JP2016533335A - 抗pdl1抗体製剤 - Google Patents
抗pdl1抗体製剤 Download PDFInfo
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- JP2016533335A JP2016533335A JP2016517363A JP2016517363A JP2016533335A JP 2016533335 A JP2016533335 A JP 2016533335A JP 2016517363 A JP2016517363 A JP 2016517363A JP 2016517363 A JP2016517363 A JP 2016517363A JP 2016533335 A JP2016533335 A JP 2016533335A
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Abstract
Description
本出願は、その全内容が本明細書に参照により援用される2013年9月27日出願の米国特許仮出願番号第61/883953号の優先権の利益を主張する。
ASCIIテキストファイルでの以下の提出の内容は、その全内容が本明細書に参照により援用される:コンピュータで読み取り可能な形式(CRF)の配列表(ファイル名:146392022040SEQLIST.TXT、データ記録:2014年9月26日、サイズ:24KB)。
(a)(1)アミノ酸配列RASQDVSTAVA(配列番号1)を含むHVR−L1;
(2)アミノ酸配列SASFLYS(配列番号2)を含むHVR−L2;
(3)アミノ酸配列QQYLYHPAT(配列番号3)を含むHVR−L3
を含む軽鎖可変領域;及び
(b)(1)アミノ酸配列GFTFSDSWIH(配列番号4)を含むHVR−H1;
(2)アミノ酸配列AWISPYGGSTYYADSVKG(配列番号5)を含むHVR−H2;
(3)アミノ酸配列RHWPGGFDY(配列番号6)を含むHVR−H3
を含む重鎖可変領域を含む。
本発明を詳細に説明する前に、本発明は特定の組成物又は生物系に限定されず、それらはもちろん変化し得ることを理解されたい。本明細書で使用した用語は、特定の実施態様を説明するためだけのものであり、限定するものではないことも理解されたい。本明細書及び添付の特許請求の範囲で使用したように、単数形「a」、「an」及び「the」は、文脈で特に明確に規定していなければ、複数の指示対象を含む。したがって、例えば、「1分子」という場合、任意選択的にこのような分子の2個以上の組み合わせなどを含む。
HVRは、以下の通りの「拡大HVR」を含んでいてもよい:VLの24−36又は24−34(L1)、46−56又は50−56(L2)及び89−97又は89−96(L3)、及びVHの26−35(H1)、50−65又は49−65(H2)及び93−102、94−102、又は95−102(H3)。可変ドメイン残基は、これらの定義それぞれについて、上記のKabat等に従って番号が付されている。
本明細書では、本発明は抗PDL1抗体などの抗体を含む安定な水性製剤に関する。いくつかの実施態様では、この製剤は、抗体(例えば、モノクローナル抗体)、スクロース、バッファー及び界面活性剤を含み、この製剤のpHは約5.0から約7.0である。いくつかの実施態様では、製剤中の抗体(例えば、本明細書で記載した抗PDL1抗体)の量は約40mg/mLから約125mg/mLである。いくつかの実施態様では、バッファーはヒスチジン(例えば、ヒスチジンアセテート)又は酢酸ナトリウムである。いくつかの実施態様では、製剤中のバッファーの濃度は約15mMから約25mMである。いくつかの実施態様では、製剤中のスクロースは約60mMから約240mMである。いくつかの実施態様では、製剤中の界面活性剤はポリソルベート(例えば、ポリソルベート20)である。いくつかの実施態様では、製剤中のポリソルベートの濃度は約0.005%(w/v)から約0.06%(w/v)である。いくつかの実施態様では、製剤のpHは約5.0から約6.3である。いくつかの実施態様では、本明細書では安定な水性薬学的製剤を提供し、この製剤は約40mg/mLから約125mg/mLの濃度の抗PDL1モノクローナル抗体、約15mMから約25mMの濃度のヒスチジンアセテート又は酢酸ナトリウム、約60mMから約240mMの濃度のスクロース、約0.005%(w/v)から約0.06%(w/v)の濃度のポリソルベートを含み、pHは約5.0から約6.3である。いくつかの実施態様では、製剤は、約125mg/mLの量の抗PDL1モノクローナル抗体、約240mMの濃度のスクロースを含み、pHは約5.5である。いくつかの実施態様では、製剤は、約60mg/mLの量の抗PDL1モノクローナル抗体、約120mMの濃度のスクロースを含み、pHは約5.8である。
いくつかの実施態様では、製剤中の抗体は、重鎖及び/又は軽鎖配列中に少なくとも1個のトリプトファン(例えば、少なくとも2個、少なくとも3個又は少なくとも4個)を含む。いくつかの実施態様では、アミノ酸トリプトファンは、抗体のCDR領域、フレームワーク領域及び/又は定常領域中にある。いくつかの実施態様では、抗体はCDR領域中に2個又は3個のトリプトファン残基を含む。いくつかの実施態様では、製剤中の抗体は抗PDL1抗体である。PD−L1(プログラム細胞死1リガンド1)はまた、PDL1、B7−H1、B7−4、CD274及びB7−Hとして知られており、膜貫通タンパク質であり、PD−1との相互作用によってT細胞活性化及びサイトカイン産生を阻害する。いくつかの実施態様では、本明細書で記載した抗PDL1抗体はヒトPD−L1に結合する。本明細書で記載した製剤を使用して製剤化することができる抗PDL1抗体の例は、本明細書に参照により援用されるPCT特許出願国際公開第2010/077634号A1及び米国特許第8217149号に記載されている。
(a)HVR−H1配列はGFTFSX1SWIH (配列番号11);
(b)HVR−H2配列はAWIX2PYGGSX3YYADSVKG (配列番号12);
(c)HVR−H3配列はRHWPGGFDY(配列番号13)であり、
さらに、X1はD又はGであり、X2はS又はLであり、X3はT又はSである。
HC−FR1はEVQLVESGGGLVQPGGSLRLSCAAS (配列番号14)
HC−FR2はWVRQAPGKGLEWV (配列番号15)
HC−FR3はRFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (配列番号16)
HC−FR4はWGQGTLVTVSA (配列番号17)である。
(a)HVR−L1配列はRASQX4X5X6TX7X8A (配列番号18);
(b)HVR−L2配列はSASX9LX10S (配列番号19);
