JP6893223B2 - 医薬品組成物およびキット - Google Patents
医薬品組成物およびキット Download PDFInfo
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- JP6893223B2 JP6893223B2 JP2019075388A JP2019075388A JP6893223B2 JP 6893223 B2 JP6893223 B2 JP 6893223B2 JP 2019075388 A JP2019075388 A JP 2019075388A JP 2019075388 A JP2019075388 A JP 2019075388A JP 6893223 B2 JP6893223 B2 JP 6893223B2
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- Peptides Or Proteins (AREA)
Description
配列番号1(SM101)
MAPPKAVLKL EPQWINVLQE DSVTLTCRGT HSPESDSIQW FHNGNLIPTH
TQPSYRFKAN NNDSGEYTCQ TGQTSLSDPV HLTVLSEWLV LQTPHLEFQE
GETIVLRCHS WKDKPLVKVT FFQNGKSKKF SRSDPNFSIP QANHSHSGDY
HCTGNIGYTL YSSKPVTITV QAPSSSP
配列番号1に示されるアミノ酸配列において、位置1(すなわち、アミノ酸配列の始点)でのM(メチオニン)残基は欠落してもよい。この変異体のアミノ酸配列は、配列番号11としてここに開示される。
配列番号2(SM101、cDNA)
1 ATGGCACCGC CGAAAGCAGT TCTGAAACTG GAACCGCAGT GGATTAACGT TCTGCAGGAA
61 GATAGCGTTA CCCTGACCTG TCGTGGCACC CATAGCCCGG AAAGCGATAG CATTCAGTGG
121 TTTCACAACG GCAATCTGAT TCCGACCCAT ACCCAGCCGA GCTATCGTTT TAAAGCGAAC
181 AACAACGATA GCGGCGAATA TACCTGTCAG ACCGGTCAGA CCAGCCTGAG CGATCCGGTT
241 CATCTGACCG TTCTGAGCGA ATGGCTGGTT CTGCAGACCC CGCATCTGGA ATTTCAGGAA
301 GGCGAAACCA TTGTTCTGCG TTGCCACAGC TGGAAAGATA AACCGCTGGT TAAAGTTACC
361 TTCTTCCAGA ACGGCAAAAG CAAAAAATTC AGCCGTAGCG ATCCGAATTT TAGCATTCCG
421 CAGGCGAATC ATAGCCATAG CGGCGATTAT CATTGTACCG GCAACATTGG CTATACCCTG
481 TATAGCAGCA AACCGGTGAC CATTACCGTT CAGGCGCCGA GCAGCAGCCC GTAA
配列番号3(ヒトFcγRIIB)
MGTPAAPPKA VLKLEPQWIN VLQEDSVTLT CRGTHSPESD SIQWFHNGNL IPTHTQPSYR FKANNNDSGE YTCQTGQTSL SDPVHLTVLS EWLVLQTPHL EFQEGETIVL RCHSWKDKPL VKVTFFQNGK SKKFSRSDPN FSIPQANHSH SGDYHCTGNI GYTLYSSKPV TITVQAPSSS P
配列番号4(ヒトFcγRIIB、cDNA)
1 atggggacac ctgcagctcc cccaaaggct gtgctgaaac tcgagcccca gtggatcaac 61 gtgctccagg aggactctgt gactctgaca tgccggggga ctcacagccc tgagagcgac121 tccattcagt ggttccacaa tgggaatctc attcccaccc acacgcagcc cagctacagg181 ttcaaggcca acaacaatga cagcggggag tacacgtgcc agactggcca gaccagcctc241 agcgaccctg tgcatctgac tgtgctttct