JP2019521156A - Il−17アンタゴニストを用いて初発プラーク型乾癬を治療する方法 - Google Patents
Il−17アンタゴニストを用いて初発プラーク型乾癬を治療する方法 Download PDFInfo
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- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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Abstract
Description
本出願は、2016年7月19日出願の米国仮特許出願第62/346,007号明細書(その全体が参照により本明細書に組み込まれる)に対する優先権を主張する。
各種の開示されたプロセス、キット、使用および方法は、IL−17アンタゴニスト、たとえばIL−17結合分子(たとえば、可溶性IL−17レセプター、IL−17抗体もしくはその抗原結合フラグメント、たとえばセクキヌマブ)またはIL−17レセプター結合分子(たとえば、IL−17レセプター抗体もしくはその抗原結合フラグメント)を利用する。いくつかの実施形態では、IL−17アンタゴニストは、IL−17結合分子、好ましくはIL−17抗体またはその抗原結合フラグメントである。
開示されたIL−17アンタゴニスト、たとえばIL−17結合分子(たとえば、IL−17抗体もしくはその抗原結合フラグメント、たとえばセクキヌマブ)またはIL−17レセプター結合分子(たとえば、IL−17レセプター抗体もしくはその抗原結合フラグメント)は、インビトロ、エクスビボで使用し得るか、または初発プラーク型乾癬患者(たとえば、ヒト患者)を治療するために医薬組成物に組み込んでインビボで投与し得る。
本開示はまた、初発プラーク型乾癬を治療するためのキットを包含する。かかるキットは、IL−17アンタゴニスト、たとえばIL−17結合分子(たとえば、IL−17抗体もしくはその抗原結合フラグメント、たとえばセクキヌマブ)またはIL−17レセプター結合分子(たとえば、IL−17抗体もしくはその抗原結合フラグメント)(たとえば、液体形態または凍結乾燥形態)あるいはIL−17アンタゴニストを含む医薬組成物(以上に記載のもの)を含む。加えて、かかるキットは、IL−17アンタゴニストを投与するための手段(たとえば、オートインジェクター、シリンジ、プレ充填シリンジ、プレ充填ペンおよびバイアル)ならびに使用説明書を含み得る。これらのキットは、包含されるIL−17アンタゴニスト、たとえばIL−17結合分子、たとえばIL−17抗体、たとえばセクキヌマブと組み合わせて送達するために、初発プラーク型乾癬を治療するための追加の治療用乾癬剤(以上に記載のもの)を含有し得る。かかるキットはまた、初発プラーク型乾癬患者を治療するためのIL−17アンタゴニスト(たとえば、IL−17抗体、たとえばセクキヌマブ)の投与に関する説明書も含み得る。かかる説明書は、包含されるIL−17アンタゴニスト、たとえばIL−17結合分子、たとえばIL−17抗体、たとえばセクキヌマブとともに使用するために、用量(たとえば、10mg/kg、75mg、150mg、300mg)、投与経路(たとえば、IV、SC)および投与レジメン(たとえば、1週おきに0、2および4週時にその後は8週時から始めて毎月1回、毎週1回0、1、2および3週時にその後は4週時から始めて毎月1回(4週ごとに)など)を提供し得る。
開示された方法、治療、医薬、レジメン、使用およびキットの好ましい実施形態では、IL−17アンタゴニストは、IL−17結合分子である。好ましい実施形態では、IL−17結合分子は、IL−17抗体またはその抗原結合フラグメントである。開示された方法、治療、レジメン、使用およびキットのいくつかの実施形態では、IL−17抗体またはその抗原結合フラグメントは、a)Leu74、Tyr85、His86、Met87、Asn88、Val124、Thr125、Pro126、Ile127、Val128、His129を含むヒトIL−17のエピトープに結合するIL−17抗体またはその抗原結合フラグメント、b)Tyr43、Tyr44、Arg46、Ala79、Asp80を含むヒトIL−17のエピトープに結合するIL−17抗体またはその抗原結合フラグメント、c)2つの成熟ヒトIL−17タンパク質鎖を有するIL−17ホモダイマーのエピトープに結合するIL−17抗体またはその抗原結合フラグメント(ただし、前記エピトープは、一方の鎖にLeu74、Tyr85、His86、Met87、Asn88、Val124、Thr125、Pro126、Ile127、Val128、His129、かつ他方の鎖にTyr43、Tyr44、Arg46、Ala79、Asp80を含む)、d)2つの成熟ヒトIL−17タンパク質鎖を有するIL−17ホモダイマーのエピトープに結合するIL−17抗体またはその抗原結合フラグメント(ただし、前記エピトープは、