JP2022084922A - Il-6アンタゴニスト製剤およびその使用 - Google Patents
Il-6アンタゴニスト製剤およびその使用 Download PDFInfo
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Abstract
Description
この出願は、2016年2月23日に出願された米国仮特許出願第62/298,774号(これは、参考として本明細書に援用される)の利益を主張する。
agent)のうちの1つもしくは複数、または全てを含む。一実施形態では、この医薬製剤は、5mg/ml~50mg/mlのIL-6抗体またはその断片、緩衝剤、界面活性剤および2種の張度剤(例えば、糖および塩)を含む。
本発明の実施形態において、例えば以下の項目が提供される。
(項目1)
1~100mg/mLの抗IL-6抗体またはその断片;
10~50mMのヒスチジン;
0.01%~0.1%のポリソルベート-20(Tween-20)、ポリソルベート-80(Tween-80)またはポロクサマー188;
1~150mMの塩化ナトリウム;および
1~10%のソルビトール
を含む医薬製剤であって、前記製剤のpHが5.5と7.5との間である、医薬製剤。
(項目2)
5~50mg/mlの抗IL-6抗体またはその断片を含む、項目1に記載の製剤。
(項目3)
5mg/mlの抗IL-6抗体またはその断片を含む、項目2または3に記載の製剤。(項目4)
50mg/mlの抗IL-6抗体またはその断片を含む、項目2または3に記載の製剤。
(項目5)
前記IL-6抗体またはその断片が、配列番号19の配列を含むVH CDR1、配列番号20の配列を含むVH CDR2、および配列番号21の配列を含むVH CDR3を含む、項目1から4のいずれかに記載の製剤。
(項目6)
前記IL-6抗体またはその断片が、配列番号22の配列を含むVL CDR1、配列番号23の配列を含むVL CDR2、および配列番号24の配列を含むVL CDR3をさらに含む、項目1から5のいずれかに記載の製剤。
(項目7)
前記IL-6抗体またはその断片が、
(i)配列番号28または29を含む定常領域配列、または
(ii)配列番号28に少なくとも90、91、92、93、94、95、96、97、98または99%同一である定常領域配列
を含む、項目1から6のいずれかに記載の製剤。
(項目8)
前記IL-6抗体またはその断片が、
(i)配列番号17を含む重鎖可変領域配列、または
(ii)配列番号17に少なくとも90、91、92、93、94、95、96、97、98または99%同一である重鎖可変領域配列
を含む、項目1から7のいずれかに記載の製剤。
(項目9)
前記IL-6抗体またはその断片が、
(i)配列番号13を含む重鎖配列、または
(ii)配列番号13に少なくとも90、91、92、93、94、95、96、97、98または99%同一である重鎖配列
を含む、項目1から8のいずれかに記載の製剤。
(項目10)
前記IL-6抗体またはその断片が、
(i)配列番号18を含む軽鎖可変領域配列、または
(ii)配列番号18に少なくとも90、91、92、93、94、95、96、97、98または99%同一である軽鎖可変領域配列
をさらに含む、項目1から9のいずれかに記載の製剤。
(項目11)
前記IL-6抗体またはその断片が、
i)配列番号14を含む軽鎖配列、または
ii)配列番号14に少なくとも90、91、92、93、94、95、96、97、98または99%同一である軽鎖配列
を含む、項目1から10のいずれかに記載の製剤。
(項目12)
前記IL-6抗体またはその断片が、配列番号17を含む重鎖可変領域および配列番号18を含む軽鎖可変領域を含む、項目1から11のいずれかに記載の製剤。
(項目13)
前記IL-6抗体またはその断片が、配列番号13を含む重鎖配列および配列番号14を含む軽鎖配列を含む、項目1から12のいずれかに記載の製剤。
(項目14)
10~30mMのヒスチジン緩衝液を含む、項目1から13のいずれかに記載の製剤。(項目15)
20mMのヒスチジン緩衝液を含む、項目1から14のいずれかに記載の製剤。
(項目16)
0.01%~0.05%のポリソルベート-20(Tween-20)、ポリソルベート-80(Tween-80)またはポロクサマー188を含む、項目1から15のいずれかに記載の製剤。
(項目17)
0.03%のポリソルベート-20(Tween-20)、ポリソルベート-80(Tween-80)またはポロクサマー188を含む、項目1から16のいずれかに記載の製剤。
(項目18)
10~50mMの塩化ナトリウムを含む、項目1から17のいずれかに記載の製剤。
(項目19)
10~30mMの塩化ナトリウムを含む、項目1から18のいずれかに記載の製剤。
(項目20)
20mMの塩化ナトリウムを含む、項目1から19のいずれかに記載の製剤。