gagtggctgg tgctccagac ccctcacctg301 gagttccagg agggagaaac catcgtgctg aggtgccaca gctggaagga caagcctctg361 gtcaaggtca cattcttcca gaatggaaaa tccaagaaat tttcccgttc ggatcccaac421 ttctccatcc cacaagcaaa ccacagtcac agtggtgatt accactgcac aggaaacata481 ggctacacgc tgtactcatc caagcctgtg accatcactg tccaagctcc cagctcttca
541 ccg
配列番号5(ヒトFcγRIIA)
MGTPAAPPKA VLKLEPPWIN VLQEDSVTLT CQGARSPESD SIQWFHNGNL IPTHTQPSYR
FKANNNDSGE YTCQTGQTSL SDPVHLTVLS EWLVLQTPHL EFQEGETIML RCHSWKDKPL
VKVTFFQNGK SQKFSHLDPT FSIPQANHSH SGDYHCTGNI GYTLFSSKPV TITVQVPSMG
SSSP
配列番号6(ヒトFcγRIIA、cDNA)
1 atggggacac ctgcagctcc cccaaaggct gtgctgaaac ttgagccccc gtggatcaac 61 gtgctccagg aggactctgt gactctgaca tgccaggggg ctcgcagccc tgagagcgac121 tccattcagt ggttccacaa tgggaatctc attcccaccc acacgcagcc cagctacagg181 ttcaaggcca acaacaatga cagcggggag tacacgtgcc agactggcca gaccagcctc241 agcgaccctg tgcatctgac tgtgctttcc gaatggctgg tgctccagac ccctcacctg301 gagttccagg agggagaaac catcatgctg aggtgccaca gctggaagga caagcctctg361 gtcaaggtca cattcttcca gaatggaaaa tcccagaaat tctcccattt ggatcccacc421 ttctccatcc cacaagcaaa ccacagtcac agtggtgatt accactgcac aggaaacata481 ggctacacgc tgttctcatc caagcctgtg accatcactg tccaagtgcc cagcatgggc541 agctcttcac caat
配列番号7(ヒトFcγRIIIA)
MDLPKAVVFL EPQWYRVLEK DSVTLKCQGA YSPEDNSTQWF HNESLISSQA SSYFIDAATV DDSGEYRCQ TNLSTLSDPV QLEVHIGWLL LQAPRWVFKEE DPIHLRCHSW KNTALHKVTY LQNGKGRKY FHHNSDFYIP KATLKDSGSY FCRGLVGSKNV SSETVNITIT QGLSVSTISS F
配列番号8(ヒトFcγRIIIA、cDNA)
1 atggatctcccaa aggctgtggt gttcctggag cctcaatggt acagggtgct cgagaaggac 61 agtgtgactc tgaagtgcca gggagcctac tcccctgagg acaattccac acagtggttt121 cacaatgaga gcctcatctc aagccaggcc tcgagctact tcattgacgc tgccacagtt181 gacgacagtg gagagtacag gtgccagaca aacctctcca ccctcagtga cccggtgcag241 ctagaagtcc atatcggctg gctgttgctc caggcccctc ggtgggtgtt caaggaggaa301 gaccctattc acctgaggtg tcacagctgg aagaacactg ctctgcataa ggtcacatat361 ttacagaatg gcaaaggcag gaagtatttt catcataatt ctgacttcta cattccaaaa421 gccacactca aagacagcgg ctcctacttc tgcagggggc ttgttgggag taaaaatgtg481 tcttcagaga ctgtgaacat caccatcact caaggtttgt cagtgtcaac catctcatca541 ttc
