JP2022169709A - 関節リウマチの治療 - Google Patents
関節リウマチの治療 Download PDFInfo
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- JP2022169709A JP2022169709A JP2022133957A JP2022133957A JP2022169709A JP 2022169709 A JP2022169709 A JP 2022169709A JP 2022133957 A JP2022133957 A JP 2022133957A JP 2022133957 A JP2022133957 A JP 2022133957A JP 2022169709 A JP2022169709 A JP 2022169709A
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Abstract
Description
(i)少なくとも1.0 mg/kgの用量、または
(ii)40 mg~400 mgの固定用量で
前記患者に抗GM-CSF抗体を皮下投与することを含む。
抗GM-CSF抗体は、前記治療の期間中、前記患者において少なくとも2μg/mlの前記抗体血清濃度を達成する方法で、前記患者に投与されうる。抗体は、少なくとも1.0 mg/kgの用量で少なくとも4週間の間毎週前記抗体を静脈内投与した場合と比較して同等またはより高い、前記患者の治療上有効な血中抗体濃度を達成する方法で、前記患者に投与されうる。
「GM-CSF」および「GMCSF」という用語は、下記の同義語、すなわち、コロニー刺激因子2、CSF2、GMCSF、GM-CSF、顆粒球マクロファージコロニー刺激因子、MGC131935、MGC138897、モルグラモスチン(Molgramostin)、サルグラモスチム(Sargramostim)を有する、GM-CSFまたは顆粒球マクロファージコロニー刺激因子として知られるタンパク質を指す。ヒトGM-CSFは、下記のアミノ酸配列(UniProt P04141)、すなわち、
MWLQSLLLLGTVACSISAPARSPSPSTQPWEHVNAIQEARRLLNLSRDTAAEMNET VEVISEMFDLQEPTCLQTRLELYKQGLRGSLTKLKGPLTMMASHYKQHCPPTPETS CATQIITFESFKENLKDFLLVIPFDCWEPVQE(配列番号1)を有する。
QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMNWVRQAPGKGLEWVSGIENKYAGGA TYYAASVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGFGTDFWGQGTLVTVSS(配列番号8)の可変重鎖および配列
DIELTQPPSVSVAPGQTARISCSGDSIGKKYAYWYQQKPGQAPVLVIYKKRPSGIPERFSGS NSGNTATLTISGTQAEDEADYYCSAWGDKGMVFGGGTKLTVLGQ(配列番号9)の可変軽鎖を含む。
QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMNWVRQAPGKGLEWVSGIENKYAGGA TYYAASVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGFGTDFWGQGTLVTVSS(配列番号8)の可変重鎖および配列
DIELTQPPSVSVAPGQTARISCSGDSIGKKYAYWYQQKPGQAPVLVIYKKRPSGIPERFSGS NSGNTATLTISGTQAEDEADYYCSAWGDKGMVFGGGTKLTVLGQ(配列番号9)の可変軽鎖を含む抗体である。他の実施形態では、本発明に用いられる抗体は、配列GFTFSSYWMN(配列番号2)のHCDR1領域、配列GIENKYAGGATYYAASVKG(配列番号3)のHCDR2領域、配列GFGTDF(配列番号4)のHCDR3領域、配列SGDSIGKKYAY(配列番号5)のLCDR1領域、配列KKRPS(配列番号6)のLCDR2領域、および配列SAWGDKGM(配列番号7)のLCDR3領域を含む抗体と交差競合する抗体である。他の実施形態では、本発明に用いられる抗体は、配列GFTFSSYWMN(配列番号2)のHCDR1領域、配列GIENKYAGGATYYAASVKG(配列番号3)のHCDR2領域、配列GFGTDF(配列番号4)のHCDR3領域、配列SGDSIGKKYAY(配列番号5)のLCDR1領域、配列KKRPS(配列番号6)のLCDR2領域、および配列SAWGDKGM(配列番号7)のLCDR3領域を含む、GM-CSFに特異的な抗体と同一のエピトープに結合する抗体である。
活動性関節リウマチ患者に静脈内投与される複数回投与のMOR103の安全性、予備的な臨床活性および免疫原性を評価するために、多施設共同、無作為化、二重盲検、プラセボ対照の試験を行った。
・改訂された1987年ACR基準による関節リウマチ(RA)
・活動性RA:PIP関節を除く、少なくとも1か所の手の腫脹関節を有する3か所以上の腫脹関節および3か所の圧痛関節
・CRP>5.0 mg/L(RFおよび抗CCP血清反応陰性);CRP>2 mg/l(RFおよび/または抗CCP血清反応陽性)
・DAS28≦5.1
・併用RA治療(NSAID、ステロイド、非生物学的DMARD)の安定的な治療計画
・PPDツベルクリン皮膚試験陰性
試験対象除外基準は下記の通りであった:
