JP6259436B2 - 高濃度抗体含有溶液製剤 - Google Patents
高濃度抗体含有溶液製剤 Download PDFInfo
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- JP6259436B2 JP6259436B2 JP2015223070A JP2015223070A JP6259436B2 JP 6259436 B2 JP6259436 B2 JP 6259436B2 JP 2015223070 A JP2015223070 A JP 2015223070A JP 2015223070 A JP2015223070 A JP 2015223070A JP 6259436 B2 JP6259436 B2 JP 6259436B2
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- antibody
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- arginine
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Description
なる一方で(100〜200mg-程度)、皮下注射では一般的に注射液量の制限があることから、
投与液中の抗体の高濃度化が必要となる。そこで、凍乾前より少ない容量の水を用いて凍結乾燥製剤を再溶解することにより高濃度溶液製剤を調製する、いわゆる凍乾濃縮技術を利用した高濃度製剤が使用されることが多い。しかし、再溶解の手間が要らない使い勝手のよい溶液製剤への需要も大きい。また、凍結乾燥製剤の製造において、糖などの凍結保護剤の添加により製剤の粘度が増大することは、皮下注射用の製剤としては好ましくないが、溶液製剤であれば、この問題を回避することができると思われる。
(1)アルギニン及びメチオニンを含有することを特徴とする、安定な抗体含有溶液製剤。
(2)さらにヒスチジン緩衝剤を含む、(1)に記載の溶液製剤。
(3)さらに界面活性剤を含む、(1)または(2)に記載の溶液製剤。
(4)抗体の濃度が50mg/ml以上である、(1)〜(3)に記載の溶液製剤。
(5)抗体の濃度が100mg/ml以上である、(1)〜(3)に記載の溶液製剤。
(6)抗体の濃度が120mg/ml以上である、(1)〜(3)に記載の溶液製剤。
(7)抗体が抗インターロイキン−6レセプター抗体である、(1)〜(6)に記載の溶液製剤。
(8)アルギニンまたはメチオニンを含有することを特徴とする、安定な抗インターロイキン−6レセプター抗体含有溶液製剤。
(9)抗体がヒト化抗体またはヒト抗体である、(1)〜(8)に記載の溶液製剤。
(10)さらにトリプトファンを含む、(1)〜(9)に記載の溶液製剤。
(11)pHが4〜8である、(1)〜(10)に記載の溶液製剤。
(12)アルギニンの含有量が、50〜1500mMである、(1)〜(11)に記載の溶液製剤。
(13)粘度が、2〜15mPa・sである、(1)〜(12)に記載の溶液製剤。
(14)溶液製剤が22〜28℃で少なくとも6ヶ月間安定である、(1)〜(13)に記載の溶液製剤。
(15)抗体二量体の生成が抑制されることを特徴とする、(1)〜(13)に記載の溶液製剤。
(16)抗体分子の脱アミド化が抑制されることを特徴とする、(1)〜(13)に記載の溶液製剤。
(17)皮下投与される、(1)〜(13)に記載の溶液製剤。
(18)溶液製剤の製造過程に凍結乾燥工程を含まないで製造される、(1)〜(13)に記載の溶液製剤。
(19)溶液中にアルギニンを添加することを含む,抗体含有溶液製剤の抗体分子の脱アミド化を抑制する方法。
(20)溶液中にアルギニンとメチオニンを添加することを含む,抗体含有溶液製剤の抗体二量体生成を抑制する方法。
本発明において、抗体含有溶液製剤とは、活性成分として抗体を含み、ヒト等の動物に投与できるように調製された溶液製剤を言い、好ましくは製造過程に凍結乾燥工程を含まないで製造された溶液製剤を言う。
