JP7432628B2 - 低アセチル化率シアル酸残基を有する糖タンパク質 - Google Patents
低アセチル化率シアル酸残基を有する糖タンパク質 Download PDFInfo
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- JP7432628B2 JP7432628B2 JP2022004857A JP2022004857A JP7432628B2 JP 7432628 B2 JP7432628 B2 JP 7432628B2 JP 2022004857 A JP2022004857 A JP 2022004857A JP 2022004857 A JP2022004857 A JP 2022004857A JP 7432628 B2 JP7432628 B2 JP 7432628B2
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Description
本発明を詳細に説明する前に、本発明は記載された装置の特定の構成部品又は記載された方法の過程工程に限定されず、そのような装置及び方法は変わり得ることを理解されたい。本明細書で使用する用語は、特定の実施形態を説明するためだけのものであり、限定することを意図するものではないことも理解されたい。明細書及び添付の特許請求の範囲で使用される単数形「a」、「an」及び「the」は、文脈が明らかにそうでないことを指示しない限り、単数及び/又は複数の指示対象を含む。さらに、数値で区切られたパラメータ範囲が与えられている場合、その範囲はこれらの制限値を含むと見なされることを理解されたい。
a)前記糖タンパク質のグリカン中のシアル酸残基の脱アセチル化
b)アセチル化シアル酸残基の減少をもたらす、前記糖タンパク質の全体的なグリコシル化の低減、
c)脱アセチル化若しくは非アセチル化シアル酸残基又は低アセチル化率シアル酸残基を有する糖タンパク質を発現することができる発現細胞株の使用、
d)脱グリコシル化されているか、又はグリコシル化が低減されている糖タンパク質を発現することができる発現細胞株の使用、
e)前記糖タンパク質のグリカン中のシアル酸含有量の減少、
f)低減したシアル酸の量が低減した、又はシアル酸を含まない糖タンパク質を発現することができる発現細胞株の使用。
したがって、本明細書に開示されている教示に基づいて、それぞれの生物、及び他の発現細胞株中のそれぞれのアセチルトランスフェラーゼをサイレンシングさせる、欠失させる又は変異させることは、当業者の慣用的な作業である。
・エポエチンα(Epogen(R)、ESPO(R)、Procrit(R)、Eprex(R)、Erypo(R)、Epoxitin(R)、Globuren(R)、Epopen(R)、Epoglobin(R)、Epox(R)、Eritrogen(R))
・エポエチン-β(NeoRecormon(R)、Epogin(R))
・ダルベポエチンα(アラネスプ(R)、Nespo(R))
・CERA(持続性赤血球生成受容体活性化剤(Continuous Erythropoiesis Receptor Activator))
・ErepoXen(R)
・Albupoetin(R)
・PT-401
・Epo-Fc
・CEPO(カルバミル化EPO)
・MOD-7023
・エポエチンδ(DynEpo(R))
・GO-EPO
・MK2578。
a)絶対アセチル化率≦10%、及び/又は
b)アセチル化率の50%以上の低下。
・酵素的(ノイラミニダーゼを用いる)又は化学的手法(弱酸による加水分解)を用いた糖タンパク質又は単離されたグリカンからのグリコシド結合切断後のシアル酸の相対定量
・1,2-ジアミノ-4,5-メチレンジオキシベンゼン(DMB)によるシアル酸の誘導体化とそれに続く蛍光検出高速液体クロマトグラフィー
・ペルトリメチルシリル化と、それに続くGLC(気液クロマトグラフィー)-MS
・薄層クロマトグラフィー(ラジオTLC又は濃度定量)。
・貧血
・AIDS及びがんに関連した疾患、及び化学療法などの関連療法の望ましくない結果、並びに
・低酸素症候群。
・造血幹細胞移植
・集中治療、
・例えば自己献血のための、手術前後の赤血球生成促進の必要性。
a)脱アセチル化若しくは非アセチル化シアル酸残基若しくは低アセチル化率シアル酸残基を有する糖タンパク質を発現することができ、かつ/又は
b)脱グリコシル化されているか、若しくはグリコシル化が低減している糖タンパク質を発現することができる、
細胞が提供される。
a)シアル酸アセチル化を触媒する酵素をコードする遺伝子の遺伝子発現の阻害又は減少、
b)シアル酸アセチル化を触媒する機能が不全であるか若しくは不活性な酵素の発現、又は活性が低下したシアル酸アセチル化を触媒する酵素の発現、
c)シアル酸アセチル化を触媒する酵素の活性の阻害又は低下、及び/又は
d)シアル酸残基の脱アセチル化を触媒する酵素をコードする遺伝子の異種発現又は同種過剰発現。
・N-アセチルノイラミン酸7-O(又は9-O)-アセチルトランスフェラーゼ(EC 2.3.1.45)
・ポリシアル酸O-アセチルトランスフェラーゼ(EC 2.3.1.136)
・シアル酸O-アセチルトランスフェラーゼ(neuDファミリー)
・α-N-アセチルノイラミニドα-2,8-シアルトランスフェラーゼ1(GD3合成酵素)
