JP6429784B2 - 抗体の高濃度液体製剤の製造方法 - Google Patents
抗体の高濃度液体製剤の製造方法 Download PDFInfo
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- JP6429784B2 JP6429784B2 JP2015538508A JP2015538508A JP6429784B2 JP 6429784 B2 JP6429784 B2 JP 6429784B2 JP 2015538508 A JP2015538508 A JP 2015538508A JP 2015538508 A JP2015538508 A JP 2015538508A JP 6429784 B2 JP6429784 B2 JP 6429784B2
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Description
治療用タンパク質は、薬剤としての規制上の承認のための要求を満たすために、種々の多くの基準、例えば安定性、投与および濃度に関する基準を満たす必要がある。製造、貯蔵および輸送の間に、治療用タンパク質、例えば抗体の化学的および/または物理的な分解が生ずることがあり、それは、その医薬効力の損失をもたらし、かつ副作用、例えば不所望な免疫応答の危険性を高めることがある。
本発明の一態様は、抗体の濃度CHを有する、抗体の高濃度液体製剤の製造方法であって、
a)前記抗体を出発濃度CSで含有する溶液を準備するステップと、
b)ステップ(a)の溶液を限外濾過して、抗体の中間濃度CIを有する溶液を得るステップと、
その際、CIは、少なくとも約260mg/mLである、
c)ステップ(b)の溶液を抗体の濃度CHにまで希釈して、高濃度液体製剤を得るステップと、
を含む製造方法に関する。
a)少なくとも160mg/mLのベルツズマブ抗体またはそのフラグメント、
b)220mMのソルビトール、
c)30mMのヒスチジン、
d)0.2mg/mLのポリソルベート20、
を含み、かつ
5.0〜6.0の範囲の、場合により5.5±0.3のpH値を有する液体医薬製剤に関する。
図1は、上流の透析濾過(DF)ステップを含まない、HCLFを得るための本発明による例示的方法を示している。この例における最終生成物は、5.5のpH値を有し、かつ30mMのヒスチジン(His)を含む。限外濾過(UF)の間のドナン効果を相殺するために、出発材料中で、より高いヒスチジン濃度とより低いpH値を調節できる。いわゆるドナン効果のため、UF膜を通過できる荷電分子は、その膜を通過できないタンパク質の電荷に関する電荷の符号に応じて、溶液中で減少(例えば当該場合において)または濃縮されるかのいずれかである。正電荷を有するヒスチジンの減少は、溶液中のpHシフトを伴う。出発材料として、5g/Lのベルツズマブおよび40mMのヒスチジンを含み、5.45のpH値を有するバルク原薬を使用できる。前記出発材料は、限外濾過ステップにかけられる。限外濾過ステップにおいて、ベルツズマブは、約285g/Lの濃度にまで濃縮される。この濃縮に至った後に、前記限外濾過デバイスを、40mMのヒスチジンを含み、5.45のpHを有する透析濾過緩衝液でフラッシングしてよい。これは、本願に記載される方法によって得られる抗体の収率を最大にしうる。それにより得られた、この例における医薬品プールは、195g/Lのベルツズマブ濃度、5.5のpH値を有し、かつ約30mMのヒスチジンを含む。引き続き、いわゆる10倍ポリソルベート−ソルビトールスパイク緩衝溶液(polysorbate-sorbitol spike buffer solution)という30mMのヒスチジンと、2.2Mのソルビトールと、2g/Lのポリソルベートを含み、5.5のpH値を有する緩衝溶液での更なる希釈ステップを実施してよい。前記ポリソルベート−ソルビトールスパイク緩衝溶液は、最終生成物における所望の濃度のポリソルベートとソルビトールの10倍の濃度を含む。この例における得られる医薬品プールは、175g/Lのベルツズマブ、30mMのヒスチジン、220mMのソルビトール、0.2g/Lのポリソルベート20を含み、かつ5.5のpH値を有する。その後に、所望の濃度への医薬品の最終調整を、いわゆる1倍の製剤緩衝溶液(formulation buffer solution)という30mMのヒスチジンと、220mMのソルビトールと、0.2g/Lのポリソルベート20を含み、5.5のpH値を有する緩衝溶液での希釈を介して行ってよい。前記製剤緩衝溶液は、最終医薬品プールと同様の濃度のポリソルベートおよびソルビトールを含む(すなわち、1倍濃度)。この例における最終医薬品プールは、160g/Lのベルツズマブ、30mMのヒスチジン、220mMのソルビトールおよび0.2g/Lのポリソルベート20を含み、かつ5.5のpH値を有する。
