JP6527565B2 - 脱毛障害を処置するための方法 - Google Patents
脱毛障害を処置するための方法 Download PDFInfo
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- JP6527565B2 JP6527565B2 JP2017176433A JP2017176433A JP6527565B2 JP 6527565 B2 JP6527565 B2 JP 6527565B2 JP 2017176433 A JP2017176433 A JP 2017176433A JP 2017176433 A JP2017176433 A JP 2017176433A JP 6527565 B2 JP6527565 B2 JP 6527565B2
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Description
単数形の用語は、文脈により他に明確に指示されない限り、複数形の言及を含む。
外皮(又は皮膚)は、体で最大の器官であり、体の外面を覆う高度に複雑な器官である。外皮は、多様な体の開口部において、消化管及び他の管の粘膜と統合されている。外皮は、体温及び水分の喪失;汗腺による排出の制御により定常的な内部環境を維持することなど、多数の不可欠な機能を果たすが、物理的、化学的、及び生物学的作用物質の深部組織への作用に対する防御障壁として主に作用する。皮膚は、弾性があり、足底、手掌、及び耳など、少数の領域を除き、深部組織に緩やかに接合されている。皮膚はまた、眼瞼(「薄い皮膚」)における0.5mm(0.02インチ)から、手掌及び足底(「厚い皮膚」)における4mm(0.17インチ)以上まで厚さも変化する(Ross MH、「Histology: A text and atlas」、3版、Williams and Wilkins、1995: 14章; Burkitt HGら、「Wheater's Functional Histology」、3版、Churchill Livingstone、1996: 9章)。
円形脱毛症(AA)は、最も蔓延している自己免疫疾患のうちの1つであり、米国だけで、全ての人種群にわたる男性及び女性を含む約460万人に影響を及ぼし、生涯の危険率は1.7%である(1)。AAでは、毛包に対する自己免疫が発生することから、斑点として始まり、融合し、進行して、頭皮全体を覆い(完全脱毛症;AT、最終的に全身を覆う(全身性脱毛症;AU)場合もある、非瘢痕性脱毛がもたらされる。AAは紀元後30年にコルネリウス・ケルススにより最初に記載され、頭皮にわたりゆっくりと広がるときの、脱毛の蛇行する斑点のために、「蛇」を意味する「ophiasis(蛇行状脱毛)」という用語が使用された。「アロペキア(キツネ疥癬)」というギリシャ語を最初に使用したのはヒポクラテスであったが、現代の「円形脱毛症」という用語はSauvagesが1760年にフランスのリヨンで刊行された彼の「Nosologica Medica」中で最初に使用した。
本発明は、知られている治療剤、例えば、Jak 3などのサイトカインシグナル伝達に関与するタンパク質チロシンキナーゼ(PTK)の阻害剤を、脱毛障害の処置に使用し得るという発見を提供する。脱毛障害の非限定的な例として、男性型脱毛症、円形脱毛症、休止期脱毛、円形脱毛症、完全脱毛症、及び全身性脱毛症が挙げられる。例えば、男性型脱毛症(また、女性男性型脱毛症とも呼ばれる)は、男性及び女性の両方において一般的な脱毛の形態であり、結果として毛が薄くなり、頭皮の脱毛がもたらされる。例えば、円形脱毛症(AA)は典型的に、頭皮又は体の他の部分における脱毛の斑点で始まる。AAが処置されていないか、又は処置に対して応答性でない場合は、罹患した領域における脱毛(例えば、完全脱毛症)がもたらされ得る。完全脱毛症(AT)並びに全身性脱毛症(AU)は、円形脱毛症(AA)の重篤な形態である。AUは、円形脱毛症の最も重篤な形態である。例えば、Choら(2012)、J Korean Med Sci、27: 799〜802を参照されたい。
本発明は、被験体が、脱毛障害に対して感受性であるか、又はこれを有するのかどうかを診断する方法を提供する。一実施形態では、診断法は、被験体における、CSF1R、FCER2、IFNGR1、IL20、OAS1、PTPRC、CEBPD、CRP、IL2RA、IL4、IL6ST、INSR、JAK3、NR3C1、OSM、PTPN11、SOCS3、STAT5A、STAT5B、CCND1、F2、LRG1、PRLR、MPL、又はJUNBなどのTAHC遺伝子の発現、例えば、それらが正常試料と比較して増大するのか減少するのかをモニタリングすることに基づく。本明細書で使用される「診断」という用語は、成体及び小児における早期段階、前症状段階、及び後期段階を含む多様な段階における検出、分類、モニタリング、投薬、比較を含む。診断は、発症の素因又は危険性の評価、予後診断、又は最も適切な処置(薬理遺伝学)を規定するための被験体の特徴づけを含み得る。
他に示されない限り、本発明の態様の実施は、当技術分野の範囲内にある細胞生物学、細胞培養、分子生物学、トランスジェニック生物学、微生物学、組換えDNA、及び免疫学の従来の技術を用いることができる。このような技術は、文献中で完全に説明されている。例えば、「Molecular Cloning A Laboratory Manual」、3版、Sambrook、Fritsch、及びManiatis編(2001)(Cold Spring Harbor Laboratory Press: 1989);「DNA Cloning」、I及びII巻(D. N. Glover編、1985);「Oligonucleotide Synthesis」(M. J. Gait編、1984); Mullisら、米国特許第4,683,195号;「Nucleic Acid Hybridization」(B. D. Hames及びS. J. Higgins編、1984);「Transcription and Translation」(B. D. Hames及びS. J. Higgins編、1984);「Culture Of Animal Cells」(R. I. Freshney、Alan R. Liss, Inc.、1987);「Immobilized Cells and Enzymes」(IRL Press、1986); B. Perbal、「A Practical Guide To Molecular Cloning」(1984);「Methods In Enzymology」(Academic Press, Inc.、N.Y.)、とりわけ、「Methods In Enzymology」、154及び155巻(Wuら編);「Gene Transfer Vectors For Mammalian Cells」(J. H. Miller及びM. P. Calos編、1987、Cold Spring Harbor Laboratory);「Immunochemical Methods In Cell And Molecular Biology」(Caner及びWalker編、Academic Press、London、1987);「Handbook Of Experimental Immunology」、I〜IV巻(D. M. Weir及びC. C. Blackwell編、1986);「Manipulating the Mouse Embryo」(Cold Spring Harbor Laboratory Press、Cold Spring Harbor、N.Y.、1986)を参照されたい。本明細書で引用される全ての特許、特許出願、及び参考文献は、参照によりそれらの全体において組み込まれる。
