JP2017501155A - Pd−1軸結合アンタゴニスト及びタキサンを使用する癌の治療方法 - Google Patents
Pd−1軸結合アンタゴニスト及びタキサンを使用する癌の治療方法 Download PDFInfo
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Abstract
Description
本出願は、2013年12月17日出願の米国仮特許出願第61/917,264号に対する優先権を主張するものである。
本発明について詳述する前に、本発明が、特定の組成物または生物学系に限定されるものではなく、これらは当然変動し得るということを理解すべきである。また、本明細書中で使用される専門用語が、特定の実施形態を説明することだけを目的としたものであって、限定的であるように意図されていないということも理解すべきである。
本明細書中に提供されているのは、有効量のPD−1軸結合アンタゴニストとタキサンを個体に投与することを含む、個体において癌を治療するまたは癌の進行を遅延させるための方法である。同じく本明細書中に提供されているのは、有効量のPD−1軸結合アンタゴニストとタキサンを個体に投与することを含む、癌を有する個体において免疫機能を増強させる方法である。例えば、PD−1軸結合アンタゴニストには、PD−1結合アンタゴニスト、PD−L1結合アンタゴニスト及びPD−L2結合アンタゴニストが含まれる。PD−1(プログラム死1)は、当該技術分野において「プログラム細胞死1」、「PDCD1」、「CD279」及び「SLEB2」とも呼ばれている。例示的な1つのヒトPD−1は、niProtKB/Swiss−Prot受託番号Q15116中に示されている。PD−L1(プログラム死リガンド−1)は、当該技術分野において、「プログラム細胞死1リガンド1」、「PDCD1LG1」、「CD274」、「B7−H」及び「PDL1」とも呼ばれている。例示的な1つのヒトPD−L1は、UniProtKB/Swiss−Prot受託番号Q9NZQ7.1中に示されている。PD−L2(プログラム死リガンド2)は、当該技術分野において、「プログラム細胞死1リガンド2」、「PDCD1LG2」、「CD273」、「B7−DC」、「Btdc」及び「PDL2」とも呼ばれている。例示的な1つのヒトPD−L2は、UniProtKB/Swiss−Prot受託番号Q9BQ51中に示されている。一部の実施形態において、PD−1、PD−L1及びPD−L2は、ヒトPD−1、PD−L1及びPD−L2である。
一部の実施形態において、抗PD−1抗体はMDX−1106である。「MDX−1106」の代替的名称としては、MDX−1106−04、ONO−4538、BMS−936558またはニボルマブがある。一部の実施形態において、抗PD−1抗体はニボルマブ(CAS登録番号:946414−94−4)である。またさらなる実施形態において、提供されているのは、配列番号1由来の重鎖可変領域アミノ酸配列を含む重鎖可変領域及び/または配列番号2由来の軽鎖可変領域アミノ酸配列を含む軽鎖可変領域を含む、単離された抗PD−1抗体である。またさらなる実施形態において、提供されているのは、重鎖及び/または軽鎖配列を含む単離された抗PD−1抗体であり、ここで、
(a)重鎖配列は、重鎖配列:
QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号1)に対して少なくとも85%、少なくとも90%、少なくとも91%、少なくとも92%、少なくとも93%、少なくとも94%、少なくとも95%、少なくとも96%、少なくとも97%、少なくとも98%、少なくとも99%または100%の配列同一性を有し、かつ
(b)軽鎖配列は、軽鎖配列:
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号2)に対して少なくとも85%、少なくとも90%、少なくとも91%、少なくとも92%、少なくとも93%、少なくとも94%、少なくとも95%、少なくとも96%、少なくとも97%、少なくとも98%、少なくとも99%または100%の配列同一性を有する。
一部の実施形態において、調合物中の抗体は、重鎖及び/または軽鎖配列中に少なくとも1つ(例えば少なくとも2つ、少なくとも3つまたは少なくとも4つ)のトリプトファンを含む。一部の実施形態において、アミノ酸トリプトファンは、抗体のHVR領域、フレームワーク領域及び/または定常領域内にある。一部の実施形態において、抗体は、HVR領域内に2つまたは3つのトリプトファン残基を含む。一部の実施形態において、調合物中の抗体は抗PD−L1抗体である。PDL1、B7−H1、B7−4、CD274及びB7−Hとしても公知であるPD−L1(プログラム死リガンド1)は、膜貫通タンパク質であり、それとPD−1との相互作用は、T細胞活性化及びサイトカイン産生を阻害する。一部の実施形態において、本明細書中に記載の抗PD−L1抗体は、ヒトPD−L1に結合する。本明細書中に記載の方法内で使用可能である抗PD−L1抗体の例は、その全体が参照により本明細書に援用されているPCT特許出願WO2010/077634A1及びUS8,217,149の中に記載されている。
(a)重鎖配列は、重鎖配列:
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA(配列番号3)に対して少なくとも85%、少なくとも90%、少なくとも91%、少なくとも92%、少なくとも93%、少なくとも94%、少なくとも95%、少なくとも96%、少なくとも97%、少なくとも98%、少なくとも99%または100%の配列同一性を有し、かつ
(b)軽鎖配列は、軽鎖配列:
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR(配列番号4)に対して少なくとも85%、少なくとも90%、少なくとも91%、少なくとも92%、少なくとも93%、少なくとも94%、少なくとも95%、少なくとも96%、少なくとも97%、少なくとも98%、少なくとも99%または100%の配列同一性を有する。
(a)HVR−H1配列はGFTFSX1SWIHであり(配列番号5)、
(b)HVR−H2配列はAWIX2PYGGSX3YYADSVKGであり(配列番号6)、
(c)HVR−H3配列はRHWPGGFDYであり(配列番号7)、
さらにここで、X1はDまたはGであり;X2はSまたはLであり;X3はTまたはSである。1つの特定の態様において、X1はDであり;X2はSであり、X3はTである。
HC−FR1は、EVQLVESGGGLVQPGGSLRLSCAAS(配列番号:8)
HC−FR2は、WVRQAPGKGLEWV(配列番号:9)