用語「含む」または「含んでいる」が本願明細書および特許請求の範囲で使用される場合に、それは、他の構成要素またはステップを排除しない。本発明の目的のためには、用語「からなる」は、用語「を含んでいる」の任意の一実施形態であると見なされる。この後に、群が、少なくともある特定数の実施形態を含むと定義される場合に、これは、また、任意にこれらの実施形態のみからなる群を開示しているものと理解されるべきである。
本発明は、抗体またはそのフラグメントの高濃度液体製剤(HCLF)の製造方法を提供する。本発明による方法は、HCLFを得ることを可能にし、かつ比較的高収率の抗体を得ることを可能にする。
a)前記抗体を出発濃度CSで含有する溶液を準備するステップと、
b)ステップ(a)の溶液を限外濾過して、抗体の中間濃度CIを有する溶液を得るステップと、
その際、CIは、少なくとも約260mg/mLである、
c)ステップ(b)の溶液を抗体の濃度CHにまで希釈して、高濃度液体製剤を得るステップと、
を含む製造方法を提供する。
a)少なくとも160mg/mLの抗CD20抗体またはそのフラグメント、場合によりベルツズマブ抗体またはそのフラグメント、
b)220mMのソルビトール、
c)30mMのヒスチジン、
d)0.2g/Lのポリソルベート20
を含み、かつ4.8〜7.0の範囲の、特に5.0〜6.0の範囲のpH値を有する。特定の一実施形態においては、前記液体製剤は、5.5±0.3のpH値を有する。もう一つの特定の実施形態においては、前記液体製剤は、5.5±0.2のpH値を有する。
a)少なくとも160mg/mLのベルツズマブ抗体またはそのフラグメント、
b)220mMのソルビトール、
c)30mMのヒスチジン、
d)0.2mg/mLのポリソルベート20、
を含み、かつ
4.8〜7.0の範囲の、特に5.0〜6.0の範囲のpH値を有する。特定の一実施形態においては、前記液体製剤は、5.5±0.3のpH値を有する。場合により、前記液体医薬製剤は、5.5±0.2のpH値を有する。
例1
高濃縮された液体製剤の製造
ベルツズマブのバルク原薬物質を、タンジェンシャルフロー濾過(TFF)を介して最終緩衝液系中に濃縮および透析濾過する。バルク原薬物質の一例は、60g/Lのベルツズマブ、10mMのヒスチジン、120mMのスクロースを、図2に示されるように5.5のpHで含む。次いで、最終バルク原薬物質を、滅菌濾過し、−40℃未満で貯蔵した。
ベルツズマブの高濃縮された液体製剤に関する2種の製剤の比較:製剤A(リン酸塩−クエン酸塩−マンニトール緩衝液)と製剤B(ヒスチジン−ソルビトール緩衝液)
以下の製剤を、25℃で3ヶ月貯蔵した後に比較した。
ヒスチジンとpHに関する製剤最適化
例2に定義される製剤Bは、長期貯蔵条件を使用して最適化した。
ポリソルベート20濃度に関する製剤最適化
一般的に、タンパク質溶液は、機械的応力により不溶性凝集物を形成する傾向にあることが知られている。この現象は、通常は、表面誘起タンパク質分解として説明され、ポリソルベートなどの非イオン性表面活性成分を製剤に導入することによって減らすことができる。
製剤中の種々の抗体濃度の安定性試験
種々の濃度のベルツズマブを、最適化された製剤C(ベルツズマブ160/190/220g/L、ソルビトール40g/L、L−ヒスチジン30mM、pH5.5、ポリソルベート20 0.2g/L)において試験し、そして安定性を、種々の温度および湿度条件下に特定の時間にわたり測定した。
最適化された製剤Cにおけるベルツズマブでの患者の処置
メトトレキセート(MTX)またはメトトレキセートと抗腫瘍壊死因子(抗TNF)の生物学的処置で不十分にしか抑えられていない中程度ないし重度のリウマチ様関節炎(RA)を伴う被験体において、メトトレキセートとの併用治療としての、抗CD20モノクローナル抗体ベルツズマブの3種の異なる皮下(s.c.)投薬とプラセボとを比較する、無作為化二重盲検プラセボ対照多施設多国籍第II相4群並行群間試験が行われる。400の被験体をスクリーニングして、320の適任の被験体を、1:1:1:1の比率で4種の処置群(1群あたり80の被験体)に無作為化させる。
Claims (20)
- 抗体の濃度CHを有する、抗体の高濃度液体製剤の製造方法であって、
a)前記抗体を出発濃度CSで含有する溶液を準備するステップと、
b)ステップ(a)の溶液を限外濾過して、抗体の中間濃度CIを有する溶液を得るステップと、その際、CIは、少なくとも260mg/mLである、
c)ステップ(b)の溶液を、少なくとも155mg/mLの抗体の濃度CHにまで希釈して、高濃度液体製剤を得るステップと、
を含む製造方法であって、
前記抗体がベルツズマブ抗体であり、ステップ(b)で限外濾過にかけられる溶液が、30〜60mMのヒスチジンと少なくとも0.05Mのソルビトールを含む緩衝溶液を含む製造方法。 - 請求項1に記載の方法であって、ステップ(a)の溶液が、更に、アミノ酸である緩衝剤を含有する製造方法。
- 請求項1または2に記載の方法であって、更に、ステップ(a)とステップ(b)との間に、ステップ(a)の溶液を緩衝溶液を用いて透析濾過するステップを含み、その際、前記緩衝剤が、アミノ酸である製造方法。
