JP5881950B2 - 抗体処方物 - Google Patents
抗体処方物 Download PDFInfo
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- JP5881950B2 JP5881950B2 JP2010538594A JP2010538594A JP5881950B2 JP 5881950 B2 JP5881950 B2 JP 5881950B2 JP 2010538594 A JP2010538594 A JP 2010538594A JP 2010538594 A JP2010538594 A JP 2010538594A JP 5881950 B2 JP5881950 B2 JP 5881950B2
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- Prior art keywords
- antibody
- histidine
- formulation
- trehalose
- humanized
- Prior art date
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Description
CD20分子(ヒトBリンパ球限定分化抗原またはBp35とも呼ばれる)は、プレBおよび成熟Bリンパ球上に位置する約35kDの分子量を有する疎水性膜貫通タンパク質である(Valentine et al. (1989) J. Biol. Chem. 264(19):11282-11287;およびEinfield et al. (1988) EMBO J. 7(3):711-717)。CD20は末梢血またはリンパ器官由来のB細胞の90%超の表面上に見出され、そして初期プレB細胞発生の間に発現され、そして形質細胞分化まで残存する。CD20は正常B細胞および悪性B細胞の両方の上に存在する。特に、CD20は非ホジキンリンパ腫(NHL)のB細胞の90%超の上で発現されているが(Anderson et al. (1984) Blood 63(6): 1424-1433))、造血幹細胞、プロB細胞、正常形質細胞、または他の正常組織上には見出されない(Tedder et al. (1985) J, Immunol. 135(2):973- 979)。
I型CD20エピトープ II型CD20エピトープ
CD20を脂質ラフトに局在化させる CD20を脂質ラフトに局在化させない
増加したCDC(IgG1イソタイプの場合) 減少したCDC(IgG1イソタイプの場合)
ADCC活性(IgG1イソタイプの場合) ADCC活性(IgG1イソタイプの場合)
完全な結合能 低下した結合能
ホモタイプ凝集 より強いホモタイプ凝集
架橋に際してのアポトーシス誘発 架橋なしでの強い細胞死誘発
表1:I型およびII型抗CD20抗体の特性
1つの局面において、本発明は、以下を含む医薬処方物に関する:
1〜150mg/mLの抗CD20抗体;
1〜100mMのバッファー;
場合により、0.001〜1%の界面活性剤;および
場合により、1〜800mMの等張剤;
pH4.5〜7.0の範囲。
用語「抗体」は、本発明による特徴的特性が保持されている限り、限定するものではないが、抗体全体、ヒト抗体、ヒト化抗体および遺伝子操作抗体、例えばモノクローナル抗体、キメラ抗体または組換え抗体ならびにそのような抗体のフラグメントを含む抗体の種々の形態を包含する。
I型CD20エピトープ II型CD20エピトープ
CD20を脂質ラフトに局在化させる CD20を脂質ラフトに局在化させない
増加したCDC(IgG1イソタイプの場合) 減少したCDC(IgG1イソタイプの場合)
ADCC活性(IgG1イソタイプの場合) ADCC活性(IgG1イソタイプの場合)
完全な結合能 低下した結合能
ホモタイプ凝集 より強いホモタイプ凝集
架橋に際してのアポトーシス誘発 架橋なしでの強い細胞死誘発
表2:I型およびII型抗CD20抗体の特性