1 MAPPSEETPL IPQRSCSLLS TEAGALHVLL PARGPGPPQR LSFSFGDHLA EDLCVQAAKA
61 SGILPVYHSL FALATEDLSC WFPPSHIFSV EDASTQVLLY RIRFYFPNWF GLEKCHRFGL
121 RKDLASAILD LPVLEHLFAQ HRSDLVSGRL PVGLSLKEQG ECLSLAVLDL ARMAREQAQR
181 PGELLKTVSY KACLPPSLRD LIQGLSFVTR RRIRRTVRRA LRRVAACQAD RHSLMAKYIM
241 DLERLDPAGA AETFHVGLPG ALGGHDGLGL LRVAGDGGIA WTQGEQEVLQ PFCDFPEIVD
301 ISIKQAPRVG PAGEHRLVTV TRTDNQILEA EFPGLPEALS FVALVDGYFR LTTDSQHFFC
361 KEVAPPRLLE EVAEQCHGPI TLDFAINKLK TGGSRPGSYV LRRSPQDFDS FLLTVCVQNP
421 LGPDYKGCLI RRSPTGTFLL VGLSRPHSSL RELLATCWDG GLHVDGVAVT LTSCCIPRPK
481 EKSNLIVVQR GHSPPTSSLV QPQSQYQLSQ MTFHKIPADS LEWHENLGHG SFTKIYRGCR
541 HEVVDGEARK TEVLLKVMDA KHKNCMESFL EAASLMSQVS YRHLVLLHGV CMAGDSTMVQ
601 EFVHLGAIDM YLRKRGHLVP ASWKLQVVKQ LAYALNYLED KGLPHGNVSA RKVLLAREGA
661 DGSPPFIKLS DPGVSPAVLS LEMLTDRIPW VAPECLREAQ TLSLEADKWG FGATVWEVFS
721 GVTMPISALD PAKKLQFYED RQQLPAPKWT ELALLIQQCM AYEPVQRPSF RAVIRDLNSL
781 ISSDYELLSD PTPGALAPRD GLWNGAQLYA CQDPTIFEER HLKYISQLGK GNFGSVELCR
841 YDPLGDNTGA LVAVKQLQHS GPDQQRDFQR EIQILKALHS DFIVKYRGVS YGPGRQSLRL
901 VMEYLPSGCL RDFLQRHRAR LDASRLLLYS SQICKGMEYL GSRRCVHRDL AARNILVESE
961 AHVKIADFGL AKLLPLDKDY YVVREPGQSP IFWYAPESLS DNIFSRQSDV WSFGVVLYEL
1021 FTYCDKSCSP SAEFLRMMGC ERDVPALCRL LELLEEGQRL PAPPACPAEV HELMKLCWAP
1081 SPQDRPSFSA LGPQLDMLWS GSRGCETHAF TAHPEGKHHS LSFS
1 cacacaggaa ggagccgagt gggactttcc tctcgctgcc tcccggctct gcccgccctt
61 cgaaagtcca gggtccctgc ccgctaggca agttgcactc atggcacctc caagtgaaga
121 gacgcccctg atccctcagc gttcatgcag cctcttgtcc acggaggctg gtgccctgca
181 tgtgctgctg cccgctcggg gccccgggcc cccccagcgc ctatctttct cctttgggga
241 ccacttggct gaggacctgt gcgtgcaggc tgccaaggcc agcggcatcc tgcctgtgta
301 ccactccctc tttgctctgg ccacggagga cctgtcctgc tggttccccc cgagccacat
361 cttctccgtg gaggatgcca gcacccaagt cctgctgtac aggattcgct tttacttccc
421 caattggttt gggctggaga agtgccaccg cttcgggcta cgcaaggatt tggccagtgc
481 tatccttgac ctgccagtcc tggagcacct ctttgcccag caccgcagtg acctggtgag
541 tgggcgcctc cccgtgggcc tcagtctcaa ggagcagggt gagtgtctca gcctggccgt
601 gttggacctg gcccggatgg cgcgagagca ggcccagcgg ccgggagagc tgctgaagac
661 tgtcagctac aaggcctgcc tacccccaag cctgcgcgac ctgatccagg gcctgagctt
721 cgtgacgcgg aggcgtattc ggaggacggt gcgcagagcc ctgcgccgcg tggccgcctg
781 ccaggcagac cggcactcgc tcatggccaa gtacatcatg gacctggagc ggctggatcc
841 agccggggcc gccgagacct tccacgtggg cctccctggg gcccttggtg gccacgacgg
901 gctggggctg ctccgcgtgg ctggtgacgg cggcatcgcc tggacccagg gagaacagga
961 ggtcctccag cccttctgcg actttccaga aatcgtagac attagcatca agcaggcccc
1021 gcgcgttggc ccggccggag agcaccgcct ggtcactgtt accaggacag acaaccagat
1081 tttagaggcc gagttcccag ggctgcccga ggctctgtcg ttcgtggcgc tcgtggacgg
1141 ctacttccgg ctgaccacgg actcccagca cttcttctgc aaggaggtgg caccgccgag
1201 gctgctggag gaagtggccg agcagtgcca cggccccatc actctggact ttgccatcaa
1261 caagctcaag actgggggct cacgtcctgg ctcctatgtt ctccgccgca gcccccagga
1321 ctttgacagc ttcctcctca ctgtctgtgt ccagaacccc cttggtcctg attataaggg