一方の鎖にLeu74、Tyr85、His86、Met87、Asn88、Val124、Thr125、Pro126、Ile127、Val128、His129、かつ他方の鎖にTyr43、Tyr44、Arg46、Ala79、Asp80を含み、IL−17結合分子は、約100〜200pMのKDを有し、IL−17結合分子は、約23〜約35日間のインビボ半減期を有する)およびe)i)配列番号8として示されるアミノ酸配列を含む免疫グロブリン重鎖可変ドメイン(VH)、ii)配列番号10として示されるアミノ酸配列を含む免疫グロブリン軽鎖可変ドメイン(VL)、iii)配列番号8として示されるアミノ酸配列を含む免疫グロブリンVHドメインおよび配列番号10として示されるアミノ酸配列を含む免疫グロブリンVLドメイン、iv)配列番号1、配列番号2および配列番号3として示される超可変領域を含む免疫グロブリンVHドメイン、v)配列番号4、配列番号5および配列番号6として示される超可変領域を含む免疫グロブリンVLドメイン、vi)配列番号11、配列番号12および配列番号13として示される超可変領域を含む免疫グロブリンVHドメイン、vii)配列番号1、配列番号2および配列番号3として示される超可変領域を含む免疫グロブリンVHドメイン、ならびに配列番号4、配列番号5および配列番号6として示される超可変領域を含む免疫グロブリンVLドメイン、viii)配列番号11、配列番号12および配列番号13として示される超可変領域を含む免疫グロブリンVHドメイン、ならびに配列番号4、配列番号5および配列番号6として示される超可変領域を含む免疫グロブリンVLドメイン、ix)配列番号14として示されるアミノ酸配列を含む免疫グロブリン軽鎖、x)配列番号15として示されるアミノ酸配列を含む免疫グロブリン重鎖、またはxi)配列番号14として示されるアミノ酸配列を含む免疫グロブリン軽鎖および配列番号15として示されるアミノ酸配列を含む免疫グロブリン重鎖を含む、IL−17抗体またはその抗原結合フラグメントからなる群から選択される。
イミキモドは、ヒトパピローマウイルスにより引き起こされる生殖器疣贅および会陰疣贅の局所治療に使用される。この療法の臨床適応は、他のウイルス関連皮膚異常、さらには前癌皮膚病変および癌性皮膚病変、たとえば化学線角化症および表在性基底細胞癌の治療を含むようにさらに拡大されてきた。臨床上、イミキモドは、化学線角化症および表在性基底細胞癌の局所治療時に以前に疾患が良好にコントロールされた患者において乾癬を悪化させる可能性があることが見出された。乾癬のイミキモド誘発悪化は、治療領域および興味深いことに以前に疾患の影響を受けなかった離れた皮膚部位の両方で起こる。そのため、乾癬に類似した皮膚病変を生じるイミキモドクリームによるマウスの処置は、疾患プロセスの早期に推定抗乾癬療法を研究するために使用可能である(van der Fits et al.(2009)J.Immunol 182:5836−5845)。
雌Balb/cマウス(8〜10週齢)を皮膚炎症モデルに使用した。5%イミキモド含有クリームまたは媒体クリームをマウスの剃毛背中に毎日適用した(全イミキモド用量12.5mg/マウス)。ディジタルキャリパーを用いて背中の皮膚厚さを毎日測定した。
雌Balb/cマウス(8〜10週齢)を耳炎症モデルに使用した。5%イミキモド含有クリームをマウス(全イミキモド用量12.5mg/マウス)の両耳に毎日適用した。ディジタルキャリパーを用いて両耳の耳厚さを毎日測定して平均した。
IL−17およびIL22を産生するTh17細胞の発生を駆動するサイトカインIL−23は、乾癬の病理発生に機能的に関与することが提案されてきた。(たとえば、van der Fits et al.(2009)J.Immunol 182:5836−5845を参照されたい)。乾癬皮膚病変ではIL−23の発現が増加し、数の増加したTh17細胞が存在する。マウス皮膚内にIL−23の皮内注射を行うと、紅斑、混合炎症浸潤物および表皮過形成を生じるとともに、注射を繰り返した後に注射部位に腫脹を生じる。IL−23およびIL−17は、両方とも乾癬の進行にクリティカルであることが明らかになっているため、早期乾癬の治療に有用であり得る療法を研究するために簡便かつ迅速な方法としてIL−23耳注射マウスモデルも使用可能である。