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知られてい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、ランダムに選択された健常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)アッセイを以下のプロトコルに従って行う:
i)PBMCを、標準的密度遠心分離手順を使用して単離し、そしてRPMI細胞培養培地中に5×106細胞/mlで懸濁する;
ii)標的細胞を、標準的組織培養方法によって増殖させ、90%より高い生存率で指数増殖期から回収し、RPMI細胞培養培地中で洗浄し、100μCiの’’CI−で標識し、細胞培養培地で2回洗浄し、そして細胞培養培地中に10’細胞/mlの密度で再懸濁する;
iii)100μlの上記最終標的細胞懸濁物を96ウェルマイクロタイタープレートの各々のウェルに移す;
iv)抗体を4000ng/mlから0.04ng/mlまで細胞培養培地中で段階希釈し、そして得られた抗体溶液の50μlを96ウェルマイクロタイタープレート中の標的細胞に加え、上記の濃度範囲全体をカバーする種々の抗体濃度を三連で試験する;
v)最大放出(MR)コントロールのために、標識標的細胞を含むプレート中の3つのさらなるウェルに、非イオン性界面活性剤(Nonidet、Sigma, St. Louis)の2%(VN)水溶液50μlを、抗体溶液(上記iv項)の代わりに与える;
vi)自発性放出(SR)コントロールのために、標識標的細胞を含むプレート中の3つのさらなるウェルに、RPMI細胞培養培地50μlを、抗体溶液(上記iv項)の代わりに与える;
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、そして1時間4℃でインキュベートする;
viii)PBMC懸濁物(上記i項)50μlを、25:1のエフェクター:標的細胞比率を生じるように各々の細胞に加え、そしてプレートを5%CO2雰囲気下37℃で4時間インキュベーター中に入れる;
ix)各々のウェルからの無細胞上清を回収し、そして実験的に放出された放射能(ER)をガンマカウンターを使用して定量する;
x)特異的溶解の百分率を、各々の抗体濃度について、式(ER−MR)/(MR−SR)×100[ここで、ERはその抗体濃度について定量される平均放射能(上記ix項参照)であり、MRはMRコントロール(上記v項参照)について定量される平均放射能(上記ix項参照)であり、そしてSRはSRコントロール(上記vi項参照)について定量される平均放射能(上記ix項参照)である]に従って算出する;
4)「増加したADCC」を、上記で試験する抗体濃度範囲内で観察される特異的溶解の最大百分率の増加、および/または上記で試験する抗体濃度範囲内で観察される特異的溶解の最大百分率の半分を達成するために必要とされる抗体の濃度の低下のいずれかとして定義する。ADCCの増加は、当業者に公知である、同じ標準的な産生、精製、処方および貯蔵方法を使用して、同じ型の宿主細胞によって産生されるが、GnTIIIを過剰発現するように操作された宿主細胞によっては産生されていない、同じ抗体によって媒介される、上記アッセイを用いて測定される、ADCCと相対的である。
− 約1〜約150mg/mlの抗CD20抗体、
− 約0.001〜約1%の少なくとも1つの界面活性剤、および
− 約1〜約100mMのバッファー、
− pH約4.5〜約7.0。
− 約1〜約150mg/mLの抗CD20抗体、
− 約0.005〜約0.05%の少なくとも1つの界面活性剤、および
− 約1〜約100mMのバッファー、
− pH約4.5〜約7.0。
− 約10〜約30mg/mLのII型抗CD20抗体、
− 20mM L−ヒスチジン、
− 240mMトレハロース、および
− 0.02%w/vポリソルベート20、
− pH約6。
− 約10〜約30mg/mLのII型抗CD20抗体、
− 0.02%w/vポロクサマー188(商標)、
− 20mM L−ヒスチジン、および
− 240mMトレハロース、
− pH約6。
15mg/mLのII型抗CD20抗体、好ましくはヒト化B−Ly1抗体、最も好ましくはHuMab<CD20>、
0.01%w/vポリソルベート20、
20mM L−ヒスチジン、および
140mM塩化ナトリウム、
pH6.0;
または