また、本発明の抗体含有溶液製剤の抗体濃度の上限は、製造の観点から、一般的に300mg/mLであり、好ましくは250mg/mLであり、さらに好ましくは200mg/mLである。よって、本発明の高濃度抗体溶液製剤の抗体濃度は50〜300mg/mLが好ましく、さらに100〜300mg/mLが好ましく、さらに120〜250mg/mLが好ましく、特に150〜200mg/mLが好ましい。
モノクローナル抗体を産生するハイブリドーマは、基本的には公知技術を使用し、以下のようにして作製できる。すなわち、所望の抗原や所望の抗原を発現する細胞を感作抗原として使用して、これを通常の免疫方法にしたがって免疫し、得られる免疫細胞を通常の細胞融合法によって公知の親細胞と融合させ、通常のスクリーニング法により、モノクローナルな抗体産生細胞(ハイブリドーマ)をスクリーニングすることによって作製できる。ハイブリドーマの作製は、たとえば、ミルステインらの方法(Kohler. G. and Milstein, C., Methods Enzymol. (1981) 73: 3-46 )等に準じて行うことができる。抗原の免疫原性が低い場合には、アルブミン等の免疫原性を有する巨大分子と結合させ、免疫を行えばよい。
ば、これを所望の抗体定常領域(C領域)をコードするDNA と連結し、これを発現ベクタ
ーへ組み込む。または、抗体のV 領域をコードするDNA を、抗体C 領域のDNA を含む発現ベクターへ組み込んでもよい。発現制御領域、例えば、エンハンサー、プロモーターの制御のもとで発現するよう発現ベクターに組み込む。次に、この発現ベクターにより宿主細胞を形質転換し、抗体を発現させることができる。
どを使用できる。これらの改変抗体は、既知の方法を用いて製造することができる。キメラ抗体は、ヒト以外の哺乳動物、例えば、マウス抗体の重鎖、軽鎖の可変領域とヒト抗体の重鎖、軽鎖の定常領域からなる抗体であり、マウス抗体の可変領域をコードするDNA をヒト抗体の定常領域をコードするDNA と連結し、これを発現ベクターに組み込んで宿主に導入し産生させることにより得ることができる。
体の相補性決定領域へ移植したものであり、その一般的な遺伝子組換え手法も知られている。具体的には、マウス抗体のCDR とヒト抗体のフレームワーク領域(framework region;FR)を連結するように設計したDNA 配列を、末端部にオーバーラップする部分を有するように作製した数個のオリゴヌクレオチドからPCR 法により合成する。得られたDNA をヒト抗体定常領域をコードするDNA と連結し、次いで発現ベクターに組み込んで、これを宿主に導入し産生させることにより得られる(欧州特許出願公開番号EP 239400 、国際特許出願公開番号WO 96/02576 参照)。CDR を介して連結されるヒト抗体のFRは、相補性決定領域が良好な抗原結合部位を形成するものが選択される。必要に応じ、再構成ヒト抗体の相補性決定領域が適切な抗原結合部位を形成するように抗体の可変領域のフレームワーク領域のアミノ酸を置換してもよい(Sato, K.et al., Cancer Res. (1993) 53, 851-856)。
WO 93/11236, WO 93/19172, WO 95/01438, WO 95/15388を参考にすることができる。
に、目的とする抗体遺伝子を形質転換により導入し、形質転換された細胞をin vitroで培養することにより抗体が得られる。
られる。具体的には、抗体を酵素、例えば、パパイン、ペプシンで処理し抗体断片を生成させるか、又は、これら抗体断片をコードする遺伝子を構築し、これを発現ベクターに導入した後、適当な宿主細胞で発現させる(例えば、Co, M. S. et al., J. Immunol. (1994) 152, 2968-2976 ; Better, M. and Horwitz, A. H., Methods Enzymol. (1989) 178, 476-496 ; Pluckthun, A. and Skerra, A., Methods Enzymol. (1989) 178, 497-515 ; Lamoyi, E., Methods Enzymol. (1986) 121, 652-663 ; Rousseaux, J. et al., Methods Enzymol. (1986) 121, 663-669 ; Bird, R. E. and Walker, B. W., Trends Biotechnol.