(c)HVR−L3配列はQQX11X12X13X14PX15T (配列番号20)であり、
さらに、X4はD又はVであり、X5はV又はIであり、X6はS又はNであり、X7はA又はFであり、X8はV又はLであり、X9はF又はTであり、X10はY又はAであり、X11はY、G、F又はSであり、X12はL、Y、F又はWであり、X13はY、N、A、T、G、F又はIであり、X14はH、V、P、T又はIであり、X15はA、W、R、P又はTである。
LC−FR1はDIQMTQSPSSLSASVGDRVTITC (配列番号21)
LC−FR2はWYQQKPGKAPKLLIY (配列番号22)
LC−FR3はGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (配列番号23)
LC−FR4はFGQGTKVEIKR (配列番号24)。
(a)重鎖はHVR−H1、HVR−H2及びHVR−H3を含み、さらに、
(i)HVR−H1配列はGFTFSX1SWIH (配列番号11)
(ii)HVR−H2配列はAWIX2PYGGSX3YYADSVKG(配列番号12)
(iii)HVR−H3配列はRHWPGGFDY (配列番号13)であり、
(b)軽鎖はHVR−L1、HVR−L2及びHVR−L3を含み、さらに、
(i)HVR−L1配列はRASQX4X5X6TX7X8A (配列番号18)
(ii)HVR−L2配列はSASX9LX10S (配列番号19)、及び
(iii)HVR−L3配列はQQX11X12X13X14PX15T (配列番号20)であり、
さらに、X1はD又はGであり、X2はS又はLであり、X3はT又はSであり、X4はD又はVであり、X5はV又はIであり、X6はS又はNであり、X7はA又はFであり、X8はV又はLであり、X9はF又はTであり、X10はY又はAであり、X11はY、G、F又はSであり、X12はL、Y、F又はWであり、X13はY、N、A、T、G、F又はIであり、X14はH、V、P、T又はIであり、X15はA、W、R、P又はTである。
HC−FR1 EVQLVESGGGLVQPGGSLRLSCAAS(配列番号14)
HC−FR2 WVRQAPGKGLEWV (配列番号15)
HC−FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (配列番号16)
HC−FR4 WGQGTLVTVSA (配列番号17)。
LC−FR1 DIQMTQSPSSLSASVGDRVTITC (配列番号21)
LC−FR2 WYQQKPGKAPKLLIY (配列番号22)
LC−FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (配列番号23)
LC−FR4 FGQGTKVEIKR (配列番号24)。
(a)重鎖はさらにGFTFSDSWIH(配列番号25)、AWISPYGGSTYYADSVKG(配列番号26)及びRHWPGGFDY(配列番号13)それぞれに対して少なくとも85%配列同一性を有するHVR−H1、HVR−H2及びHVR−H3配列を含み、又は
(b)軽鎖はさらにRASQDVSTAVA(配列番号27)、SASFLYS(配列番号28)及びQQYLYHPAT(配列番号29)それぞれに対して少なくとも85%配列同一性を有するHVR−L1、HVR−L2及びHVR−L3配列を含む。
HC−FR1 EVQLVESGGGLVQPGGSLRLSCAAS(配列番号14)
HC−FR2 WVRQAPGKGLEWV (配列番号15)
HC−FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (配列番号16)
HC−FR4 WGQGTLVTVSA (配列番号17)。
LC−FR1 DIQMTQSPSSLSASVGDRVTITC (配列番号21)
LC−FR2 WYQQKPGKAPKLLIY (配列番号22)
LC−FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (配列番号23)
LC−FR4 FGQGTKVEIKR (配列番号24)。
(a)重鎖配列が重鎖配列
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA(配列番号30)
に対して少なくとも85%配列同一性を有するか、又は
(b)軽鎖配列が軽鎖配列
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASF
LYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR(配列番号31)
に対して少なくとも85%配列同一性を有する。
HC−FR1 EVQLVESGGGLVQPGGSLRLSCAAS(配列番号14)
HC−FR2 WVRQAPGKGLEWV (配列番号15)
HC−FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (配列番号16)
HC−FR4 WGQGTLVTVSA (配列番号17)。
LC−FR1 DIQMTQSPSSLSASVGDRVTITC (配列番号21)
LC−FR2 WYQQKPGKAPKLLIY (配列番号22)
LC−FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (配列番号23)
LC−FR4 FGQGTKVEIKR (配列番号24)。
(a)重鎖配列は重鎖配列
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS(配列番号32)
に対して少なくとも85%配列同一性を有し、又は
(b)軽鎖配列は軽鎖配列
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASF
LYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR(配列番号31)
に対して少なくとも85%配列同一性を有する。
HC−FR1 EVQLVESGGGLVQPGGSLRLSCAAS(配列番号14)
HC−FR2 WVRQAPGKGLEWV (配列番号15)
HC−FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (配列番号16)
HC−FR4 WGQGTLVTVSS (配列番号33)。
LC−FR1 DIQMTQSPSSLSASVGDRVTITC (配列番号21)
LC−FR2 WYQQKPGKAPKLLIY (配列番号22)
LC−FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (配列番号23)
LC−FR4 FGQGTKVEIKR (配列番号24)。
HC−FR1 EVQLVESGGGLVQPGGSLRLSCAASGFTFS (配列番号34)
