBD薬物の平均数である。
特に記載がない限り、これら置換基の周知のイオン、塩、溶媒和物、及び保護形も、上記に含まれる。例えば、カルボン酸(−COOH)についての言及は、アニオン(カルボキシラート)形(−COO−)、その塩または溶媒和物、ならびに通常の保護形も含む。同様に、アミノ基についての言及は、プロトン化形(−N+HR1R2)、その塩または溶媒和物、例えば、塩酸塩、ならびにアミノ基の通常の保護形も含む。同様に、ヒドロキシル基についての言及は、アニオン形(−O−)、その塩または溶媒和物、ならびに通常の保護形も含む。
活性化合物の相当する塩、例えば、薬学上許容される塩を調製、精製、及び/または取り扱うことが、好都合であるまたは望ましい場合がある。薬学上許容される塩の例は、Berge, et al., J. Pharm. Sci., 66, 1−19(1977)に記載される。
活性化合物の相当する溶媒和物を調製、精製、及び/または取り扱うことが、好都合であるまたは望ましい場合がある。「溶媒和物」という用語は、本明細書中、従来の意味で使用され、溶質(例えば、活性化合物、活性化合物の塩)と溶媒の複合体を示す。溶媒が水である場合、溶媒和物は、都合よく、水和物、例えば、一水和物、二水和物、三水和物などと称することができる。
本発明のある特定の化合物は、1つまたは複数の特定の幾何異性体、光学異性体、鏡像異性体、ジアステレオ異性体、エピ異性体、アトロプ異性体、立体異性体、互変異性体、配座異性体、またはアノマー異性体形で存在することが可能であり、そのような異性体形として、シス及びトランス形;E及びZ形;c、t、及びr形;エンド及びエキソ形;R、S、及びメソ形;D及びL形;d及びl形;(+)及び(−)形;ケト、エノール、及びエノラート形;シン及びアンチ形;シンクリナル及びアンチクリナル形;α及びβ形;アキシャル及びエカトリアル形;舟、いす、ねじれ、封筒、及び半いす形;ならびにそれらの組み合わせが挙げられるが、これらに限定されず、本明細書中以下、まとめて「異性体」(または異性体形)と称する。
In vitro細胞増殖アッセイ
一般に、抗体薬物複合体(ADC)の細胞毒性または細胞分裂阻害活性は、以下により測定される:受容体タンパク質を有する哺乳類細胞を、細胞培地中で、ADCの抗体と接触させる;細胞を、約6時間〜約5日間の期間、培養する;そして、細胞生存度を測定する。細胞に基づくin vitroアッセイを用いて、生存度(増殖)、細胞毒性、及び本発明のADCのアポトーシス誘導(カスパーゼ活性)を測定する。
本発明の複合体は、標的部位にPBD化合物を提供するために用いることができる。
本発明の複合体は、治療方法において使用可能である。同じく提供されるのは、治療方法であり、本方法は、治療を必要としている対象に、治療上有効量の本発明の複合体化合物を投与することを含む。「治療上有効量」という用語は、患者に対して有益性を示すのに十分な量である。そのような有益性は、少なくとも1種の症候の少なくとも寛解である場合がある。投与される実際量、ならびに投与の速度及び時間経過は、治療されるものの性質及び重篤度に依存することになる。治療の処方、例えば、投薬量の決定は、一般開業医及び他の医療医師の担当範囲に含まれる。
化学療法薬のさらなる例として、以下が挙げられる:オキサリプラチン(エロキサチン(ELOXATIN)(登録商標)、Sanofi)、ボルテゾミブ(ベルケイド(登録商標)、Millennium Pharm.)、スーテント(スニチニブ(登録商標)、SU11248、Pfizer)、レトロゾール(フェマーラ(登録商標)、Novartis)、イマチニブメシル酸塩(グリベック(登録商標)、Novartis)、XL−518(MEK阻害剤、Exelixis、WO2007/044515)、ARRY−886(MEK阻害剤、AZD6244、Array BioPharma、Astra Zeneca)、SF−1126(PI3K阻害剤、Semafore Pharmaceuticals)、BEZ−235(PI3K阻害剤、Novartis)、XL−147(PI3K阻害剤、Exelixis)、PTK787/ZK222584(Novartis)、フルベストラント(フェソロデックス(登録商標)、AstraZeneca)、ロイコボリン(フォリン酸)、ラパマイシン(シロリムス、ラパミューン(登録商標)、Wyeth)、ラパチニブ(TYKERB(登録商標)、GSK572016、Glaxo Smith Kline)、ロナファルニブ(SARASAR(商標)、SCH66336、Schering Plough)、ソラフェニブ(ネクサバール(登録商標)、BAY43−9006、Bayer Labs)、ゲフィチニブ(イレッサ(登録商標)、AstraZeneca)、イリノテカン(カンプトサール(CAMPTOSAR)(登録商標)、CPT−11、Pfizer)、チピファルニブ(ザルネストラ(ZARNESTRA)(商標)、Johnson & Johnson)、アブラキサン(商標)(クレモホールを含まない)、すなわちパクリタキセルのアルブミン改変ナノ粒子製剤(American Pharmaceutical