10mg/mLのII型抗CD20抗体、好ましくはヒト化B−Ly1抗体、最も好ましくはHuMab<CD20>、
0.01%w/vポリソルベート20、
20mM L−ヒスチジン、および
140mM塩化ナトリウム、
pH6.0;
または
15mg/mLのII型抗CD20抗体、好ましくはヒト化B−Ly1抗体、最も好ましくはHuMab<CD20>、
場合により、0.001〜1%w/vの界面活性剤、
20mM L−ヒスチジン、
pH6.0;
または
10mg/mLのII型抗CD20抗体、好ましくはヒト化B−Ly1抗体、最も好ましくはHuMab<CD20>、
0.02%w/vポリソルベート20、
20mM L−ヒスチジン、および
240mMトレハロース、
pH6.0;
または
25mg/mLのII型抗CD20抗体、好ましくはヒト化B−Ly1抗体、最も好ましくはHuMab<CD20>、
0.02%w/vポリソルベート20、
20mM L−ヒスチジン、および
240mMトレハロース、
pH6.0;
または
25mg/mLのII型抗CD20抗体、好ましくはヒト化B−Ly1抗体、最も好ましくはHuMab<CD20>、
0.02%w/vポロクサマー188(商標)、
20mM L−ヒスチジン、および
240mMトレハロース、
pH6.0;
または
25mg/mLのII型抗CD20抗体、好ましくはヒト化B−Ly1抗体、最も好ましくはHuMab<CD20>、
0.01%w/vポロクサマー188(商標)、
20mM L−ヒスチジン、および
240mMトレハロース、
pH6.0;
または
25mg/mLのII型抗CD20抗体、好ましくはヒト化B−Ly1抗体、最も好ましくはHuMab<CD20>、
0.1%w/vポロクサマー188(商標)、
20mM L−ヒスチジン、および
240mMトレハロース、
pH6.0;
または
25mg/mLのII型抗CD20抗体、好ましくはヒト化B−Ly1抗体、最も好ましくはHuMab<CD20>、
0.02%w/vポリソルベート80、
20mM L−ヒスチジン、および
240mMトレハロース、
pH6.0;
または
25mg/mLのII型抗CD20抗体、好ましくはヒト化B−Ly1抗体、最も好ましくはHuMab<CD20>、
0.1%w/vポリソルベート80、
20mM酢酸塩、および
240mMトレハロース、
pH5.5;
または
25mg/mLのII型抗CD20抗体、好ましくはヒト化B−Ly1抗体、最も好ましくはHuMab<CD20>、
0.1%w/vポリソルベート80、
20mM酢酸塩、および
140mM塩化ナトリウム、
pH5.5;
または
30mg/mLのII型抗CD20抗体、好ましくはヒト化B−Ly1抗体、最も好ましくはHuMab<CD20>、
0.01%w/vポロクサマー188(商標)、
20mM L−ヒスチジン、および
200mMトレハロース、
pH6.5。
10mg/mLのII型抗CD20抗体、好ましくはヒト化B−Ly1抗体、最も好ましくはHuMab<CD20>、
0.02%w/vポリソルベート20、
20mM L−ヒスチジン、および
240mMトレハロース、
pH6.0。
25mg/mLのII型抗CD20抗体、好ましくはヒト化B−Ly1抗体、最も好ましくはHuMab<CD20>、
0.02%w/vポロクサマー188(商標)、
20mM L−ヒスチジン、および
240mMトレハロース、
pH6.0。
実施例1
液体、凍結乾燥、または凍結乾燥形態から再構成された液体のいずれかの以下の処方物を調製した:
15mg/mL HuMab<CD20>、
0.01%w/vポリソルベート20、
20mM L−ヒスチジン、および
140mM塩化ナトリウム、
pH6.0;
10mg/mL HuMab<CD20>、
0.01%w/vポリソルベート20、
20mM L−ヒスチジン、および
140mM塩化ナトリウム、
pH6.0;
15mg/mL HuMab<CD20>、
20mM L−ヒスチジン、
pH6.0;
10mg/mL HuMab<CD20>、
0.02%w/vポリソルベート20、
20mM L−ヒスチジン、および
240mMトレハロース、
pH6.0;
25mg/mL HuMab<CD20>、
0.02%w/vポリソルベート20、
20mM L−ヒスチジン、および
240mMトレハロース、