HC−FR2 WVRQAPGKGLEWVA (配列番号35)
HC−FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (配列番号16)
HC−FR4 WGQGTLVTVSS (配列番号33)。
LC−FR1 DIQMTQSPSSLSASVGDRVTITC (配列番号21)
LC−FR2 WYQQKPGKAPKLLIY (配列番号22)
LC−FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (配列番号23)
LC−FR4 FGQGTKVEIK (配列番号36)。
(c)重鎖はさらにGFTFSDSWIH(配列番号4)、AWISPYGGSTYYADSVKG(配列番号5)及びRHWPGGFDY(配列番号6)それぞれに対して少なくとも85%配列同一性を有するHVR−H1、HVR−H2及びHVR−H3配列を含み、又は
(d)軽鎖はさらにRASQDVSTAVA(配列番号1)、SASFLYS(配列番号2)及びQQYLYHPAT(配列番号3)それぞれに対して少なくとも85%配列同一性を有するHVR−L1、HVR−L2及びHVR−L3配列を含む。
HC−FR1 EVQLVESGGGLVQPGGSLRLSCAAS(配列番号34)
HC−FR2 WVRQAPGKGLEWV (配列番号35)
HC−FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (配列番号16)
HC−FR4 WGQGTLVTVSSASTK (配列番号33)。
LC−FR1 DIQMTQSPSSLSASVGDRVTITC (配列番号21)
LC−FR2 WYQQKPGKAPKLLIY (配列番号22)
LC−FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (配列番号23)
LC−FR4 FGQGTKVEIKR (配列番号24)
(a)重鎖配列は重鎖配列
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTK(配列番号8)
に対して少なくとも85%配列同一性を有し、又は
(b)軽鎖配列は軽鎖配列
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR(配列番号7)
に対して少なくとも85%配列同一性を有する。
(a)重鎖配列は重鎖配列
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(配列番号10)
に対して少なくとも85%配列同一性を有し、又は
(b)軽鎖配列は軽鎖配列
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号9)
に対して少なくとも85%配列同一性を有する。
製剤中の抗体は抗体を生成するための当該技術分野で利用可能な技術を使用して調製し、その例示的な方法を以下の項でより詳細に説明する。
その他の分子に任意選択的にコンジュゲートさせた可溶型抗原又はそれらの断片を抗体生成のための免疫原として使用することができる。膜貫通分子、例えば、受容体については、これらの断片(例えば、受容体の細胞外ドメイン)を免疫原として使用することができる。あるいは、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、がん細胞株)に由来してもよく、又は膜貫通分子を発現するために組換え技術によって形質転換させた細胞であってもよい。その他の抗原及び抗体を調製するために有用なそれらの形態は当業者には明らかであろう。
ポリクローナル抗体は、関連のある抗原及びアジュバントを複数回動物の皮下(sc)又は腹腔内(ip)に注射することによって動物で生じさせることが好ましい。免疫する種において免疫原性であるタンパク質、例えば、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又はダイズトリプシン阻害因子に、二機能性又は誘導体化剤、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(システイン残基を介するコンジュゲーション)、N−ヒドロキシスクシンイミド(リジン残基を介する)、グルタルアルデヒド、無水コハク酸、SOCl2又はR及びR1が異なるアルキル基であるR1N=C=NRを使用して、関連抗原をコンジュゲートすることが有用であり得る。
本発明の抗体は、所望する活性(一又は複数)を備えた抗体をスクリーニングするためにコンビナトリアルライブラリーを使用することによって作製することができる。例えば、ファージディスプレイライブラリーを生成するため、及び所望する結合特性を有する抗体のこのようなライブラリーをスクリーニングするための種々の方法が当該技術分野では公知である。このような方法は一般的にHoogenboom等、Methods in Molecular Biology 178:1−37(O'Brien等、Human Press, Totowa, N.J., 2001)に記載されている。例えば、対象とする抗体を生成する一方法は、Lee等、J.Mol. Biol.(2004)、340(5):1073−93において記載されたようなファージ抗体ライブラリーの使用による。
非ヒト抗体をヒト化するための様々な方法は当該技術分野では公知である。例えば、ヒト化抗体は、非ヒトである供給源からヒト化抗体に導入された1個又は複数のアミノ酸残基を有する。これらの非ヒトアミノ酸残基は、「移入」残基と呼ばれることが多く、通常は「移入」可変ドメインから得られる。ヒト化は、齧歯類のCDR(一又は複数)配列をヒト抗体の対応する配列と置換することによって、Winter及び共同研究者の方法(Jones等、Nature321:522-525(1986);Riechmann等、Nature 332:323-327(1988);Verhoeyen等、Science,239:1534-1536(1988))に従って本質的に実施することができる。したがって、このようなヒト化抗体は、キメラ抗体(米国特許第4816567号)であり、インタクトなヒト可変ドメインよりも実質的に少ない部分が非ヒト種の対応する配列によって置換されている。実際に、ヒト化抗体は通常、いくつかのCDR残基及びおそらくいくつかのFR残基が齧歯類抗体の類似部位の残基によって置換されているヒト抗体である。
抗体断片は、酵素消化などの伝統的な手段によって、又は組換え技術によって生成することができる。ある種の状況では、抗体全体よりも抗体断片を使用することが有利である。より小さなサイズの断片は迅速な排出が可能で、固形腫瘍への接近を改善することができる。ある種の抗体断片の概説については、Hudson等、(2003)Nat.Med.9:129−134を参照のこと。
