JP2020508331A - 安定化された抗体溶液 - Google Patents
安定化された抗体溶液 Download PDFInfo
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- JP2020508331A JP2020508331A JP2019546176A JP2019546176A JP2020508331A JP 2020508331 A JP2020508331 A JP 2020508331A JP 2019546176 A JP2019546176 A JP 2019546176A JP 2019546176 A JP2019546176 A JP 2019546176A JP 2020508331 A JP2020508331 A JP 2020508331A
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- aqueous solution
- antibody
- antibody protein
- use according
- protein
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/241—Tumor Necrosis Factors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/55—Fab or Fab'
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/32—Fusion polypeptide fusions with soluble part of a cell surface receptor, "decoy receptors"
Abstract
Description
水性溶液として製剤化されたとき、抗体タンパク質は、貯蔵時に構造的分解を起こしやすい。タンパク質分解に関与するプロセスは、物理的なもの(例えば、四次、三次、又は二次構造の喪失、凝集、粒子形成)と化学的なもの(すなわち、共有結合的変化を伴うプロセス、例えば、脱アミド化、アスパラギン酸異性化、酸化、加水分解的クリッピングなど)に分けることができる。分解物(例えば、可溶性凝集種、不溶性凝集種、及び化学修飾変種)の各々は、抗体タンパク質の生物学的活性、毒性、又は免疫原性に影響を及ぼし得る。
本発明は、抗体タンパク質の不安定性の問題に対処する。一実施態様において、本発明は、抗体タンパク質と、(i)多価陰イオンであるキレート剤;及び(ii)C3ポリオールの安定化混合物とを含む水性溶液に関連する。一実施態様において、本発明は、水性溶液中の抗体タンパク質を貯蔵に対して安定化する方法であって、該溶液に、(i)多価陰イオンであるキレート剤;及び(ii)C3ポリオールの混合物を添加する工程を含む、方法を提供する。
本発明は、抗体タンパク質の水性溶液を多価陰イオンであるキレート剤及びC3ポリオールの混合物によって安定化することができるという発見に関する。
(略語)
(材料)
EDTA二ナトリウム塩(Mw 372Da)、1,2-プロパンジオール(Mw 76Da)、グリセロール(Mw 92Da)、マンニトール(Mw 182Da)、NaCl(Mw 58Da)、トレハロース(Mw 342Da)をSigma Aldrichから入手した。
(a)視覚的評価
可視粒子を、好適には、2.9.20.欧州薬局方各条(微粒子汚染:可視粒子(Particulate Contamination: Visible Particles))を用いて検出する。必要とされる装置は、以下のものを含むビューイングステーションからなる:
・垂直位置に保持された適当なサイズの艶消し黒色パネル
・黒色パネルの隣に垂直位置に保持された適当なサイズの反射防止白色パネル
・好適な笠付白色光源及び好適な散光器が装着された調整可能なランプホルダー(各々長さ525mmの2本の13W蛍光管を含むビューイングイルミネーターが好適である)。ビューイングポイントにおける照明の強度は、2000ルクス〜3750ルクスに維持される。
視覚的スコア1:粒子をほとんど含まない透明な溶液
視覚的スコア2:〜5個の非常に小さい粒子
視覚的スコア3:〜10から20個の非常に小さい粒子
視覚的スコア4:巨大粒子を含む20〜50個の粒子
視覚的スコア5:巨大粒子を含む>50個の粒子