・ヒトシアル酸-O-アセチルトランスフェラーゼ(CasD1)。
アセチル-CoA+N-アセチルノイラミン酸 → CoA+N-アセチル-7-O(又は9-O)-アセチルノイラミン酸
アセチル-CoA+シアル酸のα-2,8結合ポリマー → CoA+O-7又はO-9でアセチル化されたポリシアル酸。
・シアル酸-9-O-アセチルエステラーゼ(EC 3.1.1.53)
・9-O-アセチルN-アセチルノイラミン酸エステラーゼ
・血球凝集素エステラーゼ
・サイトゾルシアル酸9-O-アセチルエステラーゼ。
N-アセチル-O-アセチルノイラミン酸+H2O → N-アセチルノイラミン酸+酢酸
・遺伝子サイレンシング
・遺伝子ノックダウン
・遺伝子ノックアウト
・ドミナントネガティブ構築物の送達
・コンディショナル遺伝子ノックアウト、及び/又は
・シアル酸アセチル化又はシアル酸残基の脱アセチル化を触媒する酵素をコードする遺伝子に関する遺伝子改変。
a)EpoRに対して異種的に発現されたアゴニストの酵素的脱O-アセチル化が所与の改変された有効性を有するという知見
b)異なる細胞発現系においてO-アセチル化又は脱O-アセチル化を触媒する例示的な酵素の開示
c)損傷若しくは欠損のある同種酵素を有するか、又は異種酵素を発現するか、又は同種酵素を過剰発現するかのいずれかを有する発現細胞株の作製を可能にする当業者に利用可能な技術の列挙。
・ベビーハムスター腎臓細胞(例えば、BHK21)
・チャイニーズハムスター卵巣細胞(例えば、CHO-K1、CHO-DG44、CHO-DXB又はCHO-dhf)
・マウス骨髄腫細胞(例えば、SP2/0又はNSO)
・ヒト胎児腎臓細胞(例えば、HEK-293)
・ヒト網膜由来細胞(例えば、PER-C6)並びに
・羊膜細胞(例えば、CAP)。
明細書を過度に長くすることなく包括的な開示を提供するために、本出願人は、上記で参照した特許及び特許出願のそれぞれを参照により本明細書に組み入れる。
本発明の目的のさらなる詳細、特徴、特性及び利点は、従属請求項、並びにそれぞれの図及び実施例の以下の説明に開示されており、それらは例示的な様式で本発明の好ましい実施形態を示す。しかし、これらの図面は、決して本発明の範囲を限定するものとして理解されるべきではない。
糖タンパク質生物製剤の薬物動態に対する糖構造の完全除去の効果
最初の研究では、糖タンパク質生物製剤の薬物動態に対する糖構造の完全除去の効果を調べた。この実験には、グリコシル化IgG1型モノクローナル抗体を使用した。抗体のFcドメインのガラクトシル化が、エフェクター細胞の効率的な動員のための役割を果たすといういくつかの証拠があるが、薬物動態学などの残りの特徴についてのグリコシル化それ自体の役割、特にシアル酸のシアル化及びO-アセチル化の役割についてはあまり理解されていない。
異なるシアル酸O-アセチル化率を有する異なるバッチの糖タンパク質生物製剤のバイオアベイラビリティの違い
異なるレベルのO-アセチル化を有する2種のバッチのCTLA-FC融合タンパク質アバタセプト(Orencia(R))が単回皮下投与時のそれらの曝露/バイオアベイラビリティにおいて異なるかどうかを試験した。それぞれのジ-O-アセチル化率は、バッチ番号1では11.4%、バッチ番号2では6.5%であった。トリ-O-アセチル化シアル酸は観察されなかった。
曝露/バイオアベイラビリティに対するシアル酸O-アセチル化率低下の影響
この実施例では、選択された糖タンパク質生物製剤のO-アセチル化率と曝露/バイオアベイラビリティとの間の因果関係を調査した。
O-アセチル化レベルの低下したシアル酸によるESAの有効性の増大
赤血球生成促進剤の典型的な例として、Aranesp(R)(ダルベポエチンアルファ)を選択した。Aranesp(R)は高度にシアル化されており、同様にO-アセチル化シアル酸を担持している。ヒトについて得られる結果に対する優れた予測性のため、ラットをモデルとして選択した。注射経路として、臨床実践の典型的な経路を代表する皮下注射をこの場合もまた選択した。用量範囲も同様に、臨床実践に従うように選択した。
Claims (4)
- 低O-アセチル化率シアル酸残基を含む、エリスロポエチン、修飾エリスロポエチン又はエリスロポエチン模倣物からなる群から選択される赤血球生成促進剤(ESA)を含む、低平均赤血球ヘモグロビン(MCH)に関連する状態を治療するための医薬組成物であって、前記低O-アセチル化率が、50%以上低下した絶対アセチル化率を指す、医薬組成物。
- 上記状態が、正常な赤血球(RBC)数であるが低ヘモグロビン(Hb)に関連する状態である、請求項1に記載の医薬組成物。
- 前記状態が、低色素性貧血である、請求項1に記載の医薬組成物。
- 薬学的に許容される担体をさらに含む、請求項1~3のいずれか一項に記載の医薬組成物。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005507426A (ja) | 2001-10-29 | 2005-03-17 | クルセル ホランド ベー ヴェー | 所定の翻訳後修飾を有する蛋白質の製造方法及び製造手段 |
JP2005530678A (ja) | 2001-11-28 | 2005-10-13 | オーソーマクニール ファーマシューティカル, インコーポレイテッド | 貧血治療用のエリスロポエチン投与療法 |