・リツキシマブ以外のB細胞またはT細胞除去剤(例えばキャンパス)による治療歴。リツキシマブ、TNF阻害剤、他の生物製剤(例えば抗IL-1治療)および全身性免疫抑制薬による治療歴は、休薬期間があれば許容される。
・進行中の、重篤な、または再発性の感染症の病歴
・RA以外の活動性炎症性疾患
・スクリーニング前6か月以内の全身性被験薬による治療
・メトトレキサートまたはレフルノミドの継続投与を受けている場合を除く、妊娠の可能性がある女性
・重篤な心疾患または肺疾患(メトトレキサート関連肺毒性を含む)
・肝不全または腎不全
患者の募集、スクリーニングおよび治療のための臨床現場は、ブルガリア、ドイツ、オランダ、ポーランドおよびウクライナに置かれた。
利用可能な観察された安全性データに基づいて、MOR103は、試験されたすべての用量で良好な安全性プロフィールを示した。重要な所見は下記の通りである:
・試験実施の間、死亡は観察されなかった。
・注入に伴う反応(infusion related reaction)は観察されなかった。
・2件の重篤な有害事象(SAE)が観察された:
-プラセボ群の1名の患者が爪周囲炎を発症した。
・活性物質群(14.5%)よりもプラセボ群(25.9%)でより多くの治療下で発現した有害作用(TEAE)が観察された。
・ほとんどのTEAEは軽度であった。
・活性物質群では重篤なTEAEは観察されなかった。
MOR103(またはプラセボ)の最初の投与の4週間後および8週間後、すべての患者のDAS28スコアを測定した。DAS28スコアの減少は疾患重症度の低下と相関する。結果は、ベースライン、すなわち治療前の疾患状態と比較した平均変化として、図2に示す。
別の有効性の評価基準として、ACR20基準が用いられた。ACR20基準は、圧痛関節数または腫脹関節数の改善および他の特定のパラメーターの改善を測定する。ACRスコアの測定方法は高度に標準化されている。本臨床試験は、それぞれの適切なガイドラインを用いた。結果は図3および4に示される。より高いスコアは、疾患重症度の改善に対応する。
上記で設計された臨床試験を更なるMOR103用量を用いて繰り返す。0.5 mg/kg(治療群1)および0.75 mg/kg(治療群2)の用量で、MOR103を患者に静脈内投与する。他のすべてのパラメーターは、実施例1と同一である。
上記で設計された臨床試験をMOR103の皮下製剤を用いて繰り返す。静脈内治療で観察されるのと同様の患者の血中MOR103濃度を達成するために、MOR103の皮下用量を増加させる。
実施例7を固定用量のMOR103を用いて繰り返す。様々な治療群において、患者に75 mg、100 mg、150 mg、200 mg、300 mgおよび400 mgの固定用量でMOR103を投与する。薬物を、毎週、2週間毎、4週間毎または6週間毎に皮下投与する。他のすべてのパラメーターは、上記の実施例と同一である。
Claims (4)
- 抗GM-CSF抗体を、製薬上許容され得る担体、賦形剤または安定剤と共に含有する、関節リウマチを患っている患者の治療における使用のための医薬組成物であって、該製薬上許容され得る担体、賦形剤または安定剤は、ヒスチジンである緩衝剤、ソルビトールである糖、及びTween-80である非イオン性界面活性剤であり、前記抗GM-CSF抗体は、配列QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMNWVRQAPGKGLEWVSGIENKYAGGATYYAASVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGFGTDFWGQGTLVTVSS(配列番号8)の可変重鎖と、配列DIELTQPPSVSVAPGQTARISCSGDSIGKKYAYWYQQKPGQAPVLVIYKKRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCSAWGDKGMVFGGGTKLTVLGQ(配列番号9)の可変軽鎖とを含み、前記治療が前記患者に150mgの用量で前記抗GM-CSF抗体を皮下投与することを含む、上記組成物。
- 前記抗GM-CSF抗体がヒトモノクローナル抗体である、請求項1に記載の使用のための医薬組成物。
- 前記抗GM-CSF抗体が毎週投与される、請求項1または2に記載の使用のための医薬組成物。
- 前記抗GM-CSF抗体が、メトトレキサートなどのDMARDと併用投与される、請求項1~3のいずれか1項に記載の使用のための医薬組成物。
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EP12185235 | 2012-09-20 | ||
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US201261703871P | 2012-09-21 | 2012-09-21 | |
US61/703,871 | 2012-09-21 | ||
JP2020002684A JP7132256B2 (ja) | 2012-09-20 | 2020-01-10 | 関節リウマチの治療 |
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JP2022133957A Pending JP2022169709A (ja) | 2012-09-20 | 2022-08-25 | 関節リウマチの治療 |
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EP (3) | EP3916013A1 (ja) |
