JP2016520049A - アフコシル化CD20抗体とCD79b抗体−薬物コンジュゲートの併用療法 - Google Patents
アフコシル化CD20抗体とCD79b抗体−薬物コンジュゲートの併用療法 Download PDFInfo
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- 150000003327 trichothecene derivatives Chemical class 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046885 vaginal cancer Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- 230000007332 vesicle formation Effects 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-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
- 229960004355 vindesine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
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Abstract
Description
モノクローナル抗体の細胞媒介性エフェクター機能は、Umana, P., et al., Nature Biotechnol. 17 (1999) 176-180及び米国特許第6602684号に記載されているように、それらのオリゴ糖成分を操作することにより高めることができる。がん免疫療法において最も一般的に使用される抗体であるIgG1型抗体は、各CH2ドメインのAsn297に保存されたN結合型グリコシル化部位を有する糖タンパク質である。Asn297に結合した2つの複合二分岐オリゴ糖はCH2ドメイン間に包埋されて、ポリペプチド骨格との広範な接触部を形成しており、それらの存在は、抗体が、抗体依存性細胞傷害性(ADCC)などのエフェクター機能を媒介するのに必須である(Lifely, M.R., et al., Glycobiology 5 (1995) 813-822; Jefferis, R., et al., Immunol. Rev. 163 (1998) 59-76; Wright, A., 及び Morrison, S.L., Trends Biotechnol. 15 (1997) 26-32)。Umana, P., et al., Nature Biotechnol. 17 (1999) 176-180及び国際公開第99/154342号は、二分されたオリゴ糖の形成を触媒するグリコシルトランスフェラーゼであるβ(1,4)−N−アセチルグルコサミニルトランスフェラーゼIII(「GnTIII」)の、チャイニーズハムスター卵巣(CHO)細胞内での過剰発現が、抗体のインビトロADCC活性を有意に増大させることを示した。また、N297炭化水素の組成の変更又はその除去は、FcγR及びC1qへのFc結合への結合に影響を及ぼす(Umana, P., et al., Nature Biotechnol. 17 (1999) 176-180; Davies, J., et al., Biotechnol. Bioeng. 74 (2001) 288-294; Mimura, Y., et al., J. Biol. Chem. 276 (2001) 45539-45547; Radaev, S., et al., J. Biol. Chem. 276 (2001) 16478-16483; Shields, R.L., et al., J. Biol. Chem. 276 (2001) 6591-6604; Shields, R.L., et al., J. Biol. Chem. 277 (2002) 26733-26740; Simmons, L.C., et al., J. Immunol. Methods 263 (2002) 133-147)。
CD20分子(ヒトBリンパ球限定分化抗原又はBp35とも呼ばれる)は、プレB及び成熟Bリンパ球に位置する疎水性の膜貫通タンパク質であり、広く文献に記載されている(Valentine, M.A., et al., J. Biol. Chem. 264 (1989) 11282-11287; and Einfeld, D.A., et al., EMBO J. 7 (1988) 711-717; Tedder, T.F., et al., Proc. Natl. Acad. Sci. U.S.A. 85 (1988) 208-212; Stamenkovic, I., et al., J. Exp. Med. 167 (1988) 1975-1980; Tedder, T.F., et al., J. Immunol. 142 1989 - 2560 -2568)。CD20は90%を上回るB細胞非ホジキンリンパ腫(NHL)に発現する(Anderson, K.C., et al., Blood 63(6) (1984) 1424-1433))が、造血幹細胞、プロB細胞、正常な形質細胞、又はその他正常な組織には見られない(Tedder, T.F., et al., J. Immunol. 135(2) (1985) 973- 979)。
CD79は、CD79a(Igα、mb−1)及びCD79b(Igβ、B29)を含む共有結合性のヘテロ二量体からなる、B細胞受容体のシグナル伝達成分である。CD79a及びCD79bの各々は、細胞外免疫グロブリン(Ig)ドメイン、膜貫通ドメイン、及び細胞内シグナル伝達ドメイン、免疫受容活性化チロシンモチーフ(ITAM)ドメインを含む。CD79は、B細胞及び非ホジキンリンパ腫細胞(NHL)に発現される(Cabezudo et al., Haematologica, 84:413-418 (1999); D’Arena et al., Am. J. Hematol., 64: 275-281 (2000); Olejniczak et al., Immunol. Invest., 35: 93-114 (2006))。CD79a及びCD79b及びsIgはみな、CD79の表面発現に必要とされる(Matsuuchi et al., Curr. Opin. Immunol., 13(3): 270-7))。NHL上でのCD79bの平均表面発現は、正常なB細胞のそれと同様であるが、範囲が広い(Matsuuchi et al., Curr. Opin. Immunol., 13(3): 270-7 (2001))。
(i)配列A1〜A15を含み、A1〜A15がKASQSVDYDGDSFLN(配列番号31)であるHVR−L1
