JP2020090523A - 組換えボツリヌス菌神経毒の生産 - Google Patents
組換えボツリヌス菌神経毒の生産 Download PDFInfo
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Abstract
Description
a)可溶性単鎖BoNT/Aタンパク質を提供するステップと、
b)溶液中で、前記BoNT/Aタンパク質を、エンドプロテアーゼLys-C(Lys-C)と接触させるステップと、
c)可溶性BoNT/Aタンパク質およびLys-Cを含有する溶液を、疎水性表面と接触させ、ここで、可溶性BoNT/Aタンパク質が疎水性表面と優先的に結合することによって、Lys-Cから可溶性BoNT/Aタンパク質を分離するステップと、
を含む前記方法を提供する。
・A1亜血清型:UniParc受託番号UPI0000ED909E(UniProt受託番号P10845、バージョン159)、UniParc受託番号UPI0000EF85BD(UniProt受託番号S8B1U4、バージョン3またはUniProt受託番号A2I2R4、バージョン41)、UniParc受託番号UPI0001A954C8(UniProt受託番号C6K838、バージョン11)、UniParc受託番号UPI0000001386(UniProt受託番号A5HZZ9、バージョン57)、UniParc受託番号UPI000003409D(UniProt受託番号A2I2U2、バージョン36)、UniParc受託番号UPI00016529B7(UniProt受託番号B1A2D5、バージョン21)、UniParc受託番号UPI00027EE164(UniProt受託番号J7FGZ9、バージョン6);
・A2亜血清型:UniParc受託番号UPI0000EF84BD(UniProt受託番号A2I2R5、バージョン28)、UniParc受託番号UPI0001C0B376(UniProt受託番号D2KCK3、バージョン15)、UniParc受託番号UPI0001C32E84(UniProt受託番号D3IV23、バージョン10)、UniParc受託番号UPI0001F3B30D(UniProt受託番号E5F1I1、バージョン11)、UniParc受託番号UPI000016EA88(UniProt受託番号Q45894、バージョン116またはUniProt受託番号Q58GH1、バージョン51)、UniParc受託番号UPI000067C53E(UniProt受託番号Q2PPK6、バージョン33)、UniParc受託番号UPI000290BEB1(UniProt受託番号K4GGE0、バージョン6);
・A3亜血清型:UniParc受託番号UPI00005B712C(UniProt受託番号 Q3LRX9、バージョン38)、UniParc受託番号UPI00016DBC11(UniProt受託番号 B1L2G5、バージョン38またはUniProt受託番号D3IV24、バージョン11)、UniParc受託番号UPI000290C3D0(UniProt受託番号K4G3L3、バージョン7);
・A4亜血清型:UniParc受託番号UPI00005B712D(UniProt受託番号Q3LRX8、バージョン35)、UniParc受託番号UPI00019DB885(UniProt受託番号C3KS13、バージョン29);
・A5亜血清型:UniParc受託番号UPI0001AE7D6A(UniProt受託番号C7BEA8、バージョン14)、UniParc受託番号UPI000198BDAE(UniProt受託番号E8ZMW0、バージョン18またはUniProt受託番号C1IPK2、バージョン20);または
・A6亜血清型:UniParc受託番号UPI0001B7D251(UniProt受託番号C9WWY7、バージョン13)、
・A7亜血清型:UniParc受託番号UPI000290B995(UniProt受託番号K4LN57)、
・A8亜血清型:UniParc受託番号UPI000559A469(UniProt受託番号A0A0A7PDB7)、UniParc受託番号UPI0003C9D2A1(UniProt受託番号 V5N8R1)。
(a)上記のような活性な二本鎖BoNT/Aタンパク質と、
(b)安定化剤と