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CN (2) | CN109999195A (ja) |
AU (2) | AU2013320261A1 (ja) |
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CA (1) | CA2884124A1 (ja) |
CL (2) | CL2015000696A1 (ja) |
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SG11201501595YA (en) * | 2012-09-20 | 2015-05-28 | Morphosys Ag | Treatment for rheumatoid arthritis |
AR093297A1 (es) * | 2012-10-31 | 2015-05-27 | Amgen Res (Munich) Gmbh | Formulacion liquida que comprende un compuesto neutralizante de gm-csf |
WO2014068029A1 (en) * | 2012-10-31 | 2014-05-08 | Takeda Gmbh | Lyophilized formulation comprising gm-csf neutralizing compound |
ES2860480T3 (es) * | 2013-08-30 | 2021-10-05 | Takeda Gmbh | Anticuerpos neutralizantes de GM-CSF para su uso en el tratamiento de la artritis reumatoide o como analgésicos |
US11299528B2 (en) * | 2014-03-11 | 2022-04-12 | D&D Pharmatech Inc. | Long acting TRAIL receptor agonists for treatment of autoimmune diseases |
US11173208B2 (en) * | 2014-05-07 | 2021-11-16 | Takeda Gmbh | Liquid formulation comprising GM-CSF neutralizing compound |
GB201519331D0 (en) * | 2015-11-02 | 2015-12-16 | Glaxosmithkline Ip Dev Ltd | Treatment paradigm |
AU2016371021B2 (en) | 2015-12-17 | 2020-04-09 | The Johns Hopkins University | Ameliorating systemic sclerosis with death receptor agonists |
EA201892260A1 (ru) | 2016-04-07 | 2019-03-29 | Дзе Джонс Хопкинс Юниверсити | Композиции и способы для лечения панкреатита и боли с применением агонистов рецептора смерти |
PT3328887T (pt) | 2016-09-19 | 2021-10-19 | I Mab Biopharma Hangzhou Co Ltd | Anticorpos anti-gm-csf e suas utilizações |
US11655293B2 (en) | 2018-02-22 | 2023-05-23 | Universitat Zurich | Ligands to GM-CSF or GM-CSF-receptor for use in leukemia in a patient having undergone allo-HCT |
EP3623382A1 (en) | 2018-09-14 | 2020-03-18 | Universität Zürich | Ligands to gm-csf or gm-csf-receptor for use in leukemia in a patient having undergone allo-hct |
WO2021204649A1 (en) | 2020-04-06 | 2021-10-14 | Glaxosmithkline Intellectual Property Development Limited | Gm-csf antagonists for use in the treatment of severe pulmonary covid-19, cytokine release syndrome and/or acute respiratory distress syndrome |
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US6267958B1 (en) | 1995-07-27 | 2001-07-31 | Genentech, Inc. | Protein formulation |
AU4344697A (en) | 1996-10-04 | 1998-04-24 | Amgen, Inc. | Pharmaceutical compositions containing an mpl ligand |