Partners、Schaumberg、Il)、バンデタニブ(rINN、ZD6474、ザクティマ(ZACTIMA)(登録商標)、AstraZeneca)、クロラムブシル、AG1478、AG1571(SU5271;Sugen)、テムシロリムス(トーリセル(登録商標)、Wyeth)、パゾパニブ(GlaxoSmithKline)、カンホスファミド(TELCYTA(登録商標)、Telik)、チオテパ及びシクロホスファミド(シトキサン(登録商標)、NEOSAR(登録商標));スルホン酸アルキル、例えば、ブスルファン、インプロスルファン、及びピポスルファンなど;アジリジン、例えば、benzodopa、カルボコン、meturedopa、及びuredopaなど;エチレンイミン及びメチラメラミン(methylamelamine)、例えばアルトレタミン、トリエチレンメラミン、トリエチレンホスホルアミド、トリエチレンチオホスホルアミド、及びトリメチロメラミンなど;アセトゲニン(特に、ブラタシン及びブラタシノン(bullatacinone));カンプトテシン(合成類似体トポテカンを含む);ブリオスタチン;callystatin;CC−1065(その合成類似体であるアドゼレシン、カルゼレシン、及びビゼレシンを含む);クリプトフィシン(特に、クリプトフィシン1及びクリプトフィシン8);ドラスタチン;ディオカルマイシン(合成類似体である、KW−2189及びCB1−TM1を含む);エリュテロビン;パンクラチスタチン;サルコジクチイン;スポンギスタチン;ナイトロジェンマスタード、例えば、クロラムブシル、クロルナファジン、クロロホスファミド、エストラムスチン、イホスファミド、メクロレタミン、メクロレタミンオキシド塩酸塩、メルファラン、ノブエンビキン、フェネステリン、プレドニムスチン、トロフォスファミド、ウラシルマスタードなど;ニトロソ尿素、例えば、カルムスチン、クロロゾトシン、ホテムスチン、ロムスチン、ニムスチン、及びラニムスチンなど;抗生物質、例えば、エンジイン抗生物質など(例えば、カリチアマイシン、カリチアマイシンガンマ1I、カリチアマイシンオメガI1(Angew Chem. Intl. Ed. Engl.(1994)33:183−186);ジネマイシン、ジネマイシンA;ビスホスホナート、例えば、クロドロネートなど;エスペラマイシン;ならびにネオカルジノスタチン発色団及び関連する色素タンパク質エンジイン抗生物質発色団など)、アクラシノマイシン、アクチノマイシン、アントラマイシン、アザセリン、ブレオマイシン、カクチノマイシン、カラビシン、カルミノマイシン、カルジノフィリン、クロモマイシン、ダクチノマイシン、ダウノルビシン、デトルビシン、6−ジアザ−5−オキソ−L−ノルロイシン、モルホリノ−ドキソルビシン、シアノモルホリノ−ドキソルビシン、2−ピロリノ−ドキソルビシン、及びデオキシドキソルビシン)、エピルビシン、エソルビシン、イダルビシン、ネモルビシン、マルセロマイシン、マイトマイシン、例えばマイトマイシンCなど、ミコフェノール酸、ノガラマイシン、オリボマイシン、ペプロマイシン、ポルフィロマイシン、ピューロマイシン、クエラマイシン、ロドルビシン、ストレプトニグリン、ストレプトゾシン、ツベルシジン、ウベニメックス、ジノスタチン、ゾルビシン;抗代謝産物、例えば、メトトレキセート及び5−フルオロウラシル(5−FU)など;葉酸類似体、例えば、デノプテリン、メトトレキセート、プテロプテリン、トリメトレキセートなど;プリン類似体、例えば、フルダラビン、6−メルカプトプリン、チアミプリン、チオグアニンなど;ピリミジン類似体、例えば、アンシタビン、アザシチジン、6−アザウリジン、カルモフル、シタラビン、ジデオキシウリジン、ドキシフルリジン、エノシタビン、フロクスウリジンなど;アンドロゲン、例えば、カルステロン、ドロモスタノロンプロピオン酸塩、エピチオスタノール、メピチオスタン、テストラクトンなど;抗副腎皮質薬、例えば、アミノグルテチミド、ミトタン、トリロスタン;葉酸補充剤、例えば、フォリン酸など;アセグラトン;アルドホスファミドグリコシド;アミノレブリン酸;エニルウラシル;アムサクリン;ベストラブシル;ビサントレン;エダトレキサート;デフォファミン(defofamine);デメコルチン;ジアジコン;エルフォルニチン;エリプチニウム酢酸塩(elliptinium acetate);エポシロン;エトグルシド;硝酸ガリウム;ヒドロキシ尿素;レンチナン;ロニダミン(lonidainine);マイタンシノイド、例えば、マイタンシン及びアンサミトシンなど;ミトグアゾン;ミトキサントロン;モピダモール;ニトラエリン(nitraerine);ペントスタチン;フェナメット;ピラルビシン;ロソキサントロン;ポドフィリン酸;2−エチルヒドラジド;プロカルバジン;PSK(登録商標)多糖複合体(JHS Natural Products、Eugene、OR);ラゾキサン;リゾキシン;シゾフィラン;スピロゲルマニウム;テヌアゾン酸;トリアジコン;2,2’,2’’−トリクロロトリエチルアミン;トリコテンセン(特に、T−2トキシン、ベラクリン(verracurin)A、ロリジンA、及びアングイジン);ウレタン;ビンデシン;ダカルバジン;マンノムスチン;ミトブロニトール;ミトラクトール;ピポブロマン;ガシトシン(gacytosine);アラビノシド(「Ara−C」);シクロホスファミド;チオテパ;6−チオグアニン;メルカプトプリン;メトトレキセート;白金類似体、例えば、シスプラチン及びカルボプラチンなど;ビンブラスチン;エトポシド(VP−16);イホスファミド;ミトキサントロン;ビンクリスチン;ビノレルビン(ナベルビン(登録商標));ノバントロン;テニポシド;エダトレキサート;ダウノマイシン;アミノプテリン;カペシタビン(ゼローダ(登録商標)、Roche);イバンドロネート;CPT−11;トポイソメラーゼ阻害剤RFS2000;ジフルオロメチルオルニチン(DMFO);レチノイド、例えば、レチノイン酸など;ならびに上記のいずれかのものの薬学上許容される塩、酸、及び誘導体。