(項目21)
2~6%のソルビトールを含む、項目1から20のいずれかに記載の製剤。
(項目22)
4%のソルビトールを含む、項目1から21のいずれかに記載の製剤。
(項目23)
6.0と7.0との間のpHである、項目1から22のいずれかに記載の製剤。
(項目24)
6.2と6.8との間のpHである、項目1から23のいずれかに記載の製剤。
(項目25)
約pH6.5である、項目1から24のいずれかに記載の製剤。
(項目26)
5~50mg/mL、例えば、5mg/mlまたは50mg/mlの抗IL-6抗体またはその断片;
20mMのヒスチジン;
0.03%のポリソルベート-20(Tween-20)、ポリソルベート-80(Tween-80)またはポロクサマー188;
20mMの塩化ナトリウム;および
4%のソルビトール
を含む医薬製剤であって、前記製剤のpHが6.5である、医薬製剤。
(項目27)
5mg/mlの抗IL-6抗体またはその断片を含む、項目26に記載の製剤。
(項目28)
50mg/mlの抗IL-6抗体またはその断片を含む、項目26に記載の製剤。
(項目29)
前記抗IL-6抗体またはその断片が、
i)配列番号19の配列を含むVH CDR1、配列番号20の配列を含むVH CDR2、および配列番号21の配列を含むVH CDR3;ならびに
ii)配列番号22の配列を含むVL CDR1、配列番号23の配列を含むVL CDR2、および配列番号24の配列を含むVL CDR3
を含む、項目26から28のいずれかに記載の製剤。
(項目30)
前記IL-6抗体またはその断片が、配列番号17を含む重鎖可変領域および配列番号18を含む軽鎖可変領域を含む、項目26から29のいずれかに記載の製剤。
(項目31)
前記IL-6抗体またはその断片が、配列番号13を含む重鎖配列および配列番号14を含む軽鎖配列を含む、項目26から30のいずれかに記載の製剤。
(項目32)
前記抗IL-6抗体がIgG2抗体である、項目1から31のいずれかに記載の製剤。(項目33)
前記IL-6抗体が全長抗体である、項目1から32のいずれかに記載の製剤。
(項目34)
前記製剤中に存在する前記抗体の少なくとも95%、例えば、96%、97%、98%または99%が、合わせて、アイソフォームAまたはA/Bである、項目1から33のいずれかに記載の製剤。
(項目35)
前記製剤中に存在する前記抗体の少なくとも85%、例えば、86%、87%、88%、89%または90%が、アイソフォームAである、項目1から34のいずれかに記載の製剤。
(項目36)
前記製剤中に存在する前記抗体の1%未満、例えば、0.9%、0.8%、0.7%、0.6%、0.5%、0.4%、0.3%、0.2%または0.1%が、アイソフォームBである、項目1から35のいずれかに記載の製剤。
(項目37)
アイソフォームBにある前記抗体を実質的に含まない、例えば、5%、4%、3%、2%または1%未満しか含まない、項目1から36のいずれかに記載の製剤。
(項目38)
アイソフォームA、A/Bおよび/またはBで存在する抗体の百分率が、HPLC、例えばRP-HPLC、または例えば非還元条件下でのペプチドマッピングとその後の質量分析的分析とによって決定される、項目34から37のいずれかに記載の製剤。
(項目39)
キレート剤、保存剤または抗酸化剤のうちの1つまたは複数をさらに含む、項目1から38のいずれかに記載の製剤。
(項目40)
第2の治療剤をさらに含む、項目1から39のいずれかに記載の製剤。
(項目41)
眼への投与に適切である、項目1から40のいずれかに記載の製剤。
(項目42)
硝子体内、眼内または結膜下投与に適切である、項目1から41のいずれかに記載の製剤。
(項目43)
少なくとも1または2年間にわたって-65℃またはそれ未満の温度で安定である、項目1から42のいずれかに記載の製剤。
(項目44)
少なくとも6ヶ月間にわたって2℃~8℃の間の温度で安定である、項目1から42のいずれかに記載の製剤。
(項目45)
IL-6関連疾患を有する被験体を処置するための、項目1から44のいずれかに記載の製剤の使用。
(項目46)
前記IL-6関連疾患が、糖尿病性黄斑浮腫(DME)、糖尿病性網膜症、ドライアイ(例えば、ドライアイ疾患またはドライアイ症候群)、アレルギー性結膜炎、ブドウ膜炎、加齢性黄斑変性(AMD)(例えば、ウエット型AMDもしくはドライ型AMD)、増殖性糖尿病性網膜症(PDR)、裂孔原性網膜剥離(RRD)、網膜静脈閉塞症(RVO)、視神経脊髄炎(NMO)、近視性脈絡膜血管新生、眼性がん、角膜移植、角膜上皮剥離または眼に対する物理的傷害からなる群から選択される、項目45に記載の製剤の使用。
(項目47)
前記IL-6関連疾患が糖尿病性黄斑浮腫(DME)である、項目45または46に記載の使用。
(項目48)
前記製剤が、前記被験体の眼に投与される、項目46から47のいずれかに記載の使用。