を含む、固体または液体医薬組成物を提供する。
(a)上記のような、活性な二本鎖BoNT/Aタンパク質と、
(b)界面活性剤である非タンパク質安定化剤と、
(c)水と
を含む液体医薬組成物であり、
ここで、前記液体医薬組成物は、タンパク質安定化剤を含まず、
前記液体医薬組成物は、Lys-Cを実質的に含まず、「Lys-Cを実質的に含まない」とは、本明細書において定義される通りである(例えば、前記液体医薬組成物は、100ngのBoNT/Aタンパク質あたり400pg未満のLys-C、100ngのBoNT/Aタンパク質あたり300pg未満のLys-C、100ngのBoNT/Aタンパク質あたり200pg未満のLys-C、100ngのBoNT/Aタンパク質あたり100pg未満のLys-C、100ngのBoNT/Aタンパク質あたり50pg未満のLys-C、100ngのBoNT/Aタンパク質あたり20pg未満のLys-C、100ngのBoNT/Aタンパク質あたり15pg未満のLys-Cまたは100ngのBoNT/Aタンパク質あたり10pg未満のLys-Cを含有する)。
(a)上記のような、活性な二本鎖BoNT/Aタンパク質と、
(b)界面活性剤である非タンパク質安定化剤と、
(c)塩化ナトリウムと
(d)5.5〜7.5の間のpHを維持するための緩衝剤と、
(e)二糖と
(f)滅菌水と
を含む液体医薬組成物であり、
ここで、前記液体医薬組成物は、タンパク質安定化剤を含まず、
前記液体医薬組成物は、Lys-Cを実質的に含まず、「Lys-Cを実質的に含まない」とは、本明細書において定義される通りである(例えば、前記液体医薬組成物は、100ngのBoNT/Aタンパク質あたり400pg未満のLys-C、100ngのBoNT/Aタンパク質あたり300pg未満のLys-C、100ngのBoNT/Aタンパク質あたり200pg未満のLys-C、100ngのBoNT/Aタンパク質あたり100pg未満のLys-C、100ngのBoNT/Aタンパク質あたり50pg未満のLys-C、100ngのBoNT/Aタンパク質あたり20pg未満のLys-C、100ngのBoNT/Aタンパク質あたり15pg未満のLys-Cまたは100ngのBoNT/Aタンパク質あたり10pg未満のLys-Cを含有する)。
配列番号2:BoNT/A1の活性化ループ
配列番号3:BoNT/A2/A6の活性化ループ
配列番号4:BoNT/A3の活性化ループ
配列番号5:BoNT/A3の活性化ループ
配列番号6:BoNT/A4の活性化ループ
配列番号7:BoNT/A5の活性化ループ
配列番号8:248個のN末端アミノ酸残基を欠く、ボツリヌス菌(Clostridium botulinum)株ATCC3502、GenBank受託番号:「CAL82988.1」に由来するタンパク分解性活性ポリペプチド
配列番号9:ボツリヌス菌(Clostridium botulinum)株ATCC3502、GenBank受託番号:「CAL82988.1」に由来するタンパク分解性に不活性なポリペプチド
配列番号10:配列番号8をコードする核酸配列
配列番号11:配列番号9をコードする核酸配列
配列番号12:「Streptag」アミノ酸配列
配列番号13:BoNT/A7の活性化ループ
配列番号14:BoNT/A8の活性化ループ
配列番号15:単鎖、組換え、カチオン性、ボツリヌス神経毒亜血清型A1誘導体(mrBoNT/A1)のアミノ酸配列
・3種の疎水性相互作用クロマトグラフィー(HIC)カラム:フェニル高性能(PhHP)、フェニルファストフロー高置換(PhFF-Hi)およびブチルHP(BuHP)を、Tris pH8を用いて試験した、
・3種の陽イオン交換クロマトグラフィー(CEC)カラム:スルホプロピル高性能(SPHP)、スルホプロピルファストフロー(SPFF)およびカルボキシメチルファストフロー(CMFF)を、酢酸ナトリウムpH4.5を用いて試験した、
・4種の陰イオン交換クロマトグラフィー(AEC)カラム:第四級アミン高性能(QHP)、第四級アミンファストフロー(QFF)、ジエチルアミノプロピル(DEAP、「ANX」)およびジエチルアミノエチル(DEAE))を、Tris pH8を用いて試験した。
以下のステップを含む、可溶性二本鎖BoNT/Aタンパク質を生産するための方法:
a)可溶性単鎖BoNT/Aタンパク質を提供するステップ;