1381 ctgcctcatc cggcgcagcc ccacaggaac cttccttctg gttggcctca gccgacccca
1441 cagcagtctt cgagagctcc tggcaacctg ctgggatggg gggctgcacg tagatggggt
1501 ggcagtgacc ctcacttcct gctgtatccc cagacccaaa gaaaagtcca acctgatcgt
1561 ggtccagaga ggtcacagcc cacccacatc atccttggtt cagccccaat cccaatacca
1621 gctgagtcag atgacatttc acaagatccc tgctgacagc ctggagtggc atgagaacct
1681 gggccatggg tccttcacca agatttaccg gggctgtcgc catgaggtgg tggatgggga
1741 ggcccgaaag acagaggtgc tgctgaaggt catggatgcc aagcacaaga actgcatgga
1801 gtcattcctg gaagcagcga gcttgatgag ccaagtgtcg taccggcatc tcgtgctgct
1861 ccacggcgtg tgcatggctg gagacagcac catggtgcag gaatttgtac acctgggggc
1921 catagacatg tatctgcgaa aacgtggcca cctggtgcca gccagctgga agctgcaggt
1981 ggtcaaacag ctggcctacg ccctcaacta tctggaggac aaaggcctgc cccatggcaa
2041 tgtctctgcc cggaaggtgc tcctggctcg ggagggggct gatgggagcc cgcccttcat
2101 caagctgagt gaccctgggg tcagccccgc tgtgttaagc ctggagatgc tcaccgacag
2161 gatcccctgg gtggcccccg agtgtctccg ggaggcgcag acacttagct tggaagctga
2221 caagtggggc ttcggcgcca cggtctggga agtgtttagt ggcgtcacca tgcccatcag
2281 tgccctggat cctgctaaga aactccaatt ttatgaggac cggcagcagc tgccggcccc
2341 caagtggaca gagctggccc tgctgattca acagtgcatg gcctatgagc cggtccagag
2401 gccctccttc cgagccgtca ttcgtgacct caatagcctc atctcttcag actatgagct
2461 cctctcagac cccacacctg gtgccctggc acctcgtgat gggctgtgga atggtgccca
2521 gctctatgcc tgccaagacc ccacgatctt cgaggagaga cacctcaagt acatctcaca
2581 gctgggcaag ggcaactttg gcagcgtgga gctgtgccgc tatgacccgc taggcgacaa
2641 tacaggtgcc ctggtggccg tgaaacagct gcagcacagc gggccagacc agcagaggga
2701 ctttcagcgg gagattcaga tcctcaaagc actgcacagt gatttcattg tcaagtatcg
2761 tggtgtcagc tatggcccgg gccgccagag cctgcggctg gtcatggagt acctgcccag
2821 cggctgcttg cgcgacttcc tgcagcggca ccgcgcgcgc ctcgatgcca gccgcctcct
2881 tctctattcc tcgcagatct gcaagggcat ggagtacctg ggctcccgcc gctgcgtgca
2941 ccgcgacctg gccgcccgaa acatcctcgt ggagagcgag gcacacgtca agatcgctga
3001 cttcggccta gctaagctgc tgccgcttga caaagactac tacgtggtcc gcgagccagg
3061 ccagagcccc attttctggt atgcccccga atccctctcg gacaacatct tctctcgcca
3121 gtcagacgtc tggagcttcg gggtcgtcct gtacgagctc ttcacctact gcgacaaaag
3181 ctgcagcccc tcggccgagt tcctgcggat gatgggatgt gagcgggatg tccccgccct
3241 ctgccgcctc ttggaactgc tggaggaggg ccagaggctg ccggcgcctc ctgcctgccc
3301 tgctgaggtt cacgagctca tgaagctgtg ctgggcccct agcccacagg accggccatc
3361 attcagcgcc ctgggccccc agctggacat gctgtggagc ggaagccggg ggtgtgagac
3421 tcatgccttc actgctcacc cagagggcaa acaccactcc ctgtcctttt catagctcct
3481 gcccgcagac ctctggatta ggtctctgtt gactggctgt gtgaccttag gcccggagct
3541 gcccctctct gggcctcaga ggccttatga gggtcctcta cttcaggaac acccccatga
3601 cattgcattt gggggggctc ccgtggcctg tagaatagcc tgtggccttt gcaatttgtt
3661 aaggttcaag acagatgggc atatgtgtca gtggggctct ctgagtcctg gcccaaagaa
3721 gcaaggaacc aaatttaaga ctctcgcatc ttcccaaccc cttaagccct ggccccctga
3781 gtttcctttt ctgtctctct ctttttattt tttttatttt tatttttatt tttgagacag
3841 agcctcgctc tgttacccag ggtggagtgc agtggtgcga tctcggctca gtgcaacctc
3901 tgcttcccag gttcaagcga ttctcctgcc tcagcctccc gagtagctgg gattacaggt
3961 gtgcaccacc acacccggct aatttttttt atttttaata gagatgaggt ttcaccatga
4021 tggccaggct gatctcgaac tcctaacctc aagtgatcct cccacctcag cctcccaaag