同じく「化学療法薬」の定義に含まれるのは、治療用抗体、例えば、アレムツズマブ(キャンパス)、ベバシズマブ(アバスチン(登録商標)、Genentech);セツキシマブ(アービタックス(登録商標)、Imclone);パニツムマブ(ベクティビックス(登録商標)、Amgen)、リツキシマブ(リツキサン(登録商標)、Genentech/Biogen Idec)、オファツムマブ(アーゼラ(登録商標)、GSK)、ペルツズマブ(パージェタ(商標)、OMNITARG(商標)、2C4、Genentech)、トラスツズマブ(ハーセプチン(登録商標)、Genentech)、トシツモマブ(ベキサール、Corixia)、及び抗体薬物複合体である、ゲムツズマブオゾガマイシン(マイロターグ(登録商標)、Wyeth)などである。
複合体化合物は、単独で使用する(例えば、投与する)ことが可能であるものの、それを組成物または配合物として存在させることが望ましい場合が多い。
当業者には当然のことながら、複合体化合物、及び複合体化合物を含む組成物の適切な投薬量は、患者ごとに異なる可能性がある。最適な投薬量の決定は、一般に、治療効果のレベルとあらゆるリスクまたは危険な副作用との兼ね合いが関与することになる。選択される投薬量レベルは、様々な要因に依存することになり、そのような要因として、特定化合物の活性、投与経路、投与時間、化合物の排泄速度、治療期間、併用される他の薬物、化合物、及び/または材料、症状の重篤度、ならびに患者の種族、性別、年齢、体重、状態、全身の健康状態、及び以前の治療歴が挙げられるが、これらに限定されない。化合物の量及び投与経路は、最終的に、医師、獣医師、または臨床医の判断に任されることになるが、一般に、投薬量は、実質的に有害なまたは危険な副作用を引き起こすことなく所望の効果を達成する局所濃度を作用部位で達成するように選択されることになる。
「治療」という用語は、症状の治療の文脈において本明細書中使用される場合、ヒトであるか動物であるか(例えば、獣医学用途において)に関わらず、概して、ある所望の治療効果、例えば、症状の増悪の阻害などが達成される治療及び療法に関し、この用語は、増悪の速度の低下、増悪の速度の停止、症状の退行、症状の寛解、及び症状の治癒を含む。予防的手段としての治療(すなわち、予防、防止)も含まれる。
本発明の抗体薬物複合体は、以下の薬物リンカー:
対象/患者は、動物、哺乳類、有胎盤哺乳類、有袋類(例えば、カンガルー、マーモット)、単孔類(例えば、カモノハシ)、齧歯類(例えば、モルモット、ハムスター、ラット、マウス)、マウス類(例えば、マウス)、ウサギ類(例えば、ウサギ)、鳥類(例えば、トリ)、イヌ類(例えば、イヌ)、ネコ類(例えば、ネコ)、ウマ類(例えば、ウマ)、ブタ類(例えば、ブタ)、ヒツジ類(例えば、ヒツジ)、ウシ類(例えば、ウシ)、霊長類、真猿類(例えば、サルまたは類人猿)、サル類(例えば、マーモセット、ヒヒ)、類人猿(例えば、ゴリラ、チンパンジー、オランウータン、テナガザル)、またはヒトの場合がある。
反応条件
ワンポットグリカン再構築のための反応条件は以下の通りである:
15mg/mlの抗体(約0.1mM)
0.15mg/mLのStreptococcus pyogenes由来のEndoSH(1%w/w)
1.13mg/mLのHis−TnGalNAcT(7.5%w/w)ガラクトース−N−アセチルトランスフェラーゼ(GalNAcT)酵素
2.5mMの6−N3GalNAc−UDP(IgGに対して25当量)
10mMのMnCl2
25mMのTrisHCl ph8.0
150mMのNaCl
30°Cで16時間インキュベートする
この例は25mg規模であり、必要に応じて変更することができる。個々の成分は順番に添加され、混合される。
106.5μLの25mMのTris pH8.0、150mMのNaCl(1667μLの最終体積を得るため)
1mLの、25mMのTris pH8.0、150mMのNaCl中25mg/mLの抗体
71.4μLの、25mMのTris pH8.0中3.5mg/mLのEndoSH
389μLの、25mMのTris pH8.0中4.82 mg/mLのHis−TnGalNAcT
16.7μLの、MQ中1MのMnCl2
83.4μLの、MQ中0.1Mの6−N3GalNAc−UDP
緩衝液
結合/洗浄緩衝液(TBS pH7.5):
20mMのTrisHCl ph7.5
150mMのNaCl
エンドトキシン除去のための洗浄緩衝液(TBS pH7.5+Triton−X100):
20mMのTrisHCl pH7.5
150mMのNaCl
0.2%のTriton X−100
溶出緩衝液:
0.1Mのグリシン pH2.7
CIP緩衝液:
0.5MのNaOH
1.試料を添加する前にカラムを清浄化するために、以下の緩衝液でMabSelectSure 5mLカラムを洗浄する(5mL/分):
少なくとも5カラム体積(CV)のTBS pH7.5でカラムを洗浄する
15CVの0.5MのNaOHでカラムを洗浄する
5CVのTBS pH 7.5でカラムを洗浄する
5CVのグリシンpH2.7でカラムを洗浄する
中性pHが得られるまで、TBS pH7.5でカラムを洗浄する
2. 遠心分離(4000gで5分間)または濾過(0.22または0.45μmのフィルター)で反応混合物から沈殿物を除去する
3. 2mL/分で試料を添加し、5mL/分で以下の工程を実施する:
少なくとも20CVのTBS=0.2%のTriton X−100で洗浄する
少なくとも20CVのTBSで洗浄する
0.1Mのグリシンph2.7で溶出する
4. 1/5体積の1MのTric−HCl ph8.0を添加して混合することによって、画分をすぐに中性化する
5. 4℃で3回の50体積以上のPBS pH7.4に対して試料を透析する(1時間以上を3回)
6. スピンフィルター装置を使用してサンプルを約20mg/mLに濃縮する
反応条件
15mg/mlのアジド修飾抗体(0.1MのIgG)