b)溶液中で前記BoNT/Aタンパク質を、エンドプロテアーゼLys-C(Lys-C)と接触させるステップ; および
c)可溶性二本鎖BoNT/Aタンパク質およびLys-Cを含有する溶液を、疎水性表面と接触させることによって、Lys-Cから可溶性二本鎖BoNT/Aタンパク質を分離するステップ、ここで、前記可溶性二本鎖BoNT/Aタンパク質は、Lys-Cの疎水性表面との結合と比較して、前記疎水性表面と優先的に結合する。
[項目2]
可溶性単鎖BoNT/Aタンパク質が、(i)前記単鎖BoNT/Aタンパク質をコードする核酸を発現系において発現させることによって宿主細胞において、または(ii)in vitro発現系において生産される、項目1に記載の方法。
[項目3]
宿主細胞が、細菌宿主細胞であり、発現系が、細菌発現系である、項目2に記載の方法。
[項目4]
細菌発現系が、大腸菌(E. coli)発現系であり、宿主細胞が、大腸菌(E. coli)細胞である、項目3に記載の方法。
[項目5]
前記可溶性単鎖BoNT/Aタンパク質が、前記宿主細胞の細胞質において発現される、項目2から4のいずれか一項に記載の方法。
[項目6]
前記可溶性単鎖BoNT/Aタンパク質が、少なくとも5mg/Lのレベルで発現される、項目2から5のいずれか一項に記載の方法。
[項目7]
前記可溶性単鎖BoNT/Aタンパク質を含有する、細菌または大腸菌(E. coli)宿主細胞ホモジネートを提供するための、細菌または大腸菌(E. coli)宿主細胞の溶解を含む、項目2から6のいずれか一項に記載の方法。
[項目8]
疎水性表面が、アリールまたはアルキル基からなるリガンドが結合される不活性マトリックスである、項目1から7のいずれか一項に記載の方法。
[項目9]
リガンドが、ブチル、フェニルまたはオクチルリガンドからなる群から選択される、項目8に記載の方法。
[項目10]
高性能疎水性表面が使用される、項目9に記載の方法。
[項目11]
以下のステップを含む、活性二本鎖BoNT/Aタンパク質を含む組成物を生産するための方法:
a)可溶性単鎖BoNT/Aタンパク質を提供するステップ;
b)溶液中で前記BoNT/Aタンパク質を、エンドプロテアーゼLys-C(Lys-C)と接触させるステップ;
c)活性二本鎖BoNT/Aタンパク質およびLys-Cを含有する溶液を、疎水性表面と接触させることによって、Lys-Cから活性二本鎖BoNT/Aタンパク質を分離するステップ、ここで、前記活性二本鎖BoNT/Aタンパク質は、Lys-Cの疎水性表面との結合と比較して、前記疎水性表面と優先的に結合する; および
d)前記活性二本鎖BoNT/Aタンパク質を組成物として製剤化するステップ;
ここで、前記組成物はエンドプロテアーゼLys-Cを実質的に含まない。
[項目12]
前記組成物が5%未満の単鎖BoNT/Aまたは2%未満の単鎖BoNT/Aを含む、項目11に記載の方法。
[項目13]
前記組成物が100ngのBoNT/Aタンパク質あたり400pg未満のエンドプロテアーゼLys-C(Lys-C)、100ngのBoNT/Aタンパク質あたり300pg未満のLys-C、100ngのBoNT/Aタンパク質あたり200pg未満のLys-C、100ngのBoNT/Aタンパク質あたり100pg未満のLys-C、100ngのBoNT/Aタンパク質あたり50pg未満のLys-C、100ngのBoNT/Aタンパク質あたり20pg未満のLys-C、100ngのBoNT/Aタンパク質あたり15pg未満のLys-Cまたは100ngのBoNT/Aタンパク質あたり10pg未満のLys-Cを含有する、項目11または12に記載の方法。
[項目14]
以下のステップを含む、液体医薬組成物を生産するための方法:
a)可溶性単鎖BoNT/Aタンパク質を提供するステップ;
b)溶液中で前記BoNT/Aタンパク質を、エンドプロテアーゼLys-C(Lys-C)と接触させるステップ;
c)活性二本鎖BoNT/Aタンパク質およびLys-Cを含有する溶液を、疎水性表面と接触させることによって、Lys-Cから活性二本鎖BoNT/Aタンパク質を分離するステップ、ここで、前記活性二本鎖BoNT/Aタンパク質は、Lys-Cの疎水性表面との結合と比較して、前記疎水性表面と優先的に結合する; および