2つの第3相二重盲検52週試験ERASURE(乾癬における2つの固定セクキヌマブレジメンの反応有効性および安全性、CAIN457A2302)およびFIXTURE(乾癬における有効性を決定するための2つの投与レジメンを用いたセクキヌマブ対エタネルセプトの通年研究試験、CAIN457A2303)の設計の詳細および結果は、Langley et al.(2014)N Engl J Med 371:326−38に提示される。12週でPASI75基準を満たした患者の割合は、プラセボまたはエタネルセプトのときよりも各セクキヌマブ用量のときの方が高かった:ERASURE試験では、PASI75レートは、300mgのセクキヌマブのときに81.6%、150mgのセクキヌマブのときに71.6%およびプラセボのときに4.5%であり、FIXTURE試験では、レートは、300mgのセクキヌマブのときに77.1%、150mgのセクキヌマブのときに67.0%、エタネルセプトのときに44.0%およびプラセボのときに4.9%であった(各セクキヌマブ用量対コンパレーターに対してP<0.001)。12週で治験医師による修正グローバルアセスメント(IGA)の反応が0または1であった患者の割合は、プラセボまたはエタネルセプトのときよりも各セクキヌマブ用量のときの方が高かった:ERASURE試験では、レートは、300mgのセクキヌマブのときに65.3%、150mgのセクキヌマブのときに51.2%およびプラセボのときに2.4%であり、FIXTURE試験では、レートは、300mgのセクキヌマブのときに62.5%、150mgのセクキヌマブのときに51.1%、エタネルセプトのとき27.2%およびプラセボのときに2.8%であった(各セクキヌマブ用量対コンパレーターに対してP<0.001)。セクキヌマブのときの感染率は、両方の試験ともプラセボのときよりも高く、エタネルセプトのときと類似していた。
Claims (16)
- 中度〜重度の初発プラーク型乾癬を有する患者を治療する方法であって、0、1、2および3週に皮下注射により、続いて4週から始めて毎月1回の投与により、約150mgまたは約300mgのセクキヌマブを前記患者に投与することを含む方法。
- 前記患者は、生物剤ナイーブである、請求項1に記載の方法。
- 0、1、2および3週に皮下注射により、続いて4週から始めて毎月1回の投与により、約300mgのセクキヌマブを前記患者に投与することを含む、請求項に記載の方法。
- 中度〜重度の初発プラーク型乾癬を有する患者の病変皮膚の組織常在メモリー細胞の数を低減する方法であって、0、1、2および3週に皮下注射により、続いて4週から始めて毎月1回の投与により、約150mgまたは約300mgのセクキヌマブを前記患者に投与することを含み、前記患者は、生物剤ナイーブである、方法。
- 初発プラーク型乾癬を有する患者を治療する方法であって、治療有効量のIL−17抗体またはその抗原結合フラグメントを、それを必要とする患者に投与することを含み、前記IL−17抗体またはその抗原結合フラグメントは、2つの成熟ヒトIL−17タンパク質鎖を有するIL−17ホモダイマーのエピトープに結合し、前記エピトープは、一方の鎖にLeu74、Tyr85、His86、Met87、Asn88、Val124、Thr125、Pro126、Ile127、Val128、His129、かつ他方の鎖にTyr43、Tyr44、Arg46、Ala79、Asp80を含み、前記IL−17抗体またはその抗原結合フラグメントは、約100〜200pMのKDを有し、前記IL−17抗体またはその抗原結合フラグメントは、約4週間のインビボ半減期を有する、方法。
- 初発プラーク型乾癬を有する患者の皮膚で乾癬疾患慢性性を引き起こす免疫機序をモジュレートする方法であって、治療有効量のIL−17抗体またはその抗原結合フラグメントを、それを必要とする患者に投与することを含み、前記IL−17抗体またはその抗原結合フラグメントは、2つの成熟ヒトIL−17タンパク質鎖を有するIL−17ホモダイマーのエピトープに結合し、前記エピトープは、一方の鎖にLeu74、Tyr85、His86、Met87、Asn88、Val124、Thr125、Pro126、Ile127、Val128、His129、かつ他方の鎖にTyr43、Tyr44、Arg46、Ala79、Asp80を含み、前記IL−17抗体またはその抗原結合フラグメントは、約100〜200pMのKDを有し、前記IL−17抗体またはその抗原結合フラグメントは、約4週間のインビボ半減期を有する、方法。
- 前記患者は、中度〜重度の初発プラーク型乾癬を有する、請求項5または6に記載の方法。
- 前記患者は、以前に乾癬の全身治療で治療されていない、請求項5〜7のいずれか一項に記載の方法。
- 前記患者は、生物剤ナイーブである、請求項5〜7のいずれか一項に記載の方法。
- 前記患者は、以前に乾癬の光線療法で治療されていない、請求項5〜9のいずれか一項に記載の方法。
- 0、1、2および3週に皮下注射により、続いて4週から始めて毎月1回の投与により、約150mg〜約300mgの前記IL−17抗体またはその抗原結合フラグメントを前記患者に投与することを含む、請求項5〜10のいずれか一項に記載の方法。
- 0、1、2および3週に皮下注射により、続いて4週から始めて毎月1回の投与により、約150mgの前記IL−17抗体またはその抗原結合フラグメントを前記患者に投与することを含む、請求項5〜11のいずれか一項に記載の方法。
- 0、1、2および3週に皮下注射により、続いて4週から始めて毎月1回の投与により、約300mgの前記IL−17抗体またはその抗原結合フラグメントを前記患者に投与することを含む、請求項5〜11のいずれか一項に記載の方法。