0.5mMの化合物4(IgGに対して5当量=アジドあたり2.5当量)
10%のDMFまたは25%のプロピレンジコール
PBS pH7.4
1. 9体積の、PBS pH7中16.67mg/mlのアジド修飾抗体を添加する
2. 1体積の、DMF中5mMの化合物4を添加してすぐに混合する
3. 一晩インキュベートする
4. RP−HPLC及びMSで変換を測定する
試料調製
カラムに添加する前に以下の要件を満たすべきである:
5%以下の有機溶媒
CVの3%以下の総試料体積(Superdex 200 10/300 GLに対して720μL以下、及びSuperdex 200 HiLoad 26/600に対して10ml以下)
沈殿物が存在しない
1. 5%以下の最終有機溶媒濃度になるようにpH7.4のPBSでサンプルを希釈する
2. 体積がCVの3%を超える場合、サンプルをAmicon Ultra遠心フィルター(MWCO 10kDa)を使用して濃縮する
3. 遠心分離(卓上型遠心分離機で、13000rpmで10分間)によって潜在的沈殿物を除去する
精製は、Akta Purifier−10でSuperdex 200 10/300 GLカラム(CV=23ml、GE healthcare)を使用して行った。以下の洗浄工程を0.5ml/分の流速で実施する:
1CVの水でカラムを洗浄する
1CVの0.5MのNaOHでカラムを洗浄する
中性pHが得られるまで、カラムをPBS pH7.4(Sigma,D8537)で平衡化する。
試料を0.5ml/分のPBS pH7.4と共に注入し、1mlの画分を集める(総実行=1.5CV)。単量体画分をプールし、3回の1Lの配合物緩衝液(30mMのヒスチジン、200mMのソルビトール、0.02%(w/v)のtween−20、pH 6.0)に対して4℃で透析する。試料を、0.22μmフィルターを使用して濾過滅菌し、液体窒素を使用して急速冷凍し、そして−80℃で保存する。
H1299細胞をATCCから取得した(ATCC番号CRL−5803)。H1299培地は、10%のGibco FBSを補充したダルベッコ改変イーグル培地(DMEM)であった。細胞を加湿インキュベーター中、37℃、5%CO2で増殖させた。細胞懸濁液を、96ウェル平底プレート中に分注した(ウェルあたり104細胞)。ADC原液の8×10倍希釈液のセットを、細胞培地中で調製した。各ADC希釈液(ウェルあたり50μl)を、96ウェルプレートの細胞懸濁液の入った4つの複製ウェルに分注した。対照ウェルは、培地のみを同体積で添加することによって調製した。96時間インキュベートした後、細胞生存率を、製造業者の取扱説明書に従って、3−(4,5−ジメチルチアゾール−2−イル)−5−(3−カルボキシメトキシ−フェニル)−2−(4−スルホフェニル)−2H−テトラゾリウム(MTS)アッセイ(Promega、カタログ番号G5421)により測定した。吸光度は490nmで測定した。細胞生存率(%)は、4つの対照ウェルにおける平均吸光度(100%)と比較した4つのADC処理ウェルにおける平均吸光度から計算した。3回の反復実験の平均データから用量反応曲線を作成し、Prism(GraphPad, San Diego, CA)を使用して可変勾配を有するシグモイド用量反応曲線にデータをフィッティングすることによってEC50値を決定した。エラーバーは標準偏差(SD)を示す。
MaxisorpプレートをヒトAxl抗原(50ng/ウェル;PBS中バッチ)で一晩+4℃でコーティングした。非反応性部位をSuperBlock緩衝液(+4℃または室温で一晩)でブロックした。ADC原液の8×3倍または5倍希釈液のセットを試料緩衝液/PBS/Tween20中で調製した。各ADC希釈液(60μL/ウェル)をコーティングされたプレートの4つの複製ウェルに分注した。対照ウェルを、同体積の試料緩衝液/PBS/Tween20を添加することによって調製した。抗ヒトカッパIgG−西洋ワサビペルオキシダーゼ(HRP)複合体を二次抗体として使用した(1:5000、1時間、室温)。HRPは、1−Step Ultra TMB−ELISA基質溶液(75μL/ウェル;室温で5分間)で検出した。基質反応を0.6MのHCl(75μL/ウェル)で停止させた。吸光度は、450nmのペルオキシダーゼプログラムを用いてEnvisionにおいて450nmで測定した。抗原結合曲線は、Prism(GraphPad, San Diego, CA)を用いた3回の反復実験の平均データから作成した。得られた結果を図1に示すが、図中:▲はConjAである。エラーバーは平均値の標準偏差(SEM)を示す。ConjAはプレート上にコーティングされたAXLの細胞外ドメインに高い親和性で結合した。
5×106個のMDA−MB−231腫瘍細胞をメスの無胸腺ヌードマウスに皮下移植した。腫瘍体積が88〜172mm3に達したときに、ビヒクルまたは試験試料を用いたADC投与を開始した。ConjAを尾静脈注射により1mg/kgの用量レベルで1回静脈内(i.v.)投与した。投薬体積は10mL/kg体重であり、各動物個体の体重に合わせて増量した。各動物を、腫瘍体積が終了体積1500mm3に到達した時点で、または試験の終了日、いずれか先に訪れた時点で安楽死させた。試験期間中、動物の体重、あらゆる有害な徴候、処置に関連した副作用および臨床的徴候をモニターした。群の平均腫瘍体積の計算のために、以下の規則を適用した:動物が腫瘍サイズのために試験を終了したとき、その動物について記録された最終腫瘍体積をその後時点での平均体積を計算するために用いたデータと共に含めた。ある群の動物の50%未満のみが試験に残っているとき、腫瘍体積および体重の値は、群平均腫瘍体積/体重を計算するためには使用されなかった。Prism(GraphPad, San Diego, CA)をグラフ表示および統計分析に使用した。得られた結果を図2に示すが、図中、▲はConjAであり、