(1991) 9, 132-137参照)。
用することもできる。本発明の「抗体」にはこれらの抗体修飾物も包含される。このような抗体修飾物を得るには、得られた抗体に化学的な修飾を施すことによって得ることができる。これらの方法はこの分野において既に確立されている。
体アゴニスト抗体、凝固第VIII因子代替抗体、抗CD3抗体、抗CD20抗体、抗GPIIb/IIIa抗
体、抗TNF抗体、抗CD25抗体、抗EGFR抗体、抗Her2/neu抗体、抗RSV抗体、抗CD33抗体、抗CD52抗体、抗IgE抗体、抗CD11a抗体、抗VEGF抗体、抗VLA4抗体、抗AXL抗体などを挙げる
ことができるが、これに限定されない。
出願番号PCT/JP05/013103を参照)などが本発明で使用する好ましい抗体
である。本発明で使用するヒト化抗体として特に好ましいのは、ヒト化抗IL−6レセプター抗体である。
公開番号WO05−05636を参照)などが好ましい。
低分子化抗体としては、抗TPO受容体アゴニストDiabody(国際特許出願公開番号WO02−33072を参照)、抗CD47アゴニストDiabody(国際特許出願公開番号WO01−
66737を参照)などが好ましい。
高濃度の抗体を溶解した溶液において、アルギニンとメチオニンの合計濃度にしてアルギニン単独の場合よりも低濃度で同様の二量体生成の抑制効果が観察されたことから、アルギニンとメチオニンの併用による相乗効果が発揮されることを見出した。また、アルギニンの添加により抗体分子の脱アミド化が抑制されることを見出した。これらの検討結果は、本明細書中の後述の実施例において、180mg/mlのヒト化抗IL−6レセプター抗体を含有する試料を用いた試験結果として例示されている。
くは2%以下、さらに好ましくは1.5%以下、あるいは25℃で6ヶ月保存後の二量体量及び分解物量の合計が5.0%以下、好ましくは2%以下、さらに好ましくは1.5%
以下である。
界面活性剤としては、非イオン界面活性剤、例えばソルビタンモノカプリレート、ソルビタンモノラウレート、ソルビタンモノパルミテート等のソルビタン脂肪酸エステル;グリセリンモノカプリレート、グリセリンモノミリテート、グリセリンモノステアレート等のグリセリン脂肪酸エステル;デカグリセリルモノステアレート、デカグリセリルジステアレート、デカグリセリルモノリノレート等のポリグリセリン脂肪酸エステル;ポリオキシエチレンソルビタンモノラウレート、ポリオキシエチレンソルビタンモノオレエート、ポリオキシエチレンソルビタンモノステアレート、ポリオキシエチレンソルビタンモノパルミテート、ポリオキシエチレンソルビタントリオレエート、ポリオキシエチレンソルビタントリステアレート等のポリオキシエチレンソルビタン脂肪酸エステル;ポリオキシエチレンソルビットテトラステアレート、ポリオキシエチレンソルビットテトラオレエート等のポリオキシエチレンソルビット脂肪酸エステル;ポリオキシエチレングリセリルモノステアレート等のポリオキシエチレングリセリン脂肪酸エステル;ポリエチレングリコールジステアレート等のポリエチレングリコール脂肪酸エステル;ポリオキシエチレンラウリルエーテル等のポリオキシエチレンアルキルエーテル;ポリオキシエチレンポリオキシプロピレングリコールエーテル、ポリオキシエチレンポリオキシプロピレンプロピルエーテル、ポリオキシエチレンポリオキシプロピレンセチルエーテル等のポリオキシエチレンポリオキシプロピレンアルキルエーテル;ポリオキシエチエレンノニルフェニルエーテル等のポリオキシエチレンアルキルフェニルエーテル;ポリオキシエチレンヒマシ油、ポリオキシエチレン硬化ヒマシ油(ポリオキシエチレン水素ヒマシ油)等のポリオキシエチレン硬化ヒマシ油;ポリオキシエチレンソルビットミツロウ等のポリオキシエチレンミツロウ誘導体;ポリオキシエチレンラノリン等のポリオキシエチレンラノリン誘導体;ポリオキシエチレンステアリン酸アミド等のポリオキシエチレン脂肪酸アミド等のHLB6〜18を有するもの;陰イオン界面活性剤、例えばセチル硫酸ナトリウム、ラウリル硫酸ナトリウム、オレイル硫酸ナトリウム等の炭素原子数10〜18のアルキル基を有するアルキル硫酸塩;ポリオキシエチレンラウリル硫酸ナトリウム等の、エチレンオキシドの平均付加モル数が2〜4でアルキル基の炭素原子数が10〜18であるポリオキシエチレンアルキルエーテル硫酸塩;ラウリルスルホコハク酸エステルナトリウム等の、アルキル基の炭素原子数が8〜18のアルキルスルホコハク酸エステル塩;天然系の界面活性剤、例えばレシチン、グリセロリン脂質;スフィンゴミエリン等のフィンゴリン脂質;炭素原子数12〜18の脂肪酸のショ糖脂肪酸エステル等を典型的例として挙げることができる。本発明の製剤には、これらの界面活性剤の1種または2種以上を組み合わせて添加することができる。