- 前記IL−17抗体またはその抗原結合フラグメントは、
i)配列番号8として示されるアミノ酸配列を含む免疫グロブリン重鎖可変ドメイン(VH)、
ii)配列番号10として示されるアミノ酸配列を含む免疫グロブリン軽鎖可変ドメイン(VL)、
iii)配列番号8として示される前記アミノ酸配列を含む免疫グロブリンVHドメインおよび配列番号10として示される前記アミノ酸配列を含む免疫グロブリンVLドメイン、
iv)配列番号1、配列番号2および配列番号3として示される超可変領域を含む免疫グロブリンVHドメイン、
v)配列番号4、配列番号5および配列番号6として示される超可変領域を含む免疫グロブリンVLドメイン、
vi)配列番号11、配列番号12および配列番号13として示される超可変領域を含む免疫グロブリンVHドメイン、
vii)配列番号1、配列番号2および配列番号3として示される前記超可変領域を含む免疫グロブリンVHドメイン、ならびに配列番号4、配列番号5および配列番号6として示される前記超可変領域を含む免疫グロブリンVLドメイン、
viii)配列番号11、配列番号12および配列番号13として示される前記超可変領域を含む免疫グロブリンVHドメイン、ならびに配列番号4、配列番号5および配列番号6として示される前記超可変領域を含む免疫グロブリンVLドメイン、
ix)配列番号14として示されるアミノ酸配列を含む免疫グロブリン軽鎖、
x)配列番号15として示されるアミノ酸配列を含む免疫グロブリン重鎖、または
xi)配列番号14として示される前記アミノ酸配列を含む免疫グロブリン軽鎖および配列番号15として示される前記アミノ酸配列を含む免疫グロブリン重鎖
を含む、請求項5〜13のいずれか一項に記載の方法。 - 前記IL−17抗体またはその抗原結合フラグメントは、ヒト抗体またはヒト化抗体である、請求項14に記載の方法。
- 前記IL−17抗体またはその抗原結合フラグメントは、セクキヌマブである、請求項15に記載の方法。
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AU2020225202B2 (en) | 2019-02-18 | 2023-10-26 | Eli Lilly And Company | Therapeutic antibody formulation |
WO2021018191A1 (zh) * | 2019-07-30 | 2021-02-04 | 江苏恒瑞医药股份有限公司 | Il-17拮抗剂治疗自身免疫疾病的方法 |
EP3797779A1 (en) * | 2019-09-30 | 2021-03-31 | Servei de Salut de Les Illes Balears - Ibsalut | Combined therapy comprising an inhibitor of interleukin-17 activity and a vitamin d receptor agonist |
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RU2430110C2 (ru) | 2006-01-31 | 2011-09-27 | Новартис Аг | Антитела - антагонисты интерлейкина-17 (ил-17) для лечения рака |
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SG11201505330QA (en) | 2013-02-08 | 2015-08-28 | Novartis Ag | Anti-il-17a antibodies and their use in treating autoimmune and inflammatory disorders |
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JP2023064023A (ja) * | 2021-10-25 | 2023-05-10 | 良丹 孫 | 乾癬を治療/抑制するための医薬の製造における試薬の使用 |
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US20190194311A1 (en) | 2019-06-27 |
CN109476733A (zh) | 2019-03-15 |
WO2018015880A1 (en) | 2018-01-25 |
US20230303677A1 (en) | 2023-09-28 |
JP2024001125A (ja) | 2024-01-09 |
JP2022126791A (ja) | 2022-08-30 |
EP3487881A1 (en) | 2019-05-29 |
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