(外1)
はビヒクル単独である。エラーバーはSEMを示す。
方法
ConjA1を、単回静脈内用量のラット忍容性試験で評価した。オスsprague−dawleyラット(n=3/群)に、1日目、ConjAについて3及び6mg/kgで投与し、投与後21日目に死体解剖した。体重及び摂食量は、頻繁にモニタリングし、臨床病理学用に生存中サンプリング(8日目及び21日目に採血)及び薬物動態学用に繰り返しサンプリングを行った。死体解剖では、選択した臓器について、目視で観察し、重量を測定し、組織病理学検査が可能であれば保存した。
メス重症複合免疫不全マウス(Fox Chase SCID(登録商標)、CB17/Icr−Prkdcscid/IcrIcoCrl、Charles River)は、試験1日目において、10週齢であり、体重(BW)範囲は18.0〜21.6gであった。腫瘍移植当日、5×106のSN12C細胞(50%マトリゲル(登録商標)マトリクス(Corning(登録商標))含有リン酸緩衝生理食塩水に加えた細胞懸濁液0.1mL)を、各試験マウスの右側腹部に皮下移植した。SN12Cは、高レベルのAXL発現(細胞あたり約88,000コピー)を有するヒト腎細胞癌由来の異種移植モデルである。
腫瘍体積(mm3)=w2×1/2
式中、腫瘍のw=幅、及び1=長さ(mm)である。腫瘍の重さは、1mgが腫瘍体積1mm3に等しいという仮定を用いて推定可能である。
(外2)
はビヒクル単独であり;
(外3)
は1mg/kgで投与されたConjBであり;
(外4)
は0.3mg/kgで投与されたConjAであり;
(外5)
は0.6mg/kgで投与されたConjAであり;
(外6)
は1mg/kgで投与されたConjAである。
エラーバーはSEMを示す。
メス重症複合免疫不全マウス(Fox Chase SCID(登録商標)、CB17/Icr−Prkdcscid/IcrIcoCrl、Charles River)は、試験1日目において、9週齢であり、体重(BW)範囲は17.0〜22.5gであった。腫瘍移植当日、1×107 Karpas−299細胞(PBS中0.1mLの細胞懸濁液)を、各試験マウスの右側腹部に皮下移植した。
腫瘍体積(mm3)=w2×1/2
式中、腫瘍のw=幅、及び1=長さ(mm)である。腫瘍の重さは、1mgが腫瘍体積1mm3に等しいという仮定を用いて推定可能である。
Charles Riverからのメスnu/nuマウス(NU−Foxn1nu)は、0日目において、少なくとも8週齢であり、体重(BW)範囲は22.0〜30.0gであった。移植当日、腫瘍断片をヌードマウス内の異種移植から得た。ドナーマウスから取り出したのち、腫瘍を断片(3〜4mm辺長)に切断し、10%のペニシリン/ストレプトマイシンを含むPBS中に入れた。レシピエント動物をイソフルランの吸入により麻酔し、片側または両側の腹部に、腫瘍移植片を皮下移植した。
腫瘍体積(mm3)=w2×1/2
式中、w=腫瘍の幅、及び1=腫瘍の長さ(mm)である。
(外9)
はビヒクル単独であり;
(外10)
は1mg/kgで投与されたConjBであり;
(外11)
は0.3mg/kgで投与されたConjAであり;
(外12)
は0.6mg/kgで投与されたConjAであり;
(外13)
は1mg/kgで投与されたConjAである。
エラーバーはSEMを示す。垂直の点線は投与の開始を示す(1日目)。
Beijing AniKeeper Bio−Technology Co. Ltd.からのメスのBalb/cヌードマウスは、試験開始時に、5〜6週齢であり、体重範囲は20.2〜24.6gであった。移植断片(氷冷無血清RPMI1640培地中直径2〜3mm)を24匹のメスBalb/cヌードマウスの右側腹部に皮下播種した。
(外14)
はビヒクル単独であり;
(外15)
は1mg/kgで投与されたConjAであり;
(外16)
は1mg/kgで投与されたConjBであり;
エラーバーはSEMを示す。垂直の点線は投与の開始を示す(1日目)。
SN12CおよびKarpas−299細胞株におけるConjAおよびアイソタイプ対照ADC、ConjBのin vitro細胞毒性を比較した。Karpas−299はAXL陰性であり、SN12CはAXL陽性である。接着性SN12C細胞をトリプシン処理し、1mlの増殖培地に再懸濁し、穏やかに混合してから細胞密度を決定するため計数した。懸濁Karpas299細胞を前処理なしで計数した。細胞密度は、LUNA−II(商標)自動細胞計数器を用いてトリパンブルー排除アッセイにより複製して決定した。SN12C細胞懸濁液を細胞特異的増殖培地で1×104細胞/mlに希釈し、100μl/ウェルを滅菌白色96ウェル平底マイクロプレートに分注し、一晩インキュベートして細胞を接着させた。Karpas299細胞をADC適用と同一の日に播種した。
EIVLTQSPGTLSLSPGERATLSCSASSSVSSGNFHWYQQKPGLAPRLLIYRTSNLASGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQWSGYPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SYGMS
TISSGGSYTYYPDSVKG
HPIYYTYDDTMDY
SASSSVSSGNFH
RTSNLAS
QQWSGYPWT
RYWMS
EINPDSSTINYTPSLKD
PYYYGPFAY