多重特異性抗体は、少なくとも2つの異なるエピトープに対して結合特異性を有し、このエピトープは通常異なる抗原から得られる。このような分子は通常は2つの異なるエピトープに結合するのみであるが(すなわち、二重特異性抗体、BsAb)、三重特異性抗体のようなさらなる特異性を備えた抗体も本明細書で使用する場合この表現に包含される。二重特異性抗体は完全長抗体又は抗体断片(例えばF(ab’)2二重特異性抗体)として調製することができる。
いくつかの実施態様では、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て若しくは一部又は軽鎖可変ドメインの全て若しくは一部を含む単一ポリペプチド鎖である。ある種の実施態様では、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6248516号B1を参照のこと)。一実施態様では、単一ドメイン抗体は抗体の重鎖可変ドメインの全て又は一部からなる。
いくつかの実施態様において、本明細書で記載した抗体のアミノ酸配列改変(複数)を検討する。例えば、抗体の結合親和性及び/又はその他の生物学的特性の改善が所望されることがある。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に適切な変化を導入することによって、又はペプチド合成によって調製することができる。このような改変には、例えば、抗体のアミノ酸配列内の残基の欠失、及び/又は挿入及び/又は置換が含まれる。最終コンストラクトが所望の特性を有していることを条件として、最終コンストラクトに到達するために欠失、挿入、及び置換を任意に組み合わせることができる。配列形成時に、アミノ酸変更を対象の抗体アミノ酸配列に導入してもよい。
本発明の抗体は、当該技術分野で公知の容易に入手可能な追加の非タンパク質部分を含有するようにさらに改変することができる。ある種の実施態様では、抗体の誘導体化に適切な部分は、水溶性ポリマーである。水溶性ポリマーの非限定的な例には、限定はされないが、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共重合体、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/無水マレイン酸共重合体、ポリアミノ酸(ホモ重合体又はランダム共重合体の何れか)及びデキストラン又はポリ(n−ビニルピロリドン)ポリエチレングリコール、プロピレングリコールホモ重合体、プロピレンオキシド/エチレンオキシド共重合体、ポリオキシエチル化ポリオール(例えばグリセロール)、ポリビニルアルコール及びこれらの混合物が含まれる。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での安定性のために製造上の利点を有し得る。ポリマーは任意の分子量であってもよく、分枝鎖であっても分枝鎖でなくてもよい。抗体に結合したポリマーの数は変動していてもよく、1つ以上のポリマーが結合する場合は、これらは同じか又は異なる分子であってもよい。一般的に、誘導体化に使用するポリマーの数及び/又は種類は、限定されないが、改善するべき抗体の特定の特性又は機能、抗体誘導体が規定の条件下で治療に使用されるかどうかなどを考慮して決定することができる。
抗体はまた、組換え法を使用して生成することができる。抗−抗原抗体の組換え生成のために、抗体をコードする核酸を単離し、さらにクローニングするため(DNAの増幅)又は発現のために複製可能なベクターに挿入する。抗体をコードするDNAは、従来の手順を使用して(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することができるオリゴヌクレオチドプローブを使用することによって)、容易に単離し配列決定することができる。多くのベクターが利用可能である。ベクター成分は一般的に、限定はしないが、以下の1つ又は複数を含む:シグナル配列、複製開始点、1つ又は複数のマーカー遺伝子、エンハンサーエレメント、プロモーター及び転写終結配列。
本発明の抗体は、直接的だけでなく、異種ポリペプチドとの融合ポリペプチドとしても組換えによって生成することができ、この異種ポリペプチドは、好ましくは、シグナル配列又はその成熟タンパク質若しくはポリペプチドのN末端に特異的な切断部位を有するその他のポリペプチドである。選択された異種シグナル配列は、好ましくは、宿主細胞によって認識されプロセシングを受ける(例えば、シグナルペプチダーゼによって切断される)シグナル配列である。天然の抗体シグナル配列を認識せずプロセシングしない原核宿主細胞に関しては、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、lpp又は熱安定性エンテロトキシンIIリーダーの群から選択される原核生物シグナル配列によって置換される。酵母での分泌に関しては、天然のシグナル配列は、例えば、酵母インベルターゼリーダー、α因子リーダー(サッカロマイセス(Saccharomyces)及びクリベロマイセス(Kluyveromyces)α因子リーダーを含む)又は酸ホスファターゼリーダー、C.アルビカンス(albicans)グルコアミラーゼリーダー又は国際公開第90/13646号に記載されたシグナルによって置換されていてもよい。哺乳動物細胞の発現においては、哺乳動物シグナル配列並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。
発現ベクター及びクローニングベクターの両方とも、1つ又は複数の選択された宿主細胞中においてベクターが複製するのを可能にする核酸配列を含有する。一般的に、クローニングベクター内においては、この配列はベクターが宿主の染色体DNAとは独立して複製することを可能にする配列であり、複製起点又は自己複製配列を含む。このような配列は、種々の細菌、酵母及びウイルスについて周知である。プラスミドpBR322由来の複製開始点は、ほとんどのグラム陰性細菌に適しており、2μプラスミド開始点は、酵母に適しており、種々のウイルス開始点(SV40、ポリオーマ、アデノウイルス、VSV又はBPV)が、哺乳動物細胞中におけるクローニングベクターのために有用である。一般的に、複製開始点成分は哺乳動物の発現ベクターには必要ではない(SV40開始点は、単に初期プロモーターを含有するために一般的に使用することができる)。
発現ベクター及びクローニングベクターは、選択マーカーとも呼ばれる選択遺伝子を含有することができる。代表的な選択遺伝子は、(a)抗生物質又はその他の毒素、例えば、アンピシリン、ネオマイシン、メトトレキサート若しくはテトラサイクリンに耐性を付与し、(b)栄養要求性欠損を補完し、あるいは(c)複合培地からは利用不可能な重要な栄養素を供給するタンパク質をコードし、例えば、桿菌属(Bacilli)についてはD−アラニンラセマーゼをコードする遺伝子である。