4081 tgttggaata ataggcatga gccactgcac ccaggctttt ttttttttaa atttattatt
4141 attattttta agagacagga tcttgctacg ttgcccaggc tggtcttgaa ctcctgggct
4201 acagtgatcc tcctgcctta tcctcctaaa tagctgggac tacagcacct agttttgagt
4261 ttcctgtctt atttccaatg gggacattca tgtagctttt tttttttttt tttttttgag
4321 acggagtctc gctctgtcgc ccaggctgga gtacagtggc gcaatctagg ctcactgcaa
4381 gctccgcctc ctgggttcac accattctct cgcctcagcc tcccaagtag ctgggactac
4441 aggcgcccgc caccacaccc ggctaatttt ttgtattttt agtagagacg gggtttcacc
4501 ttgttagcca ggatggtttc catctcctga cctcgtgatc tgcccgtctc ggcctcccaa
4561 agtgctggga ttacaggcat gagccactgc gcccggccct catgtagctt taaatgtatg
4621 atctgacttc tgctccccga tctctgtttc tctggaggaa gccaaggaca agagcagttg
4681 ctgtggctgg gactctgcct tttaggggag cccgtgtatc tctttgggat cctgaaaggg
4741 ggcaggaaag gctggggtcc cagtccaccc taatggtatc tgagtgtcct agggcttcag
4801 ttttcccacc tgtccaatgg gaccctttct gtcctcaccc tacaaggggc acaaagggat
4861 gacaccaaac ctggcaggaa cttttcacgc aatcaaggga aggaaaggca ttcctggcag
4921 agggaacagc atgccaagcg tgagaaggct cagagtaagg aggttaagag cccaagtatt
4981 ggagcctaca gttttgcccc ttccatgcag tgtgacagtg ggcaagttcc tttccctctc
5041 tgggtctcag ttctgtcccc tgcaaaatgg tcagagctta ccccttggct gtgcagggtc
5101 aactttctga ctggtgagag ggattctcat gcaggttaag cttctgctgc tcctcctcac
5161 ctgcaaagct tttctgccac ttttgcctcc ttggaaaact cttatccatc tctcaaaact
5221 ccagctacca catccttgca gccttccctc atataccccc actactactg tagccctgtc
5281 cttccctcca gccccactct ggccctgggg ctggggaagt gtctgtgtcc agctgtctcc
5341 cctgacctca gggttccttg ggggctgggc tgaggcctca gtacagaggg ggctctggaa
5401 atgtttgttg actgaataaa ggaattcagt ggaaaaaaaa aaaaaaaaa。
ベクターのヌクレオチド配列によりコードされるタンパク質を作製するために、真核生物の発現ベクターを使用して、細胞にトランスフェクトすることができる。哺乳動物細胞(毛球からの単離細胞;例えば、真皮鞘細胞及び真皮乳頭細胞など)は、当技術分野で知られている方法を介して、適切な宿主細胞に発現ベクターを導入することにより、発現ベクター(例えば、Jak3タンパク質又はポリペプチドをコードする遺伝子を含有する発現ベクター)を含有し得る。
培養される宿主細胞に関して、多様な培養パラメータを使用することができる。哺乳動物細胞に適切な培養条件は、当技術分野においてよく知られている(Cleveland WLら、J Immunol Methods、1983、56(2): 221〜234)か、又は当業者が決定することができる(例えば、「Animal Cell Culture: A Practical Approach」、2版、Rickwood, D.及びHames, B. D.編(Oxford University Press: New York、1992)を参照されたい)。細胞の培養条件は、選択される宿主細胞の型に従い変化し得る。市販の培地を活用することができる。培地の非限定的な例は、例えば、最小必須培地(MEM、Sigma、St. Louis、Mo.);ダルベッコ改変イーグル培地(DMEM、Sigma); Ham F10培地(Sigma); HyClone細胞培養培地(HyClone、Logan、Utah); RPMI-1640培地(Sigma);及び多様な細胞型に応じて処方される合成(CD)培地、例えば、CD-CHO培地(Invitrogen、Carlsbad、Calif.)を含む。
本明細書で使用される「Jak3調節化合物」は、Jak3遺伝子又はJak3タンパク質若しくはポリペプチドと相互作用し、その活性及び/又はその発現を調節する化合物を指す。化合物は、Jak3遺伝子によりコードされるタンパク質の活性又は発現を増大させることができる。逆に、化合物は、Jak3遺伝子によりコードされるタンパク質の活性又は発現を低下させることができる。化合物は、Jak3アゴニスト又はJak3アンタゴニスト(例えば、Jak3阻害剤)であり得る。Jak3調節化合物のいくつかの非限定的な例は、ペプチド(Jak3遺伝子によりコードされるポリペプチドを含むペプチド断片、又はその抗体若しくは断片など)、低分子、及び核酸(Jak3遺伝子を含む核酸に特異的なsiRNA又はアンチセンスRNAなど)を含む。Jak3タンパク質のアゴニストは、Jak3タンパク質に結合すると、Jak3タンパク質の活性を増大させるか又は延長する分子であり得る。Jak3アゴニストは、Jak3タンパク質を活性化させるタンパク質、核酸、低分子、又は他の任意の分子を含むがこれらに限定されない。Jak3タンパク質のアンタゴニストは、Jak3タンパク質に結合すると、Jak3タンパク質の量又は活性の持続を低下させる分子であり得る。アンタゴニストは、Jak3タンパク質の活性を低下させるタンパク質、核酸、抗体、低分子、又は他の任意の分子を含む。
Jak3調節化合物は、in vivo及び/又はin vitroにおいて、Jak3タンパク質の活性及び/又は発現に影響を及ぼす化合物であり得る。Jak3調節化合物は、Jak3タンパク質のアゴニスト及びアンタゴニストであり得、発現、翻訳後修飾、又は他の手段を介して、Jak3タンパク質の活性にその効果を及ぼす化合物であり得る。