d)前記活性二本鎖BoNT/Aタンパク質を液体医薬組成物として製剤化するステップ;
ここで、前記液体医薬組成物は、活性二本鎖BoNT/Aタンパク質、界面活性剤である非タンパク質安定化剤、および水を含み、かつ、
前記液体医薬組成物は、安定化剤としてのタンパク質を含まず、かつ、
前記液体医薬組成物は、エンドプロテアーゼLys-C(Lys-C)を実質的に含まない。
[項目15]
前記液体医薬組成物が100ngのBoNT/Aタンパク質あたり400pg未満のLys-C、100ngのBoNT/Aタンパク質あたり300pg未満のLys-C、100ngのBoNT/Aタンパク質あたり200pg未満のLys-C、100ngのBoNT/Aタンパク質あたり100pg未満のLys-C、100ngのBoNT/Aタンパク質あたり50pg未満のLys-C、100ngのBoNT/Aタンパク質あたり20pg未満のLys-C、100ngのBoNT/Aタンパク質あたり15pg未満のLys-Cまたは100ngのBoNT/Aタンパク質あたり10pg未満のLys-Cを含有する、項目14に記載の方法。
[項目16]
前記液体医薬組成物が塩化ナトリウムと、
5.5から7.5の間のpHを維持するための緩衝剤と、
二糖と
をさらに含み、
水が、滅菌水である、項目14または15に記載の方法。
Elution profiles of BoNT/A1 and Lys-C for PhHP: PhHPのための、BoNT/A1およびLys-Cの溶出プロファイル
Elution profiles of BoNT/A1 and Lys-C for PhFF-Hi: PhFF-Hiのための、BoNT/A1およびLys-Cの溶出プロファイル
Elution profiles of BoNT/A1 and Lys-C for BuHP: BuHPのための、BoNT/A1およびLys-Cの溶出プロファイル
Elution profiles of BoNT/A1 and Lys-C for SPHP: SPHPのための、BoNT/A1およびLys-Cの溶出プロファイル
Elution profiles of BoNT/A1 and Lys-C for SPFF: SPFFのための、BoNT/A1およびLys-Cの溶出プロファイル
Elution profiles of BoNT/A1 and Lys-C for CMFF: CMFFのための、BoNT/A1およびLys-Cの溶出プロファイル
Elution profiles of BoNT/A1 and Lys-C for QHP: QHPのための、BoNT/A1およびLys-Cの溶出プロファイル
Elution profiles of BoNT/A1 and Lys-C for QFF: QFFのための、BoNT/A1およびLys-Cの溶出プロファイル
Elution profiles of BoNT/A1 and Lys-C for ANX: ANXのための、BoNT/A1およびLys-Cの溶出プロファイル
Elution profiles of BoNT/A1 and Lys-C for DEAE: DEAEのための、BoNT/A1およびLys-Cの溶出プロファイル
280nm Absorption: 280nm吸収
Fraction: 画分
405nm Absorption: 405nm吸収
[図11〜15]
Benchmark: ベンチマーク
Load: ロード
Wash: 洗浄
Claims (13)
- 以下のステップを含む方法によって得られる可溶性二本鎖BoNT/Aタンパク質を含む組成物:
a)可溶性単鎖BoNT/Aタンパク質を提供するステップ;
b)溶液中で前記BoNT/Aタンパク質を、エンドプロテアーゼLys-C(Lys-C)と接触させるステップ; 及び
c)可溶性二本鎖BoNT/Aタンパク質及びLys-Cを含有する溶液を、疎水性表面と接触させることによって、Lys-Cから可溶性二本鎖BoNT/Aタンパク質を分離するステップ、ここで、前記可溶性二本鎖BoNT/Aタンパク質は、Lys-Cの疎水性表面との結合と比較して、前記疎水性表面と優先的に結合する;
ここで、前記組成物は2%未満の単鎖BoNT/Aタンパク質を含む。 - 1%未満の単鎖BoNT/Aタンパク質を含む、請求項1に記載の組成物。