HC−FR3は、RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR(配列番号:10)
HC−FR4は、WGQGTLVTVSA(配列番号:11)。
(a)HVR−L1配列は、RASQX4X5X6TX7X8Aであり(配列番号:12);
(b)HVR−L2配列は、SASX9LX10Sであり(配列番号:13);
(c)HVR−L3配列は、QQX11X12X13X14PX15Tであり(配列番号:14);
ここで、X4はDまたはV;X5はVまたはI;X6はSまたはN;X7はAまたはF;X8はVまたはL;X9はFまたはT;X10はYまたはA;X11はY、G、F、またはS;X12はL、Y、FまたはW;X13はY、N、A、T、G、FまたはI;X14はH、V、P、TまたはI;X15はA、W、R、PまたはTである。またさらなる態様において、X4はD;X5はV;X6はS;X7はA;X8はV;X9はF;X10はY;X11はY;X12はL;X13はY;X14はH;X15はAである。
LC−FR1は、DIQMTQSPSSLSASVGDRVTITC(配列番号15)
LC−FR2は、WYQQKPGKAPKLLIY(配列番号16)
LC−FR3は、GVPSRFSGSGSGTDFTLTISSLQPEDFATYY(配列番号17)
LC−FR4は、FGQGTKVEIKR(配列番号18)。
(a)重鎖は、HVR−H1、HVR−H2及びHVR−H3を含み、ここでさらに、
(i) HVR−H1配列は、GFTFSX1SWIHであり(配列番号5)
(ii) HVR−H2配列は、AWIX2PYGGSX3YYADSVKGであり(配列番号6)
(iii) HVR−H3配列は、RHWPGGFDYであり(配列番号7)、及び
(b)軽鎖は、HVR−L1、HVR−L2及びHVR−L3を含み、ここでさらに、
(i) HVR−L1配列は、RASQX4X5X6TX7X8Aであり(配列番号12)
(ii) HVR−L2配列は、SASX9LX10Sであり(配列番号13);及び
(iii) HVR−L3配列は、QQX11X12X13X14PX15Tであり(配列番号14)、ここで式中、X1はDまたはG;X2はSまたはL;X3はTまたはS;X4はDまたはV;X5はVまたはI;X6はSまたはN;X7はAまたはF;X8はVまたはL;X9はFまたはT;X10はYまたはA;X11はY、G、FまたはS;X12はL、Y、FまたはW;X13はY、N、A、T、G、FまたはI;X14はH、V、P、TまたはI;X15はA、W、R、PまたはTである。特定の一態様において、X1はD;X2はS及びX3はTである。別の態様において、X4はD;X5はV;X6はS;X7はA;X8はV;X9はF;X10はY;X11はY;X12はL;X13はY;X14はH;X15はAである。なお、さらに別の態様では、X1はD;X2はSでありX3はT、X4はD;X5はV;X6はS;X7はA;X8はV;X9はF;X10はY;X11はY;X12はL;X13はY;X14はH及びX15はAである。
(a)重鎖はさらに、それぞれGFTFSDSWIH(配列番号19)、AWISPYGGSTYYADSVKG(配列番号20)、及びRHWPGGFDY(配列番号21)に対して少なくとも85%の配列同一性を有するHVR−H1、HVR−H2及びHVR−H3配列をさらに含むか、または
(b)軽鎖はさらに、それぞれRASQDVSTAVA(配列番号22)、SASFLYS(配列番号23)及びQQYLYHPAT(配列番号24)に対して少なくとも85%の配列同一性を有するHVR−L1、HVR−L2及びHVR−L3配列をさらに含む。
(a)重鎖配列は、重鎖配列:
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS(配列番号25)に対して少なくとも85%の配列同一性を有する、かつ/または
(b)軽鎖配列は、軽鎖配列:
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR(配列番号4)に対して少なくとも85%の配列同一性を有する。
HC−FR1 EVQLVESGGGLVQPGGSLRLSCAASGFTFS(配列番号29)
HC−FR2 WVRQAPGKGLEWVA(配列番号30)
HC−FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR(配列番号10)
HC−FR4 WGQGTLVTVSS(配列番号27)。
LC−FR1 DIQMTQSPSSLSASVGDRVTITC(配列番号15)
LC−FR2 WYQQKPGKAPKLLIY(配列番号16)
LC−FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(配列番号17)
LC−FR4 FGQGTKVEIK(配列番号28)。
(c)重鎖はさらに、それぞれGFTFSDSWIH(配列番号19)、AWISPYGGSTYYADSVKG(配列番号20)、及びRHWPGGFDY(配列番号21)に対して少なくとも85%の配列同一性を有するHVR−H1、HVR−H2及びHVR−H3配列をさらに含み、かつ/または
(d)軽鎖はさらに、それぞれRASQDVSTAVA(配列番号22)、SASFLYS(配列番号23)及びQQYLYHPAT(配列番号24)に対して少なくとも85%の配列同一性を有するHVR−L1、HVR−L2及びHVR−L3配列を含む。
(a)重鎖配列は、重鎖配列:
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTK(配列番号26)に対して少なくとも85%の配列同一性を有する、または
(b)軽鎖配列は、軽鎖配列:
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR(配列番号4)に対して少なくとも85%の配列同一性を有する。
(a)重鎖配列が、重鎖配列:
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(配列番号32)に対して少なくとも85%の配列同一性を有し、かつ/または
(b)軽鎖配列が、軽鎖配列:
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号33)に対して少なくとも85%の配列同一性を有する、単離された抗PD−L1抗体である。
本明細書中に記載の抗体は、抗体生成のための当該技術分野において利用可能な技術を用いて調製され、その例示的方法について以下の節でより詳細に説明する。