本発明はまた、被験体における脱毛障害を処置又は防止するための方法も提供する。一実施形態では、該方法は、被験体に由来する試料中のJak3遺伝子の変化の存在であって、脱毛障害又は脱毛障害に対する素因を示す変化の存在を検出するステップと、それを必要とする被験体に、脱毛障害に対する治療的処置を施すステップとを含む。治療的処置は、薬物投与(例えば、Jak3核酸を指向するsiRNAを含む医薬組成物)であり得る。一実施形態では、投与される治療用分子は、配列番号1のアミノ酸配列のうちの約75%、約80%、約85%、約90%、約93%、約95%、約97%、約98%、約99%、又は100%を含む、Jak3遺伝子によりコードされるポリペプチドを含み、Jak3遺伝子によりコードされるタンパク質の発現を低下させる機能を示す。これは、毛包又は皮膚に由来する細胞における毛の成長を誘発する能力を回復させ得る。別の実施形態では、投与される治療用分子は、配列番号2の核酸配列のうちの約75%、約80%、約85%、約90%、約93%、約95%、約97%、約98%、約99%、又は100%を含む、ポリペプチドをコードするJak3遺伝子を含む核酸配列を含み、Jak3遺伝子によりコードされるタンパク質の発現を低下させる機能を伴うポリペプチドをコードし、したがって、毛包細胞又は皮膚に由来する細胞における毛の成長を誘発する能力を回復させる。
本明細書で示される通り、Jak3遺伝子により占有される染色体領域の変化又はJak3遺伝子の発現の変化はまた、Jak3遺伝子によりコードされるポリペプチドの配列又は発現レベルの変化についてスクリーニングすることによって検出することもできる。特異的抗体など、異なる種類のリガンドを使用することができる。一実施形態では、試料を、Jak3遺伝子によりコードされるポリペプチドに特異的な抗体と接触させ、その後、免疫複合体の形成を決定する。ELISA、ラジオイムノアッセイ(RIA)、及び免疫酵素アッセイ(IEMA)など、免疫複合体を検出するための多様な方法を使用することができる。一実施形態では、配列番号1を指向する抗体を使用するELISA;配列番号1を指向する抗体を使用するウェスタンブロット;質量分析、等電点電気泳動、又は配列番号1のエピトープをターゲティングする電気泳動ベースの技術;又はそれらの組合せによりレベルを測定する。
生細胞への核酸の送達は、ウイルス(例えば、レンチウイルス、アデノウイルス、アデノ随伴ウイルス、又はレトロウイルス)ベクターなどのベクターを使用することにより、ex vivo、in situ、若しくはin vivoで、又は物理的DNA移植法(例えば、リポソーム又は化学的処理)を使用することにより、ex vivoで行うこともできる。in vitroにおける、哺乳動物細胞への核酸の移植に適する非限定的な技術は、リポソーム、電気穿孔、マイクロインジェクション、細胞融合、DEAE-デキストラン、及びリン酸カルシウム沈殿法(例えば、Anderson、Nature、392(6679): 25 (1998)を参照されたい)の使用を含む。核酸又は本発明のポリペプチドをコードする遺伝子の導入はまた、染色体外基質(一過性発現)又は人工染色体(安定的発現)によって達成することもできる。細胞はまた、このような細胞に対する所望の効果又は活性を増進するか又はもたらすために、本発明の治療用組成物の存在下で、ex vivoにおいて培養することもできる。次いで、処理された細胞を、in vivoにおいて、治療的目的で導入することができる。
7)、マウス起源のレトロウイルス(Millerら(1992)、Mol Cell Biol.、12(7):3262〜72; Millerら(1985)、J Virol.、55(3):521〜6; Sorgeら(1984)、Mol Cell Biol.、4(9):1730〜7; Mann及びBaltimore (1985)、J Virol.、54(2):401〜7; Millerら(1988)、J Virol.、62(11):4337〜45)、及びヒト起源のレトロウイルス(Shimadaら(1991)、J Clin Invest.、88(3):1043〜7; Helsethら(1990)、J Virol.、64(12):6314〜8; Pageら(1990)、J Virol.、64(11):5270〜6; Buchschacher及びPanganiban (1992)、J Virol.、66(5):2731〜9)が、遺伝子導入用ベクターとして使用されている。
タンパク質補充療法は、注入を介して野生型のタンパク質又は生物学的に機能的なタンパク質を外因的に導入することにより、タンパク質の量を増大させ得る。補充用のポリペプチドは、既知の化学的技術に従い合成され得るか、又は既知の分子生物学的技術を介して作製及び精製され得る。タンパク質補充療法は、多様な障害のために開発されている。例えば、野生型のタンパク質は、組換え細胞発現系(例えば、哺乳動物細胞又は昆虫細胞; Desnickらによる米国特許第5,580,757号; Seldenらによる米国特許第6,395,884号及び同第6,458,574号;Calhounらによる米国特許第6,461,609号;Miyamuraらによる米国特許第6,210,666号;Seldenらによる米国特許第6,083,725号;Rasmussenらによる米国特許第6,451,600号;Rasmussenらによる米国特許第5,236,838号;並びにGinnsらによる米国特許第5,879,680号を参照されたい)、ヒト胎盤、又は動物ミルク(Reuserらによる米国特許第6,188,045号を参照されたい)、又は当技術分野で知られている他の供給源から精製することができる。注入後、外因性タンパク質は、非特異的又は受容体媒介機構を介して組織により取り込まれ得る。
サイトカインは、近傍の細胞を活性化させて、互いと危険シグナルを伝達し合い、炎症性応答を拡大させて増幅するように産生される。多年にわたり、どのようにして、これらのサイトカインを阻害性抗体で中和するか、及び応答性細胞におけるそれらのシグナル伝達を低分子のタンパク質チロシンキナーゼ阻害剤で阻害するかの両方について考究された。FDAは、両手法に関して存在する薬物を承認した。全身毒性を制限しながら、可能な限り有効性を改善する局所用低分子製剤(治療指標の改善)が追及され、生物医薬品パイプライン内の他の低分子阻害剤のAAにおける臨床評価が奨励されている。
円形脱毛症(AA)は、最も蔓延している自己免疫疾患のうちの1つであり、非瘢痕性脱毛として現れる。該疾患の経過は予測不可能であり、一貫して有効な利用可能な治療は、現在は存在しない。疾患の病原性の研究及び標的に対する治療の開発は欠如しているが、疾患を高頻度で有するマウス移植モデルの作成は、前臨床試験の新たな道を開いた。
円形脱毛症(AA)の根底にある具体的な自己免疫メカニズムは未だ不明であり、したがってAAの臨床研究は、他の自己免疫疾患よりも歴史的に遅れている。
ヒトAA及びAAマウスモデルの両方において、局所的な毛包(HF)IL-15/NKG2DLの上方制御を、CD8+T細胞を動員/活性化する鍵となる炎症シグナル、IFN−ガンマの生産及び毛包(HF)毒性に関与する重要な見込みのあるAA免疫エフェクターとして同定した。これらの観察は、療法的にIL-15/NKG2Dをターゲティングする研究の理論的根拠を提供した。