(ii) 配列B1〜B7を含み、B1〜B7がAASNLES(配列番号32)であるHVR−L2
(iii)配列C1〜C9を含み、C1〜C9がQQSNEDPLT(配列番号33)であるHVR−L3
(iv)配列D1〜D10を含み、D1〜D10がGYTFSSYWIE(配列番号34)であるHVR−H1
(v)配列E1〜E18を含み、E1〜E18がGEILPGGGDTNYNEIFKG(配列番号35)であるHVR−H2、及び
(vi)配列F1〜F10を含み、F1〜F10がTRRVPVYFDY(配列番号36)であるHVR−H3。
(i)配列A1〜A15を含み、A1〜A15がKASQSVDYDGDSFLN(配列番号31)又はKASQSVDYEGDSFLN(配列番号37)であるHVR−L1;
(ii)配列B1〜B7を含み、B1〜B7がAASNLES(配列番号32)であるHVR−L2;
(iii)配列C1〜C9を含み、C1〜C9がQQSNEDPLT(配列番号33)であるHVR−L3;
(iv)配列D1〜D10を含み、D1〜D10がGYTFSSYWIE(配列番号34)であるHVR−H1;
(v)配列E1〜E18を含み、E1〜E18がGEILPGGGDTNYNEIFKG(配列番号35)であるHVR−H2、及び
(vi)配列F1〜F10を含み、F1〜F10がTRRVPVYFDY(配列番号36)又はTRRVPIRLDY(配列番号38)である、HVR−H3。
(a)配列A1〜A15を含み、A1〜A15がKASQSVDYDGDSFLN(配列番号31)又はKASQSVDYEGDSFLN(配列番号37)であるHVR−L1;
(b)配列B1〜B7を含み、B1〜B7がAASNLES(配列番号32)であるHVR−L2;
(c)配列C1〜C9を含み、C1〜C9がQQSNEDPLT(配列番号33)であるHVR−L3;
(d)配列D1〜D10を含み、D1〜D10がGYTFSSYWIE(配列番号34)であるHVR−H1;
(e)配列E1〜E18を含み、E1〜E18がGEILPGGGDTNYNEIFKG(配列番号35)であるHVR−H2、及び
(f)配列F1〜F10を含み、F1〜F10がTRRVPVYFDY(配列番号36)又はTRRVPIRLDY(配列番号38)であるHVR−H3。
(a)Abは本明細書に定義されるCD79b抗体であり、
(b)Lはリンカーであり、
(c)Dは薬物部分である。
(i)配列A1〜A15を含み、A1〜A15がKASQSVDYDGDSFLN(配列番号31)であるHVR−L1
(ii)配列B1〜B7を含み、B1〜B7がAASNLES(配列番号32)であるHVR−L2
(iii)配列C1〜C9を含み、C1〜C9がQQSNEDPLT(配列番号33)であるHVR−L3
(iv)配列D1〜D10を含み、D1〜D10がGYTFSSYWIE(配列番号34)であるHVR−H1
(v)配列E1〜E18を含み、E1〜E18がGEILPGGGDTNYNEIFKG(配列番号35)であるHVR−H2、及び
(vi)配列F1〜F10を含み、F1〜F10がTRRVPVYFDY(配列番号36)であるHVR−H3。
(a)Abは本明細書に定義されるCD79b抗体であり、
(b)Lはリンカーであり、
(c)Dは薬物部分である。
(i)配列A1〜A15を含み、A1〜A15がKASQSVDYDGDSFLN(配列番号31)であるHVR−L1
(ii)配列B1〜B7を含み、B1〜B7がAASNLES(配列番号32)であるHVR−L2
(iii)配列C1〜C9を含み、C1〜C9がQQSNEDPLT(配列番号33)であるHVR−L3
(iv)配列D1〜D10を含み、D1〜D10がGYTFSSYWIE(配列番号34)であるHVR−H1
(v)配列E1〜E18を含み、E1〜E18がGEILPGGGDTNYNEIFKG(配列番号35)であるHVR−H2、及び
(vi)配列F1〜F10を含み、F1〜F10がTRRVPVYFDY(配列番号36)であるHVR−H3。
(a)Abは本明細書に開示されるCD79b抗体であり、
(b)Lはリンカーであり、
(c)Dは薬物部分である。
(i)配列A1〜A15を含み、A1〜A15がKASQSVDYDGDSFLN(配列番号31)であるHVR−L1
(ii)配列B1〜B7を含み、B1〜B7がAASNLES(配列番号32)であるHVR−L2
(iii)配列C1〜C9を含み、C1〜C9がQQSNEDPLT(配列番号33)であるHVR−L3
(iv)配列D1〜D10を含み、D1〜D10がGYTFSSYWIE(配列番号34)であるHVR−H1
(v)配列E1〜E18を含み、E1〜E18がGEILPGGGDTNYNEIFKG(配列番号35)であるHVR−H2、及び
(vi)配列F1〜F10を含み、F1〜F10がTRRVPVYFDY(配列番号36)であるHVR−H3。
(a)Abは本明細書に開示されるCD79b抗体であり、
(b)Lはリンカーであり、
(c)Dは薬物部分である。
1)アッセイは、抗体の抗原結合領域によって認識される標的抗原を発現することが既知である標的細胞を使用する;
2)アッセイは、エフェクター細胞として、無作為に選ばれた健常なドナーの血液から単離されたヒト末梢血単核細胞(PBMC)を使用する;
3)アッセイは、以下のプロトコールに従って実行される:
i)PBMCを、標準の密度遠心分離手順を用いて単離し、RPMI細胞培地において、5×106細胞/mlで懸濁する;
ii)標的細胞を、標準の組織培養法によって増殖させ、指数増殖期に90%を上回る生存率で回収し、RPMI細胞培地中で洗浄し、100マイクロキュリーの51Crで標識し、細胞培地で二回洗浄し、細胞培地中に105細胞/mlの密度で再懸濁する;
iii)100マイクロリットルの上記最終的な標的細胞懸濁液を、96ウェルマイクロタイタープレートの各ウェルに移す;
iv)抗体を、細胞培地において4000ng/mlから0.04ng/mlへ連続的に希釈し、得られた抗体溶液50マイクロリットルを96ウェルマイクロタイタープレートの標的細胞に加え、上記全濃度範囲をカバーする種々の抗体濃度を三重に試験する;
v)最大放出(MR)コントロールのために、標識した標的細胞を含むプレート内の更に3つのウェルに、抗体溶液(上記iv)の代わりに非イオン性洗剤(Nonidet、Sigma、St.Louis)の2%(VN)水溶液50マイクロリットルを入れる;
vi)自然放出(SR)コントロールのために、標識した標的細胞を含むプレート内の更に3つのウェルに、抗体溶液(上記iv)の代わりにRPMI細胞培地50マイクロリットルを入れる;
vii)次いで96ウェルマイクロタイタープレートを50×gで1分間遠心分離し、1時間4℃でインキュベートする;
viii)PBMC懸濁液50マイクロリットル(上記i)を各ウェルに加えて、エフェクター対標的の比を25:1とし、プレートを、5%のCO2雰囲気下で37℃で4時間インキュベーター内に置く;