w/v)であり、好ましくは0.001〜5%であり、さらに好ましくは0.005〜3%である。
A)抗IL−6レセプター抗体
B)アルギニンおよび/またはメチオニン、および任意の追加成分としてさらに別のアミノ酸(例えばトリプトファン)
C)緩衝剤、及び
D)界面活性剤
から実質的に構成される。
保存剤としては例えば、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、ソルビン酸、フェノール、クレゾール、クロロクレゾール等を挙げることができる。
好ましくは、本発明の抗体含有溶液製剤の粘度は、約2〜15mPa・s、さらに好ましくは約4〜10mPa・sである。ただし,本発明の粘度はコーンプレート型粘度計を用いた回転粘度計法(第15改正 日本薬局方 一般試験法 2.53 粘度測定法)で測定したものである。
さらに別の態様として、溶液中にアルギニンとメチオニンを添加することを含む、抗体含有溶液製剤の抗体二量体生成を抑制する方法が提供される。
本発明を以下の実施例によってさらに詳しく説明するが、本発明の範囲はこれらのみに限定されるものではない。
抗体試料
抗IL−6レセプターヒト化抗体は国際特許出願公開番号WO92/19759号公報の実施例10に記載されたヒトエロンゲーションファクターIαプロモーターを利用し、特開平8−99902号公報の参考例2に記載された方法に準じて作成したヒト化抗体である。なお、実施例の表中ではMRAと記載することもある。
抗IL-6レセプターヒト化抗体を含む溶液製剤について、アルギニンとメチオニンの組合せが製剤の安定化に及ぼす影響を評価した。
の評価試料を調製した。各評価試料の処方は以下の通りである。
[ゲルろ過クロマトグラフ法]
試料をそのまま測定溶液とする。
測定し、その量(%)を求める。
本実施例で得られたゲルろ過クロマトグラフ法(SEC)の評価結果を表1及び図2、図
3に示した。このように、アルギニンを添加した試料(試料No. A2〜A6)について、40℃−3ヶ月間及び25℃−6ヶ月間の加速による二量体量はアルギニン非添加の試料(試料No. A1)に比べて低く、アルギニンによる二量体生成の抑制効果を確認することができた。また、アルギニン添加量に比例して二量体量は低くなることも確認することができた。一方、アルギニン(100 mM)にメチオニンを添加した試料(試料No. A7〜A9)について、40℃−3ヶ月間及び25℃−6ヶ月間の加速による二量体量は、全安定化剤濃度としてほぼ同じであるアルギニン濃度が150 mMの試料(試料No. A3, A4)より低く、アルギニン濃度が300 mMの試料(試料No. A6)と同等であった。この結果は、アルギニンとメチオニンの組合わせによる相乗効果としての二量体生成の抑制効果を示すと考えられる。
抗IL-6レセプターヒト化抗体を含む溶液製剤について、アルギニンによる脱アミド化の抑制効果を評価した。
び試料No.A16〜A18の評価試料を調製した。各評価試料の処方は以下の通りである。
[イオン交換クロマトグラフ法]
試料に精製水を加えて1mL中に抗IL-6レセプターヒト化抗体を約1mg 相当量含む液を調
製したものを各試料の測定溶液とする。
ピーク面積を自動分析法により測定し、面積百分率法によりMRA Pre, MRA Main, MRA Sub-1, MRA Sub-2, MRA R-1, 1Q(H)-MRA, 2Q(H)-MRA及びその他の類縁物質(Others)の量(%)を求める。
ターヒト化抗体の脱アミド体を中心とした複数の分解物が含まれる。このPreピークの生
成量が少ないことは本抗体の脱アミド化が抑制されていることを意味する。
ークの総和である。
本実施例によるイオン交換クロマトグラフ法(IEC)の評価結果を表2及び図5、図6
に示した。このように、アルギニンを添加した試料(試料No. A11〜A15)について、40℃−3ヶ月間及び25℃−6ヶ月間の加速によるPreピーク量は、アルギニン非添加の試料(試
料No. A10)に比べて低く、アルギニンによるPreピーク生成の抑制効果を確認することができた。また、アルギニン添加量に比例してPreピーク量は低くなることも確認すること
ができた。一方、メチオニンを添加した試料(試料No. A16〜A18)について、40℃−3ヶ
月間及び25℃−6ヶ月間の加速によるPreピーク量はアルギニン非添加の試料(試料No. A10)と同等であり、メチオニン添加の影響は認められなかった。
実施例1と同様に抗IL-6レセプターヒト化抗体を含む溶液製剤について、アルギニンとメチオニンの組合せが製剤の安定化に及ぼす影響を評価した。