- 請求項1から3までのいずれか1項に記載の方法であって、ステップ(b)で限外濾過にかけられる溶液が、40mMのヒスチジンを含有し、かつ5.45のpH値を有する製造方法。
- 請求項1から4までのいずれか1項に記載の方法であって、ステップ(b)で限外濾過にかけられる溶液が、界面活性剤を含まない製造方法。
- 請求項1から5までのいずれか1項に記載の方法であって、ステップ(b)は、限外濾過デバイス中で行われ、かつ更に、ステップ(b)とステップ(c)との間に、前記限外濾過デバイスを緩衝溶液でフラッシングするステップを含む製造方法。
- ベルツズマブ抗体またはそのフラグメントを液体医薬製剤中で少なくとも155mg/mLの濃度で安定化させる方法であって、凍結乾燥されていない前記抗体またはそのフラグメントを、ヒスチジンを含む水溶液と合わせることによって行う安定化方法。
- ベルツズマブ抗体またはそのフラグメントの液体医薬製剤であって、少なくとも155mg/mLのベルツズマブ抗体またはそのフラグメントと、ヒスチジンと、ソルビトールとを含み、ヒスチジンの濃度が1mM〜100mM、ソルビトールの濃度が5.5mM〜550mMである液体医薬製剤。
- 請求項8に記載の液体医薬製剤であって、ベルツズマブ抗体またはそのフラグメントの濃度が、少なくとも175mg/mLである液体医薬製剤。
- 請求項8または9に記載の液体医薬製剤であって、ベルツズマブ抗体またはそのフラグメントの濃度が、少なくとも200mg/mLである液体医薬製剤。
- 請求項8に記載の液体医薬製剤であって、ヒスチジンの濃度が、10mM〜60mMの範囲にある液体医薬製剤。
- 請求項8から11までのいずれか1項に記載の液体医薬製剤であって、更に界面活性剤を含む液体医薬製剤。
- 請求項12に記載の液体医薬製剤であって、前記界面活性剤が、ポリソルベートである液体医薬製剤。
- 請求項12または13に記載の液体医薬製剤であって、前記界面活性剤が、少なくとも0.01mg/mLの濃度で存在する液体医薬製剤。
- 請求項8から14までのいずれか1項に記載の液体医薬製剤であって、4.8〜7.0の範囲のpH値を有する液体医薬製剤。
- 請求項8に記載の液体医薬製剤であって、
a)少なくとも160mg/mLのベルツズマブ抗体またはそのフラグメント、
b)220mMのソルビトール、
c)30mMのヒスチジン、
d)0.2mg/mLのポリソルベート20、
を含み、かつ
5.0〜6.0の範囲のpH値を有する液体医薬製剤。 - 医薬品として使用するための、請求項8から16までのいずれか1項に記載の液体医薬製剤。
- 請求項17に記載の液体医薬製剤であって、前記医薬品が皮下投与用の医薬品である液体医薬製剤。
- 癌または非悪性疾患の処置において使用するための、請求項8から18までのいずれか1項に記載の液体医薬製剤。
- 請求項8から19までのいずれか1項に記載の液体医薬製剤であって、バーキットリンパ腫、エプスタイン・バールウイルス感染症、B細胞性白血病、慢性リンパ球性B細胞性白血病、急性リンパ芽球性白血病、リンパ性白血病、前リンパ球性白血病、毛様細胞性白血病、多発性骨髄腫、B細胞性リンパ腫、辺縁帯B細胞性リンパ腫、濾胞性リンパ腫、びまん性大細胞性B細胞性リンパ腫、免疫芽細胞性大細胞性リンパ腫、マントル細胞リンパ腫、非ホジキンリンパ腫、リンパ腫様肉芽腫症、形質細胞腫瘍、前駆リンパ芽球性白血病リンパ腫、腫瘍ウイルス感染症、ヴァルデンストレームマクログロブリン血症、リウマチ様関節炎、免疫増殖疾患、前リンパ球性リンパ腫、リンパ増殖性疾患、パラプロテイン血症、血小板減少性紫斑病、突発性血小板減少性紫斑病(ITP)、血液凝固障害、血小板異常、血液蛋白障害、血液学的疾患、出血性疾患、止血障害、リンパ系疾患、紫斑病、血小板減少症、血栓性細小血管障害、血管疾患、全身性エリテマトーデス(SLE)、多発性硬化症、リウマチ病、若年性リウマチ様関節炎、骨関節症、乾癬の関節炎、乾癬、炎症性腸疾患、クローン病、潰瘍性大腸炎、結合組織病、ヘルペスウイルス感染症、およびDNAウイルス感染症からなる群から選択される疾患の処置において使用するための液体医薬製剤。
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US201261720421P | 2012-10-31 | 2012-10-31 | |
EP12190855.2A EP2727602A1 (en) | 2012-10-31 | 2012-10-31 | Method for preparation of a high concentration liquid formulation of an antibody |
EP12190855.2 | 2012-10-31 | ||
US61/720,421 | 2012-10-31 | ||