ix)各ウェルの無細胞上清を回収し、γ計数器を用いて実験的に放出された放射能(ER)を定量化する;
x)特異的溶解のパーセンテージを、各抗体濃度について、式(ER−MR)/(MR−SR)×100(ERは、その抗体濃度について定量化された平均放射能(上記ix参照)であり、MRはMRコントロール(上記V参照)について定量化された平均放射能(上記ix参照)であり、SRはSRコントロール(上記vi参照)について定量化された平均放射能(上記ix参照)である)に従って算出する;
4)「ADCCの増大」は、上記試験された抗体濃度範囲内で観察される特異的溶解の最大パーセンテージの上昇、及び/又は上記試験された抗体濃度範囲内で観察される特異的溶解の最大パーセンテージの二分の一を達成するために必要な抗体濃度の低減と定義される。ADCCの増大は、同じ標準的な生成、精製、製剤化、及び貯蔵方法(当業者に既知の)を用いて、但しGnTIIIを過剰発現するように改変された宿主細胞により生成されたものでない、同じ型の宿主細胞により生成され、同じ抗体により媒介される、上記アッセイを用いて測定されたADCCと相対的なものである。
DIQMTQSPSSLSASVGDRVTITC(配列番号39)−L1−WYQQKPGKAPKLLIY(配列番号40)−L2−GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(配列番号41)−L3−FGQGTKVEIKR(配列番号42)。
リンカー成分:
MC=6−マレイミドカプロイル
Val−Cit又は「vc」=バリン−シトルリン(プロテアーゼ切断可能リンカー内の例示的ジペプチド)
シトルリン=2−アミノ−5−ウレイド ペンタン酸
PAB=p−アミノベンジルオキシカルボニル(「自壊的(self immolative)」リンカー成分の一例)
Me−Val−Cit=N−メチル−バリン−シトルリン(リンカーペプチド結合が、カテプシンBによるその切断を防止するように修飾されている)
MC(PEG)6−OH=マレイミドカプロイル− ポリエチレングリコール(抗体システインに結合できる)
細胞傷害性薬:
MMAE=モノ−メチル アウリスタチンE(MW 718)
MMAF=薬物のC末端にフェニルアラニン(MW 731.5)を有するアウリスタチンE(MMAE)の変異体
MMAF−DMAEA=C末端フェニルアラニン(MW 801.5)へのアミド結合にDMAEA(ジメチルアミノエチルアミン)を有するMMAF
MMAF−TEG=フェニルアラニンにエステル化されたテトラエチレングリコールを有するMMAF
MMAF−NtBu=MMAFのC末端にアミドとして結合したN−t−ブチル
DM1=N(2’)−デアセチル−N(2’)−(3−メルカプト−1−オキソプロピル)−メイタンシン
DM3=N(2’)−デアセチル−N2−(4−メルカプト−1−オキソペンチル)−メイタンシン
DM4=N(2’)−デアセチル−N2−(4−メルカプト−4−メチル−1−オキソペンチル)−メイタンシン
(a)配列A1〜A15を含み、A1〜A15がKASQSVDYDGDSFLN(配列番号31)又はKASQSVDYEGDSFLN(配列番号37)であるHVR−L1;
(b)配列B1〜B7を含み、B1〜B7がAASNLES(配列番号32)であるHVR−L2;
(c)配列C1〜C9を含み、C1〜C9がQQSNEDPLT(配列番号33)であるHVR−L3;
(d)配列D1〜D10を含み、D1〜D10がGYTFSSYWIE(配列番号34)であるHVR−H1;
(e)配列E1〜E18を含み、E1〜E18がGEILPGGGDTNYNEIFKG(配列番号35)であるHVR−H2、及び
(f)配列F1〜F10を含み、F1〜F10がTRRVPVYFDY(配列番号36)又はTRRVPIRLDY(配列番号38)である、HVR−H3。
別の態様では、本発明は、本明細書において定義される抗CD20抗体とイムノコンジュゲートとの組み合わせ、即ち抗体−薬物コンジュゲート(ADC)を提供し、これは、細胞傷害性剤、例えば化学療法剤、薬物、成長阻害剤、毒素(例えば、細菌、真菌、植物、若しくは動物起源の酵素活性毒素、又はそれらの断片)、又は放射性同位元素(即ち、ラジオコンジュゲート)にコンジュゲートした抗体を含む。別の態様では、本発明は更に、イムノコンジュゲートを使用する方法を提供する。一態様では、イムノコンジュゲートは、細胞傷害性薬剤又は検出可能な薬剤に共有結合した上記抗CD79b抗体のいずれかを含む。
一態様では、本発明は、上記又は後述のポリペプチドに対し、好ましくは特異的に結合する抗体を提供する。任意選択的に、抗体は、モノクローナル抗体、Fab、Fab’、F(ab’)2、及びFv断片を含む抗体断片、ダイアボディ、シングルドメイン抗体、キメラ抗体、ヒト化抗体、一本鎖抗体、又は抗CD79bポリペプチド抗体の対応する抗原エピトープへの結合を競合的に阻害する抗体である。本発明の抗体は、任意選択的に、増殖阻害剤又は毒素のような細胞傷害性薬剤とすることができ、これには例えば、アウリスタチン、メイタンシノイド、ドロスタチン(dolostatin)誘導体又はカリケアマイシン、抗生物質、放射性同位体、核酸分解酵素などが含まれる。本発明の抗体は、任意選択的に、CHO細胞又は細菌細胞中において生成され、好ましくは、それが結合する細胞の死を誘導する。検出目的のために、本発明の抗体は、検出可能に標識する、固体支持体に結合させるなどすることができる。
(i)配列A1〜A15を含み、A1〜A15がKASQSVDYDGDSFLN(配列番号31)であるHVR−L1
(ii)配列B1〜B7を含み、B1〜B7がAASNLES(配列番号32)であるHVR−L2
(iii)配列C1〜C9を含み、C1〜C9がQQSNEDPLT(配列番号33)であるHVR−L3
(iv)配列D1〜D10を含み、D1〜D10がGYTFSSYWIE(配列番号34)であるHVR−H1
(v)配列E1〜E18を含み、E1〜E18がGEILPGGGDTNYNEIFKG(配列番号35)であるHVR−H2、及び
(vi)配列F1〜F10を含み、F1〜F10がTRRVPVYFDY(配列番号36)であるHVR−H3
からなる群より選択される少なくとも一つ、二つ、三つ、四つ、五つ、又は六つのHVRを含む。
(a)配列A1〜A15を含み、A1〜A15がKASQSVDYDGDSFLN(配列番号31)又はKASQSVDYEGDSFLN(配列番号37)であるHVR−L1;
(b)配列B1〜B7を含み、B1〜B7がAASNLES(配列番号32)であるHVR−L2;
(c)配列C1〜C9を含み、C1〜C9がQQSNEDPLT(配列番号33)であるHVR−L3;
(d)配列D1〜D10を含み、D1〜D10がGYTFSSYWIE(配列番号34)であるHVR−H1;
(e)配列E1〜E18を含み、E1〜E18がGEILPGGGDTNYNEIFKG(配列番号35)であるHVR−H2、及び