pH6.0。
10mg/mL HuMab<CD20>、
0.02%w/vポリソルベート20、
20mM L−ヒスチジン、および
240mMトレハロース、
pH6.0。
HuMab<CD20>の処方物を、生産バッファー(例えば、20mMヒスチジンバッファー(pH約6.0)、または140mM塩化ナトリウムおよび0.01%(w/v)ポリソルベート20を含む20mMヒスチジンバッファー(pH約6.0))中のHuMab<CD20>の溶液の均質化によって調製した。HuMab<CD20>の処方物を、バッファーでの希釈によってタンパク質濃度を所望の濃度に調整することによって調製することもできる。タンパク質の安定化のためおよび等張性調整のための賦形剤を必要に応じて加えた。これを溶解形態であるいは固体として加えることができる。界面活性剤を処方物にストック溶液として必要に応じて加えた。全ての処方物を0.22μmフィルターを通して無菌濾過し、そして無菌ガラスバイアル中に無菌的に小分けし、そしてゴム栓およびアルクリンプ(alucrimp)キャップで閉じた。これらの処方物を様々な温度で様々な時間間隔で貯蔵し、そして個々の段落に示す時点で分析のために取り出した。処方物を、1)UV分光光度法によって、2)サイズ排除クロマトグラフィー(SEC)によって、3)可視および可視下(subvisible)粒子について、4)イオン交換クロマトグラフィー(IEC)によって、そして5)溶液の濁度によって分析した。
HuMab<CD20>の溶液を、液体処方物について上記したように調製するか、または糖および界面活性剤を含む20mMヒスチジンバッファー(pH約6.0)中のHuMab<CD20>のHuMab<CD20>溶液を均質化することによって製造するかのいずれかをした。全ての処方物を0.22μmフィルターを通して無菌濾過し、そして無菌ガラスバイアル中に無菌的に小分けした。バイアルを凍結乾燥プロセスにおける使用のために適切なゴム栓である程度閉め、そして凍結乾燥器の乾燥チャンバーに移した。当技術分野において公知の任意の凍結乾燥方法が本発明の範囲内にあることが意図される。例えば、本研究のために使用される凍結乾燥プロセスは、処方物の室温から約5℃への冷却(事前冷却)およびそれに続く約1℃/分〜5℃/分のランプ速度(ramping rate)での−40℃での凍結(凍結I)を含んだ。第1の乾燥工程は、0.3〜0.5℃/分のランプ速度で−40℃から−30℃まで生じ、次いで、−30℃で少なくとも50時間、約75〜80mTorrのチャンバー圧で保持することができる。第2の乾燥工程は、0.1〜0.3℃/分のランプ速度で−30℃から25℃まで生じ、そして、25℃で少なくとも5時間、約50〜80mTorrのチャンバー圧で保持することができる(適用された乾燥スケジュールを表1に与える)。記載した凍結乾燥プロセスを使用して乾燥させたHuMab<CD20>処方物は、約2〜3分の好都合に迅速な再構成時間を有することが見出された。本研究における全ての凍結乾燥ケーキは、カール・フィッシャー方法によって決定した場合約0.1〜1.0%の残存水含量を有した。凍結乾燥バイアルを様々な温度で様々な時間間隔で貯蔵した。凍結乾燥処方物を、1)UV分光光度法による分析、2)再構成時間の決定、3)サイズ排除クロマトグラフィー(SEC)による分析、4)イオン交換クロマトグラフィー(IEC)による分析、5)可視下および可視粒子の決定、および6)溶液の濁度による分析の前にそれぞれの容量の注射用水(WFI)で再構成した。
処方物 15mg/mL HuMab<CD20>、20mM L−ヒスチジン、pH6.0、
合格:可視粒子なし〜本質的になし、最大6000粒子≧10μm/容器、最大600粒子≧25μm/容器
合格:可視粒子なし〜本質的になし、最大6000粒子≧10μm/容器、最大600粒子≧25μm/容器
処方物 10mg/mL HuMab<CD20>、20mM L−ヒスチジン、240mMトレハロース、0.02%w/vポリソルベート20、pH6.0、
合格:可視粒子なし〜本質的になし、最大6000粒子≧10μm/容器、最大600粒子≧25μm/容器
液体、凍結乾燥、または凍結乾燥形態から再構成された液体のいずれかの以下の処方物を調製した:
25mg/mL HuMab<CD20>、