任意には、他の分子にコンジュゲートされた可溶性抗原またはフラグメントを、抗体生成用免疫原として使用することができる。レセプターなどの膜貫通分子については、これらのフラグメント(例えばレセプターの細胞外ドメイン)を免疫原として使用することができる。代替的には、膜貫通分子を発現する細胞を免疫原として使用することができる。このような細胞は、天然の供給源(例えば癌の細胞株)に由来するものであり得、あるいは膜貫通分子を発現するために組換え型技術により形質転換された細胞であってもよい。抗体を調製するのに有用である他の抗原及びその形態は、当業者には明らかとなるものである。
好ましくは関連する抗原及びアジュバントを、皮下(sc)または腹腔内(ip)に多数回注射することにより、動物の体内にポリクローナル抗体を産生させる。例えば、マレイミドベンゾイルスルホスクシンイミドエステル(システイン残基を通したコンジュゲーション)、N−ヒドロキシスクシンイミド(リジン残基を通して)、グルタルアルデヒド、無水コハク酸、SOCl2またはR1N=C=NR(式中R及びR1は異なるアルキル基である)などの二官能性剤または誘導体化剤を用いてキーホールリンペットヘモシアニン、血清アルブミン、ウシサイログロブリンまたはダイズトリプシン阻害剤など、免疫付与すべき種の体内で免疫原性のあるタンパク質に対して、関連する抗原をコンジュゲートすることが、有用であるかもしれない。
本発明の抗体は、所望の活性(単複)を有する抗体についてコンビナトリアルライブラリをスクリーニングすることによって単離されてもよい。例えば、ファージディスプレイライブラリを生成し、所望の結合特性を有する抗体についてこのようなライブラリをスクリーニングするためのさまざまな方法が、当該技術分野において公知である。追加の方法は例えばHoogenboom et al.,in Methods in Molecular Biology 178:1〜37(O’Brien et al.,ed.,Human Press,Totowa,NJ,2001)において概説され、例えばMcCafferty et al.,Nature 348:552〜554;Clackson et al.,Nature 352:624〜628(1991);Marks et al.,J.Mol.Biol.222:581〜597(1992);Marks and Bradbury,in Methods in Molecular Biology 248:161〜175(Lo,ed.,Human Press,Totowa,NJ,2003);Sidhu et al.,J.Mol.Biol.338(2):299〜310(2004);Lee et al.,J.Mol.Biol.340(5):1073〜1093(2004);Fellouse,Proc.Natl.Acad.Sci.USA 101(34):12467〜12472(2004);及びLee et al.,J.Immunol.Methods284(1−2):119〜132(2004)の中にさらに記載されている。
ある特定の実施形態において、本明細書中に提供されている抗体はキメラ抗体である。ある特定のキメラ抗体は、例えば米国特許第4,816,567号;及びMorrison et al.,Proc.Natl.Acad.Sci.USA,81:6851〜6855(1984)中に記載されている。一実施例において、キメラ抗体は、非ヒト可変領域(例えばマウス、ラット、ハムスター、ウサギまたは非ヒト霊長類、例えばサルに由来する可変領域)及びヒト定常領域を含む。さらなる実施例において、キメラ抗体は、クラスまたはサブクラスが親抗体のものから変更されている「クラススイッチ型」抗体である。キメラ抗体は、その抗原結合フラグメントを含む。
抗体フラグメントは、酵素消化などの従来の手段によってかまたは組換え技術により生成されてよい。ある特定の状況においては、全抗体ではなく抗体フラグメントを使用するのが有利である。フラグメントはサイズが比較的小さいことから、急速なクリアランスを可能にし、固形腫瘍に対するアクセスの改善を導くかもしれない。ある特定の抗体フラグメントの概説については、Hudson et al.(2003)Nat.Med.9:129〜134を参照のこと。
多特異性抗体は、少なくとも2つの異なるエピトープに対する結合特異性を有し、ここでエピトープは通常、異なる抗原に由来する。このような分子は通常、2つの異なるエピトープ(すなわち二重特異性抗体、BsAb)に結合するものの、本明細書中で使用される場合この表現には、三重特異性抗体などの追加の特異性を有する抗体も包含される。二重特異性抗体は、完全長抗体または抗体フラグメント(例えばF(ab’)2二重特異性抗体)として調製可能である。
aアミノ酸の分子量から水の分子量を減じたもの。数値の出典は、Handbook of Chemistry and Physic,43th ed.Cleveland,Chemical Rubber Publishing Co.,1961。
b 数値の出典は、A.A.Zamyatnin,Prog. Biophys.Mol.Biol.24:107〜123,1972。
c 数値の出典は、C.Chothia,J.Mol.Biol.105:1〜14,1975。アクセス可能な表面積は、この参考文献の図6〜20内に定義されている。
突然変異は、原初の残基と、それに続く、Kabat付番システムを用いた位置、そして次にインポート残基(全ての残基は、一文字アミノ酸コードで提供されている)によって表示されている。複数の突然変異はコロンで分けられている。
一部の実施形態において、本発明の抗体は、単一ドメイン抗体である。単一ドメイン抗体は、抗体の重鎖可変ドメインの全部または一部分あるいは軽鎖可変ドメインの全部または一部分を含む単一ポリペプチド鎖である。ある特定の実施形態では、単一ドメイン抗体はヒト単一ドメイン抗体である(Domantis,Inc.,Waltham,Mass.;例えば米国特許第6,248,516B1号参照)。一実施形態において、単一ドメイン抗体は、抗体の重鎖ドメインの全部または一部分で構成される。
一部の実施形態において、本明細書中に記載の抗体のアミノ酸配列の修飾(単複)が企図されている。例えば、抗体の結合親和性及び/または他の生物学的特性を改善することが所望されるかもしれない。抗体のアミノ酸配列変異体は、抗体をコードするヌクレオチド配列内に適切な変化を導入することによってか、またはペプチド合成によって調製されてよい。このような修飾には、例えば、抗体のアミノ酸配列内部の残基からの欠失、及び/またはその中への挿入及び/またはその置換が含まれる。最終的構成体が所望の特性を有することを条件として、最終的構成体に到達するために、欠失、挿入及び置換の任意の組合せを行なうことができる。配列が作製される時に、対象の抗体アミノ酸配列内にアミノ酸改変を導入してよい。