配列番号9(ヒトFcγRIIIB)
MDLPKAVVFLE PQWYSVLEKD SVTLKCQGAY SPEDNSTQWF HNENLISSQA SSYFIDAATVNDSGEYRCQT NLSTLSDPVQ LEVHIGWLLL QAPRWVFKEE DPIHLRCHSW KNTALHKVTYLQNGKDRKYF HHNSDFHIPK ATLKDSGSYF CRGLVGSKNV SSETVNITIT QGLAVSTISSF
配列番号10(ヒトFcγRIIIB、cDNA)
1 atggatctcc caaaggctgt ggtgttcctg gagcctcaat ggtacagcgt gcttgagaag 61 gacagtgtga ctctgaagtg ccagggagcc tactcccctg aggacaattc cacacagtgg 121 tttcacaatg agaacctcat ctcaagccag gcctcgagct acttcattga cgctgccaca 181 gtcaacgaca gtggagagta caggtgccag acaaacctct ccaccctcag tgacccggtg 241 cagctagaag tccatatcgg ctggctgttg ctccaggccc ctcggtgggt gttcaaggag 301 gaagacccta ttcacctgag gtgtcacagc tggaagaaca ctgctctgca taaggtcaca 361 tatttacaga atggcaaaga caggaagtat tttcatcata attctgactt ccacattcca 421 aaagccacac tcaaagatag cggctcctac ttctgcaggg ggcttgttgg gagtaaaaat 481 gtgtcttcag agactgtgaa catcaccatc actcaaggtt tggcagtgtc aaccatctca 541 tcattc
配列番号11(SM101変異体)
APPKAVLKL EPQWINVLQE DSVTLTCRGT HSPESDSIQW FHNGNLIPTH
TQPSYRFKAN NNDSGEYTCQ TGQTSLSDPV HLTVLSEWLV LQTPHLEFQE
GETIVLRCHS WKDKPLVKVT FFQNGKSKKF SRSDPNFSIP QANHSHSGDY
HCTGNIGYTL YSSKPVTITV QAPSSSP
配列番号1に示されるアミノ酸配列において、位置1(すなわち、アミノ酸配列の始点)でのM(メチオニン)残基は欠落してもよい。この変異体のアミノ酸配列は、配列番号11としてここに開示されており、本発明の好適なアミノ酸配列である。
配列番号12(SM101変異体、cDNA)
1 GCACCGC CGAAAGCAGT TCTGAAACTG GAACCGCAGT GGATTAACGT TCTGCAGGAAGAT
61 AGCGTTA CCCTGACCTG TCGTGGCACC CATAGCCCGG AAAGCGATAG CATTCAGTGGTTT
121 CACAACG GCAATCTGAT TCCGACCCAT ACCCAGCCGA GCTATCGTTT TAAAGCGAACAAC
181 AACGATA GCGGCGAATA TACCTGTCAG ACCGGTCAGA CCAGCCTGAG CGATCCGGTTCAT
241 CTGACCG TTCTGAGCGA ATGGCTGGTT CTGCAGACCC CGCATCTGGA ATTTCAGGAAGGC
301 GAAACCA TTGTTCTGCG TTGCCACAGC TGGAAAGATA AACCGCTGGT TAAAGTTACCTTC
361 TTCCAGA ACGGCAAAAG CAAAAAATTC AGCCGTAGCG ATCCGAATTT TAGCATTCCGCAG
421 GCGAATC ATAGCCATAG CGGCGATTAT CATTGTACCG GCAACATTGG CTATACCCTGTAT
481 AGCAGCA AACCGGTGAC CATTACCGTT CAGGCGCCGA GCAGCAGCCC GTAA