0.02%w/vポロクサマー188(商標)、
20mM L−ヒスチジン、および
240mMトレハロース、
pH6.0;
または
25mg/mL HuMab<CD20>、
0.01%w/vポロクサマー188(商標)、
20mM L−ヒスチジン、および
240mMトレハロース、
pH6.0;
または
25mg/mL HuMab<CD20>、
0.1%w/vポロクサマー188(商標)、
20mM L−ヒスチジン、および
240mMトレハロース、
pH6.0;
または
25mg/mL HuMab<CD20>、
0.02%w/vポリソルベート80、
20mM L−ヒスチジン、および
240mMトレハロース、
pH6.0;
または
25mg/mL HuMab<CD20>、
0.1%w/vポリソルベート80、
20mM酢酸塩、および
240mMトレハロース、
pH5.5;
または
25mg/mL HuMab<CD20>、
0.1%w/vポリソルベート80、
20mM酢酸塩、および
140mM塩化ナトリウム、
pH5.5;
または
30mg/mL HuMab<CD20>、
0.01%w/vポロクサマー188(商標)、
20mM L−ヒスチジン、および
200mMトレハロース、
pH6.5。
HuMab<CD20>の処方物を、生産バッファー(例えば、240mMトレハロースおよび0.02%(w/v)ポロクサマー188(商標)を含む20mMヒスチジンバッファー(pH約6.0))中のHuMab<CD20>の溶液の均質化によって調製した。HuMab<CD20>の処方物を、タンジェンシャルフローフィルトレーション(TFF)により生産バッファー(例えば、20mMヒスチジンバッファー(pH約6.0))中の約10〜40mg/ml HuMab<CD20>の溶液をダイアフィルトレーションして、タンパク質濃度を標的タンパク質濃度より上に増加させ、そしてバッファーを交換することによって調製することもできる。HuMab<CD20>の処方物を、バッファーでの希釈によってタンパク質濃度を所望の濃度に調整することによって調製することもできる。タンパク質の安定化のためおよび等張性調整のための賦形剤を溶解形態であるいは固体として加えることができる。界面活性剤を処方物にストック溶液として必要に応じて加えた。全ての処方物を0.22μmフィルターを通して無菌濾過し、そして無菌ガラスバイアル中に無菌的に小分けし、そしてゴム栓およびアルクリンプキャップで閉じた。これらの処方物を様々な温度で様々な時間間隔で貯蔵し、そして個々の段落に示す時点で分析のために取り出した。処方物を、1)UV分光光度法によって、2)サイズ排除クロマトグラフィー(SEC)によって、3)可視および可視下粒子について、4)イオン交換クロマトグラフィー(IEC)によって、そして5)溶液の濁度によって分析した。
<CD20>の溶液を、液体処方物について上記したように調製した。全ての処方物を0.22μmフィルターを通して無菌濾過し、そして無菌ガラスバイアル中に無菌的に小分けした。バイアルを凍結乾燥プロセスにおける使用のために適切なゴム栓である程度閉め、そして凍結乾燥器の乾燥チャンバーに移した。当技術分野において公知の任意の凍結乾燥方法が本発明の範囲内にあることが意図される。例えば、本研究のために使用される凍結乾燥プロセスは、処方物の室温から約5℃への冷却(事前冷却)およびそれに続く約1℃/分〜5℃/分のランプ速度での−40℃での凍結(凍結I)を含んだ。第1の乾燥工程は、0.3〜0.5℃/分のランプ速度で−40℃から−30℃まで生じ、次いで、−30℃で少なくとも50時間、約75〜80mTorrのチャンバー圧で保持することができる。第2の乾燥工程は、0.1〜0.3℃/分のランプ速度で−30℃から25℃まで生じ、そして、25℃で少なくとも5時間、約50〜80mTorrのチャンバー圧で保持することができる(適用された乾燥スケジュールを表1に与える)。記載した凍結乾燥プロセスを使用して乾燥させたHuMab<CD20>処方物は、カール・フィッシャー方法によって決定した場合約0.1〜1.0%の残存水含量を有することが見出された。凍結乾燥バイアルを様々な温度で様々な時間間隔で貯蔵した。凍結乾燥処方物を、1)UV分光光度法による分析、2)サイズ排除クロマトグラフィー(SEC)による分析、3)イオン交換クロマトグラフィー(IEC)による分析、4)可視下および可視粒子の決定、および5)溶液の濁度による分析の前にそれぞれの容量の注射用水(WFI)で再構成した。