高分子量種の量は、ガードカラムを備えた300×7.8mmのS3000(又は同等の)サイズ排除カラムを用いて測定される。移動相は、リン酸カリウムpH 6.5であり、流速は0.4ml/分であり、注入量は1μlであり、210nm及び280nmで検出される。結果は、%高分子種(HMWS)、すなわち、クロマトグラム上の全てのタンパク質関連ピークの和に対する凝集タンパク質に対応する全てのピーク面積の和として表される。%HMWSの絶対値に関しては、例えば、サイズ排除カラムの反復使用が原因で、時点間のわずかなばらつきが観察されることがある。しかしながら、所与の時点内で、試料は、同じ条件下のカラムを用いて試験されるので、その時点内で得られた値は、試験された水性溶液中のタンパク質の相対的安定性の非常に良い指標となる。
関連種の量は、Protein-Pak Hi Res SPカラムを用いて測定される。移動相Aは、20mMリン酸ナトリウム(pH 6.5)であり;移動相Bは、20mMリン酸ナトリウム+0.5M NaCl(pH 6.0)である。以下の勾配溶出が使用される: 0分-100%A、4分-80%A、10分-55%A、12分-0%A。1.0ml/分の流速;注入量は3μlであり、UV検出は214nmで行われる。結果は、%主ピーク(すなわち、ネイティブタンパク質)、%酸性種、及び%塩基性種として表される。%関連種=%酸性種+%塩基性種。
アバタセプト(125mg/ml)の安定性に対するEDTA及びC3ポリオールの効果を調べた。この効果を、リン酸ナトリウム(5mM)及びポリソルベート80(0.5mg/ml)を含有するバックグラウンド溶液中で試験した。試験される全ての製剤をpH 6.5に調整した。試験された製剤中のさらなる賦形剤を表1に示す。
表1:試験されたアバタセプトの製剤中のさらなる成分。製剤は全て、アバタセプト(125mg/ml)、リン酸ナトリウム(5mM)、及びポリソルベート80(0.5mg/ml)を含有し、pH 6.5に調整された。
表2: 25℃及び40℃で貯蔵した後のアバタセプト製剤1〜12の視覚的スコア。視覚的スコア1:粒子をほとんど含まない透明な溶液;視覚的スコア2:〜5個の非常に小さい粒子;視覚的スコア3:〜10から20個の非常に小さい粒子;視覚的スコア4:巨大粒子を含む20〜50個の粒子;視覚的スコア5:巨大粒子を含む>50個の粒子
ベバシズマブ(25mg/ml)の安定性に対するEDTA及びポリオールの効果を40℃で調べた。この効果を、リン酸ナトリウム(5mM)及びポリソルベート20(0.4mg/ml)を含有するバックグラウンド溶液中で試験した。試験される全ての製剤をpH 6.2に調整した。試験された製剤中のさらなる賦形剤を表4に示す。安定性を現在市販されているベバシズマブ製品(Avastin(登録商標))の組成物とも比較した。
表4:試験されたアバタセプトの製剤中のさらなる成分。製剤は全て、ベバシズマブ(25mg/ml)及びポリソルベート20(0.5mg/ml)を含有し、pH 6.2に調整された。
表5: 40℃で貯蔵した後のベバシズマブ製剤1〜9の視覚的スコア。視覚的スコア1:粒子をほとんど含まない透明な溶液;視覚的スコア2:〜5個の非常に小さい粒子;視覚的スコア3:〜10から20個の非常に小さい粒子;視覚的スコア4:巨大粒子を含む20〜50個の粒子;視覚的スコア5:巨大粒子を含む>50個の粒子。
Claims (52)
- 抗体タンパク質と、(i)多価陰イオンであるキレート剤;及び(ii)C3ポリオールの安定化混合物とを含む、水性溶液。
- 水性溶液中の抗体タンパク質を貯蔵に対して安定化する方法であって、該溶液に、(i)多価陰イオンであるキレート剤;及び(ii)C3ポリオールの混合物を添加する工程を含む、前記方法。
- 水性溶液中の抗体タンパク質を貯蔵に対して安定化するための、(i)多価陰イオンであるキレート剤;及び(ii)C3ポリオールの混合物の使用。
- 前記キレート剤が4つのイオン中心を有するキレートイオンである、請求項1記載の水性溶液、請求項2記載の方法、又は請求項3記載の使用。
- 前記多価陰イオンであるキレート剤がEDTAである、請求項1〜4のいずれか一項記載の水性溶液、方法、又は使用。
- 前記多価陰イオンであるキレート剤が、約0.1mM〜約50mM、例えば、約0.1mM〜約20mM、例えば、約0.1mM〜約10mMの濃度で存在する、請求項1〜5のいずれか一項記載の水性溶液、方法、又は使用。
- 前記C3ポリオールが1,2-プロパンジオールである、請求項1〜6のいずれか一項記載の水性溶液、方法、又は使用。
- 前記C3ポリオールがグリセロールである、請求項1〜6のいずれか一項記載の水性溶液、方法、又は使用。