本発明者らは、驚くべきことに、FcガンマRIIレセプタ(sCD32=SM101)、特に好適には、ここに記載されたようにSM101であるsCD32がインビトロでIgG免疫複合体(IC)により活性化された好中球からの反応性酸素種(ROS)の放出を抑制することが可能であることを見出した。また、sCD32は、末梢血単核細胞(PBMCs)の存在下で水疱性類天疱瘡患者の血清とともにインキュベートしたヒト皮膚における低温切片上での真皮−表皮分離を減少させることができる。目立つこととして、sCD32の有望な治療上の可能性は、後天性表皮水疱症(EBA)のマウスモデルにおいて確認され得るものであり:コントロールと比較して、sCD32が臨床疾患重症度を顕著に減少させ、組織学的には、真皮白血球浸潤での顕著な減少および循環型の抗原特異的自己抗体でのおよそ20%の減少である。これらの有望な結果は、可溶性Fcガンマレセプタが自己免疫水疱性疾患の治療のための重要な可能性を有することを示唆している。
他のいずれかに記載されたように、ヒトsCD32(SM101)を発現させ、精製した(ゾンダーマンおよびヤコブ(Sondermann and Jacob)、1999)。
(実施例2.1:維持)
SJL/Jマウスをジャクソンラボラトリーズ(The Jackson Laboratories)(バーハーバー(Bar Harbor)、メイン州)から入手した。動物に酸性化飲料水および標準固型飼料を自由に与え、リューベック大学(University of Lubeck)の動物施設において、12時間毎の明暗サイクルで維持した。8−10週齢のマウスを実験に用いた。全ての臨床検査、生検および採血を、ケタミン(100μg/g)およびキシラジン(15μg/g)の混合物の腹腔内投与による麻酔下で行った。実験は、動物保護および使用委員会(the Animal Care and Use Committee)(キール、ドイツ(Kiel, Germany))により承認されており、認証された職員により行われた。
免疫化および評価を既に報告されたように行った(イワタら(Iwata et al.)、2013)。簡潔には、非イオン性ブロック共重合体のアジュバントであるタイターマックス(TiterMax、アレクシス バイオケミカルス(ALEXIS Biochemicals))中で乳化したCOL7の組換え型マウスvWFA2ドメインの60μgによりマウスを後足肉球(hind footpad)で免疫化した(ラインウェーバーら(Leineweber et al.)、2011)。皮膚障害(すなわち、紅斑、水疱、びらん、脱毛および痂皮)の存在について毎週マウスを評価した。疾患重症度を皮膚障害により影響された体表面積のパーセンテージとして表し、観察期間中の総合疾患重症度をその観察期間中に記録した疾患重症度の曲線の下側面積(AUC)として算出した。相対疾患スコアを割り当て治療(allocation treatment)での疾患スコアとして算出した。体表面積の2%またはそれ以上が皮膚障害により影響されたときに、sCD32またはPBSでの治療的処置を腹腔内注入により開始した。マウスを200μgのsCD32で毎週治療し、コントロールのマウスをPBSで行った。血清を毎週収集した。血清、耳の皮膚、尾の皮膚のサンプルを治療4週後の最終日に採取し、病理組織学および免疫蛍光(IF)顕微鏡による検査用に調製した。
(実施例3.1:ROS産生)
水疱性類天疱瘡の自己抗体による反応性酸素種(ROS)放出能力を、以前に報告されたように(ユゥら(Yu et al.)、2010)、エクスビボでのアッセイを用いて評価した。簡潔には、ROS産生を調査するために、96ウェルプレート(マキシソーブ(Maxisorb);ヌンク(Nunc)、ロスキレ(Roskilde)、デンマーク)における500ngのヒトIgG(50μL×10μg/mL)の4℃、一晩でのインキュベーションにより、免疫複合体(IC)を生成させた。プレートを洗浄後、sCD32の0.01、0.1および0.5mg/mLの存在下または不在下で、新たに分離したヒト好中球を添加した(50μL×107cells/mL)。ROSの産生を計測するために、好中球の活性化をプレートリーダ(ビクター3(VICTOR3)、パーキンエルマ(PerkinElmer)、サンタクララ(Santa Clara)、カリフォルニア州)で評価した。