ある特定の実施形態においては、1つ以上のアミノ酸置換を有する抗体変異体が提供される。置換による突然変異誘発のための目的の部位としては、HVRとFRがある。保存的置換が、表1中で「保存的置換」の見出しの下で示されている。より実質的な変化は、表1中に、「例示的置換」という見出しの下で、かつアミノ酸側鎖クラスに関連して以下でさらに説明する通りに提供されている。アミノ酸置換を、目的の抗体内に導入し、所望の活性、例えば抗原結合の保持/改善、免疫原性の減少またはADCCまたはCDCの改善について生成物をスクリーニングしてよい。
a.疎水性:ノルロイシン、Met、Ala、Val、Leu、Ile;
b.中性親水性:Cys、Ser、Thr、Asn、Gln;
c.酸性:Asp、Glu;
d.塩基性:His、Lys、Arg;
e.鎖配向に影響を及ぼす残基:Gly、Pro;
f.芳香族:Trp、Tyr、Phe。
ある特定の実施形態において、本明細書中で提供されている抗体は、抗体がグリコシル化される程度を増減させるために改変される。抗体に対するグリコシル化部位の付加または欠失は、1つ以上のグリコシル化部位が創出または除去されるようにアミノ酸配列を改変することによって、簡便に達成可能である。
ある特定の実施形態において、本明細書中で提供された抗体のFc領域内に1つ以上のアミノ酸修飾を導入して、Fc領域変異体を生成することが可能である。Fc領域変異体は、1つ以上のアミノ酸位置にアミノ酸修飾(例えば置換)を含むヒトFc領域配列(例えばヒトIgG1、IgG2、IgG3またはIgG4Fc領域)を含んでいてよい。
本発明の抗体はさらに、当該技術分野において公知であり容易に入手可能な追加の非タンパク質様部分を含むようにさらに修飾され得る。ある特定の実施形態において、抗体の誘導体化に好適な部分は、水溶性ポリマーである。水溶性ポリマーの非限定的例としては、ポリエチレングリコール(PEG)、エチレングリコール/プロピレングリコールのコポリマー、カルボキシメチルセルロース、デキストラン、ポリビニルアルコール、ポリビニルピロリドン、ポリ−1,3−ジオキソラン、ポリ−1,3,6−トリオキサン、エチレン/マレイン酸無水物コポリマー、ポリアミノ酸(ホモポリマーまたはランダムコポリマーのいずれか)、及びデキストランまたはポリ(n−ビニルピロリドン)ポリエチレングリコール、プロプロピレングリコールホモポリマー、プロリプロピレンオキシド/エチレンオキシドコポリマー、ポリオキシエチレン化ポリオール(例えばグリセロール)、ポリビニルアルコール及びその混合物が含まれるが、これらに限定されない。ポリエチレングリコールプロピオンアルデヒドは、その水中安定性に起因する製造上の利点があるかもしれない。ポリマーは、任意の分子量のものであってよく、分岐または非分岐であってよい。抗体に付着するポリマーの数は、変動する場合があり、2つ以上のポリマーが付着する場合、それらは同じ分子でも異なる分子でもあり得る。概して、誘導体化のために使用されるポリマーの数及び/またはタイプは、改善すべき抗体の特定の特性または機能、抗体誘導体が1つの療法において規定の条件下で使用されるか否かなどを含めた(ただしこれらに限定されない)考慮事項に基づいて決定可能である。
抗体は、組換え方法を用いて生産することもできる。抗抗原抗体の組換え生産のためには、抗体をコードする核酸が単離され、さらなるクローニング(DNAの増幅)または発現のために複製可能なベクター内に挿入される。抗体をコードするDNAは、従来の手順を用いて(例えば抗体の重鎖及び軽鎖をコードする遺伝子に特異的に結合できるオリゴヌクレオチドプローブを使用することなどによって)、直ちに単離され配列決定されてよい。多くのベクターが利用可能である。ベクター構成成分には概して、シグナル配列、複製起点、1つ以上のマーカー遺伝子、エンハンサー要素、プロモーター、及び転写終結配列のうちの1つ以上が含まれるが、これらに限定されない。
本発明の抗体は、組換えによって直接的にのみならず、好ましくはシグナル配列または成熟タンパク質またはポリペプチドのN末端に特異的分割を有する他のポリペプチドである異種ポリペプチドとの融合ポリペプチドとして生産されてよい。選択される異種シグナル配列は好ましくは、宿主細胞により認識され処理された(例えばシグナルペプチダーゼにより分割された)ものである。天然抗体シグナル配列を認識し処理しない原核生物宿主細胞については、シグナル配列は、例えば、アルカリホスファターゼ、ペニシリナーゼ、Ippまたは耐熱性エンテロトキシンIIリーダーからなる群から選択された原核生物シグナル配列により置換される。酵母分泌については、天然シグナル配列は、例えば、酵母インベルターゼリーダー、因子リーダー(Saccharomyces及びKluyveromyses α−因子リーダーを含む)または酸ホスファターゼリーダー、C.albicansグルコアミラーゼリーダーまたはWO90/13646中に記載のシグナルによって置換され得る。哺乳動物細胞発現においては、哺乳動物シグナル配列ならびにウイルス分泌リーダー、例えば単純ヘルペスgDシグナルが利用可能である。
発現及びクローニングベクターは両方共、1つ以上の選択された宿主細胞中でベクターが複製できるようにする核酸配列を含む。概して、クローニングベクター内で、この配列は、ベクターが宿主染色体DNAに依存せずに複製できるようにする配列であり、複製起点または自己複製配列を含む。このような配列は、さまざまな細菌、酵母及びウイルスについて周知である。プラスミドpBR322由来の複製起点は、大部分のグラム陰性菌に好適であり、2μプラスミド起点は酵母に好適であり、さまざまなウイルス起点(SV40、ポリオーマ、アデノウイルス、VSVまたはBPV)が、哺乳動物細胞内のクローニングベクターに好適である。概して、複製起点構成成分は、哺乳動物発現ベクターには必要とされない(SV40起点は、それが初期プロモーターを含むことのみを理由として、典型的に使用され得る。
発現及びクローニングベクターは、選択可能マーカーとも呼ばれる選択遺伝子を含んでいてよい。典型的な選択遺伝子は、(a)アンピシリン、ネオマイシン、メトトレキセートまたはテトラサイクリンなどの、抗生物質または他の毒素に対する耐性を付与するか、(b)栄養要求性欠損症を補足するか、または(c)例えば、BacilliのためのD−アラニンラセマーゼをコードする遺伝子など、複合培地から入手可能でない必須栄養素を供給するタンパク質をコードする。
発現及びクローニングベクターは、概して、宿主生体により認識され抗体をコードする核酸に作動的に結合されたプロモーターを含んでいる。原核生物宿主と共に使用するのに好適なプロモーターとしては、phoAプロモーター、β−ラクタマーゼ及びラクトースプロモーター系、アルカリホスファターゼプロモータ、トリプトファン(trp)プロモーター系、及びハイブリッドプロモーター、例えばtacプロモーターが含まれる。しかしながら、他の公知の菌株プロモーターも好適である。細菌系内で使用するためのプロモーターはまた、抗体をコードするDNAに対して作動的に結合されたShine−Dalgarno(S.D.)配列を含む。