KASQSVSFAGTSLMH
RASNLEA
QQSREYPRT
QVQLVESGGGVVQPGRSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVAEINPDSSTINYTPSLKDRFAISRDNSKNTLYLQMNSLRAEDTAVYYCASPYYYGPFAYWGQGTLVTVS
EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVAEINPDSSTINYTPSLKDRFTISRDNAKNSLYLQMNSLRAEDTAVYYCASPYYYGPFAYWGQGTLVTVS
EVQLLESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVSEINPDSSTINYTPSLKDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYYYGPFAYWGQGTLVTVS
EIVLTQSPLSLPVTPGEPASISCKASQSVSFAGTSLMHWYLQKPGQSPQLLIYRASNLEAGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQSREYPRTFGQGTKVEIK
MAWRCPRMGRVPLAWCLALCGWACMAPRGTQAEESPFVGNPGNITGARGLTGTLRCQLQVQGEPPEVHWLRDGQILELADSTQTQVPLGEDEQDDWIVVSQLRITSLQLSDTGQYQCLVFLGHQTFVSQPGYVGLEGLPYFLEEPEDRTVAANTPFNLSCQAQGPPEPVDLLWLQDAVPLATAPGHGPQRSLHVPGLNKTSSFSCEAHNAKGVTTSRTATITVLPQQPRNLHLVSRQPTELEVAWTPGLSGIYPLTHCTLQAVLSDDGMGIQAGEPDPPEEPLTSQASVPPHQLRLGSLHPHTPYHIRVACTSSQGPSSWTHWLPVETPEGVPLGPPENISATRNGSQAFVHWQEPRAPLQGTLLGYRLAYQGQDTPEVLMDIGLRQEVTLELQGDGSVSNLTVCVAAYTAAGDGPWSLPVPLEAWRPGQAQPVHQLVKEPSTPAFSWPWWYVLLGAVVAAACVLILALFLVHRRKKETRYGEVFEPTVERGELVVRYRVRKSYSRRTTEATLNSLGISEELKEKLRDVMVDRHKVALGKTLGEGEFGAVMEGQLNQDDSILKVAVKTMKIAICTRSELEDFLSEAVCMKEFDHPNVMRLIGVCFQGSERESFPAPVVILPFMKHGDLHSFLLYSRLGDQPVYLPTQMLVKFMADIASGMEYLSTKRFIHRDLAARNCMLNENMSVCVADFGLSKKIYNGDYYRQGRIAKMPVKWIAIESLADRVYTSKSDVWSFGVTMWEIATRGQTPYPGVENSEIYDYLRRGNRLKQPADCLDGLYALMSRCWELNPQDRPSFTELREDLENTLKALPPAQEPDEILYVNMDEGGGYPEPPGAAGGADPPTQPDPKDSCSCLTAAEVHPAGRYVLCPSTTPSPAQPADRGSPAAPGQEDGA
Claims (81)
- 以下の式(I)の複合体:
Ab−(DL)p (I)
であって、式中:
Abは、AXLに結合する抗体であり;
DLは、以下
Xは、単結合、−CH2−、及び−C2H4−からなる群より選択され;
nは、1〜8であり;
mは、0または1であり;
R7は、メチルまたはフェニルであり;
C2とC3の間に二重結合が存在する場合、R2は、以下からなる群より選択され:
(ia)C5−10アリール基、この基は、以下からなる群より選択される1つまたは複数の置換基により任意選択で置換され:ハロ、ニトロ、シアノ、エーテル、カルボキシ、エステル、C1−7アルキル、C3−7ヘテロシクリル、及びビス−オキシ−C1−3アルキレン;
(ib)C1−5飽和脂肪族アルキル;
(ic)C3−6飽和シクロアルキル;
(id)
(ie)
(if)
C2とC3の間に単結合が存在する場合、R2は、以下
C2’とC3’の間に二重結合がある場合、R12は、以下からなる群より選択され:
(iia)C5−10アリール基、この基は、以下からなる群より選択される1つまたは複数の置換基により任意選択で置換され:ハロ、ニトロ、シアノ、エーテル、カルボキシ、エステル、C1−7アルキル、C3−7ヘテロシクリル、及びビス−オキシ−C1−3アルキレン;
(iib)C1−5飽和脂肪族アルキル;
(iic)C3−6飽和シクロアルキル;
(iid)
(iie)
(iif)
C2’とC3’の間に単結合が存在する場合、R12は、以下
ならびにpは、1〜8である、
前記複合体。 - Xは、単結合である、請求項1に記載の複合体。
- Xは、−CH2−である、請求項1に記載の複合体。
- Xは、−C2H4−である、請求項1に記載の複合体。
- nは、1〜4である、請求項1から4のいずれか1項に記載の複合体。
- nは、1である、請求項5に記載の複合体。
- nは、2である、請求項5に記載の複合体。
- nは、4である、請求項5に記載の複合体。
- C2とC3の間には二重結合が存在し、かつR2は、C5−7アリール基である、請求項1から8のいずれか1項に記載の化合物。
- R2は、フェニルである、請求項9に記載の化合物。
- C2とC3の間には二重結合が存在し、かつR2は、C8−10アリール基である、請求項1から8のいずれか1項に記載の化合物。