WO2007083683A1 (ja) | 2006-01-18 | 2007-07-26 | Chugai Seiyaku Kabushiki Kaisha | シアル酸の除去方法及びアシアロエリスロポエチンの製造方法 |
JP2010031017A (ja) | 2000-12-29 | 2010-02-12 | Kenneth S Warren Inst Inc | エリスロポエチン応答性細胞、組織及び器官の保護、回復ならびに増強 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH03151399A (ja) * | 1989-11-07 | 1991-06-27 | Snow Brand Milk Prod Co Ltd | 変異ヒトエリスロポエチン |
WO2007105305A1 (ja) * | 2006-03-14 | 2007-09-20 | Japan Tobacco Inc. | 新規なβ-ガラクトシド-α2,6-シアル酸転移酵素、それをコードする遺伝子およびその製造方法 |
CN101456911A (zh) | 2007-12-12 | 2009-06-17 | 江苏豪森药业股份有限公司 | 促红细胞生成素模拟肽衍生物及其可药用盐和其制备方法与用途 |
DK2331701T3 (da) * | 2008-08-08 | 2013-06-24 | Vib Vzw | Celler, der danner glycoproteiner med ændrede glycosyleringsmønstre og fremgangsmåder dermed og anvendelse deraf |
US20120045816A1 (en) | 2008-09-09 | 2012-02-23 | Sialix, Inc. | Novel Glycosylated Polypeptides |
EP2325296A1 (en) * | 2009-11-20 | 2011-05-25 | LEK Pharmaceuticals d.d. | Production of glycoproteins with low N-glycolylneuraminic acid (Neu5Gc) content |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010031017A (ja) | 2000-12-29 | 2010-02-12 | Kenneth S Warren Inst Inc | エリスロポエチン応答性細胞、組織及び器官の保護、回復ならびに増強 |
JP2005507426A (ja) | 2001-10-29 | 2005-03-17 | クルセル ホランド ベー ヴェー | 所定の翻訳後修飾を有する蛋白質の製造方法及び製造手段 |
JP2005530678A (ja) | 2001-11-28 | 2005-10-13 | オーソーマクニール ファーマシューティカル, インコーポレイテッド | 貧血治療用のエリスロポエチン投与療法 |
WO2007083683A1 (ja) | 2006-01-18 | 2007-07-26 | Chugai Seiyaku Kabushiki Kaisha | シアル酸の除去方法及びアシアロエリスロポエチンの製造方法 |
Non-Patent Citations (3)
Title |
---|
Molecular Pharmaceutics (2011) Vol.8, No.1, pp.286-296 |
NDT Plus (2009) Vol.2, Suppl.1, pp.i9-i17 |
Trends in Analytical Chemistry (2015) Vol.68, pp.18-27 |
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EP3484910B1 (en) | 2023-06-07 |
US20190177385A1 (en) | 2019-06-13 |
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CN109415426B (zh) | 2022-03-11 |
AU2017297767A1 (en) | 2019-01-03 |
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JP2019532618A (ja) | 2019-11-14 |
KR20190026840A (ko) | 2019-03-13 |
KR20230048469A (ko) | 2023-04-11 |
CA3026863A1 (en) | 2018-01-18 |
WO2018011302A1 (en) | 2018-01-18 |
AU2017297767B2 (en) | 2021-09-09 |
ZA201808275B (en) | 2019-07-31 |
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BR112019000549A2 (pt) | 2019-05-21 |
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