5匹のマウスをトファシチニブ(CP-69055;アルゼットポンプ中で10mg/kg/day)で全身処置した。トファシチニブは、ヒトの全血アッセイでIL-15シグナリングを阻害することが知られているJak3阻害剤である。処置したマウスのいずれでも、円形脱毛症又は皮膚リンパ節腫脹を発症しなかったが、未処置マウスでは、AA及び関連の皮膚リンパ節腫脹がみられた(図1)。臨床開発のための改善された治療係数という重要な利点を有する、マウスモデルにおけるAAからの復帰のための局所送達アプローチを研究する。
細胞、炎症性、及び分子バイオマーカーを、処置マウスにおいて評価した。トファシチニブによる標的に対する療法は、皮膚及び皮膚所属リンパ節の両方に由来する病原性CD8+NKG2Dhiを消失させ、さらにMHC分子及びAA関連IFNサインをはじめとする皮膚における炎症性バイオマーカーを下方制御した(図2)。HF NKG2DL発現は抑制されたが、完全には消失せず(例えば、免疫染色によるH60発現)(図2及び3)、これはH60の上方制御が近接した事象であることを示唆している。
PTKiは、その標的キナーゼに対する選択性において、大幅に異なる。トファシチニブについて、JAK感度は、JAK3>JAK1>>JAK2で高い(全血でのIC50は、それぞれ28-50nM、140-180nM、1000-5000nMである)。処置したマウスでは、トファシチニブ血清レベルは30-40nMであり、JAK1及び3活性の両方に対する潜在的影響が評価される。ルクソリチニブ(JAK1/2阻害剤)について、感度はJAK2>JAK1>>JAK3である(in vitroキナーゼ阻害では、IC50はそれぞれ3.3nM、2.8nM、及び428nMである)。ルクソリチニブの投与量は一日一回であり、げっ歯類における半減期は3〜6時間であるため、マウスにおける薬力学的なJAK阻害は一過性であろう。
図4に示すリボンプロットは、Jak3阻害剤CP690550及びPBS対照で13週間処置したマウスから選択した遺伝子の、標準化した皮膚発現プロフィールのマイクロアレイデータを示す。手短には、Jak3阻害剤による処置の13週間後に、皮膚を回収してマイクロアレイ解析に供し、PBSで処置したマウスのものと比較した。データは、IFN−応答ケモカイン及びCD8細胞傷害エフェクターのマーカーの、処置関連の消失を示す。発現プロフィール及び最終的には処置への応答を比較するために、マウス及びヒト由来の発現アレイを統合する。
「NK型」CD8αβ+T細胞は、脱毛症の皮膚及び所属LNにおいて大規模に増殖しており、T細胞媒介移植に必要であり、これはこの細胞傷害性細胞サブセットが病原性エフェクターであることが示唆している。
円形脱毛症(AA)は、毛包への免疫攻撃をもたらす一般的な自己免疫疾患である1。T細胞が疾患の経過に関わることが示されているが、その活性化の根底にある経路は、決定されていない2。GWAS研究の前、AAの遺伝的背景は、ほとんど不明確であった。驚くべきことに、強い関連のある領域が、それまで自己免疫疾患に関わることが示されていなかった、ナチュラルキラー細胞受容体であるNKG2Dの活性化リガンドをコードしている染色体6q25.1のULBP遺伝子クラスター中で同定された。NKG2Dリガンド(NKG2DL)を示唆するGWASの研究に導かれ3、本発明では「NK型」CD8+T細胞を、疾患の誘導に必要かつ十分な主なエフェクターとして同定した。マウス及びヒトAA皮膚の網羅的転写プロファイリングは、強いIFNγ応答及び細胞傷害性T細胞浸潤の存在の、著しいサイン指標を明らかにした。
脱毛症のマウスから得られた皮膚性リンパ節から単離されたCD8+NKG2D+メモリーT細胞とCD8+NKG2D-メモリーT細胞において示差的に発現された遺伝子。RNAseqを、二匹の脱毛症マウス由来の全皮膚性リンパ節からフローソートした細胞(BD influx)から単離して調製したcRNAについて行った。
ヒト円形脱毛症由来の皮膚と、正常個体由来の皮膚において示差的に発現された遺伝子。局所又は全身処置を受けていない、斑点を伴う円形脱毛症を有する5人の患者由来の、病変周囲のパンチ生検を集め、5人の無関係な罹患していない個体由来の頭皮生検と比較した。
マウス
7〜10週齢の雌C57Bl.6及びC3H/HeJマウス(Jackson Laboratories、Bar Harbor、ME)を用い、特定の病原菌フリーな条件下で維持した。
正常な毛のC3H/HeJマウスに、(第二の休止期の間の)8週齢で、自然にAAを発症したC3H/HeJマウス由来の皮膚を、以前に記載した通りに移植した7。手短には、AAに自然に罹患したマウスを安楽死させ、直径約2cmの完全な厚みの皮膚移植片を除去し、正常な毛のC3H/HeJマウスに移植した。脱毛は、典型的に移植後約4〜6週間で始まった。
マウス皮膚の単一細胞懸濁液を作成するために、冷PBS中で皮膚の覆いから脂肪を除去し、その後I型コラゲナーゼ上(2mg/PBSml)で、32℃で75分間インキュベートした。消化後、皮膚をRPMI/10%ウシ胎児血清中で細分化し、70mMセルスレイナーでろ過し、1100gで5分間遠心した。ペレットをRPMI/10%ウシ胎児血清中で再懸濁し、40mMセルスレイナーでろ過し、5分間400gでスピンした。ペレットをFACsバッファー(PBS/5% BSA)、生細胞をゲートするためのDAPI、及び(補助データに列挙した)染色抗体で再懸濁した。皮膚リンパ節をRPMIにプールし細分化し、40mMセルスレイナーでろ過し、5分間400gで遠心し、染色してBD LSR IIフローサイトメーターで解析した。
T細胞集団のポジティブ選択のために、リンパ節を5匹のC3H/HeJ脱毛症マウスから得、抗CD4、抗CD8、及び抗NKG2Dで染色し、その後ソート(BD Influx)して、CD8+NKG2D+ T細胞及びCD8+NKG2D- T細胞の二つの画分を得た。群あたり3〜5匹の7週齢のC3H/HeJマウスに、二百万のソートした各集団の細胞を皮下注射した。ネガティブ選択した集団のためには、3匹の脱毛症C3H/HeJに由来する全リンパ節細胞をビオチン化抗NKG2D(CX5)と、その後ストレプトアビジン結合ビーズ(Miltenyi)とインキュベートした後にMiltenyi磁性カラムを除去することによりNKG2D+細胞を枯渇させた。五百万の細胞(CD8/NKG2D枯渇、又は全リンパ節細胞のいずれか)を、100μlのPBSに懸濁し、皮下注射により5匹のマウスのそれぞれに移植した。
防止研究のために、マウスを移植の初日から処置した(群あたりn=5〜10)。JAK3i実験:ビヒクル(ポリエチレングリコール(PEG)300)又はJAK3iトファシチニブ(Abmole)を含むビヒクルを15mg/kg/dayで12週間送達するために、各マウスの背部に、Alzet浸透圧ミニポンプ(ポンプ、モデル2004、Durect Corporation)を皮下移植した。
8mMのアセトン固定凍結マウス皮膚切片を風乾させ、湿室で4℃で、抗マウスAb(以下参照)により一晩染色した。ヒトの毛包を顕微解剖し、OCT化合物に包埋した後に切片化及び染色した(以下参照)。
真皮鞘(DS)細胞を、顕微解剖マウス感覚毛包から単離し、5ng/mlマウスFGF(Pepro Tech)を含む20% FBS DMEMで培養した。LAK細胞を、50nM JAK3i(トファシチニブ)又は50ng/ml マウスIL-15及び50nM JAK3iを含む6ウェルプレートに4×106で脾臓細胞を播種し、96時間、5%CO2インキュベーターで37℃でインキュベートして作成した。