PCT/EP2013/072750 WO2014068021A1 (en) | 2012-10-31 | 2013-10-31 | Method for preparation of a high concentration liquid formulation of an antibody |
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EP (2) | EP2727602A1 (ja) |
JP (1) | JP6429784B2 (ja) |
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ES2572919T3 (es) | 2014-05-23 | 2016-06-03 | Ares Trading S.A. | Composición farmacéutica líquida |
EP2946767B1 (en) | 2014-05-23 | 2016-10-05 | Ares Trading S.A. | Liquid pharmaceutical composition |
DK2946765T3 (en) | 2014-05-23 | 2016-10-31 | Ares Trading Sa | Liquid pharmaceutical composition |
MX2017004975A (es) * | 2014-10-18 | 2017-06-30 | Pfizer | Composiciones de anticuerpos anti-il-7r. |
HUP1400510A1 (hu) | 2014-10-28 | 2016-05-30 | Richter Gedeon Nyrt | Gyógyászati TNFalfa ellenes antitest készítmény |
KR20200035496A (ko) * | 2015-09-22 | 2020-04-03 | 화이자 인코포레이티드 | 치료학적 단백질 제형의 제조 방법 및 이러한 방법에 의해 생산된 항체 제형 |
WO2018096445A1 (en) * | 2016-11-22 | 2018-05-31 | Biocon Limited | Stable formulation of recombinant humanized monoclonal antibody |
JP7449243B2 (ja) * | 2018-05-25 | 2024-03-13 | ドクター レディズ ラボラトリーズ リミテッド | 安定な融合タンパク質製剤 |
WO2020006266A1 (en) * | 2018-06-28 | 2020-01-02 | Alexion Pharmaceuticals, Inc. | Methods of producing anti-c5 antibodies |
US11634485B2 (en) | 2019-02-18 | 2023-04-25 | Eli Lilly And Company | Therapeutic antibody formulation |
CN111944046B (zh) * | 2020-08-28 | 2021-04-09 | 江苏荃信生物医药有限公司 | 高浓度、低粘度抗人il-23单克隆抗体溶液的制备方法 |
WO2024098180A1 (en) * | 2022-11-07 | 2024-05-16 | Wuxi Biologics (Hong Kong) Limited | Pharmaceutical compositions comprising anti-human tslp receptor antibodies and methods of using the same |
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CN101914158A (zh) | 2002-02-14 | 2010-12-15 | 免疫医疗公司 | 抗cd 20抗体及其融合蛋白和使用方法 |
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US9415102B2 (en) * | 2002-09-06 | 2016-08-16 | Alexion Pharmaceuticals, Inc. | High concentration formulations of anti-C5 antibodies |
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AU2004229335C1 (en) | 2003-04-04 | 2010-06-17 | Genentech, Inc. | High concentration antibody and protein formulations |
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