(項目49)
前記製剤が、硝子体内投与される、項目46から48のいずれかに記載の使用。
(項目50)
項目1から44のいずれかに記載の製剤を含む容器またはデバイス。
(項目51)
前記製剤の容積が、少なくとも0.1、0.5、1、2または5mlである、項目50に記載の容器。
(項目52)
多用量容器である、項目50または51に記載の容器。
(項目53)
項目1から44のいずれか一項に記載の製剤を含む薬物送達デバイス。
(項目54)
項目1から44のいずれか一項に記載の製剤を含む容器またはデバイス、および任意選択で、使用のための指示を含む、キット。
(項目55)
IL-6関連疾患、例えば、上昇したIL-6発現と関連する疾患を有する被験体を処置する方法であって、項目1から44のいずれかに記載の医薬製剤を前記被験体に投与することを含む、方法。
(項目56)
前記製剤が眼に投与される、項目55に記載の方法。
(項目57)
前記製剤が、例えば、硝子体内注射によって硝子体内投与される、項目56に記載の方法。
(項目58)
前記IL-6関連疾患が、糖尿病性黄斑浮腫(DME)、糖尿病性網膜症、ドライアイ(例えば、ドライアイ疾患またはドライアイ症候群)、アレルギー性結膜炎、ブドウ膜炎、加齢性黄斑変性(AMD)(例えば、ウエット型AMDもしくはドライ型AMD)、増殖性糖尿病性網膜症(PDR)、裂孔原性網膜剥離(RRD)、網膜静脈閉塞症(RVO)、視神経脊髄炎(NMO)、近視性脈絡膜血管新生、眼性がん、角膜移植、角膜上皮剥離または眼に対する物理的傷害からなる群から選択される、項目55~57のいずれかに記載の方法。
(項目59)
前記IL-6関連疾患が糖尿病性黄斑浮腫(DME)である、項目55から58のいずれかに記載の方法。
(項目60)
第2の治療剤を前記被験体に投与することをさらに含む、項目55から59のいずれかに記載の方法。
(項目61)
前記第2の治療剤が、抗VEGF剤、ステロイド、例えばコルチコステロイド、または抗PDGF剤である、項目60に記載の方法。
(項目62)
前記被験体が、抗VEGF剤、ステロイドまたは抗PDGF剤で以前に処置されている、項目55から51のいずれかに記載の方法。
(項目63)
前記被験体が、抗VEGF剤、ステロイドまたは抗PDGF剤による処置に応答しなかった、項目52に記載の方法。
(項目64)
前記被験体が哺乳動物である、項目55から63のいずれかに記載の方法。
(項目65)
前記被験体がヒトである、項目55から64のいずれかに記載の方法。
Sci 35巻:900頁(1994年);Miaoら、Molec Vis 18巻:574頁(2012年)を参照のこと)。
(i)GYX1LX2NYLIE(配列番号30)の配列を含むVH CDR1、
(ii)VX3TPGX4GTIN(配列番号31)の配列を含むVH CDR2、および
(ii)VH CDR3、
(ここで、以下のうちの1つもしくは複数(例えば、1、2、3、または全て)が真である:X1がAでない、X2がSでない、X3がIでない、およびX4がSでない)を含む重鎖可変領域を含む単離された抗体または抗原結合断片が、本明細書に提供される。ある実施形態では、X1がAでない、X2がSでない、X3がIでない、かつX4がSでない。
Biological Chemistry. 2008年、283巻:16194~16205頁)。この構造的不均一性は、Fabアームを重鎖ヒンジ領域に連結するジスルフィド結合の異なる立体配置に起因する。IgG2-Aアイソフォームでは、Fabアームをヒンジ領域に連結するジスルフィド結合は存在しない。IgG2-Bアイソフォームでは、両方のFabアームが、重鎖および軽鎖をヒンジ領域に連結するジスルフィド結合を有する。IgG2-A/Bアイソフォームは、IgG2-AアイソフォームとIgG2-Bアイソフォームとの間のハイブリッドであり、一方のFabアームだけが、この一方のFabアームの重鎖および軽鎖をヒンジ領域に連結するジスルフィド結合を有する。ジスルフィドシャッフリングとも呼ばれる、異なる構造的アイソフォームのうちの2つまたは全ての間でのIgG2抗体の変換が、天然に存在する抗体および組換え抗体の両方について、in vivoおよびin vitroで天然に発生する。結果として、当該分野におけるIgG2抗体の製剤は、IgG2-A、IgG2-BおよびIgG2-A/Bアイソフォームの不均一な混合物を含む。異なるIgG2アイソフォームは、独自のおよび異なる機能的特性、例えば、安定性、凝集、粘度、Fc受容体結合または効力における差異を有し得る。IgG2抗体製剤中の、複数のアイソフォームの存在、または特定のアイソフォームの増加したレベルは、安定性、凝集または効力に負の影響を与え得る。ジスルフィドシャッフリングをなおも受けることができ、構造的アイソフォームA、A/Bおよび/またはBのいずれかで存在するIgG2抗体の一部の断片、例えば、ジスルフィド結合のシャッフリングに関与する残基(例えば、図10に示される)を保持する断片が容易に想定され得、例えば、この断片は、少なくとも1つのIgG2ヒンジ領域を含む。