高等真核生物による本発明の抗体をコードするDNAの転写は、多くの場合、ベクター内にエンハンサー配列を挿入することによって増大させられる。現在、哺乳動物遺伝子由来の多くのエンハンサー配列が公知である(グロビン、エラスターゼ、アルブミン、α−フェトタンパク質及びインスリン)。しかしながら典型的には、真核細胞ウイルス由来のエンハンサーが使用される。例としては、複製起点の後期側のSV40エンハンサー(bp100〜270)、サイトメガロウイルス初期プロモーターエンハンサー、複製起点の後期側のポリオーマエンハンサー、及びアデノウイルスエンハンサーが含まれる。また、真核生物プロモーターの活性化のための増強要素についてのYaniv,Nature 297:17〜18(1982)も参照のこと。エンハンサーは、抗体コーディング配列に対し5’位または3’位にあるベクター内にスプライシングされてよいが、好ましくはプロモーターから部位5’のところに位置設定される。
真核宿主細胞(酵母、真菌、昆虫、植物、動物、ヒトまたは他の多細胞生体由来の有核細胞)中で使用される発現ベクターはまた、転写の終結及びmRNAの安定化に必要な配列を含むものである。このような配列は、一般に、真核生物またはウイルスのDNAまたはcDNAの5’及び場合によっては3’未翻訳領域から入手可能である。これらの領域は、抗体をコードするmRNAの未翻訳部分内のポリアデニル化フラグメントとして転写されたヌクレオチドセグメントを含む。1つの有用な転写終結構成成分は、ウシ成長ホルモンポリアデニル化領域である。WO94/11026及びその中で開示されている発現ベクターを参照のこと。
本明細書中のベクター内でDNAをクローニングまたは発現するための好適な宿主細胞は、上述した原核生物、酵母または高等真核細胞である。この目的での好適な原核生物には、真正細菌、例えばグラム陰性またはグラム陽性微生物、例えば、腸内細菌科、例えばエシェリキア属、例えばE.coli、Enterobacter、Erwinia、Klebsiella、Proteus、サルモネラ菌、例えばSalmonella typhimurium、セラシア属、例えばSerratia marcescans、及び赤痢菌、ならびにバチルス菌、例えばB.subtilis及びB.licheniformis(例えば1989年4月12日公開のDD266,710中に開示されたB.licheniformis41P)、シュードモナス菌、例えばP.aeruginosa及びストレプトミセス、が含まれる。1つの好ましいE.coliクローニング宿主はE.coli 294(ATCC 31,446)であるが、E.coli B、E.coli X1776(ATCC 31,537)、及びE.coli W3110(ATCC 27,325)などの他の菌株も好適である。これらの例は、限定的ではなくむしろ例示的なものである。
本発明の抗体を生産するために使用される宿主細胞は、さまざまな培地中で培養されてよい。宿主細胞の培養のためには、Ham’s F10(Sigma)、Minimal Essential Medium((MEM),(Sigma)、RPMI−1640(Sigma)及びダルベッコ変法イーグル培地((DMEM)、(Sigma)などの市販の培地が好適である。さらに、Ham et al.,Meth.Enz.58:44(1979)、Barnes et al.,Anal.Biochem.102:255(1980)、米国特許第4,767,704号;同第4,657,866号;同第4,927,762号;同第4,560,655号;または同第5,122,469号;WO90/03430;WO87/00195;または米国特許再発行第30,985号中に記載の培地のいずれかを、宿主細胞用の培地として使用してよい。これらの培地のうちのいずれも、必要に応じて、ホルモン及び/または他の成長因子(例えばインシュリン、トランスフェリンまたは表皮成長因子)、塩(例えば塩化ナトリウム、カルシウム、マグネシウム及びリン酸塩)、緩衝液(例えばHEPES)、ヌクレオチド(例えばアデノシン及びチミジン)、抗生物質(例えばGENTAMYCIN(商標)薬剤)、微量元素(ミクロモル範囲内の最終濃度で通常存在する無機化合物として定義される)、及びグルコースまたは等価のエネルギー源で補足されてよい。当業者にとって公知と思われる他の任意の必要な補足物質も含まれていてよい。温度、pHなどの培養条件は、発現のために選択された宿主細胞で従来使用されたものであり、当業者にとっては明らかである。
組換え型技術を使用する場合、抗体は、細胞膜周辺腔内において細胞内で産生されるか、または培地内に直接分泌され得る。抗体が細胞内で産生される場合、最初のステップとして、宿主細胞または溶解したフラグメントのいずれかである粒子状残屑が、例えば遠心分離または限外濾過によって除去される。Carter et al.,Bio/Technology 10:163〜167(1992)は、E.coliの細胞膜周辺腔に分泌される抗体を単離するための手順について記載している。簡単に言うと、細胞ペーストが酢酸ナトリウム(pH3.5)、EDTA及びフェニルメチルスルホニルフルオリド(PMSF)の存在下で約30分間かけて解凍される。細胞残屑は、遠心分離によって除去することができる。抗体が培地内に分泌される場合、このような発現系由来の上清が、概してまず市販のタンパク質濃縮フィルター、例えばAmiconまたはMillipore Pellicon限外濾過ユニットを用いて濃縮される。上述のステップのいずれかの中に、タンパク質分解を阻害するためにPMSFなどのプロテアーゼ阻害薬を含み入れてよく、外来性汚染物質の成長を防止するために抗生物質を含み入れてもよい。
上述の通りに産生された抗体を、1つ以上の「生物活性」検定に付して、治療的見地から有益な特性をもつ抗体を選択するかまたは、抗体の生物活性を保持する調合及び条件を選択することができる。抗体を、その産生対象である抗原を結合する能力についてテストすることができる。例えば、当該技術分野において公知の方法(例えばELISA、Western Blotなど)を使用してよい。
本明細書中でまた提供されているのは、本明細書中に記載のPD−1軸結合アンタゴニスト及び/または抗体(例えば抗PD−L1抗体)そして薬学的に許容可能な担体を含む医薬組成物及び調合物である。本発明はまた、ナブ−パクリタキセル(ABRAXANE(登録商標))、パクリタキセルまたはドセタキセルなどのタキサンを含む医薬組成物及び調合物をも提供する。