- 前記C3ポリオールが1,2-プロパンジオールとグリセロールの混合物である、請求項1〜6のいずれか一項記載の水性溶液、方法、又は使用。
- 前記C3ポリオールが、約100mM〜約500mM、例えば、約150mM〜約400mM、又は約150mM〜約300mMの濃度で存在する、請求項1〜9のいずれか一項記載の水性溶液、方法、又は使用。
- 前記抗体タンパク質が治療的抗体タンパク質である、請求項1〜10のいずれか一項記載の水性溶液、方法、又は使用。
- 前記抗体タンパク質が、抗体、抗体断片、活性部分にコンジュゲートされた抗体、1以上の抗体断片を含む融合タンパク質、又は前述のもののいずれかの誘導体である、請求項1〜11のいずれか一項記載の水性溶液、方法、又は使用。
- 前記抗体タンパク質がモノクローナル抗体である、請求項12記載の水性溶液、方法、又は使用。
- 前記モノクローナル抗体が、マウス抗体、キメラ抗体、ヒト化抗体、又はヒト抗体である、請求項13記載の水性溶液、方法、又は使用。
- 前記モノクローナル抗体が、トラスツズマブ、リツキシマブ、ベバシズマブ、セツキシマブ、及びイピリムマブから選択される、請求項13記載の水性溶液、方法、又は使用。
- 前記モノクローナル抗体がベバシズマブである、請求項15記載の水性溶液、方法、又は使用。
- 前記抗体タンパク質が1以上の免疫グロブリンFc断片に融合された活性タンパク質ドメインを含む融合タンパク質である、請求項12記載の水性溶液、方法、又は使用。
- 前記抗体タンパク質が、エタネルセプト、アバタセプト、又はベラタセプトである、請求項12記載の水性溶液、方法、又は使用。
- 前記誘導体が1以上の抗体又は抗体断片及び化学的に不活性なポリマーを含む、コンジュゲートされた誘導体である、請求項12記載の水性溶液、方法、又は使用。
- 前記コンジュゲートされた誘導体がセルトリズマブペゴールである、請求項19記載の水性溶液、方法、又は使用。
- 前記抗体タンパク質が、約1mg/mL〜約300mg/mL、例えば、約10mg/mL〜約300mg/mL、約1mg/mL〜約200mg/mL、又は約10mg/mL〜約200mg/mLの濃度で存在する、請求項1〜20のいずれか一項記載の水性溶液、方法、又は使用。
- 前記溶液のpHが、約pH 4.0〜約pH 8.0、例えば、約pH 5.0〜約pH 7.0又は約pH 5.0〜約pH 6.5である、請求項1〜21のいずれか一項記載の水性溶液、方法、又は使用。
- 緩衝剤をさらに含む、請求項1〜22のいずれか一項記載の水性溶液、方法、又は使用。
- 前記緩衝剤が、ヒスチジン、コハク酸塩、マレイン酸塩、酢酸塩、リン酸塩、及びTRISからなる群から選択される、請求項23記載の水性溶液、方法、又は使用。
- 前記緩衝剤が、約0.5mM〜約50mM、例えば、約1mM〜約20mM、例えば、約2mM〜約5mMの濃度で存在する、請求項23又は請求項24記載の水性溶液、方法、又は使用。
- 非イオン性界面活性剤をさらに含む、請求項1〜25のいずれか一項記載の水性溶液、方法、又は使用。
- 前記非イオン性界面活性剤が、アルキルグリコシド、例えば、ドデシルマルトシドである、請求項26記載の水性溶液、方法、又は使用。
- 前記非イオン性界面活性剤が、ポリソルベート界面活性剤、例えば、ポリソルベート80又はポリソルベート20である、請求項26記載の水性溶液、方法、又は使用。
- 前記非イオン性界面活性剤がポリエチレングリコールのアルキルエーテルである、請求項26記載の水性溶液、方法、又は使用。
- 前記ポリエチレングリコールのアルキルエーテルが、ポリエチレングリコール(2)ドデシルエーテル、ポリエチレングリコール(2)オレイルエーテル、及びポリエチレングリコール(2)ヘキサデシルエーテルから選択される、請求項29記載の水性溶液、方法、又は使用。
- 前記非イオン性界面活性剤が、ポリエチレングリコールとポリプロピレングリコールのブロックコポリマー、例えば、ポロキサマー188、ポロキサマー407、ポロキサマー171、又はポロキサマー185である、請求項26記載の水性溶液、方法、又は使用。
- 前記非イオン性界面活性剤が、ポリエチレングリコールのアルキルフェニルエーテル、例えば、4-(1,1,3,3-テトラメチルブチル)フェニル-ポリエチレングリコールである、請求項26記載の水性溶液、方法、又は使用。
- 前記非イオン性界面活性剤が、約10μg/mL〜約2000μg/mL、例えば、約50μg/mL〜約1000μg/mL、例えば、約100μg/mL〜約500μg/mLの濃度で存在する、請求項26〜32のいずれか一項記載の水性溶液、方法、又は使用。