紫外照射エネルギー 200 W・h/m2)を行った。そして、光加速前後における抗体の純度を、実施例1、2と同様のゲルろ過クロマトグラフ法(SEC)及びイオン交換クロマトグラ
フ法(IEC)により評価した。
た。このように、アルギニンを添加した試料(試料No. A20〜A24)について、光加速による二量体量はアルギニン非添加の試料(試料No. A19)に比べて低く、アルギニンによる
二量体生成の抑制効果を確認することができた。また、アルギニン添加量に比例して二量体量は低くなることも確認することができた。一方、アルギニン(100 mM)にメチオニンを添加した試料(試料No. A25〜A27)について、光加速による二量体量は、全安定化剤濃度としてほぼ同じであるアルギニン濃度が150 mMの試料(試料No. A22)より低く、また
、アルギニン濃度が200mM及び300 mMの試料(試料No. A23, A24)よりも低かった。この
結果は、アルギニンとメチオニンの組合わせによる相乗効果としての二量体生成の抑制効果を示すと考えられる。
このように、アルギニンを添加した試料(試料No. A20〜A24)について、光加速によるPre peak量はアルギニン非添加の試料(試料No. A19)に比べて低く、アルギニンによるPre
peak生成の抑制効果を確認することができた。また、アルギニン添加量に比例してPre peak量は低くなることも確認することができた。一方、アルギニン(100 mM)にメチオニ
ンを添加した試料(試料No. A25〜A27)について、光加速による二量体量は、全安定化剤濃度としてほぼ同じであるアルギニン濃度が150 mMの試料(試料No. A22)より低く、ま
た、アルギニン濃度が200mM及び300 mMの試料(試料No. A23, A24)よりも低かった。こ
の結果は、アルギニンとメチオニンの組合わせによる相乗効果としてのPre peak生成の抑制効果を示すと考えられる。
Claims (18)
- モノクローナルIgG抗体およびアルギニン40〜1000mM及びメチオニン10〜200mM、及び非イオン界面活性剤を緩衝液中に含有する、安定な抗体含有溶液製剤であって、製剤中のモノクローナルIgG抗体の濃度が50mg/ml以上である、前記溶液製剤。
- 非イオン界面活性剤がポリソルベートまたはポロキサマーである、請求項1に記載の溶液製剤。
- 抗体の濃度が100mg/ml以上である、請求項1または2に記載の溶液製剤。
- 抗体の濃度が120mg/ml以上である、請求項1または2に記載の溶液製剤。
- 溶液製剤のpHが4〜8である、請求項1〜4のいずれかに記載の溶液製剤。
- ヒスチジン緩衝剤を含む、請求項1〜5のいずれかに記載の溶液製剤。
- 抗体がヒト化抗体またはヒト抗体である、請求項1〜6のいずれかに記載の溶液製剤。
- 抗体が抗インターロイキン−6レセプター抗体である、請求項1〜7のいずれかに記載の溶液製剤。
- 界面活性剤がポリソルベート80である、請求項2〜8のいずれかに記載の溶液製剤。
- 抗体がヒト化抗インターロイキン−6レセプター抗体MRAであり、アルギニン濃度が100〜300mM、メチオニン濃度が10〜50mM、ポリソルベート80濃度が0.005〜3%(w/v)、ヒスチジン緩衝液濃度が10〜20mM、抗体濃度が150〜200mg/mlであることを特徴とする、請求項9に記載の溶液製剤。
- さらにトリプトファンを含む、請求項1〜10のいずれかに記載の溶液製剤。
- 粘度が、2〜15mPa・sである、請求項1〜11のいずれかに記載の溶液製剤。
- 溶液製剤が22〜28℃で少なくとも6ヶ月間安定である、請求項1〜12のいずれかに記載の溶液製剤。
- 抗体分子の脱アミド化が抑制されることを特徴とする、請求項1〜13のいずれかに記載の溶液製剤。
- 皮下投与される、請求項1〜14のいずれかに記載の溶液製剤。
- 溶液製剤の製造過程に凍結乾燥工程を含まないで製造される、請求項1〜15のいずれかに記載の溶液製剤。
- 50mg/ml以上のモノクローナルIgG抗体を含有する溶液中にアルギニン40〜1000mM及びメチオニン10〜200mM並びにポリソルベートまたはポロキサマーを添加することを含む、抗体含有溶液製剤における光加速による抗体二量体生成を抑制する方法。
- 溶液が濃度10〜20mM、pH6〜6.5のヒスチジン緩衝液であり、抗体がヒト化抗インターロイキン−6レセプター抗体であり、溶液中のアルギニン濃度が100〜300mM、メチオニン濃度が10〜50mM、抗体濃度が150〜200mg/ml、ポリソルベート80の濃度が0.005〜3%(w/v)となるように各成分を添加することを特徴とする、請求項17に記載の方法。
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