本明細書中に提供されているのは、有効量のPD−1軸結合アンタゴニスト及びタキサン(例えばナブ−パクリタキセル(ABRAXANE(登録商標))またはパクリタキセル)を個体に投与することを含む、個体において癌を治療するかまたは癌の進行を遅延させる方法である。一部の実施形態において、治療の結果、治療後の個体の体内に応答がもたらされる。一部の実施形態において、応答は、完全寛解である。一部の実施形態において、治療は、治療の中止後、個体の体内に持続性寛解を結果としてもたらす。本明細書中に記載の方法は、癌治療のために腫瘍免疫原性を増大させる場合など、免疫原性の増強が所望される状態を治療する上で使用することができる。また、本明細書中に提供されているのは、有効量のPD−1軸結合アンタゴニスト及びタキサン(例えばナブ−パクリタキセル(ABRAXANE(登録商標))またはパクリタキセル)を個体に対して投与することを含む、癌を有する個体において免疫機能を増強する方法である。当該技術分野において公知であり本明細書中に記載されているPD−1軸結合アンタゴニスト及びタキサンのいずれも、本方法内で使用してよい。一部の実施形態において、方法はさらに、白金系の化学療法剤を投与することを含む。一部の実施形態において、白金系の化学療法剤は、カルボプラチンである。
また本明細書中で提供されているのは、個体に対して、別の抗癌剤または癌療法と併用してヒトPD−1軸結合アンタゴニスト及びタキサンを投与することを含む、個体において癌を治療するかまたは癌の進行を遅延させるための方法である。一部の実施形態において、方法には、個体に対して、別の抗癌剤または癌療法と併用して、ヒトPD−1軸結合アンタゴニスト、タキサン及び白金系化学療法剤を投与することが含まれる。
本発明の別の実施形態においては、PD−1軸結合アンタゴニスト及び/またはタキサンを含む製造品及び/またはキットが提供されている。一部の実施形態において、製造品またはキットはさらに、個体において癌を治療するかまたは癌の進行を遅延させるためまたは癌を有する個体の免疫機能を増強する目的でタキサンと併用してPD−1軸結合アンタゴニストを使用するための指示書を含む添付文書を含んでいる。本明細書中に記載のPD−1軸結合アンタゴニスト及び/またはタキサンのいずれも、製造品またはキット内に含まれていてよい。
材料及び方法
インビボ腫瘍モデル
MC38結腸直腸腫瘍細胞株をGenentechにおいて維持した。7〜10週齢のC57BL/6雌マウス(Charles River Laboratories;Hollister,CA)の右片側脇腹に、100000個のMC38細胞を皮下接腫した。腫瘍がおよそ100〜300mm3の平均腫瘍体積に達した時点で、マウスを採用し、治療グループへと無作為に選び、次の初日に抗体及び/または化学治療を開始した。
96ウェルのU字底プレート内で、10ng/mlのホルボール12−ミリステート13−アセテート(PMA)及び1μg/mlのイオノマイシン(Sigma−Alrich;St.Louis,MO)プラスGOLGIPLUG(商標)(ブレフェルジンA)(BD Biosciences;San Jose,CA))を用いて、37℃で4時間、1ウェルあたり1000000個の細胞の割合で3連で脾細胞を培養した。細胞を収穫し、表面マーカーCD4 FITC(フルオレセインイソチオシアネート)、CD3 PE(フィコエリスリン)、及びCD8 PerCp−Cy5.5(BD Biosciences)で染色し、氷上で30分間4%のパラホルムアルデヒドを用いて定着させた。1倍の透過化緩衝液(BD Biosciences)で細胞を透過化しラット抗マウス抗インターフェロン−γ(IFN−γ)−アロフィコシアニン(APC)でコンジュゲートされた抗体またはラットIgG1−APCアイソタイプ対照抗体(BD Biosciences)で染色し、FACSDIVA(商標)ソフトウェアを用いてBD Biosciences LSRIIに流した。FlowJoソフトウェア(TreeStar)を用いて、フローサイトメトリー分析を行なった。
全ての治療抗体をGenentechにおいて生成した。対照抗体は、抗gp120マウスIgG1(mIgG1)、クローン10E7.1D2であった。抗PD−L1を、ヒト/マウス逆キメラ、クローンYW243.55.S70 mIgG2a.DANAまたは完全マウスクローン25A1 mIgG2a.DANAのいずれかであった。ABRAXANE(登録商標)は、Abraxis Bioscience,Inc(Celgene;Summit,NJ所有)から得た。カルボプラチンは、Hospira,Inc.(Lake Forest,IL)から得た。デキサメタゾンは、West−Ward Pharmaceuticals(Eatontown,NJ)から得た。服薬スケジュール及び投与経路は、図面の簡単な説明において示した。抗体をPBSまたは20mMの酢酸ヒスチジン、240mMのスクロース、0.02%のポリソルベート20、pH5.5のいずれかの中で希釈した。化学療法剤及びデキサメタゾンを生理食塩水中で希釈した。
ドナーOTI Thy1.1雌の脾臓及び腸間膜リンパ節(Genentcchコロニー)から、MACS CD8単離キット(Miltenyi Biotec)を用いて、OTI Thy1.1CD8+ T細胞を負の選択により単離した。精製したCD8+細胞をCFSE(Life Technologies;Grand Island,NY)で標識化し、2.5×106個の細胞を、雌のC57BL/6の雌レシピエント(Charles River Laboratories)の体内に静脈内(IV)注射した。翌日、完全長オバルブミン(Genentech生産)に融合した抗DEC205を250ng腹腔内注射(IP)によりマウスにワクチン接種し、これに加えて体重1kgあたり4mgの割合で生理食塩水またはデキサメタゾンをIV注射した。ワクチン接種から2日後に、マウスを安楽化させ、分析のために脾臓を収穫した。脾臓細胞懸濁液の総細胞計数を、定量の公知の濃度の蛍光ビーズ(カタログ番号9003−53−6,Polysciences,Inc.;Warrington,PA))に対する、生細胞事象の比率を用いてフローサイトメトリーにより決定した。Thy1.1 PE−Cy7及びCD8 Pacific Blue(BD Biosciences)で染色することによりフローサイトメトリーによってOTI CD8+ T細胞を同定し、FACSDIVA(商標)ソフトウェアを用いてBD Biosciences LSRIIに流した。フローサイトメトリー分析を、FlowJoソフトウェア(TreeStar)を用いて行なった。