- R2は、1つ〜3つの置換基を有する、請求項9から11のいずれか1項に記載の化合物。
- 前記置換基は、メトキシ、エトキシ、フルオロ、クロロ、シアノ、ビス−オキシ−メチレン、メチルピペラジニル、モルホリノ、及びメチルチオフェニルから選択される、請求項9から12のいずれか1項に記載の化合物。
- C2とC3の間には二重結合が存在し、かつR2は、C1−5飽和脂肪族アルキル基である、請求項1から8のいずれか1項に記載の化合物。
- R2は、メチル、エチル、またはプロピルである、請求項14に記載の化合物。
- C2とC3の間には二重結合が存在し、かつR2は、C3−6飽和シクロアルキル基である、請求項1から8のいずれか1項に記載の化合物。
- R2は、シクロプロピルである、請求項16に記載の化合物。
- 前記R2基の炭素原子の合計数は、4以下である、請求項18に記載の化合物。
- 前記R2基の炭素原子の合計数は、3以下である、請求項19に記載の化合物。
- R21、R22、及びR23のうち1つはHであり、その他の2つの基は、H、C1−3飽和アルキル、C2−3アルケニル、C2−3アルキニル、及びシクロプロピルから選択される、請求項18から20のいずれか1項に記載の化合物。
- R21、R22、及びR23のうち2つはHであり、その他の1つの基は、H、C1−3飽和アルキル、C2−3アルケニル、C2−3アルキニル、及びシクロプロピルから選択される、請求項18から20のいずれか1項に記載の化合物。
- R24は、H、メチル、エチル、エテニル、及びエチニルから選択される、請求項25に記載の化合物。
- R24は、H及びメチルから選択される、請求項26に記載の化合物。
- C2’とC3’の間には二重結合が存在し、かつR12は、C5−7アリール基である、請求項1から30のいずれか1項に記載の化合物。
- R12は、フェニルである、請求項31に記載の化合物。
- C2’とC3’の間には二重結合が存在し、かつR12は、C8−10アリール基である、請求項1から30のいずれか1項に記載の化合物。
- R12は、1つ〜3つの置換基を有する、請求項31から33のいずれか1項に記載の化合物。
- 前記置換基は、メトキシ、エトキシ、フルオロ、クロロ、シアノ、ビス−オキシ−メチレン、メチルピペラジニル、モルホリノ、及びメチルチオフェニルから選択される、請求項31から34のいずれか1項に記載の化合物。
- C2’とC3’の間には二重結合が存在し、かつR12は、C1−5飽和脂肪族アルキル基である、請求項1から30のいずれか1項に記載の化合物。
- R12は、メチル、エチル、またはプロピルである、請求項36に記載の化合物。
- C2’とC3’の間には二重結合が存在し、かつR12は、C3−6飽和シクロアルキル基である、請求項1から30のいずれか1項に記載の化合物。
- R12は、シクロプロピルである、請求項38に記載の化合物。
- 前記R12基の炭素原子の合計数は、4以下である、請求項40に記載の化合物。
- 前記R12基の炭素原子の合計数は、3以下である、請求項41に記載の化合物。
- R31、R32、及びR33のうち1つはHであり、その他の2つの基は、H、C1−3飽和アルキル、C2−3アルケニル、C2−3アルキニル、及びシクロプロピルから選択される、請求項40から42のいずれか1項に記載の化合物。
- R31、R32、及びR33のうち2つはHであり、その他の1つの基は、H、C1−3飽和アルキル、C2−3アルケニル、C2−3アルキニル、及びシクロプロピルから選択される、請求項40から42のいずれか1項に記載の化合物。
- R34は、H、メチル、エチル、エテニル、及びエチニルから選択される、請求項47に記載の化合物。
- R34は、H及びメチルから選択される、請求項48に記載の化合物。
- 前記抗体が配列番号7のアミノ酸配列を持つVH CDR3を有するVHドメインを含む、請求項1から52のいずれか1項に記載の複合体。
- 前記抗体は、配列番号6のアミノ酸配列を持つVH CDR2、及び/または配列番号5のアミノ酸配列を持つVH CDR1を含むVHドメインを含む、請求項1から53のいずれか1項に記載の複合体。
- 前記抗体は、配列番号7のアミノ酸配列を持つVH CDR3、配列番号6のアミノ酸配列を持つVH CDR2、及び配列番号5のアミノ酸配列を持つVH CDR1を含むVHドメインを含む、請求項1から53のいずれか1項に記載の複合体。
- 前記抗体は、配列番号1の配列を有するVHドメインを含む、請求項1から55のいずれか1項に記載の複合体。
- 前記抗体は、配列番号10のアミノ酸配列を持つVL CDR3を有するVLドメインを含む、請求項1から56のいずれか1項に記載の複合体。
- 前記抗体は、配列番号9のアミノ酸配列を持つVL CDR2、及び/または配列番号8のアミノ酸配列を持つVL CDR1を含むVHドメインを含む、請求項1から57のいずれか1項に記載の複合体。
- 前記抗体は、配列番号10のアミノ酸配列を持つVL CDR3、配列番号9のアミノ酸配列を持つVL CDR2、及び配列番号8のアミノ酸配列を持つVL CDR1を含むVLドメインを含む、請求項1から58のいずれか1項に記載の複合体。
- 前記抗体は、配列番号2の配列を有するVHドメインを含む、請求項1から59のいずれか1項に記載の複合体。
- 前記抗体は、無傷抗体である、請求項1から60のいずれか1項に記載の複合体。
- 前記抗体は、配列番号3または配列番号24の配列を有する重鎖を含む、請求項1から61のいずれか1項に記載の複合体。
- 前記抗体は、配列番号4の配列を有する軽鎖との対形成を含む、請求項1から62のいずれか1項に記載の複合体。
- 前記抗体は、ヒト化、脱免疫化、または表面再構成されている、請求項1から63のいずれか1項に記載の複合体。