発現ベクター及びクローニングベクターは一般的に、宿主生物によって認識され、抗体をコードする核酸に動作可能に連結されたプロモーターを含有する。原核生物宿主での使用に適したプロモーターには、phoAプロモーター、β−ラクタマーゼプロモーター系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ー、トリプトファン(trp)プロモーター系並びにtacプロモーターなどのハイブリッドプロモーターが含まれる。しかし、その他の公知の細菌プロモーターも適している。細菌系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に動作可能に連結されたシャインダルガノ(S.D.)配列を含有する。
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、そのベクターにエンハンサー配列を挿入することによって増加することが多い。哺乳動物遺伝子(グロビン、エラスターゼ、アルブミン、α−フェトプロテイン及びインスリン)由来の多くのエンハンサー配列が現在知られている。しかし、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。例には、複製開始点(100−270bp)の下流側のSV40エンハンサー、サイトメガロウイルス初期プロモーターエンハンサー、複製開始点の下流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。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は、Yaniv、Nature 297:17−18(1982)も参照のこと。このエンハンサーは、5’位又は3’位でベクターの抗体コード配列にスプライスすることができるが、そのプロモーターの5’部位に位置することが好ましい。
真核宿主細胞(酵母、真菌、昆虫、植物、動物、ヒト又はその他の多細胞生物由来の有核細胞)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有する。このような配列は通常、真核生物又はウイルスのDNA又はcDNAの5’、時には3’非翻訳領域から利用可能である。これらの領域は、抗体をコードするmRNAの非翻訳部分中のポリアデニル化断片として転写されるヌクレオチドセグメントを含有する。1つの有用な転写終結成分は、ウシ成長ホルモンポリアデニル化領域である。国際公開第94/11026号及びそこに開示される発現ベクターを参照のこと。
本明細書のベクターにおいて、DNAのクローニング又は発現に適した宿主細胞は、前述の原核細胞、酵母細胞又は高等真核細胞である。この目的に適した原核生物には、真正細菌、例えば、グラム陰性生物又はグラム陽性生物、例えば、腸内細菌科(Enterobacteriaceae)、例えば、大腸菌などの大腸菌属(Escherichia)、エンテロバクター属(Enterobacter)、エルウイニア属(Erwinia)、クレブシエラ属(Klebsiella)、プロテウス属(Proteus)、ネズミチフス菌(Salmonella typhimurium)などのサルモネラ属(Salmonella)、セラチア・マルセセンス(Serratia marcescens)などのセラチア属(Serratia)及びシゲラ属(Shigella)並びに枯草菌(B.subtilis)及びB.リケニフォルミス(B.licheniformis)などの桿菌(Bacilli)(例えば、B.リケニフォルミスは1989年4月12日に公開されたDD266710の41ページに開示されている)、緑膿菌(P.aeruginosa)などのシュードモナス属(Pseudomonas)並びにストレプトミセス属(Streptomyces)が含まれる。宿主をクローニングする1つの好ましい大腸菌は、大腸菌294(ATCC31446)であるが、その他の株、例えば、大腸菌B、大腸菌X1776(ATCC31537)及び大腸菌W3110(ATCC27325)も適している。これらの例は、限定的ではなく例示的である。
本発明の抗体を産生するために使用する宿主細胞は、種々の培地中で培養することができる。市販の培地、例えば、Ham’s F10(Sigma)、最小必須培地(MEM)(Sigma)、RPMI−1640(Sigma)及びダルベッコ変法イーグル培地(DMEM)(Sigma))が、宿主細胞の培養に適している。さらに、Ham等、Meth.Enz.58:44(1979)、Barnes等、Anal.Biochem. 102:255(1980)、米国特許第4767704号、第4657866号、第4927762号、第4560655号、又は第5122469号、国際公開第90/03430号、国際公開第87/00195号、又は米国再発行特許第30985号に記載される培地の何れかを宿主細胞の培地として使用することができる。これらの培地の何れにも、必要ならば、ホルモン及び/又はその他の増殖因子(例えば、インスリン、トランスフェリン又は上皮増殖因子)、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)、バッファー(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)薬物)、微量元素(通常、マイクロモル範囲の最終濃度で存在する無機化合物と定義される)並びにグルコース又は同等のエネルギー源を補給することができる。当業者に公知の任意のその他の必要な補給物も適切な濃度で含めることができる。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既に使用されているものであり、当業者には明らかであろう。
組換え技術を使用する場合、抗体は細胞内、細胞周辺腔内又は培地中に直接分泌して産生させることができる。第1工程として抗体を細胞内で産生する場合、宿主細胞又は溶解した断片の何れかの微粒子デブリは、例えば、遠心又は限外濾過によって除去する。Carter等、Bio/Technology 10:163−167(1992)は、大腸菌の細胞周辺腔に分泌される抗体を単離するための手法について記載している。簡単に説明すると、細胞ペーストを、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分間にわたって解凍する。細胞デブリは、遠心によって除去することができる。抗体が培地中に分泌される場合、このような発現系からの上清は一般的に市販のタンパク質濃縮フィルター、例えば、Amicon又はMillipore Pellicon限外濾過装置を使用してまず濃縮する。PMSFなどのプロテアーゼ阻害剤は、タンパク質分解を阻害するために前述の工程の何れかに含めることができ、抗生物質は外来の夾雑物の増殖を防止するために含めることができる。