標的細胞の特異的な殺傷の決定を、CFSEラベルしたDS細胞を標的として用いて、ラット抗マウスNKG2D中和抗体(Biolegend、CX5)の存在下(20μg/ml)又は非存在下で37℃、5%CO2で5時間インキュベートしたエフェクター細胞と異なる比で混合して行った。DS細胞の特異的な溶解を、Annexin V/7-AADを用いてCFSE+ DS細胞の細胞死を測定することによって、フローサイトメトリーにより決定した。
RNaseフリーDNaseセット(Qiagen Inc.、Valencia、CA、USA)を用いたオンカラムDNA消化と共に、miRNeasyミニキット(Qiagen Inc.、Valencia、CA、USA)を用いて全RNAを単離した。RNAseq解析のために、CD3+CD8+CD44+NKG2D+及びCD3+CD8+CD44+NKG2D-細胞を脱毛症のC3H/HeJマウスのリンパ節からフローソートした。RNAを上記の通り抽出し、TruSeq RNA Sample Prep Kit v2を用いてRNA-seqのために調製した。サンプルを、HiSeq 2000シーケンサー(Illumina、San Diego、CA)により50サイクルで配列決定した。RNA-SeqファイルをRockefeller University Genomics Core Facilityにより、デマルチプレックした。
フローサイトメトリー解析では、以下の抗マウス抗体を用いた:CD3(17A2、Ebioscience)、CD4(GK1.5、BD)、CD8α(53-6.7、BD)、CD8α(YTS156.7.7、Biolegend)、NKG2D(CX5、Ebioscience)、NKG2A/C/E(クローン20d5、Ebioscience)、CD44(IM7、BD)、CD45(30-F11、BD)、CD49b(Dx5、BD)、CD62L(MEL-14、BD)、CD69(H1.2F3、BD)、CD103(2E7、eBioscience)、IFNγ(XMG1.2、Ebioscience)、グランザイムB(NGZB、eBioscience)、Rae-1(186107、R&D)。
RNA-seq解析
サンプルを、HiSeq 2000シーケンサー(Illumina、San Diego、CA)で50サイクルで配列決定した。RNA-Seqファイルを、Rockefeller University Genomics Core Facilityによりデマルチプレックスした。サンプルのfastqファイルの質の制御を、fastqc s1を用いて行った。TopHats2を用いてiGenome由来のUCSC mm9参照ゲノムに対して転写物をマッピングした。UCSC mm9のこのiGenomeバージョンでパッケージされたRefSeq遺伝子アノテーションを用いた。HTSeqパッケージのhtseqカウントユーティリティを、TopHat bamファイルをedgeRs3による示差的発現の下流解析のための入力として用い得るカウントに変換するのに用いた。存在しない遺伝子を除き、下流解析におけるゼロによる分割を避けるために、1の偽カウントを加えた。EdgeRを、3つの生物学的反復によるマッチペアデザインを用いて示差的に発現される遺伝子を同定するために用いた。
質制御、前処理
マウスcDNAサンプルをマウスゲノム430 2.0遺伝子チップにハイブリダイズし、次に洗浄し、ストレプトアビジン−フィコエリトリンにより染色し、HP遺伝子アレイスキャナー(Hewlett-Packard Company、Palo Alto、CA)でスキャンした。ヒトについては、増幅したcDNAをU133A 2.0遺伝子チップにハイブリダイズした。
目的変数なしの解析
閾値abs(logFC)>1、未調整p値≦0.05となるように、ヒト5×5の363遺伝子及び自然マウス3×3の583遺伝子についてClusterS5を用いて階層クラスタリングを行った。閾値logFC>1及び未調整p値≦0.05となる遺伝子を最初に選択した。遺伝子を中央値に置き、標準化した。Spearman順位相関を、類似性の尺度として用い、平均連結法を、行(遺伝子)及び列(サンプル)クラスタリングを行うために用いた。階層クラスターの視覚化を、java TreeViewS6を用いて行った。遺伝子発現動的係数(GEDI)解析を、自己組織化マップアルゴリズムにより同定された「メタ遺伝子」がサンプルごとにどのように異なるかを視覚化するために用いたS7。メタ遺伝子は、サンプル間で類似の発現パターンを示す遺伝子のクラスターであり、二次元グリッドにおいて単一のピクセルに割り当てられる。隣接するピクセルは、互いの類似の発現パターンを示す。
異なる遺伝子発現の最初の解析を、limma S8、1.5倍の変化の閾値及び0.05の未調整のp値を用いて自然マウス3×3及びヒト5×5データセットについて行った。
ヒト及びマウスにおいて予測される、示差的に発現される遺伝子を、RT-PCTを用いて確認した。最初のcDNA鎖を、2:1の比のランダムプライマー:オリゴ(dT)プライマー及びSuperScript III RT (Invitrogen)を用いて、製造業者の説明書に従って合成した。qRT-PCRを、ABI 7300機器を用いて行い、ABI Relative Quantification Studyソフトウェア(Applied Biosystems、Foster City、CA、USA)により解析した。プライマーをABIのガイドラインに従って設計し、全ての反応をPower SYBR Green PCRマスターミックス(Applied Biosystems)、20μL反応溶液中に250nMプライマー(Invitrogen)及び20ng cDNAを用いて行った。プライマー配列を表5に示す。
IFN及びCTLサインを、二変数スコア統計を開発するために用いた。IFN及びCTLの各サインのスコアを、ヒトSLEで用いた以下の手順で決定したS9、10。本発明者のIFN及びCTLサインを含むように選択された遺伝子のセットは、CTLサインについてはCD8A、GZMB、及びICOSであり、IFNサインについてはCXCL9、CXCL10、CXCL11、STAT1、及びMX1であった。予防マウスでのスコアは、偽手術マウスに対して計算した;一方、局所治療試験のスコアは、全てのサンプルの0週目に対して計算した。
JAK-STATシグナリング経路は、幾つかの発生プロセス、並びに最近では幹細胞維持、活性化、及び分化に関係づけられている。C3H/HeJ AAマウスモデルにおいてJAK3を用いる本発明者の局所治療の経過において、全身投与とは異なる二つの顕著な特徴を有して毛が再成長したことが認められた:1)毛の再成長は非常に迅速であった;及び2)被毛は暗い色がついた。理論により拘束されるものではないが、Jak3阻害剤は皮膚から病原性のT細胞を消失させるのに加えて、Jak3阻害剤は、例えば発育期の促進効果を介して、毛包自身に直接の効果も有する。
Claims (20)