- 非荷電性浸透圧調節剤、例えば、スクロース、トレハロース、マンニトール、ソルビトール、PEG300、又はPEG400をさらに含む、請求項1〜33のいずれか一項記載の水性溶液、方法、又は使用。
- 前記非荷電性浸透圧調節剤が、50mM〜約1000mM、例えば、約100mM〜約500mM、例えば、約300mMの濃度で存在する、請求項34記載の水性溶液、方法、又は使用。
- 例えば、塩化ナトリウム、硫酸ナトリウム、酢酸ナトリウム、乳酸ナトリウム、グリシン、ヒスチジン、及びアルギニンからなる群から選択される、荷電性浸透圧調節剤をさらに含む、請求項1〜35のいずれか一項記載の水性溶液、方法、又は使用。
- 前記荷電性浸透圧調節剤が、約25mM〜約500mM、例えば、約50mM〜約250mM、例えば、約150mMの濃度で存在する、請求項36記載の水性溶液、方法、又は使用。
- 前記水性溶液が等張である、請求項1〜37のいずれか一項記載の水性溶液、方法、又は使用。
- 防腐剤をさらに含む、請求項1〜38のいずれか一項記載の水性溶液、方法、又は使用。
- 前記防腐剤が、フェノール、m-クレゾール、クロロクレゾール、ベンジルアルコール、プロピルパラベン、メチルパラベン、塩化ベンザルコニウム、及び塩化ベンゼトニウムからなる群から選択される、請求項39記載の水性溶液、方法、又は使用。
- 前記防腐剤が約0.01mM〜約100mMの濃度で存在する、請求項39又は請求項40記載の水性溶液、方法、又は使用。
- 前記抗体タンパク質を安定化する方法が貯蔵時の該抗体タンパク質の高分子量種の形成を阻害する方法である、請求項2又は請求項4〜41のいずれか一項記載の方法。
- 前記抗体タンパク質を安定化する方法が貯蔵時の該抗体タンパク質の関連種の形成を阻害する方法である、請求項2又は請求項4〜41のいずれか一項記載の方法。
- 前記抗体タンパク質を安定化する方法が貯蔵時の該抗体タンパク質の脱アミド化を阻害する方法である、請求項2又は請求項4〜41のいずれか一項記載の方法。
- 前記抗体タンパク質を安定化する方法が貯蔵時の前記水性溶液中の低分子量分解産物の形成を阻害する方法である、請求項2又は請求項4〜41のいずれか一項記載の方法。
- 前記抗体タンパク質を安定化する方法が貯蔵時の該抗体タンパク質の組成物中での可視粒子の形成を阻害する方法である、請求項2又は請求項4〜41のいずれか一項記載の方法。
- 貯蔵時の前記抗体タンパク質の高分子量種の形成を阻害するための、請求項3〜41のいずれか一項記載の使用。
- 貯蔵時の前記抗体タンパク質の関連種の形成を阻害するための、請求項3〜41のいずれか一項記載の使用。
- 貯蔵時の前記抗体タンパク質の脱アミド化を阻害するための、請求項3〜41のいずれか一項記載の使用。
- 貯蔵時の前記抗体タンパク質の低分子量分解産物の形成を阻害するための、請求項3〜41のいずれか一項記載の使用。
- 貯蔵時の前記抗体タンパク質の組成物中での可視粒子の形成を阻害するための、請求項3〜41のいずれか一項記載の使用。
- 前記溶液が、皮下もしくは筋肉内への注射によるか又は静脈内への注射もしくは注入による投与のためのものである、請求項1又は請求項4〜41のいずれか一項記載の水性溶液。
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US11608357B2 (en) | 2018-08-28 | 2023-03-21 | Arecor Limited | Stabilized antibody protein solutions |
EP3372242A1 (en) | 2017-03-06 | 2018-09-12 | Ares Trading S.A. | Liquid pharmaceutical composition |
EP3372241A1 (en) | 2017-03-06 | 2018-09-12 | Ares Trading S.A. | Liquid pharmaceutical composition |
BR112021015034A2 (pt) | 2019-02-18 | 2021-10-05 | Eli Lilly And Company | Formulação de anticorpo terapêutico |
CN112618482A (zh) * | 2019-09-24 | 2021-04-09 | 江苏恒瑞医药股份有限公司 | 新型蛋白制剂 |