- 100ngのBoNT/Aタンパク質あたり400pg未満のエンドプロテアーゼLys-C(Lys-C)、100ngのBoNT/Aタンパク質あたり300pg未満のLys-C、100ngのBoNT/Aタンパク質あたり200pg未満のLys-C、100ngのBoNT/Aタンパク質あたり100pg未満のLys-C、100ngのBoNT/Aタンパク質あたり50pg未満のLys-C、100ngのBoNT/Aタンパク質あたり20pg未満のLys-C、100ngのBoNT/Aタンパク質あたり15pg未満のLys-C又は100ngのBoNT/Aタンパク質あたり10pg未満のLys-Cを含有する、請求項1又は2に記載の組成物。
- 以下を含む液体医薬組成物:
a) 以下のステップを含む方法によって得られる活性二本鎖BoNT/Aタンパク質:
i) 可溶性単鎖BoNT/Aタンパク質を提供するステップ;
ii) 溶液中で前記BoNT/Aタンパク質を、エンドプロテアーゼLys-C(Lys-C)と接触させるステップ; 及び
iii) 活性二本鎖BoNT/Aタンパク質及びLys-Cを含有する溶液を、疎水性表面と接触させることによって、Lys-Cから活性二本鎖BoNT/Aタンパク質を分離するステップ、ここで、前記活性二本鎖BoNT/Aタンパク質は、Lys-Cの疎水性表面との結合と比較して、前記疎水性表面と優先的に結合する;
b) 界面活性剤である非タンパク質安定化剤; 及び
c) 水;
ここで、前記液体医薬組成物は、安定化剤としてのタンパク質を含まず、かつ、2%未満の単鎖BoNT/Aタンパク質を含む。 - 100ngのBoNT/Aタンパク質あたり400pg未満のエンドプロテアーゼLys-C(Lys-C)、100ngのBoNT/Aタンパク質あたり300pg未満のLys-C、100ngのBoNT/Aタンパク質あたり200pg未満のLys-C、100ngのBoNT/Aタンパク質あたり100pg未満のLys-C、100ngのBoNT/Aタンパク質あたり50pg未満のLys-C、100ngのBoNT/Aタンパク質あたり20pg未満のLys-C、100ngのBoNT/Aタンパク質あたり15pg未満のLys-C又は100ngのBoNT/Aタンパク質あたり10pg未満のLys-Cを含有する、請求項4に記載の液体医薬組成物。
- 前記界面活性剤が、非イオン性界面活性剤、ポリソルベート、又はポロキサマーである、請求項4又は5に記載の液体医薬組成物。
- 前記界面活性剤が、1% v/v未満の濃度で存在する、請求項4から6の何れかに記載の液体医薬組成物。
- 塩化ナトリウムと、
5.5から7.5の間のpHを維持するための緩衝剤と、
二糖と
をさらに含み、
水が、滅菌水である、
請求項4から7の何れかに記載の液体医薬組成物。 - 前記二糖がスクロース、トレハロース、マンニトール及びラクトースからなる群から選択されるか、又は、前記二糖がスクロースであり、且つ/又は
前記二糖の濃度が5〜50mM、5〜25mM、10〜20mM、又は約11.7mMである、
請求項8に記載の液体医薬組成物。 - 前記緩衝剤がコハク酸、リン酸二ナトリウム/クエン酸、アミノ酸、及びヒスチジンからなる群から選択され、且つ/又は
前記緩衝剤の濃度が1〜50mM、5〜20mM、又は約10mMである、
請求項8又は9に記載の液体医薬組成物。 - 二本鎖BoNTプロテアーゼ機能が、25℃で少なくとも12週間安定なままである、請求項1から3の何れかに記載の組成物、又は、請求項4から10の何れかに記載の液体医薬組成物。
- 療法において使用するための、請求項1から3及び11の何れかに記載の組成物、又は、請求項4から11の何れかに記載の液体医薬組成物。
- 以下の疾患及び障害のうち少なくとも1種の予防及び/又は治療のために使用するための、請求項1から3及び11の何れかに記載の組成物、又は、請求項4から11の何れかに記載の液体医薬組成物:
随意筋強度、頸部、頭部ジストニアを含めた局所性ジストニア及び良性本態性眼瞼痙攣、片側顔面痙攣及び局所性痙縮、胃腸障害、発汗過多及び美容的しわ取り、眼瞼痙攣、口顎部ジストニア、開口型、閉口型、歯ぎしり、メージュ症候群、舌ジストニア、眼瞼の失行、開口頸部ジストニア、頸部前屈(antecollis)、頸部後屈(retrocollis)、頸部側屈(laterocollis)、斜頸、咽頭ジストニア、喉頭ジストニア、痙攣性発声障害/内転筋型、痙攣性発声障害/外転筋型、痙攣性呼吸困難、四肢ジストニア、上肢ジストニア、動作特異性ジストニア、書痙、音楽家痙攣、ゴルファー痙攣、下肢ジストニア、大腿内転、大腿外転膝屈曲、膝伸展、足首屈曲、足首伸展、内反尖足、変形足ジストニア、線条体足指、足指屈曲、足指伸展、体幹ジストニア、ピサ(pisa)症候群、バレエダンサージストニア、分節性ジストニア、ヘミジストニア、全身性ジストニア、ルバグ(lubag)におけるジストニア、皮質基底核変性症におけるジストニア、ルバグ(lubag)におけるジストニア、遅発性ジストニア、脊髄小脳失調症におけるジストニア、パーキンソン病におけるジストニア、ハンチントン舞踏病におけるジストニア、ハラーホルデン・スパッツ症候群におけるジストニア、ドパ誘導性ジスキネジア/ドパ誘導性ジストニア、遅発性ジスキネジア/遅発性ジストニア、発作性ジスキネジア/ジストニア、運動誘発性、非運動誘発性作用誘導性口蓋ミオクロヌス、ミオクロヌスミオキミア、硬直、良性筋肉痙攣、遺伝性下顎振戦、奇異性顎筋肉活性、片側咀嚼筋痙攣、肥大性鰓弓筋疾患、咬筋(maseteric)肥大、前脛骨肥大、眼振、動揺視核上性注視麻痺、持続性部分てんかん(epilepsia, partialis continua)、痙性斜頚手術の計画、外転筋声帯麻痺、不応性の突然変異性身体違和感、上部食道括約筋機能不全、声帯ヒダ肉芽腫、吃音ジル・ド・ラ・トゥーレット症候群、中耳ミオクロヌス、防御性喉頭閉鎖、喉頭摘出後発語不全、防御性眼瞼下垂、眼瞼内反括約筋オディ(Odii)機能不全、偽性アカラシア(pseudoachalasia)、非アラカシア、食道運動障害、腟痙、術後固定振戦、膀胱機能不全、排尿筋括約筋協調障害、膀胱括約筋痙攣、片側顔面痙攣、神経再支配ジスキネジア、美容的使用目じりのしわ、渋面顔面非対照、頤の凹み、全身硬直症候群、破傷風前立腺肥大症、肥満症、治療脳性小児麻痺斜視、混合性麻痺性随伴性、網膜剥離手術後の、白内障手術後の、無水晶体症における筋炎性斜視、ミオパチー性斜視、交代性上斜位、斜視手術の付属物として、内斜視、外斜視、アカラシア、裂肛、外分泌腺活動亢進、フライ症候群、ワニの涙症候群、発汗過多、腋窩手掌足底鼻漏、卒中における、パーキンソンにおける、筋萎縮性側索硬化症痙性状態における、脳炎及び脊髄炎自己免疫プロセスにおける関連唾液分泌過多、多発性硬化症、横断性脊髄炎、デビック症候群、ウイルス感染症、細菌感染症、寄生虫感染症、真菌感染症、遺伝性痙攣性不全対麻痺卒中後症候群半球状梗塞、脳幹梗塞、脊髄梗塞における、片頭痛、中枢神経系外傷、半球状損傷、脳幹損傷、脊髄損傷における、中枢神経系出血、脳内出血、くも膜下出血、硬膜下出血、脊髄内出血における、腫瘍、半球状腫瘍、脳幹腫瘍、脊髄腫瘍における、いびき。
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US8168206B1 (en) * | 2005-10-06 | 2012-05-01 | Allergan, Inc. | Animal protein-free pharmaceutical compositions |
BRPI1015938A2 (pt) * | 2009-06-25 | 2016-09-27 | Revance Therapeutics Inc | formulações da toxina botulínica livre de albumina |
CN102666396B (zh) * | 2009-10-21 | 2015-05-13 | 雷文斯治疗公司 | 用于纯化非复合的肉毒杆菌神经毒素的方法和系统 |
GB201219602D0 (en) * | 2012-10-31 | 2012-12-12 | Syntaxin Ltd | Recombinant clostridium botulinum neurotoxins |
BR112015003591B1 (pt) * | 2012-11-21 | 2022-02-01 | Ipsen Bioinnovation Limited | Usos de lys-c e métodos para fabricação de um polipeptídeo proteoliticamente processado |