この研究は、前臨床マウス腫瘍モデルにおける癌療法という情況下での抗PD−L1抗体の効能を評価した。同系MC38結腸直腸腫瘍モデルにおける対照の抗体またはパクリタキセル+カルボプラチン単独での治療(図1)に比べた場合、抗PD−L1抗体(クローン25A1 mIgG2a.DANA)及びパクリタキセル+カルボプラチンでの組合せ治療は、結果として、相乗的抗腫瘍応答をもたらした。対照の抗体またはパクリタキセル+カルボプラチン単独のグループ(図1)では部分寛解を有するマウスがいなかったのに比べて、10%のマウス(1/10)が、抗PD−L1及びパクリタキセル+カルボプラチンの組合せに対する部分寛解を有していた。腫瘍サイズの縮小を結果としてもたらした強い抗腫瘍応答を、本実施例において初期腫瘍体積からの50%超で100%未満の減少として定義される部分寛解(PR)、または本実施例において腫瘍体積の100%減少として定義される完全寛解として追跡した。抗PD−L1抗体及びパクリタキセル+カルボプラチンでの組合せ治療はまた、無憎悪時間を延長した。対照抗体についての無憎悪時間(TTP)(この実施例では初期腫瘍体積の5倍として定義される)は、11日であり、パクリタキセル+カルボプラチンについては、15.5日であり、抗PD−L1抗体及びパクリタキセル+カルボプラチンの組合せ治療については、25日であった。
非小細胞肺癌(NSCLS)患者について、抗PD−L1抗体(MPDL3280A)を、タキサン(ナブ−パクリタキセル(ABRAXANE(登録商標))またはパクリタキセル)及びカルボプラチンと組合せた形で用いた組合せ治療の効能を評価するために第1b相臨床研究を実施した。
1)MPDL3280A/ABRAXANE(登録商標)/カルボプラチン組合せ療法:(a)3週間に一回(q3w)1200mgの割合でIV投与されるMPDL3280A;(b)一週間に一回(q1w)100mg/m2の割合でIV投与されるABRAXANE(登録商標);及び(c)3週間に一回(q3w)、6mg/mlの標的曲線下面積(AUC)でIV投与されるカルボプラチン。
2)MPDL3280A/パクリタキセル/カルボプラチン組合せ療法:(a)3週間に一回(q3w)1200mgの割合でIV投与されるMPDL3280A;(b)3週間に一回(q3w)220mg/m2の割合でIV投与されるパクリタキセル;(c)3週間に一回(q3w)6mg/mlの標的AUCでIV投与されるカルボプラチン。
Claims (74)
- 個体において癌を治療するかまたは癌の進行を遅延させるための方法であって、該個体に対して有効量のヒトPD−1軸結合アンタゴニストとタキサンとを投与することを含む方法。
- PD−1軸結合アンタゴニストが、PD−1結合アンタゴニスト、PD−L1結合アンタゴニスト及びPD−L2結合アンタゴニストからなる群から選択される、請求項1に記載の方法。
- PD−1軸結合アンタゴニストが、PD−1結合アンタゴニストである、請求項2に記載の方法。
- PD−1結合アンタゴニストが、PD−1のそのリガンド結合パートナーに対する結合を阻害する、請求項3に記載の方法。
- PD−1結合アンタゴニストが、PD−L1に対するPD−1の結合を阻害する、請求項4に記載の方法。
- PD−1結合アンタゴニストが、PD−L2に対するPD−1の結合を阻害する、請求項4に記載の方法。
- PD−1結合アンタゴニストが、PD−L1及びPD−L2の両方に対するPD−1の結合を阻害する、請求項4に記載の方法。
- PD−1結合アンタゴニストが抗体である、請求項4〜7のいずれか一項に記載の方法。
- PD−1結合アンタゴニストが、MDX−1106(ニボルマブ)、MK−3475(ランブロリズマブ)、CT−011(ピジリズマブ)及びAMP−224からなる群から選択される、請求項4に記載の方法。
- PD−1軸結合アンタゴニストが、PD−L1結合アンタゴニストである、請求項2に記載の方法。
- PD−L1結合アンタゴニストが、PD−1に対するPD−L1の結合を阻害する、請求項10に記載の方法。
- PD−L1結合アンタゴニストが、B7−1に対するPD−L1の結合を阻害する、請求項10に記載の方法。
- PD−L1結合アンタゴニストが、PD−1及びB7−1の両方に対するPD−L1の結合を阻害する、請求項10に記載の方法。
- PD−L1結合アンタゴニストが抗体である、請求項11〜13のいずれか一項に記載の方法。
- 抗体が、YW243.55.S70、MPDL3280A、MDX−1105及びMEDI4736からなる群から選択される、請求項14に記載の方法。
- 抗体が、配列番号19のHVR−H1配列、配列番号20のHVR−H2配列及び配列番号21のHVR−H3配列を含む重鎖と;配列番号22のHVR−L1配列、配列番号23のHVR−L2配列及び配列番号24のHVR−L3配列を含む軽鎖とを含む、請求項14に記載の方法。
- 抗体が、配列番号26のアミノ酸配列を含む重鎖可変領域と、配列番号4のアミノ酸配列を含む軽鎖可変領域とを含む、請求項14に記載の方法。
- PD−1軸結合アンタゴニストがPD−L2結合アンタゴニストである、請求項2に記載の方法。
- PD−L2結合アンタゴニストが抗体である、請求項18に記載の方法。
- PD−L2結合アンタゴニストがイムノアドヘシンである、請求項18に記載の方法。
- 癌が肺癌、膀胱癌、乳癌、腎細胞癌腫、黒色腫、結腸直腸癌、またはヘム悪性腫瘍である、請求項1〜20のいずれか一項に記載の方法。
- 肺癌が非小細胞肺癌(NSCLC)である、請求項21に記載の方法。
- 個体が癌を有するかまたは癌と診断されている、請求項1〜22のいずれか一項に記載の方法。
- 個体における癌細胞がPD−L1を発現する、請求項23に記載の方法。
- 治療が結果として、個体においての応答をもたらす、請求項1〜24のいずれか一項に記載の方法。
- 応答が完全寛解である、請求項25に記載の方法。
- 応答が、治療の中止後の持続性寛解である、請求項25または請求項26に記載の方法。
- タキサンが、PD−1軸結合アンタゴニストの前に、PD−1軸結合アンタゴニストと同時に、またはPD−1軸結合アンタゴニストの後に投与される、請求項1〜27のいずれか一項に記載の方法。
- タキサンがナブ−パクリタキセル(ABRAXANE(登録商標))、パクリタキセルまたはドセタキセルである、請求項1〜28のいずれか一項に記載の方法。
- タキサンがナブ−パクリタキセル(ABRAXANE(登録商標))である、請求項29に記載の方法。
- タキサンがパクリタキセルである、請求項29に記載の方法。
- 有効量のPD−1軸結合アンタゴニスト及びタキサンを投与することを含む、癌を有する個体における免疫機能増強方法。
- 個体におけるCD8+T細胞が、PD−1軸結合アンタゴニスト及びタキサンの投与前に比べ増強されたプライミング、活性化、増殖及び/または細胞溶解活性を有する、請求項32に記載の方法。