(f)配列F1〜F10を含み、F1〜F10がTRRVPVYFDY(配列番号36)又はTRRVPIRLDY(配列番号38)であるHVR−H3。
Ab−(L−D)p I
リンカーは、一又は複数のリンカー成分を含むことができる。例示的リンカー成分には、6−マレイミドカプロイル(「MC」)、マレイミドプロパノイル(「MP」)、バリン−シトルリン(「val−cit」又は「vc」)、アラニン−フェニルアラニン(「ala−phe」)、p−アミノベンジルオキシカルボニル(「PAB」)、及びリンカー試薬とのコンジュゲーションにより生じるもの、即ち:N−スクシンイミジル4−(2−ピリジルチオ)ペンタノエート(「SPP」)、N−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(本明細書で「MCC」とも呼ばれる「SMCC」)、及びN−スクシンイミジル(4−ヨード−アセチル)アミノベンゾエート(「SIAB」)が含まれる。様々なリンカー成分が当技術分野で既知であり、そのうちのいくつかについて後述する。
式中、Aはストレッチャー単位であり、aは0〜1の整数であり;Wはアミノ酸単位であり、wは0〜12の整数であり;Yはスペーサー単位であり、yは0、1、又は2であり;Ab、D、及びpは式Iについて上述したように定義される。このようなリンカーの例示的実施態様は、米国特許出願公開第2005−0238649号に記載されており、これは参照により本明細書に包含される。
ここで、Qは−C1−C8アルキル、−O−(C1−C8アルキル)、−ハロゲン、−ニトロ又は−シアノであり;mは0〜4の整数であり;nは0又は1であり;pは1〜約20の範囲である。
Val−Cit又はVC
MC−val−cit
MC−val−cit−PAB
(1)メイタンシン及びメイタンシノイド
いくつかの実施態様では、本明細書に定義される抗CD20抗体とイムノコンジュゲートの組み合わせは、一又は複数のメイタンシノイド分子にコンジュゲートした抗体を含む。メイタンシノイドは、チューブリン重合を阻害することにより作用する有糸分裂阻害剤である。メイタンシンは、東アフリカの灌木メイテナスセラタ(Maytenus serrata)から最初に単離された(米国特許第3896111号)。続いて、特定の微生物も、メイタンシノイド、例えばメイタンシノール及びC−3メイタンシノールエステル等のマイタンシノイドを生成することが発見された(米国特許第4151042号)。合成メイタンシノイド及びその誘導体及びアナログは、例えば、米国特許第4137230号;同第4248870号;同第4256746号;同第4260608号;同第4265814号;同第4294757号;同第4307016号;同第4308268号;同第4308269号;同第4309428号;同第4313946号;同第4315929号;同第4317821号;同第4322348号;同第4331598号;同第4361650号;同第4364866号;同第4424219号;同第4450254号;同第4362663号;及び同第4371533号に開示されている。
を有するものを含み、構造中、波線は、メイタンシノイド薬物部分の硫黄原子の、ADCのリンカーへの共有結合を示す。Rは、独立して、H又はC1−C6アルキルでよい。硫黄原子へアミド基を結合するアルキレン鎖は、メタニル、エタニル、又はプロピルでよく、即ちmは1、2、又は3である(米国特許第633410号;同第5208020号;同第7276497号;Chari et al (1992) Cancer Res. 52:127-131; Liu et al (1996) Proc. Natl. Acad. Sci USA 93:8618-8623)。
を有するDM1;DM3;及びDM4が含まれ、ここで波線は、薬物の硫黄原子の、抗体−薬物コンジュゲートのリンカー(L)への共有結合を示す。(国際公開第2005/037992;米国特許出願公開第2005/0276812号)。
Ab −SPP−DM1
Ab−SPDB−DM4
Ab−SMCC−DM1
を有し、ここでAbは抗体であり;nは0、1、又は2であり;pは1、2、3、又は4である。
いくつかの実施態様では、本明細書に定義される抗CD20抗体とイムノコンジュゲートの組み合わせは、ドラスタチン又はドラスタチンのペプチド性アナログ若しくは誘導体、例えばアウリスタチン(米国特許第5635483号;同第5780588号)にコンジュゲートした抗体を含む。ドラスタチン及びアウリスタチンは、微小管動態、GTP加水分解、並びに核及び細胞分裂に干渉し(Woyke et al (2001) Antimicrob. Agents and Chemother. 45(12):3580-3584)抗がん活性(米国特許第5663149号)及び抗真菌活性(Pettit et al (1998) Antimicrob. Agents Chemother. 42:2961-2965)を有することが示されている。ドラスタチン又はアウリスタチン薬物部分は、ペプチド性薬物部分のN(アミノ)末端又はC(カルボキシル)末端を介して抗体に結合しうる(国際公開第02/088172)。
式中、DE及びDFの波線は、抗体又は抗体リンカー成分への共有結合部位を示し、各位置において独立して:
R2はH及びC1−C8アルキルから選択され;
R3はH、C1−C8アルキル、C3−C8炭素環、アリール、C1−C8アルキル−アリール、C1−C8アルキル−(C3−C8炭素環)、C3−C8複素環及び C1−C8アルキル−(C3−C8複素環)から選択され;
R4はH、C1−C8アルキル、C3−C8炭素環、アリール、C1−C8アルキル−アリール、C1−C8アルキル−(C3−C8炭素環)、C3−C8複素環及び C1−C8アルキル−(C3−C8複素環)から選択され;
R5はH及びメチルから選択されるか;
又はR4及びR5は一緒に炭素環式環を形成し、式(CRaRb)n(Ra及びRbは独立してH、C1−C8アルキル及びC3−C8炭素環から選択され、nは2、3、4、5及び6から選択される)を有し;
R6はH及びC1−C8アルキルから選択され;
R7はH、C1−C8アルキル、C3−C8炭素環、アリール、C1−C8アルキル−アリール、C1−C8アルキル−(C3−C8炭素環)、C3−C8複素環及び C1−C8アルキル−(C3−C8複素環)から選択され;
各R8は独立してH、OH、C1−C8アルキル、C3−C8炭素環及びO−(C1−C8アルキル)から選択され;
R9はH及びC1−C8アルキルから選択され;
R10はアリール又はC3−C8複素環から選択され;
ZはO、S、NH、又はNR12(R12はC1−C8アルキル)であり;
R11はH、C1−C20アルキル、アリール、C3−C8複素環、−(R13O)m−R14、又は−(R13O)m−CH(R15)2から選択され;
mは1〜1000にわたる整数であり;
R13はC2−C8アルキルであり;