Pharma、USA);およびVisulex(登録商標)1(Aciont Inc.、USA)が含まれる。AmoおよびUrtti、Drug Discovery Today、13巻:143頁(2008年)を参照のこと。
hamartoma)、血管濾胞性リンパ節過形成(angiofollicular
lymph node hyperplasia))、若年性特発性関節炎(多関節型若年性特発性関節炎(polyarticular juvenile idiopathic arthritis)および全身型若年性特発性関節炎が含まれる)、スチル病(若年性特発性関節炎および成人発症スチル病を包含する)、成人発症スチル病、アミロイドAアミロイドーシス、リウマチ性多発筋痛、圧痕浮腫を伴う寛解型血清反応陰性対称滑膜炎(remitting seronegative symmetrical synovitis with pitting edema)、脊椎関節炎(spondyloarthritides)、ベーチェット病(眼の症状発現の処置を含む)、アテローム動脈硬化症、乾癬、全身性エリテマトーデス、多発性筋炎(炎症性ミオパチー)、再発性多発軟骨炎、後天性血友病A、多発性硬化症、炎症による貧血、およびクローン病を処置するためにも使用され得る。
kDによる製剤研究
異なる緩衝液および賦形剤の動的光散乱(DLS)スクリーニング
0日目および7日目における産物純度製剤研究
撹拌研究
例示的な製剤の調製
-緩衝液Qおよび緩衝液RについてのpHは、水酸化ナトリウム25%溶液を用いて調整される。
-表3の緩衝液の室温での保存有効期間は3日間である。
-緩衝液Q:1.7mL/Lの水酸化ナトリウム(25%)を必要とする。逆滴定は許容されない。最終緩衝液密度=1.0132kg/L。質量オスモル濃度の仕様=300~340mOsm/kg。
-緩衝液R:1.7mL/Lの水酸化ナトリウム(25%)を必要とする。逆滴定は許容されない。最終緩衝液密度=1.01160kg/L。質量オスモル濃度の仕様=300~340mOsm/kg。
-緩衝液U:この緩衝液は、9部の緩衝液Rを1部の緩衝液Qに混合することによって作製する。特定された容積の緩衝液Rが作製され、次いで、必要な容積の緩衝液Qが添加される。
IgG2 IL-6抗体の構造的アイソフォームの特徴付け
Claims (1)
- 本明細書に記載の発明。
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CN112739378A (zh) * | 2018-09-14 | 2021-04-30 | 田边三菱制药株式会社 | 含有人抗il-33单克隆抗体的医药用组合物 |
US20210393783A1 (en) * | 2018-10-31 | 2021-12-23 | Richter Gedeon Nyrt | Aqueous pharmaceutical formulations |
IL300245A (en) * | 2020-07-31 | 2023-03-01 | Alamab Therapeutics Inc | Anti-connexin antibody formulations |
EP4199965A1 (en) * | 2020-08-19 | 2023-06-28 | Bio-Thera Solutions, Ltd. | Liquid formulations comprising high concentrations humanized antibodies for treating il-6 related diseases |
KR20220028972A (ko) * | 2020-08-31 | 2022-03-08 | (주)셀트리온 | 안정한 약제학적 제제 |
US20230073821A1 (en) * | 2021-08-27 | 2023-03-09 | International Business Machines Corporation | Antigen-binding proteins targeting coronavirus (cov) variants |
CN116355825A (zh) * | 2022-02-25 | 2023-06-30 | 南京工业大学 | 一种强化纤维素合成来提高人表皮生长因子分泌生产效率的方法 |
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BR112018017031A2 (pt) | 2019-01-22 |
CA3012350A1 (en) | 2017-08-31 |
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