処方物 25mg/mL HuMab<CD20>、20mM L−ヒスチジン、240mMトレハロース、0.02%w/vポロクサマー188(商標)、pH6.0、
合格:可視粒子なし〜本質的になし、最大6000粒子≧10μm/容器、最大600粒子≧25μm/容器
合格:可視粒子なし〜本質的になし、最大6000粒子≧10μm/容器、最大600粒子≧25μm/容器
合格:可視粒子なし〜本質的になし、最大6000粒子≧10μm/容器、最大600粒子≧25μm/容器
合格:可視粒子なし〜本質的になし、最大6000粒子≧10μm/容器、最大600粒子≧25μm/容器
処方物 25mg/mL HuMab<CD20>、20mM L−ヒスチジン、240mMトレハロース、0.02%w/vポロクサマー188(商標)
合格:可視粒子なし〜本質的になし、最大6000粒子≧10μm/容器、最大600粒子≧25μm/容器
Claims (5)
- 以下を含む、処方物:
10mg/mL VH B−HH6およびVL B−KV1を含むヒト化B−Ly1抗体、
0.02%w/v ポリソルベート20、
20mM L−ヒスチジン、および
240mM トレハロース、
pH6.0
を製造する方法であって、
VH B−HH6およびVL B−KV1を含むヒト化B−Ly1抗体と、ポリソルベート20と、L−ヒスチジンおよびトレハロースを含む液体形態である処方物の凍結乾燥物を得るステップと、
該凍結乾燥物を再構成するステップとを含む、方法。 - 以下を含む、処方物:
25mg/mL VH B−HH6およびVL B−KV1を含むヒト化B−Ly1抗体、
0.02%w/vポリオキシエチレン(160)ポリオキシプロピレン(30)グリコール、
20mM L−ヒスチジン、および
240mMトレハロース、
pH6.0;
または
25mg/mL VH B−HH6およびVL B−KV1を含むヒト化B−Ly1抗体、
0.01%w/vポリオキシエチレン(160)ポリオキシプロピレン(30)グリコール、
20mM L−ヒスチジン、および
240mMトレハロース、
pH6.0;
または
25mg/mL VH B−HH6およびVL B−KV1を含むヒト化B−Ly1抗体、
0.1%w/vポリオキシエチレン(160)ポリオキシプロピレン(30)グリコール、
20mM L−ヒスチジン、および
240mMトレハロース、
pH6.0;
または
25mg/mL VH B−HH6およびVL B−KV1を含むヒト化B−Ly1抗体、
0.02%w/vポリソルベート80、
20mM L−ヒスチジン、および
240mMトレハロース、
pH6.0;
または
30mg/mL VH B−HH6およびVL B−KV1を含むヒト化B−Ly1抗体、
0.01%w/vポリオキシエチレン(160)ポリオキシプロピレン(30)グリコール、
20mM L−ヒスチジン、および
200mMトレハロース、
pH6.5。 - 液体形態であり、そして以下を含む、請求項2記載の処方物:
25mg/mL VH B−HH6およびVL B−KV1を含むヒト化B−Ly1抗体、
0.02%w/vポリオキシエチレン(160)ポリオキシプロピレン(30)グリコール、
20mM L−ヒスチジン、および
240mMトレハロース、
pH6.0。 - CD20関連処置疾患のために有用な医薬の調製のための、請求項1記載の方法により製造された処方物か、請求項2又は3記載の処方物かの使用。
- 疾患が、B細胞非ホジキンリンパ腫(NHL)、マントル細胞リンパ腫(MCL)、急性リンパ球性白血病(ALL)、慢性リンパ球性白血病(CLL)、B細胞びまん性大細胞型リンパ腫(DLCL)、バーキットリンパ腫、ヘアリー細胞白血病、濾胞性リンパ腫、多発性骨髄腫、周辺帯リンパ腫、移植後リンパ増殖性障害(PTLD)、HIV関連リンパ腫、ワルデンシュトレームマクログロブリン血症、または原発性CNSリンパ腫からなる群より選択される、請求項4記載の使用。
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