- それを必要とする哺乳動物被験体における脱毛障害を処置するための組成物であって、有効量の、デセルノチニブ(VX-509)、JAK3阻害剤IV(ZM-39923)及びPF-956980からなる群より選択されるJAK3阻害剤を含み、上記脱毛障害が、男性型脱毛症、休止期脱毛、頭部白癬、完全脱毛症、貧毛症及び遺伝性単純型貧毛症からなる群より選択される、上記組成物。
- 被験体において毛の成長を誘導するための組成物であって、有効量の、デセルノチニブ(VX-509)、JAK3阻害剤IV(ZM-39923)及びPF-956980からなる群より選択されるJAK3阻害剤を含み、上記被験体が、男性型脱毛症、休止期脱毛、頭部白癬、完全脱毛症、貧毛症及び遺伝性単純型貧毛症からなる群より選択される脱毛障害に罹患している、上記組成物。
- 局所用組成物である、請求項1又は2に記載の組成物。
- 組成物が、毎日、毎週、毎週2回、毎月、毎月2回、毎年、週1回、週2回、週3回、週4回、週5回、週6回、週7回、週8回、週9回、週10回、週11回、週12回、週13回、又は週14回の投与に適している、請求項1又は2に記載の組成物。
- 組成物が、少なくとも1週間、少なくとも2週間、少なくとも3週間、少なくとも4週間、少なくとも5週間、少なくとも6週間、少なくとも8週間、少なくとも12週間、又は少なくとも16週間の投与に適している、請求項1又は2に記載の組成物。
- Jak1/2阻害剤をさらに含む、請求項1又は2に記載の組成物。
- Jak1/2阻害剤が、INCB 018424、GLPG0634、AG490、CYT387、SB1518、LY3009104、TG101348、BMS-911543、又はCEP-701である、請求項6に記載の組成物。
- JAK3阻害剤がデセルノチニブ(VX-509)である、請求項1又は2に記載の組成物。
- JAK3阻害剤が、0.1%、0.2%、0.3%、0.4%、0.5%、0.6%、0.7%、0.8%、0.9%、1.0%、1.1%、1.2%、1.3%、1.4%、1.5%、1.6%、1.7%、1.8%、1.9%、2.0%、2.1%、2.2%、2.3%、2.4%、2.5%、2.6%、2.7%、2.8%、2.9%、3.0%、3.5%、4%、4.5%、5%、5.5%、6%、6.5%、7%、7.5%、8%、8.5%、9%、9.5%、又は10%から選択される濃度で存在する、請求項1又は2に記載の組成物。
- 対象のためのJAK3阻害剤の有効量が、1mg/体重kg、1.5mg/体重kg、2mg/体重kg、2.5mg/体重kg、3mg/体重kg、3.5mg/体重kg、4mg/体重kg、4.5mg/体重kg、5mg/体重kg、5.5mg/体重kg、6mg/体重kg、6.5mg/体重kg、7mg/体重kg、7.5mg/体重kg、8mg/体重kg、9.5mg/体重kg、10mg/体重kg、10.5mg/体重kg、11.0mg/体重kg、11.5mg/体重kg、12mg/体重kg、12.5mg/体重kg、13mg/体重kg、13.5mg/体重kg、14mg/体重kg、14.5mg/体重kg、15mg/体重kg、15.5mg/体重kg、16mg/体重kg、16.5mg/体重kg、17mg/体重kg、17.5mg/体重kg、18mg/体重kg、19.5mg/体重kg、20mg/体重kg、21.5mg/体重kg、22mg/体重kg、22.5mg/体重kg、23mg/体重kg、23.5mg/体重kg、24mg/体重kg、24.5mg/体重kg、25mg/体重kg、25.5mg/体重kg、26mg/体重kg、26.5mg/体重kg、27mg/体重kg、27.5mg/体重kg、28mg/体重kg、29.5mg/体重kg、又は30mg/体重kgから選択される、請求項1又は2に記載の組成物。
- 脱毛障害が男性型脱毛症である、請求項1又は2に記載の組成物。
- 溶液、軟膏剤(ointment)、軟膏(salve)、ゲル、又はクリームである、請求項1又は2に記載の組成物。
- 哺乳動物被験体における脱毛障害を処置するための医薬組成物であって、唯一の治療有効成分としての有効量の、デセルノチニブ(VX-509)、JAK3阻害剤IV(ZM-39923)及びPF-956980からなる群より選択されるJAK3阻害剤と、医薬用賦形剤を含み、上記脱毛障害が、男性型脱毛症、休止期脱毛、円形脱毛症、頭部白癬、完全脱毛症、貧毛症、遺伝性単純型貧毛症及び全身性脱毛症からなる群より選択される、上記医薬組成物。
- 被験体において毛の成長を誘導するための医薬組成物であって、唯一の治療有効成分としての有効量の、デセルノチニブ(VX-509)、JAK3阻害剤IV(ZM-39923)及びPF-956980からなる群より選択されるJAK3阻害剤と、医薬用賦形剤を含み、上記被験体が、男性型脱毛症、休止期脱毛、円形脱毛症、頭部白癬、完全脱毛症、貧毛症、遺伝性単純型貧毛症及び全身性脱毛症からなる群より選択される脱毛障害に罹患している、上記医薬組成物。
- JAK3阻害剤がデセルノチニブ(VX-509)である、請求項13又は14に記載の医薬組成物。
- 円形脱毛症が、斑点を伴う円形脱毛症、全身性脱毛症又は完全脱毛症である、請求項13又は14に記載の医薬組成物。
- 脱毛障害が男性型脱毛症である、請求項13又は14に記載の医薬組成物。
- 脱毛障害が円形脱毛症である、請求項13又は14に記載の医薬組成物。
- 皮下注射、筋肉内注射、腹腔内注射、静脈内注射、注入、経口、経鼻、局所、皮内、吸入、経皮、経粘膜、直腸内、又はそれらの組合せに適したものである、請求項1、2、13又は14に記載の医薬組成物。
- 溶液、懸濁液、カプセル剤、錠剤、丸剤、トローチ剤、鼻腔内スプレー、坐剤、軟膏剤(ointment)、軟膏(salve)、ゲル、又はクリームである、請求項13又は14に記載の医薬組成物。
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PT2830662T (pt) | 2018-11-29 |
WO2013149194A1 (en) | 2013-10-03 |
HRP20181976T1 (hr) | 2019-01-25 |
SI2830662T1 (sl) | 2019-01-31 |
EP2830662B1 (en) | 2018-08-29 |
ES2694681T3 (es) | 2018-12-26 |
JP2015515470A (ja) | 2015-05-28 |
KR20140148459A (ko) | 2014-12-31 |
PL2830662T3 (pl) | 2019-02-28 |
KR102135601B1 (ko) | 2020-07-20 |
EP3459565A1 (en) | 2019-03-27 |
EP2830662A1 (en) | 2015-02-04 |
DK2830662T3 (da) | 2019-01-02 |
CN104334191A (zh) | 2015-02-04 |
EP2830662A4 (en) | 2015-09-09 |
JP2018027959A (ja) | 2018-02-22 |
HUE040127T2 (hu) | 2019-02-28 |
JP6212107B2 (ja) | 2017-10-11 |
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