R14は、H又はC1−C8−アルキルであり;
R15の各発生は独立してH、COOH、−(CH2)n−N(R16)2、−(CH2)n−SO3H、又は−(CH2)n−SO3−C1−C8アルキルであり;
R16の各発生は独立してH、C1−C8アルキル、又は−(CH2)n−COOHであり;
R18は−C(R8)2−C(R8)2−アリール、−C(R8)2−C(R8)2−(C3−C8複素環)、及び−C(R8)2−C(R8)2−(C3−C8炭素環)から選択され;
nは0〜6にわたる整数である。
MMAE
MMAF
,
,
,
,
、及び
他の実施態様では、本明細書に定義される抗CD20抗体とイムノコンジュゲートの組み合わせは、一又は複数のカリケアマイシン分子にコンジュゲートした抗体を含む。カリケアマイシンファミリーの抗生物質は、ピコモル濃度未満で二本鎖DNA切断を生じさせる能力がある。カリケアマイシンファミリーのコンジュゲートの調製については、米国特許第5712374号、同第5714586号、同第5739116号、同第5767285号、同第5770701号、同第5770710号、同第5773001号、同第5877296号(すべてAmerican Cyanamid Company)を参照のこと。使用されうるカリケアマイシンの構造的アナログには、限定されないが、γ1 I、α2 I、α3 I、N−アセチル−γ1 I、PSAG及びθI 1が含まれる(Hinman et al., Cancer Research 53:3336-3342 (1993), Lode et al., Cancer Research 58:2925-2928 (1998)、及び上述のAmerican Cytents to American Cyanamidの米国特許)。抗体をコンジュゲートすることができる別の抗腫瘍薬は、抗葉酸薬であるQFAである。カリケアマイシンとQFAはどちらも、細胞内作用部位を有しており、原形質膜を容易に越えない。したがって、細胞が抗体媒介性の内部移行を通じてこれらの薬剤を取り込むと、その細胞傷害効果は大きく強化される。
抗体にコンジュゲートすることができる他の抗腫瘍剤には、BCNU、ストレプトゾイシン、ビンクリスチン及び5−フルオロウラシル、総称的にLL−E33288複合体として知られる薬剤ファミリー(米国特許第5053394号、同第5770710号に記載)、並びにエスペラマイシン(米国特許第5877296号)が含まれる。
薬物負荷は、式Iの一分子中の抗体一つ当たりの薬物部分の平均数であるpにより表される。薬物負荷は、抗体一つ当たり1〜20個の薬物部分(D)にわたってよい。式IのADCは、1〜20個の範囲の薬物部分にコンジュゲートした抗体の集団を含む。コンジュゲート反応に基づくADCの調製における抗体一つ当たりの薬物部分の平均数は、質量分析、ELISAアッセイ、及びHPLCのような一般的な手段により特徴づけられる。pの観点からADCの量的分布も決定される。場合によっては、均一なADCの分離、精製、及び特徴づけ(pは他の薬物負荷を伴うADCに基づく何らかの値である)は、逆相HPLC又は電気泳動などの手段により達成される。このように、式Iの抗体−薬物コンジュゲートの薬学的製剤は、このようなコンジュゲートと1、2、3、4、又はそれより多い薬物部分に結合した抗体との不均一な混合物でありうる。
本明細書に記載される、本組み合わせ発明の抗体薬物コンジュゲート(ADC)は、当業者に既知の方法により調製される。例示的方法は、例えば国際公開第2009/099728号に記載されている。前記方法は、例えば国際公開第2009/099728号の段落538−545(イムノコンジュゲートの調製)、段落546−585(例示的なイムノンジュゲート−チオ抗体薬物コンジュゲート)、段落586−591(リンカー)、段落592−605(ストレッチャー単位)、段落606−610(アミノ酸単位)、段落611−617(スペーサー単位)、段落618−624(樹状リンカー)、段落625−632(リンカー試薬);段落633−636(システイン操作抗CD79b抗体−薬物コンジュゲートの調製)に記載されており、これらすべては参照により包含される。
「IC50」は、測定された比活性の50%を阻害するために必要な特定の化合物の濃度を指す。CD79bの相互作用を阻害する薬剤のIC50は、特に以下のようにして測定することができる。
様々な量でその表面上にCD79bを発現している19のリンパ腫細胞株を培養し、ログ段階増殖において収穫した。細胞を、それぞれ100μg/mlの正常なマウスIgG及び正常なヒトIgGを含むFACS洗浄バッファー(PBS;0.5%ウシ血清アルブミン;0.1%アジ化ナトリウム)中に懸濁し、氷上に維持した。100μl当たり約1×106個の細胞を、抗huCD79b APC(mIgG1、クローンRFB4、Southern Biotech #9361−11)又はマウスIgG1 APCアイソタイプ(BD Pharmingen #555751)で30分間氷上で染色した。死細胞は7−AAD(BD Pharmingen #559925)で染色した。データは、BD FacsCaliburTMフローサイトメーター上で取得し、FlowJoTMソフトウェアで分析した。huMA79b.v28−MCvcPAB−DM1又はhuMA79b.v28−MCvcPAB−MMAF又はhuMA79b.v28−MCvcPAB−MMAE又は各遊離薬物(DM1、MMAF、又はMMAE)のIC50の決定は、上述のようにリンパ腫細胞を培養すること、ログ段階の培養細胞を収穫すること、及び5000個の細胞を、96ウェルプレートの一ウェル当たり90μlの培地に播種することによって行われた。ADC及び遊離薬物を、検出範囲内で順番に希釈した(ADCについて300μg/mlから、又は遊離薬物について90nMから開始して、本質的にゼロのアッセイ標的まで希釈)。10μlの希釈ADC又は遊離薬物のアリコートを、細胞を含有する複製ウェルに加え、3日間37℃でインキュベートした。各ウェルに対し、100μlのCellTiter GloTMを加え、30分間インキュベートした。化学発光を検出し、データを、PrismTMソフトウェアを用いて分析した。
薬学的組成物は、本発明による抗CD20抗体及び/又はCD79b抗体−薬物コンジュゲートを、薬学的に許容される、無機又は有機担体を用いて処理することにより得られる。ラクトース、コーンスターチ又はその誘導体、タルク、ステアリン酸又はその塩などを、例えば、錠剤、コーティングされた錠剤、ドラフェ及び硬質ゼラチンカプセルのためのこのような担体として使用することができる。軟質ゼラチンカプセルに適した担体は、例えば、植物油、ワックス、油脂、半固体及び液状ポリオールなどである。しかしながら、活性物質の性質によっては、通常軟質ゼラチンカプセルの場合担体は不要である。溶液及びシロップ剤生成ための適切な担体は、例えば、水、ポリオール、グリセロール、植物油などである。坐剤に適した担体は、例えば、天然油又は硬化油、ワックス、油脂、半液状又は液状ポリオールなどである。