- 前記抗体には、複合体形成していないアジド基は存在しない、請求項1から64のいずれか1項に記載の複合体。
- pは、1、2、3、または4である、請求項1から65のいずれか1項に記載の複合体。
- 請求項1から66のいずれか1項に定義されるとおりの抗体薬物複合体化合物の混合物を含む組成物であって、前記抗体薬物複合体化合物混合物中の抗体あたりの平均薬物担持数は、約1〜約4である、前記組成物。
- 治療に使用するための、請求項1から66のいずれか1項に記載の複合体。
- 対象における増殖性疾患の治療に使用するための、請求項1から66のいずれか1項に記載の複合体。
- 前記疾患は、がんである、請求項69に記載の複合体。
- 疾患またはがんが、AXL+veとAXL−ve細胞との両方を含む新生物の存在によって特徴づけられる、請求項69または70のいずれか1項に記載の複合体。
- 抗体−薬物複合体を投与することを含む、AXL+ve細胞の近傍の新生物性AXL−ve細胞に細胞毒性を引き起こす方法における使用のための、請求項1から66のいずれか1項に記載の複合体。
- (i)対象において、AXL+veとAXL−ve細胞との両方を含む新生物の存在を同定することと、
(ii)前記対象に前記抗体薬物複合体を投与することと、
を含む、増殖性疾患を治療するための方法における使用のための請求項1から66のいずれか1項に記載の複合体。 - 請求項1から66のいずれか1項に記載の複合体による治療のための対象を選択する方法であって、AXL+veとAXL−ve細胞との両方を含む新生物の存在を同定するために前記対象をスクリーニングすることを含む、方法。
- 前記スクリーニングまたは同定が、免疫組織化学によってAXL+ve細胞を同定するコンパニオン診断によってなされる、請求項73または請求項74に記載の方法または複合体。
- AXL+veとAXL−ve細胞との両方が、新生物細胞である、請求項1から75のいずれか1項に記載の方法または複合体。
- 請求項1から66のいずれか1項に記載の複合体、及び薬学上許容される希釈剤、キャリア、または賦形剤を含む、医薬組成物。
- さらに、治療上有効量の化学療法薬を含む、請求項77に記載の医薬組成物。
- 対象における増殖性疾患の治療に使用するための医薬の調製における、請求項1から66のいずれか1項に記載の複合体の使用。
- 患者に、請求項78に記載の医薬組成物を投与することを含む、がんの治療方法。
- 前記患者は、前記複合体と組み合わせて、化学療法薬を投与される、請求項80に記載の方法。
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GB201506399D0 (en) | 2015-04-15 | 2015-05-27 | Berkel Patricius H C Van And Howard Philip W | Site-specific antibody-drug conjugates |
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HUE054689T2 (hu) | 2021-09-28 |
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US20210093731A1 (en) | 2021-04-01 |
EP3544636A1 (en) | 2019-10-02 |
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US11160872B2 (en) | 2021-11-02 |
UA125198C2 (uk) | 2022-01-26 |
DK3544636T3 (da) | 2021-05-10 |
KR102181375B1 (ko) | 2020-11-25 |
CA3047683C (en) | 2020-03-10 |
ES2871001T3 (es) | 2021-10-28 |
JP6671555B2 (ja) | 2020-03-25 |
KR20200032243A (ko) | 2020-03-25 |
CY1124402T1 (el) | 2022-07-22 |
LT3544636T (lt) | 2021-06-25 |
WO2018146189A1 (en) | 2018-08-16 |
HRP20210979T1 (hr) | 2021-09-17 |
MX2019009428A (es) | 2019-10-07 |
CN110267686B (zh) | 2023-06-09 |
PT3544636T (pt) | 2021-05-04 |
NZ754810A (en) | 2023-04-28 |
AU2018217926B2 (en) | 2019-10-03 |
RS61795B1 (sr) | 2021-06-30 |
CA3047683A1 (en) | 2018-08-16 |
SI3544636T1 (sl) | 2021-08-31 |
US20220008552A1 (en) | 2022-01-13 |
AU2018217926A1 (en) | 2019-07-18 |
CN110267686A (zh) | 2019-09-20 |
BR112019016373A2 (pt) | 2020-04-07 |
US11813335B2 (en) | 2023-11-14 |
PL3544636T3 (pl) | 2021-12-06 |
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