前述のように産生された抗体は、治療的観点から有利な特性を有する抗体を選択するため、又は抗体の生物活性を保持する製剤及び条件を選択するために、1つ又は複数の「生物活性」のアッセイを行うことができる。抗体が生じる抗原に対して、抗体が結合する能力について試験することができる。例えば、抗PDL1抗体については、抗体の抗原結合特性は、PDL1に結合する能力を検出するアッセイにおいて評価することができる。いくつかの実施態様では、抗体の結合は、例えば、飽和結合、ELISA及び/又は競合アッセイ(例えばRIA)によって測定することができる。また、抗体は、例えば、治療剤としての効率を評価するために、その他の生物活性アッセイを行うことができる。このようなアッセイは当該技術分野において公知であり、標的抗原及び抗体の目的の用途に左右される。例えば、抗体によるPD−L1ブロックの生物学的効果はCD8+T細胞、リンパ球性脈絡髄膜炎ウイルス(LCMV)マウスモデル及び/又は、例えば、米国特許第8217149に記載されたような同系の腫瘍モデルにおいて評価することができる。
対象とする抗体を調製した後(例えば、本明細書で開示したように製剤化することができる抗体の産生技術を以下に詳述するが、当該技術分野においては公知である)、この抗体を含む薬学的製剤を調製する。ある種の実施態様では、製剤化する抗体は、事前の凍結乾燥に供されておらず、本明細書で対象とする製剤は水性製剤である。ある種の実施態様では、抗体は完全長抗体である。一実施態様では、製剤中の抗体はF(ab’)2などの抗体断片であり、この場合、完全長抗体では生じないであろう問題(Fabへの抗体のクリッピングなど)に対処する必要があり得る。製剤中に存在する抗体の治療的有効量は、例えば、投与の所望される投与量及び方法(複数)を考慮することによって決定する。約25mg/mLから約150mg/mL、又は約30mg/mLから約140mg/mL、又は約35mg/mLから約130mg/mL、又は約40mg/mLから約120mg/mL、又は約50mg/mLから約130mg/mL、又は約50mg/mLから約125mg/mL、又は約50mg/mLから約120mg/mL、又は約50mg/mLから約110mg/mL、又は約50mg/mLから約100mg/mL、又は約50mg/mLから約90mg/mL、又は約50mg/mLから約80mg/mL、又は約54mg/mLから約66mg/mLが、製剤中の例示的抗体濃度である。
製剤は、抗体による治療を必要とする哺乳動物、好ましくはヒトに、公知の方法、例えば、静脈内投与によって(例えば、ボーラスとして、又は一定期間にわたる連続的注入によって)、筋肉内、腹腔内、脳脊髄内、皮下、関節内、滑膜内、髄腔内、経口、局所又は吸入経路によって投与する。一実施態様では、製剤は哺乳動物に静脈内投与によって投与する。このような目的で、製剤は、例えば、シリンジを使用して又はIVラインを介して注射することができる。一実施態様では、製剤は哺乳動物に皮下投与によって投与する。
本発明の別の実施態様では、本発明の水性薬学的製剤を保持する容器を含む製品又はキットを提供し、任意選択的にその使用についての指示を提供する。適切な容器には、例えば、瓶、バイアル、バッグ及びシリンジが含まれる。この容器は、ガラス、プラスティック(例えば、ポリ塩化ビニル又はポリオレフィン)又は金属合金(例えば、ステンレススチール又はハステロイ)などの様々な材料から形成することができる。例示的容器は、300cc金属合金容器(例えば、−20℃で保存するため)である。別の例示的容器は、10−50ccガラスバイアル(例えば、2−8℃で保存するため)である。例えば、この容器は10cc、15cc、20cc又は50ccガラスバイアルである。容器は、製剤を保持し、ラベルが貼ってあるか又は関連付けられており、容器には使用の指示を示すことができる。さらに、製造品には、その他のバッファー、希釈剤、フィルター、針及びシリンジを含む商業的な、及び使用者の立場から所望されるその他の材料、並びに使用説明書を含む添付文書を含めることができる。いくつかの実施態様では、製造品はさらに、1つ又は複数の別の薬剤(例えば、化学療法剤及び抗腫瘍性剤)を含む。1つ又は複数の薬剤のために適した容器には、例えば、瓶、バイアル、バッグ及びシリンジが含まれる。
抗PDL1抗体(α−PDL1)は、PDL1/PD1相互作用を阻害することによってT細胞機能を回復させることを目的としたCHO由来のグリコシル化されていなIgG1抗体である。開発着手時の課題には、Trp酸化の可能性及びCDR領域内又はCDR近くの糖化及びいくつかのメチオニン酸化が含まれた。予備頑健性研究によって、以前標的としたpH(pH5.5)よりも高いpHが最適であることが示された。標的とする投与量は固定用量であるが、重量をベースにした用量も考慮した。様々な製剤の安定性を分析する分析研究を実施し、一製剤(α−PDL1 60mg/mL、His AcO 20mM pH5.8、スクロース 120mM、PS20 0.04%)を選択した。最初の製剤研究では、原体(DS)及び薬物製品(DS)中における3年までの安定性が支持される。
α−PDL1製剤の製造
限外濾過/ダイアフィルトレーションを行ったα−PDL1材料で製剤開発研究を行った。10000ダルトン透析カセットを使用して、材料を様々な製剤バッファー中で透析した。透析後、タンパク質濃度を調節して標的濃度に到達させ、PS20 10%保存溶液を添加して、標的PS20濃度を実現した。製剤化した材料を無菌的に充填容積1mLの2−cc Forma Vitrumガラスバイアルに充填し、13mm Daikyo 777−1栓で密閉した。試料を直立で5℃、25℃又は40℃の何れかで保存した。
試料の色、外観及び透明性は、欧州薬局方(EP)の方法(Council of Europe. European Pharmacopoeia, 2008, 7版、EP 2.2.2及びEP 2.2.1)に記載されたように、室温で、白色蛍光灯下で、黒及び白の背景の下で目視検査によって測定した。3ccガラスバイアルに各試験した試料1mLを充填した。対応する試料容量のネガティブコントロール(精製水)を比較用に使用した。
タンパク質濃度は、0.9%生理食塩水で約0.5mg/mLに試料体積を希釈し、Agilent8453分光光度計(Santa Clara、CA)でUV吸光度を測定して決定した。試料は、0.9%生理食塩水をブランクとして、約280nm及びまた320nmのAmaxで吸光度を測定した。AmaxとA320の間の差を計算して修正Amaxを得、1.5mL cm−1mg−1の吸収率で最終タンパク質濃度を測定するために使用した。
試料の350nmでの平均光学濃度をAgilent8453分光光度計で光路長1−cmの石英キュベット中で測定した。精製水をブランクとして使用した。