BJAB−ルシフェラーゼ(バーキットリンパ腫)異種移植片
インビボ腫瘍細胞死滅アッセイ
A.異種移植片−DM1コンジュゲート
HVR−L2及びHVR−H3(huMA79b L2/H3)に変化を有するMA79bを移植された「ヒト化」抗体変異体のIgG変異体の有効性を試験するために、huMA79b L2/H3変異体をDM1にコンジュゲートし、コンジュゲートされた変異体のマウスの腫瘍に対する影響を分析した。
陰性コントロールには、抗HER2(HERCEPTIN(登録商標)(トラスツズマブ))ベースのコンジュゲート(SMCC−DM1)が含まれていた。同様の研究において、実施例A(上記)に開示されているものと同じ異種移植片試験プロトコールを用いて、薬物コンジュゲート及び投与用量を変化させ、追加の薬物コンジュゲートの有効性を、CB17 SCIDマウス内のBJAB−ルシフェラーゼ異種移植片(バーキットリンパ腫)において試験した。薬物コンジュゲート及び用量(すべてのADC及びコントロールについて0日目に投与)を以下の表3に示す。
この実験パートは、CD79b抗体薬物コンジュゲート抗CD79b−MC−vc−PAB−MMAEと併用されるGA101(本明細書に定義されるオビヌツズマブ)に関し、ここでこのCD79b抗体−薬物コンジュゲート中の抗CD79b抗体はhuMA79b.v28である。このCD79b抗体薬物コンジュゲートは、本明細書では「CD79b−ADC」と呼ばれる。本試験の主要な目的は、SCIDベージュマウスに播種されたZ138マントル細胞リンパ腫(MCL)異種移植モデルにおいて、CD79b−ADCと併用されるGA101の効果を、GA101を用いた単剤療法、リツキシマブを用いた単剤療法及びリツキシマブとCD79b−ADCの併用と比較して調べることである。試験設計を表4に示す。
Z138ヒトマントル細胞リンパ腫(MCL)細胞は、最初にMartin Dyerから得られ、増殖後Glycart社内部細胞バンクに寄託された。腫瘍細胞株を、常套的に、10%FCS(Gibco)を含むDMEM中において、5%CO2の水飽和雰囲気中37℃で培養した。生存率96.4%において、継代26を移植に使用した。動物1当たり10x106個の細胞を、200μlのAim V細胞培地(GIBCO)において、尾静脈に静脈内注入した。CD20及びCD79bの発現を、Z138 MCL細胞上においてFACSにより確認した。この目的のために、0.2Mioの細胞を、抗ヒトCD20 PE(BD Bioscience #555623)、抗ヒトCD79b−PE(BD Bioscience #555679)又はアイソタイプコントロールのマウスIgG1(BD Bioscience #555749)又はマウスIgG2b(BD Bioscience #555743)を用いて3重に染色した。平均蛍光を、FACS CantoII(Software FACS Diva)において、プレートプロトコールを用いて測定した。
62のSCIDベージュのメスのマウス;実験開始時に週齢7〜8(Taconic、Denmarkから購入)を、関連するガイドライン(GV−Solas;Felasa;TierschG)に従い、毎日、12時間明所/12時間暗所のサイクルで、特定の病原体のいない条件下で保持した。実験的な試験プロトコールは、地域の獣医(免許証番号P2008016)により確認及び承認された。動物は到着後1週間、新しい環境への馴致及び観察のために保持された。継続的な健康モニタリングが定期的に実施された。
治療は、細胞移植の21日後に開始された。治療抗体及び対応するビヒクルを、試験の21、28及び35日目に、30mg/kgの用量で、単剤として静脈内に与えた。CD79bADCを、試験21日目に4mg/kgの用量で1回与えた。抗体希釈物を、使用前に在庫から新しく調製した。試験は309日目に終了した。
動物は、臨床症状及び有害作用の検出について毎日検査した。動物の終了基準は目に見える病気、即ち:汚い毛皮、背中の湾曲、荒い呼吸、運動障害、HLP(後肢麻痺)であった。マウスは、終了基準に従って屠殺した。腫瘍量をチェックするために、実験開始時に1のスカウトを採取した。マウスは、終了基準に従って屠殺した。
生存データを、ペア毎のWilcoxon及びペア毎のログランク検定により統計学的に分析した。
ヒトマントル細胞リンパ腫細胞株Z138を、マウスの尾静脈中に静脈内接種(細胞10x106個)した。マウスを、第1療法の前に無作為化し、治療を細胞移植後21日目に開始した。抗体薬物コンジュゲートは、21日目に4mg/kgの用量で1回与えられ、GA101、リツキシマブ及び対応するビヒクルは、試験日21、28及び35に30mg/kgの用量で静脈内に与えられた。コントロール群の動物にはPBSを与えた。すべての動物を、臨床症状及び有害作用の検出について毎日検査し、設定された終了基準に従って屠殺した。試験終了は試験日309であった。生存データは生存曲線で表され(図1)、ペア毎のWilcoxon及びペア毎のログランク検定によって統計学的に分析された(図2)。図2の*でマークした値は、有意な差異を示す。異なる治療群の中央値及び全生存期間値を、表4及び表5に示す。実験が終了した309日目まで生存したすべての動物は、生検中見かけ上腫瘍を有していなかった。
Claims (47)
- CD79b抗体−薬物コンジュゲートを併用するがんの治療のための、Asn297においてオリゴ糖(糖類)の総量の60%以下の量のフコースを有するアフコシル化抗CD20抗体。
- 前記がんがCD20を発現するがんであることを特徴とする、請求項1に記載の抗体。
- 前記CD20を発現するがんがリンパ腫又はリンパ性白血病であることを特徴とする、請求項1又は2に記載の抗体。
- 前記抗CD20抗体がヒト化B−Ly1抗体であることを特徴とする、請求項1から3のいずれか一項に記載の抗体。
- 前記抗CD20抗体がオビヌツズマブであることを特徴とする、請求項1から4のいずれか一項に記載の抗体。
- 一又は複数の追加の他の細胞傷害性剤、化学療法剤若しくは抗がん剤、又はこのような薬剤の効果を増強する化合物若しくは電離放射線が投与されることを特徴とする、請求項1から5のいずれか一項に記載の抗体。
- CD79b抗体−薬物コンジュゲート中の前記CD79b抗体が、以下、即ち:
(i)配列A1〜A15を含み、A1〜A15がKASQSVDYDGDSFLN(配列番号131)であるHVR−L1;
(ii)配列B1〜B7を含み、B1〜B7がAASNLES(配列番号132)であるHVR−L2;
(iii)配列C1〜C9を含み、C1〜C9がQQSNEDPLT(配列番号133)であるHVR−L3;
(iv)配列D1〜D10を含み、D1〜D10がGYTFSSYWIE(配列番号134)であるHVR−H1;