この調査では、水疱性類天疱瘡の患者21人からの血清サンプルを用いた。全ての患者は以下の組み入れ基準:(i)皮膚の水疱形成疾患の臨床画像、(ii)1Mの食塩分離した正常ヒト皮膚において、間接免疫蛍光(IF)顕微鏡により示されるような、水疱の表皮側に対するIgG自己抗体の結合、(iii)ELISAによるNC16Aに対する反応性、を満たしている。健康なボランティアからの血清をネガティブコントロールとして用いた。全ての手続の前に、全ての患者およびコントロールから書面のインフォームドコンセントを得た。この調査は、リューベック大学倫理委員会により承認されており、ヘルシンキ宣言に従い行われた。
耳の皮膚のサンプルを4%緩衝ホルマリン中で固定した。パラフィン埋め込み組織からの厚さ4μmの切片をH&Eで染色した。組織学的に、相対真皮浸潤を0(浸潤なし)、1(軽度、mild)、2(中間度、intermediate)および3(重度、severe)で盲検的に(blindly)定量化した。ウサギIgG(ダコ・サイトメーション、DakoCytomation)およびマウス(murine)C3(カペル オルガノン−テクニカ、Cappel Organon-Teknika)に特異的な100倍希釈したFITCラベル抗体を用いて、組織生検から調製した6μmの凍結切片上での直接IF顕微鏡法により組織結合抗体を検出した。バックグラウンド除去用に真皮の蛍光を用い、DEJでの蛍光強度をイメージJ(ImageJ、http://rsbweb.nih.gov/ij/)により測定した。
血清抗−vWFA2抗体レベルを、既に報告されたように(イワタら(Iwata H et al.)、2013)、ELISAにより計測した。マウスIgGのELISA定量化セット(ベチルラボラトリーズ(Bethyl Laboratories)、モンゴメリー(Montgomery)、テキサス州)により、製造者の指示に従い、全IgGを計測した。
PBSで治療したマウスと比較して、sCD32での治療は循環性抗原特異的自己抗体においておよそ20%の減少を示したものの(図5、p=0.048、t−検定)、全IgGでは顕著な差異がなかった(データ未掲載)。同じ時点で、全てのマウスは、直接免疫蛍光により測定されたように、DEJで同様のIgG沈着を示した(図6A)。DIFの代表的な写真は、DEJでのIgG沈着を示す(図6B)。循環型自己抗体および組織結合型自己抗体間のこの不一致は、異なる半減期に起因するかもしれない(カスペルキーヴィッツら(Kasperkiewicz et al.)、2010)。
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Claims (8)
- 対象での自己免疫水疱性疾患の治療の方法で使用される、可溶性ヒトFcガンマレセプタを含む医薬品組成物であって、前記レセプタは、配列番号:1または配列番号:11に示されるアミノ酸配列からなり、1から30mg/kgまでの用量で投与されることを特徴とする医薬品組成物。
- 前記対象は、ヒトであることを特徴とする請求項1に記載の医薬品組成物。
- 前記レセプタは、静脈内または皮内に投与されることを特徴とする請求項1または請求項2に記載の医薬品組成物。
- 前記レセプタは、繰り返し投与されることを特徴とする請求項1ないし請求項3のいずれか1項に記載の医薬品組成物。
- 前記疾患は、尋常性天疱瘡、落葉状天疱瘡、水疱性類天疱瘡、粘膜類天疱瘡、妊娠性疱疹、粘膜類天疱瘡、線状IgA疾患、扁平苔癬類天疱瘡、後天性表皮水疱症、疱疹状皮膚炎および水疱性全身エリテマトーデスのグループから選択されることを特徴とする請求項1ないし請求項4のいずれか1項に記載の医薬品組成物。
- 抗炎症剤、免疫抑制剤および/または抗−CD20抗体のグループから選択される1またはそれ以上の薬剤を薬学的に容認できるキャリアまたは希釈剤とともにさらに含むことを特徴とする請求項1ないし請求項5のいずれか1項に記載の医薬品組成物。
- 自己免疫水疱性疾患の治療の方法で使用される、可溶性Fcガンマレセプタを含むキットであって、前記レセプタは、配列番号:1または配列番号:11に示されるアミノ酸配列からなり、1から30mg/kgまでの用量で投与されることを特徴とするキット。
- 抗炎症剤、免疫抑制剤および/または抗−CD20抗体のグループから選択される1またはそれ以上の薬剤を薬学的に容認できるキャリアまたは希釈剤とともにさらに含むことを特徴とする請求項7に記載のキット。
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