- CD8+T細胞の数が、前記組合せの投与前に比べて増加している、請求項32に記載の方法。
- CD8+T細胞が、抗原特異的CD8+T細胞である、請求項34に記載の方法。
- Treg機能が、前記組合せの投与前に比べて抑制されている、請求項32に記載の方法。
- T細胞の消耗が、前記組合せの投与前に比べて減少している、請求項32に記載の方法。
- PD−1軸結合アンタゴニストが、PD−1結合アンタゴニスト、PD−L1結合アンタゴニスト及びPD−L2結合アンタゴニストからなる群から選択される、請求項32〜37のいずれか一項に記載の方法。
- PD−1軸結合アンタゴニストが、PD−1結合アンタゴニストである、請求項38に記載の方法。
- PD−1結合アンタゴニストが、PD−1のそのリガンド結合パートナーに対する結合を阻害する、請求項39に記載の方法。
- PD−1結合アンタゴニストが、PD−L1に対するPD−1の結合を阻害する、請求項40に記載の方法。
- PD−1結合アンタゴニストが、PD−L2に対するPD−1の結合を阻害する、請求項40に記載の方法。
- PD−1結合アンタゴニストが、PD−L1及びPD−L2の両方に対するPD−1の結合を阻害する、請求項40に記載の方法。
- PD−1結合アンタゴニストが抗体である、請求項40〜43のいずれか一項に記載の方法。
- PD−1結合アンタゴニストが、MDX−1106(ニボルマブ)、MK−3475(ランブロリズマブ)、CT−011(ピジリズマブ)及びAMP−224からなる群から選択される、請求項40に記載の方法。
- PD−1軸結合アンタゴニストが、PD−L1結合アンタゴニストである、請求項38に記載の方法。
- PD−L1結合アンタゴニストが、PD−1に対するPD−L1の結合を阻害する、請求項46に記載の方法。
- PD−L1結合アンタゴニストが、B7−1に対するPD−L1の結合を阻害する、請求項46に記載の方法。
- PD−L1結合アンタゴニストが、PD−1及びB7−1の両方に対するPD−L1の結合を阻害する、請求項46に記載の方法。
- PD−L1結合アンタゴニストが抗体である、請求項46〜49のいずれか一項に記載の方法。
- 抗体が、YW243.55.S70、MPDL3280A、MDX−1105及びMEDI4736からなる群から選択される、請求項50に記載の方法。
- 抗体が、配列番号19のHVR−H1配列、配列番号20のHVR−H2配列及び配列番号21のHVR−H3配列を含む重鎖と;配列番号22のHVR−L1配列、配列番号23のHVR−L2配列及び配列番号24のHVR−L3配列を含む軽鎖とを含む、請求項50に記載の方法。
- 抗体が、配列番号26のアミノ酸配列を含む重鎖可変領域と、配列番号4のアミノ酸配列を含む軽鎖可変領域とを含む、請求項50に記載の方法。
- PD−1軸結合アンタゴニストがPD−L2結合アンタゴニストである、請求項38に記載の方法。
- PD−L2結合アンタゴニストが抗体である、請求項54に記載の方法。
- PD−L2結合アンタゴニストがイムノアドヘシンである、請求項54に記載の方法。
- 癌が肺癌、膀胱癌、乳癌、腎細胞癌腫、黒色腫、結腸直腸癌、またはヘム悪性腫瘍である、請求項32〜56のいずれか一項に記載の方法。
- 肺癌が非小細胞肺癌(NSCLC)である、請求項57に記載の方法。
- 個体における癌細胞がPD−L1を発現する、請求項32〜58のいずれか一項に記載の方法。
- タキサンがナブ−パクリタキセル(ABRAXANE(登録商標))、パクリタキセルまたはドセタキセルである、請求項32〜59のいずれか一項に記載の方法。
- タキサンがナブ−パクリタキセル(ABRAXANE(登録商標))である、請求項60に記載の方法。
- タキサンがパクリタキセルである、請求項60に記載の方法。
- PD−1軸結合アンタゴニスト及び/またはタキサンが静脈内、筋内、皮下、局所、経口、経皮、腹腔内、眼窩内、移植、吸入、髄腔内、脳室内または鼻腔内投与される、請求項1〜62のいずれか一項に記載の方法。
- 有効量の化学療法剤を投与することをさらに含む、請求項1〜63のいずれか一項に記載の方法。
- 化学療法剤が白金系の化学療法剤である、請求項64に記載の方法。
- 白金系の化学療法剤がカルボプラチンである、請求項65に記載の方法。
- 個体において癌を治療するかまたは癌の進行を遅延させるための医薬の製造におけるヒトPD−1軸結合アンタゴニストの使用であって、該医薬が、ヒトPD−1軸結合アンタゴニスト及び任意の薬学的に許容可能な担体を含み、治療が、タキサンと任意の薬学的に許容可能な担体とを含む組成物と組合せた該医薬の投与を含む、使用。
- 個体において癌を治療するかまたは癌の進行を遅延させるための医薬の製造におけるタキサンの使用であって、該医薬が、前記タキサン及び任意の薬学的に許容可能な担体を含み、治療が、ヒトPD−1軸結合アンタゴニストと任意の薬学的に許容可能な担体とを含む組成物と組合せた該医薬の投与を含む、使用。
- 個体において癌を治療するかまたは癌の進行を遅延させる上で使用するための、ヒトPD−1軸結合アンタゴニストと任意の薬学的に許容可能な担体とを含む組成物であって、治療が、第2の組成物と組合せた該組成物の投与を含み、該第2の組成物がタキサンと任意の薬学的に許容可能な担体とを含む、組成物。
- 個体において癌を治療するかまたは癌の進行を遅延させる上で使用するための、タキサンと任意の薬学的に許容可能な担体とを含む組成物であって、治療が、第2の組成物と組合せた該組成物の投与を含み、該第2の組成物がヒトPD−1軸結合アンタゴニストと任意の薬学的に許容可能な担体とを含む、組成物。
- PD−1軸結合アンタゴニストと任意の薬学的に許容可能な担体とを含む医薬と;個体において癌を治療するかまたは癌の進行を遅延させるためのタキサンと任意の薬学的に許容可能な担体とを含む組成物と組合せて該医薬を投与するための指示書を含む添付文書とを含む、キット。
- PD−1軸結合アンタゴニストと任意の薬学的に許容可能な担体とを含む第1の医薬と、タキサンと任意の薬学的に許容可能な担体とを含む第2の医薬とを含む、キット。
- 個体において癌を治療するかまたは癌の進行を遅延させるために第1の医薬及び第2の医薬を投与するための指示書を含む添付文書をさらに含む、請求項72に記載のキット。
- タキサンと任意の薬学的に許容可能な担体とを含む医薬と;個体において癌を治療するかまたは癌の進行を遅延させるためのPD−1軸結合アンタゴニストと任意の薬学的に許容可能な担体とを含む組成物と組合せて該医薬を投与するための指示書とを含む添付文書と、を含むキット。
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