(v)配列E1〜E18を含み、E1〜E18がGEILPGGGDTNYNEIFKG(配列番号135)であるHVR−H2;及び
(vi)配列F1〜F10を含み、F1〜F10がTRRVPVYFDY(配列番号136)であるHVR−H3
からなる群より選択される少なくとも一つ、二つ、三つ、四つ、五つ、又は六つのHVRを含むことを特徴とする、請求項1から6のいずれか一項に記載の抗体。 - CD79b抗体−薬物コンジュゲートが式Ab−(L−D)pを有し、式中
(a)Abは請求項7に記載のCD79b抗体であり、
(b)Lはリンカーであり、
(c)Dは薬物部分である、
請求項1から7のいずれか一項に記載の抗体。 - CD79b抗体−薬物コンジュゲートが式Ab−(L−D)pを有し、ここでLは6−マレイミドカプロイル(MC)、マレイミドプロパノイル(MP)、バリン−シトルリン(val−cit)、アラニン−フェニルアラニン(ala−phe)、p−アミノベンジルオキシカルボニル(PAB)、N−スクシンイミジル4−(2−ピリジルチオ)ペンタノエート(SPP)、N−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)、及びN−スクシンイミジル(4−ヨード−アセチル)アミノベンゾエート(SIAB)から選択される、請求項1から8のいずれか一項に記載の抗体。
- CD79b抗体−薬物コンジュゲートが式Ab−(L−D)pを有し、ここでDはアウリスタチン、ドロスタンチン(dolostantin)、DM1、DM3、DM4、MMAE及びMMAFからなる群より選択される、請求項1から9のいずれか一項に記載の抗体。
- CD79b抗体−薬物コンジュゲートが抗CD79b−MC−vc−PAB−MMAEである、請求項1から10のいずれか一項に記載の抗体。
- 前記CD79b抗体−薬物コンジュゲート中の抗CD79b抗体がhuMA79b.v28である、請求項1から11のいずれか一項に記載の抗体。
- がんの治療のための、Asn297においてオリゴ糖(糖類)の総量の60%以下の量のフコースでアフコシル化されたヒト化B−Ly1抗体、及びCD79b抗体−薬物コンジュゲートを含む組成物。
- 前記抗CD20抗体がオビヌツズマブであることを特徴とする、請求項13に記載の組成物。
- 一又は複数の追加の他の細胞傷害性剤、化学療法剤若しくは抗がん剤、又はこのような薬剤の効果を増強する化合物若しくは電離放射線が投与されることを特徴とする、請求項13又は14に記載の組成物。
- CD79b抗体−薬物コンジュゲート中の前記CD79b抗体が、以下、即ち:
(i)配列A1〜A15を含み、A1〜A15がKASQSVDYDGDSFLN(配列番号131)であるHVR−L1;
(ii)配列B1〜B7を含み、B1〜B7がAASNLES(配列番号132)であるHVR−L2;
(iii)配列C1〜C9を含み、C1〜C9がQQSNEDPLT(配列番号133)であるHVR−L3;
(iv)配列D1〜D10を含み、D1〜D10がGYTFSSYWIE(配列番号134)であるHVR−H1;
(v)配列E1〜E18を含み、E1〜E18がGEILPGGGDTNYNEIFKG(配列番号135)であるHVR−H2;及び
(vi)配列F1〜F10を含み、F1〜F10がTRRVPVYFDY(配列番号136)であるHVR−H3
からなる群より選択される少なくとも一つ、二つ、三つ、四つ、五つ、又は六つのHVRを含むことを特徴とする、請求項13から15のいずれか一項に記載の組成物。 - CD79b抗体−薬物コンジュゲートが式Ab−(L−D)pを有し、式中
(a)Abは請求項16に記載のCD79b抗体であり、
(b)Lはリンカーであり、
(c)Dは薬物部分である、
請求項14から18のいずれか一項に記載の組成物。 - CD79b抗体−薬物コンジュゲートが式Ab−(L−D)pを有し、ここでLは6−マレイミドカプロイル(MC)、マレイミドプロパノイル(MP)、バリン−シトルリン(val−cit)、アラニン−フェニルアラニン(ala−phe)、p−アミノベンジルオキシカルボニル(PAB)、N−スクシンイミジル4−(2−ピリジルチオ)ペンタノエート(SPP)、N−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)、及びN−スクシンイミジル(4−ヨード−アセチル)アミノベンゾエート(SIAB)から選択される、請求項14から19のいずれか一項に記載の組成物。
- CD79b抗体−薬物コンジュゲートが式Ab−(L−D)pを有し、ここでDはアウリスタチン、ドロスタンチン(dolostantin)、DM1、DM3、DM4、MMAE及びMMAFからなる群より選択される、請求項13から18のいずれか一項に記載の組成物。
- CD79b抗体−薬物コンジュゲートが抗CD79b−MC−vc−PAB−MMAEである、請求項13から19のいずれか一項に記載の組成物。
- 前記CD79b抗体−薬物コンジュゲート中の抗CD79b抗体がhuMA79b.v28である、請求項13から20のいずれか一項に記載の組成物。
- Asn297においてオリゴ糖(糖類)の総量の60%以下の量のフコースを有するアフコシル化抗CD20抗体を、CD79b抗体−薬物コンジュゲートと併せてそのような治療を必要とする患者に投与することによる、がんに罹患している患者の治療方法。
- 前記がんがCD20を発現するがんであることを特徴とする、請求項22に記載の方法。
- 前記CD20を発現するがんがリンパ腫又はリンパ性白血病であることを特徴とする、請求項22又は23に記載の方法。
- 前記抗CD20抗体がヒト化B−Ly1抗体であることを特徴とする、請求項22から24のいずれか一項に記載の方法。
- 前記抗CD20抗体がオビヌツズマブであることを特徴とする、請求項22から25のいずれか一項に記載の方法。
- 一又は複数の追加の他の細胞傷害性剤、化学療法剤若しくは抗がん剤、又はこのような薬剤の効果を増強する化合物若しくは電離放射線が投与されることを特徴とする、請求項22から26のいずれか一項に記載の方法。
- CD79b抗体−薬物コンジュゲート中の前記CD79b抗体が、以下、即ち:
(i)配列A1〜A15を含み、A1〜A15がKASQSVDYDGDSFLN(配列番号131)であるHVR−L1;
(ii)配列B1〜B7を含み、B1〜B7がAASNLES(配列番号132)であるHVR−L2;
(iii)配列C1〜C9を含み、C1〜C9がQQSNEDPLT(配列番号133)であるHVR−L3;
(iv)配列D1〜D10を含み、D1〜D10がGYTFSSYWIE(配列番号134)であるHVR−H1;
(v)配列E1〜E18を含み、E1〜E18がGEILPGGGDTNYNEIFKG(配列番号135)であるHVR−H2;及び
(vi)配列F1〜F10を含み、F1〜F10がTRRVPVYFDY(配列番号136)であるHVR−H3