US7455836B2 (en) | 2000-05-08 | 2008-11-25 | The University Of Melbourne | Method of treatment and agents useful for same |
KR101308087B1 (ko) * | 2005-05-18 | 2013-10-16 | 모르포시스 아게 | 항-gm-csf 항체 및 이의 용도 |
US7790679B2 (en) | 2005-08-05 | 2010-09-07 | Amgen Inc. | Pharmaceutical formulations |
US9399061B2 (en) * | 2006-04-10 | 2016-07-26 | Abbvie Biotechnology Ltd | Methods for determining efficacy of TNF-α inhibitors for treatment of rheumatoid arthritis |
US8093360B2 (en) * | 2006-09-28 | 2012-01-10 | Elusys Therapeutics, Inc. | Antibodies that bind B. anthracis exotoxin, formulations thereof, and methods of use |
BRPI0719109A2 (pt) * | 2006-11-21 | 2013-12-10 | Kalobios Pharmaceuticals Inc | Métodos para tratar doenças inflamatórias crônicas usando um antagonista de gm-csf |
CA2682170A1 (en) * | 2007-03-30 | 2008-10-09 | Medimmune, Llc | Antibodies with decreased deamidation profiles |
AU2008232506A1 (en) * | 2007-04-02 | 2008-10-09 | Genentech, Inc. | Biological markers predictive of rheumatoid arthritis response to B-cell antagonists |
SI2142174T1 (sl) | 2007-04-05 | 2011-04-29 | Sandoz Ag | Stabilne vodne G-CSF formulacije |
US20090004189A1 (en) * | 2007-06-18 | 2009-01-01 | Genentech, Inc. | Biological markers predictive of rheumatoid arthritis response to b-cell antagonists |
TW200918553A (en) * | 2007-09-18 | 2009-05-01 | Amgen Inc | Human GM-CSF antigen binding proteins |
CA2705539A1 (en) | 2007-11-13 | 2009-05-22 | Evec Inc. | Monoclonal antibodies that bind to hgm-csf and medical compositions comprising same |
EP2196476A1 (en) * | 2008-12-10 | 2010-06-16 | Novartis Ag | Antibody formulation |
CN108014335A (zh) * | 2008-12-22 | 2018-05-11 | 墨尔本大学 | 粒细胞巨噬细胞集落刺激因子的拮抗剂的用途 |
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JP2010241718A (ja) | 2009-04-03 | 2010-10-28 | Kyowa Hakko Kirin Co Ltd | 安定な抗体の水溶液製剤 |
KR20140064943A (ko) * | 2009-05-05 | 2014-05-28 | 모르포시스 아게 | 다발성 경화증의 치료 |
PT2341061E (pt) | 2009-12-31 | 2013-11-05 | Arven Ilac Sanayi Ve Ticaret As | Um processo novo para a preparação de g-csf (fator de estimulação de colónias de granulócitos) |
MX347504B (es) * | 2010-03-01 | 2017-04-28 | Cytodyn Inc | Formulaciones concentradas de proteina y usos de las mismas. |
KR20140061379A (ko) | 2011-07-06 | 2014-05-21 | 모르포시스 아게 | 항cd20 및 항gmcsf 항체의 치료 조합물 및 이의 용도 |
SG11201501595YA (en) * | 2012-09-20 | 2015-05-28 | Morphosys Ag | Treatment for rheumatoid arthritis |
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