CN111665352A (zh) * | 2020-06-23 | 2020-09-15 | 广州市丹蓝生物科技有限公司 | 一种储存剂及由其制备的抗体溶液制剂及其应用 |
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JP2006502116A (ja) * | 2002-07-12 | 2006-01-19 | メダレックス, インク. | タンパク質の酸化分解を防ぐ方法及び組成物 |
US20130209465A1 (en) * | 2010-07-30 | 2013-08-15 | Arecor Ltd. | Stabilized Aqueous Antibody Compositions |
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CA2466034C (en) * | 2001-11-08 | 2012-12-18 | Protein Design Labs, Inc. | Stable aqueous pharmaceutical formulations of daclizumab antibodies |
WO2006096488A2 (en) | 2005-03-08 | 2006-09-14 | Pharmacia & Upjohn Company Llc | Composition comprising human igg2 antibody and chelating agent |
CL2007002880A1 (es) * | 2006-10-06 | 2008-05-09 | Amgen Inc | Formulacion estable que comprende un tampon de acido acetico, un tampon de acido glutamico o un tampon de acido succinico con un ph de 4,5 a 7, por lo menos un excipiente que comprende un azucar o un poliol, y un anticuerpo anti-receptor del factor d |
WO2008051363A2 (en) * | 2006-10-20 | 2008-05-02 | Amgen Inc. | Stable polypeptide formulations |
GB0700523D0 (en) | 2007-01-11 | 2007-02-21 | Insense Ltd | The Stabilisation Of Proteins |
CN102301235B (zh) | 2008-11-28 | 2014-11-19 | Abbvie公司 | 稳定的抗体组合物和用于稳定其的方法 |
GB2499015A (en) | 2012-02-03 | 2013-08-07 | Reckitt Benckiser Nv | Detergent dispensing device. |
GB201612317D0 (en) * | 2016-07-15 | 2016-08-31 | Philogen Spa | Antibody compositions |
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2018
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JP2006502116A (ja) * | 2002-07-12 | 2006-01-19 | メダレックス, インク. | タンパク質の酸化分解を防ぐ方法及び組成物 |
US20130209465A1 (en) * | 2010-07-30 | 2013-08-15 | Arecor Ltd. | Stabilized Aqueous Antibody Compositions |
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US20200023061A1 (en) | 2020-01-23 |
GB201703062D0 (en) | 2017-04-12 |
JP2023071755A (ja) | 2023-05-23 |
EP3585360A1 (en) | 2020-01-01 |
WO2018154320A1 (en) | 2018-08-30 |
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