試料の粒子カウントは、HIAC−Roycoモデル9703(HACH、Loveland、CO.)によって測定した光遮蔽を使用して実施した。PharmSpec v2.0を使用して、ミリリットル当たりの粒子の平均累積数≧2μm、≧5μm、≧10μm及び≧25μmを各試料について作表した。各試料について全部で1.6mLを消費して4回の読み取りを試験毎に実施し、最初の読み取りは廃棄し、残りを3回の読み取りを平均化した。
サイズ変種の分布は、サイズ排除クロマトグラフィー(SEC)によってTosoHaas Bioscience column G3000 SWXL(South San Francisco、CA)を使用して30℃でAgilent 1200 HPLC(Santa Clara、CA.USA)で測定した。試料は全て希釈せずに50μgをカラムに注射し60分間かけて溶出し、280nmでのUV吸収を調べた。2つの異なるSEC法を試料試験に使用した。方法1は、リン酸カリウム0.20M、塩化カリウム0.25M、pH6.2を使用し、方法2はリン酸カリウム0.20M、塩化カリウム0.25M、pH6.2、移動相として10%(v/v)イソプロパノールを使用した。結果は、曲線下面積全体に対する相対的なパーセントピーク面積として報告する。
電荷変異体の分布は、iCE280分析器(ProteinSimple)を使用してフルオロカーボンをコーティングしたキャピラリーカートリッジ(100μm×5cm)を用いてiCIEFによって評価した。両性電解質溶液は、精製水中のメチルセルロース(MC)0.35%、Pharmalyte3−10担体両性電解質0.75%、Pharmalyte8−10.5担体両性電解質4.2%及びpIマーカー7.40 0.2%及びpIマーカー9.77 0.15%の混合物からなった。陽極液は、リン酸80mMで、陰極液は水酸化ナトリウム100mMであり、何れもメチルセルロース0.10%の溶液であった。試料は精製水で希釈し、CpBを各希釈試料に酵素対基質比1:100で添加し、その後37℃で20分間インキュベートした。CpB処理した試料は、両性電解質溶液と混合し、次いで1500Vの電位を1分間、その後3000Vの電位を10分間導入することによって泳動した。泳動したα−PDL1電荷変異体の画像は、280nm紫外線をキャピラリーから電荷結合素子デジタルカメラのレンズに通過させることによって得た。次に、この画像を分析して、様々な電荷変異体の分布を測定した。
ペプチドマッピング技術を使用してトリプトファン(W)及びメチオニン(M)の酸化をモニターした。α−PDL1ペプチドマップを作成するために、ジスルフィド結合を低減し、カルボキシメチル誘導体を生成するために得られた遊離チオールを変化させる方法において、タンパク質をジチオスレイトール(DTT)及びヨード酢酸(IAA)に曝露した後、タンパク質をトリプシンで消化した。得られたペプチドを逆相高速液体クロマトグラフィー(RP−HPLC)によって分離し、214nmでモニターした。トリプシンペプチドの質量は、ThermoFisher Scientific LTQ Orbitrap質量分析計を使用して、分離した消化混合物のLC−MS分析によって測定した。
バッファー系の選択
製剤開発中に、2種類のバッファー系を評価した。1つは、スクロース240mMを含むヒスチジンアセテート20mM、pH5.5であり、もう1つはコハク酸アルギニン200mM、pH5.5であった。安定性の促進研究によって、α−PDL1はコハク酸アルギニンバッファーと比較してヒスチジンアセテートバッファーにおいてより安定であることが明らかになった(表1)。したがって、さらに製剤を開発するためにヒスチジンアセテートを選択した。
スクロース(120mM)は、凍結/解凍によって誘導される凝集からタンパク質を保護する能力並びに原体(DS)及びその後の薬物製品(DP)の2℃−8℃保存の長期凍結保存中における凍結保護物質としての機能に基づいて、α−PDL1液体製剤用の安定剤として選択した。
α−PDL1製剤パラメータのタンパク質安定性に対する効果をさらに調べるために一部実施要因実験計画(DOE)を使用した。全部で12種の異なるα−PDL1製剤を試験した(10個の実験及び2個の中心点)。研究で変化させた3つの要素は、0.5単位間隔で5.0−6.0の範囲のpH、40−120mg/mLの濃度範囲のタンパク質及び0.005%−0.06%(w/v)の濃度範囲のポリソルベート20であった(表4)。製剤は全て、表4に示したように最後の2つ製剤以外はスクロース120mMを含むヒスチジンアセテート20mMで緩衝化した。ヒスチジンアセテート25mM製剤は、酸化の危険性に関して最悪の場合と考えられるので評価した。酢酸ナトリウム20mMバッファーは、予備のバッファー系として評価し、ヒスチジンアセテートバッファーと比較した。製剤は、25℃で2カ月間及び40℃で1カ月間保存した。前記の研究による安定性データは、製剤パラメータ間の相互作用についてJMPソフトウェア(JMP、バージョン9、SAS Institute Inc.、Cary、NC)を使用して統計学的に解析した。
表8.40℃でヒスチジンアセテート及び酢酸ナトリウム中でのICIEF及びSE HPLCメインピークによるα-PDL1のゼロ次分解率
ガラスバイアル中において撹拌ストレスを受けたとき、漸増濃度のPS20の存在下での薬物製品の安定性を調べた。ヒスチジンアセテート20mM、スクロース120mM、pH5.5中において57mg/mLを含有する製剤を0.005%から0.06%の範囲の様々な濃度のPS20と共に2ccガラスバイアルに1mL充填して評価した。ガラスバイアルを室温で70rpmで3日間撹拌してから、SEC(図9A)及び濁度(図9B)測定によって安定性を測定した。PS20レベルが0.005−0.06%の間の製剤は、撹拌中に安定性に変化はなかった。しかし、PS20を欠如した製剤は、HMWS増加のためにモノマー減少の増加が示された。この実験では、PS20 0.005%はガラスバイアル中での撹拌ストレスからタンパク質を保護するために十分であった。
マスターセルバンク及びワーキングセルバンクから生成した材料に対して、ヒスチジンアセテート20mM、スクロース120mM及びPS20 0.04%を含有する製剤において5.2から6.3のpH範囲にわたるpHスクリーニングをさらに実施した(表10)。SE−HPLC及びICIEFによる分析によって、pH5.7−6.3が化学的及び物理的にかなり安定で、製剤においてpH5.5−6.3の可能な範囲が適切であることが示された(図11A及びB)。pHが高いとモノマー及びメインピーク分解率が低下し、約pH5.7と6.3の間で減少率は平坦化する。
α−PDL1軽鎖可変領域
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR(配列番号7)
α−PDL1重鎖可変領域
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTK(配列番号8)