からなる群より選択される少なくとも一つ、二つ、三つ、四つ、五つ、又は六つのHVRを含むことを特徴とする、請求項22から27のいずれか一項に記載の方法。 - CD79b抗体−薬物コンジュゲートが式Ab−(L−D)pを有し、式中
(a)Abは請求項28に記載のCD79b抗体であり、
(b)Lはリンカーであり、
(c)Dは薬物部分である、
請求項22から28のいずれか一項に記載の方法。 - CD79b抗体−薬物コンジュゲートが式Ab−(L−D)pを有し、ここでLは6−マレイミドカプロイル(MC)、マレイミドプロパノイル(MP)、バリン−シトルリン(val−cit)、アラニン−フェニルアラニン(ala−phe)、p−アミノベンジルオキシカルボニル(PAB)、N−スクシンイミジル4−(2−ピリジルチオ)ペンタノエート(SPP)、N−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)、及びN−スクシンイミジル(4−ヨード−アセチル)アミノベンゾエート(SIAB)から選択される、請求項22から29のいずれか一項に記載の方法。
- CD79b抗体−薬物コンジュゲートが式Ab−(L−D)pを有し、ここでDはアウリスタチン、ドロスタンチン(dolostantin)、DM1、DM3、DM4、MMAE及びMMAFからなる群より選択される、請求項22から30のいずれか一項に記載の方法。
- CD79b抗体−薬物コンジュゲートが抗CD79b−MC−vc−PAB−MMAEである、請求項22から31のいずれか一項に記載の方法。
- 前記CD79b抗体−薬物コンジュゲート中の抗CD79b抗体がhuMA79b.v28である、請求項22から32のいずれか一項に記載の方法。
- CD79b抗体−薬物コンジュゲートを併用するがんの治療のための医薬の製造のための、Asn297においてオリゴ糖(糖類)の総量の60%以下の量のフコースを有するアフコシル化抗CD20抗体の使用。
- 前記がんがCD20を発現がんするであることを特徴とする、請求項34に記載の使用。
- 前記CD20を発現するがんがリンパ腫又はリンパ性白血病であることを特徴とする、請求項34又は35に記載の使用。
- 前記抗CD20抗体がヒト化B−Ly1抗体であることを特徴とする、請求項34から36のいずれか一項に記載の使用。
- 前記抗CD20抗体がオビヌツズマブであることを特徴とする、請求項34から37のいずれか一項に記載の使用。
- 一又は複数の追加の他の細胞傷害性剤、化学療法剤若しくは抗がん剤、又はこのような薬剤の効果を増強する化合物若しくは電離放射線が投与されることを特徴とする、請求項34から38のいずれか一項に記載の使用。
- CD79b抗体−薬物コンジュゲート中の前記CD79b抗体が、以下、即ち:
(i)配列A1〜A15を含み、A1〜A15がKASQSVDYDGDSFLN(配列番号131)であるHVR−L1;
(ii)配列B1〜B7を含み、B1〜B7がAASNLES(配列番号132)であるHVR−L2;
(iii)配列C1〜C9を含み、C1〜C9がQQSNEDPLT(配列番号133)であるHVR−L3;
(iv)配列D1〜D10を含み、D1〜D10がGYTFSSYWIE(配列番号134)であるHVR−H1;
(v)配列E1〜E18を含み、E1〜E18がGEILPGGGDTNYNEIFKG(配列番号135)であるHVR−H2;及び
(vi)配列F1〜F10を含み、F1〜F10がTRRVPVYFDY(配列番号136)であるHVR−H3
からなる群より選択される少なくとも一つ、二つ、三つ、四つ、五つ、又は六つのHVRを含むことを特徴とする、請求項34から39のいずれか一項に記載の使用。 - CD79b抗体−薬物コンジュゲートが式Ab−(L−D)pを有し、式中
(a)Abは請求項40に記載のCD79b抗体であり、
(b)Lはリンカーであり、
(c)Dは薬物部分である、
請求項34から40のいずれか一項に記載の使用。 - CD79b抗体−薬物コンジュゲートが式Ab−(L−D)pを有し、ここでLは6−マレイミドカプロイル(MC)、マレイミドプロパノイル(MP)、バリン−シトルリン(val−cit)、アラニン−フェニルアラニン(ala−phe)、p−アミノベンジルオキシカルボニル(PAB)、N−スクシンイミジル4−(2−ピリジルチオ)ペンタノエート(SPP)、N−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)、及びN−スクシンイミジル(4−ヨード−アセチル)アミノベンゾエート(SIAB)から選択される、請求項34から41のいずれか一項に記載の使用。
- CD79b抗体−薬物コンジュゲートが式Ab−(L−D)pを有し、ここでDはアウリスタチン、ドロスタンチン(dolostantin)、DM1、DM3、DM4、MMAE及びMMAFからなる群より選択される、請求項34から42のいずれか一項に記載の使用。
- CD79b抗体−薬物コンジュゲートが抗CD79b−MC−vc−PAB−MMAEである、請求項34から43のいずれか一項に記載の使用。
- 前記CD79b抗体−薬物コンジュゲート中の抗CD79b抗体がhuMA79b.v28である、請求項34から44のいずれか一項に記載の使用。
- 一又は複数の追加の他の細胞傷害性剤、化学療法剤若しくは抗がん剤、又はこのような薬剤の効果を増強する化合物若しくは電離放射線が投与されることを特徴とする、請求項34から45のいずれか一項に記載の使用。
- 本明細書に記載される発明。
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US20170315132A1 (en) * | 2016-03-25 | 2017-11-02 | Genentech, Inc. | Multiplexed total antibody and antibody-conjugated drug quantification assay |
US20180140703A1 (en) * | 2016-11-18 | 2018-05-24 | The Regents Of The University California | Tumor radiosensitization with antibody conjugates |
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US20210138213A1 (en) | 2017-03-30 | 2021-05-13 | Progenity, Inc. | Treatment of a disease of the gastrointestinal tract with an immune modulatory agent released using an ingestible device |
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