GB201312317D0 (en) * | 2013-07-09 | 2013-08-21 | Syntaxin Ltd | Cationic neurotoxins |
WO2017035508A1 (en) | 2015-08-27 | 2017-03-02 | Collier R John | Compositions and methods for treatment of pain |
GB201517450D0 (en) * | 2015-10-02 | 2015-11-18 | Ipsen Biopharm Ltd | Method |
GB201607901D0 (en) * | 2016-05-05 | 2016-06-22 | Ipsen Biopharm Ltd | Chimeric neurotoxins |
SI3463432T1 (sl) * | 2016-05-27 | 2021-02-26 | Ipsen Biopharm Limited | Tekoča nevrotoksinska formulacija, stabilizirana s triptofanom ali tirozinom |
CN109803672A (zh) | 2016-09-13 | 2019-05-24 | 阿勒根公司 | 稳定的非蛋白质梭菌毒素组合物 |
US20200330563A1 (en) * | 2017-10-13 | 2020-10-22 | Wisconsin Alumni Research Foundation | Botulinum neurotoxin a subtype 6 and pharmacological methods of use |
EP3752128A1 (de) * | 2018-02-16 | 2020-12-23 | Bontana Therapies Gmbh | Nukleinsäure-basiertes botulinum neurotoxin zur therapeutischen anwendung |
US20220016221A1 (en) | 2018-12-05 | 2022-01-20 | Ipsen Biopharm Limited | Treatment of symptoms of traumatic brain injury |
KR102447441B1 (ko) * | 2019-04-15 | 2022-09-27 | (주)제테마 | 보툴리눔 독소의 정제방법 |
KR102485146B1 (ko) | 2019-04-15 | 2023-01-06 | (주)제테마 | 보툴리눔 독소의 제조방법 |
BR112022018456A2 (pt) | 2020-03-16 | 2022-11-01 | Ipsen Biopharm Ltd | Tratamento de espasticidade de membro |
GB202003813D0 (en) | 2020-03-16 | 2020-04-29 | Ipsen Biopharm Ltd | Treatment of upper facial lines |
CN114958887A (zh) * | 2021-02-26 | 2022-08-30 | 重庆誉颜制药有限公司 | 一种经修饰的毒素多肽的制备方法 |
EP4401759A1 (en) | 2021-09-16 | 2024-07-24 | Ipsen Biopharm Limited | Modified bont/a for use in the treatment of cervical dystonia |
KR20240067100A (ko) | 2021-09-23 | 2024-05-16 | 입센 바이오팜 리미티드 | 대상체의 안검 근육에 이환된 장애의 치료에 사용하기 위한 변형된 bont/a |
GB202113602D0 (en) | 2021-09-23 | 2021-11-10 | Ipsen Biopharm Ltd | Treatment of a disorder affecting an eyelid muscle of a subject |
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