α−PDL1完全軽鎖
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号9)
α−PDL1完全重鎖
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(配列番号10)
Claims (41)
- 約40mg/mLから約125mg/mLの濃度の抗PDL1モノクローナル抗体、約15mMから約25mMの濃度のヒスチジンアセテート又は酢酸ナトリウム、約60mMから約240mMの濃度のスクロース、約0.005%(w/v)から約0.06%(w/v)の濃度のポリソルベートを含むpH約5.0から約6.3の安定な水性薬学的製剤。
- 製剤中の前記モノクローナル抗体が約40mg/mLから約80mg/mLである、請求項1に記載の製剤。
- 製剤中の前記モノクローナル抗体が約54mg/mLから約66mg/mLである、請求項1に記載の製剤。
- 製剤中の前記モノクローナル抗体が約60mg/mLである、請求項1に記載の製剤。
- 製剤中の前記モノクローナル抗体が約60mg/mLから約125mg/mLである、請求項1に記載の製剤。
- 製剤中の前記モノクローナル抗体が約125mg/mLである、請求項1に記載の製剤。
- 前記ヒスチジンアセテート又は酢酸ナトリウムが約17mMから約22mMの濃度である、請求項1から6の何れか一項に記載の製剤。
- 前記ヒスチジンアセテート又は酢酸ナトリウムが約20mMの濃度である、請求項1から6の何れか一項に記載の製剤。
- 製剤中の前記スクロースが約60mMから約180mMである、請求項1から8の何れか一項に記載の製剤。
- 製剤中の前記スクロースが約120mMである、請求項1から8の何れか一項に記載の製剤。
- pHが約5.5から約6.1である、請求項1から10の何れか一項に記載の製剤。
- pHが約5.5又は約5.8である、請求項1から10の何れか一項に記載の製剤。
- 製剤中の前記ポリソルベートがポリソルベート20である、請求項1から12の何れか一項に記載の製剤。
- 製剤中の前記ポリソルベートが約0.02%から約0.04%である、請求項1から13の何れか一項に記載の製剤。
- 製剤中の前記モノクローナル抗体が約60mg/mLであり、製剤中のスクロースが約120mMであり、pHが約5.8である、請求項1から5及び7から14の何れか一項に記載の製剤。
- 製剤中の前記モノクローナル抗体が約125mg/mLであり、製剤中のスクロースが約240mMであり、pHが約5.5である、請求項1、6から8及び11から14の何れか一項に記載の製剤。
- 前記モノクローナル抗体が事前の凍結乾燥に供されない、請求項1から16の何れか一項に記載の製剤。
- 前記モノクローナル抗体が完全長抗体である、請求項1から17の何れか一項に記載の製剤。
- 前記モノクローナル抗体がIgG1、IgG2、IgG3又はIgG4抗体である、請求項1から18の何れか一項に記載の製剤。
- 前記モノクローナル抗体がヒト化抗体である、請求項1から19の何れか一項に記載の製剤。
- 前記モノクローナル抗体が抗原結合領域を含む抗体断片である、請求項1から20の何れか一項に記載の製剤。
- 前記抗体断片がFab又はF(ab’)2断片である、請求項21に記載の製剤。
- 前記モノクローナル抗体が、
(a)(1)アミノ酸配列RASQDVSTAVA(配列番号1)を含むHVR−L1;
(2)アミノ酸配列SASFLYS(配列番号2)を含むHVR−L2;
(3)アミノ酸配列QQYLYHPAT(配列番号3)を含むHVR−L3
を含む軽鎖可変領域;及び
(b)(1)アミノ酸配列GFTFSDSWIH(配列番号4)を含むHVR−H1;
(2)アミノ酸配列AWISPYGGSTYYADSVKG(配列番号5)を含むHVR−H2;
(3)アミノ酸配列RHWPGGFDY(配列番号6)を含むHVR−H3
を含む重鎖可変領域
を含む、請求項1から22の何れか一項に記載の製剤。 - 前記モノクローナル抗体が、配列番号7のアミノ酸配列を含む軽鎖可変領域及び配列番号8のアミノ酸配列を含む重鎖可変領域を含む、請求項1から23の何れか一項に記載の製剤。
- 前記モノクローナル抗体が、配列番号7のアミノ酸配列を含む軽鎖可変領域及び配列番号32のアミノ酸配列を含む重鎖可変領域を含む、請求項1から23の何れか一項に記載の製剤。
- 前記モノクローナル抗体が、配列番号9のアミノ酸配列を含む軽鎖及び配列番号10のアミノ酸配列を含む重鎖を含む、請求項24又は25に記載の製剤。
- 前記モノクローナル抗体が、ガラスバイアル又は金属合金容器中で保存される、請求項1から26の何れか一項に記載の製剤。
- 金属合金が、316Lステンレススチール又はハステロイである、請求項27に記載の製剤。
- 2−8℃で少なくとも6カ月、少なくとも12カ月、少なくとも18カ月又は少なくとも24カ月間安定である、請求項1から28の何れか一項に記載の製剤。
- 製剤中の抗体が保存後にその生物活性の少なくとも約80%を保持している、請求項29に記載の製剤。
- 生物活性がPD−L1に結合する抗体によって測定される、請求項30に記載の製剤。
- 滅菌されている、請求項1から31の何れか一項に記載の製剤。
- 対象への投与に適している、請求項1から32の何れか一項に記載の製剤。
- 静脈内(IV)投与用である、請求項1から33の何れか一項に記載の製剤。
- 前記モノクローナル抗体が約60mg/mLの量であり、前記ヒスチジンアセテートが約20mMの濃度であり、前記スクロースが約120mMの濃度であり、前記ポリソルベートが0.04%(w/v)の濃度のポリソルベート20であり、pHが約5.8である、請求項1に記載の製剤。
- 前記モノクローナル抗体が約125mg/mLの量であり、前記ヒスチジンアセテートが約20mMの濃度であり、前記スクロースが約240mMの濃度であり、前記ポリソルベートが0.02%(w/v)の濃度のポリソルベート20であり、pHが約5.5である、請求項1に記載の製剤。
- 請求項1から36の何れか一項に記載の安定な水性薬学的製剤を保持する容器を含む製造品。
- 容器がガラスバイアル又は金属合金容器である、請求項37に記載の製造品。
- 金属合金が316Lステンレススチール又はハステロイである、請求項38に記載の製造品。
- 対象における疾患又は障害を治療するための方法であって、請求項1から36の何れか一項に記載の製剤の有効量を対象に投与することを含み、疾患又は障害が、感染、がん及び炎症疾患からなる群から選択される方法。
- モノクローナル抗体が定常領域にN297A又はD265A/N297A置換を含み、残基の番号付けがカバットと同様のEUインデックスの番号付けである、請求項1から36の何れか一項に記載の製剤。
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