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TR201815608T4 - Onkastatin m reseptörü antijeni bağlayıcı proteinler. - Google Patents

Onkastatin m reseptörü antijeni bağlayıcı proteinler. Download PDF

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TR201815608T4
TR201815608T4 TR2018/15608T TR201815608T TR201815608T4 TR 201815608 T4 TR201815608 T4 TR 201815608T4 TR 2018/15608 T TR2018/15608 T TR 2018/15608T TR 201815608 T TR201815608 T TR 201815608T TR 201815608 T4 TR201815608 T4 TR 201815608T4
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osmr
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A Arnett Heather
S Escobar Sabine
T King Chadwick
Ching Lim Ai
Narayanan Saravanakumar
H Weinreb Paul
E Pederson Nels
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Kiniksa Pharmaceuticals Ltd
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Abstract

Mevcut buluş, anti-onkosfatin M reseptörü-ß (OSMR) antijen bağlayıcı proteinlerini, örneğin bunun antikorlarını ve fonksiyonel fragmanlarını, türevlerini, muteinlerini ve varyantlarını sağlar. OSMR antijeni bağlayıcı proteinleri, OSMR ve/veya IL-31'in OSMR'ye bağlanmasına müdahale eder. Bazı uygulamalarda anti-OSMR antijen bağlayıcı proteinleri, OSMR ile ilişkili hastalıklar ve bozuklukların araştırılmasında yararlı araçlardır ve OSMR ve OSMR ve/veya IL-31'in OSMR'ye bağlanması ile ilişkili hastalıklar ve bozuklukların tedavi edilmesine yönelik yöntemlerde özellikle yararlıdır.

Description

Tarifnamede yer alan herhangi bir dil kullaniminin, herhangi bir talep edilmemis unsurun bulusun uygulanmasi için zorunlu oldugu seklinde yorumlanmamalidir. ÖRNEKLER Heni gerçek heni de gelecege yönelik olarak verilen asagidaki örnekler, mevcut bulusun spesifik uygulamalarini veya özelliklerini tasvir etme amaciyla saglanmistir ve bulusun kapsamini sinirlandirmasi amaçlanmamistir. ÖRNEK 1: XENOMOUSE® Platformu Kullanilarak Anti-OSMR Antikorlarinin Üretilmesi Insan OSMR'ye karsi yönlendirilmis tamamen insan antikorlar, edildigi üzere) XENOMOUSE® teknolojisi kullanilarak olusturulmustur. OSMR'ye yönelik antikorlar olusturmak için XENOMOUSEG hayvanlarinin iki farkli susu, Örnegin XMGZ-KL ve XMG4-KL fareleri, (Amgen, Seattle, WA tarafindan hazirlanan) insan OSMR- Fc çözünebilir proteinleri ile bagisiklanmistir. Uygun bir miktarda immünojen (on pg/fare çözülebilir insan OSMR-Fc proteini), 3 Aralik 1996'da dosyalanmis U.S. Patenti Basvuru Uluslararasi Patent Basvurusu No. WO 98/24893 ve 21 Aralik yöntemlere göre XENOMOUSEG hayvanlarinin ilk immünizasyonu için kullanilmistir. Ilk immünizasyonun ardindan immünojen sonraki arttirici immünizasyonlari (bes ug/fare çözünür insan OSMR-Fc proteini), bir zaman çizelgesine göre ve farelerde uygun bir titrede anti-OSMR antikorunun indüklenmesi için gerekli bir sürede uygulanmistir. Ilk enjeksiyondan yaklasik dört hafta sonra serumlar toplanmis ve spesifik titreler ELISA ile belirlenmistir. XENOMOUSE® hayvanlarini titrelemek için kullanilan protokol su sekildedir: Costar 3368 ortamini baglayici plakalar, neutravadin @ 8 ug/mL (50 uL/kuyucuk) ile kaplanmis ve 4°C'de lXPBS/%0,05 azit içinde gece boyunca inkübe edilmistir. Plakalar, RO suyu ile TiterTek 3 devirli yikama kullanilarak yikanmistir. Plakalar, 250 pL 1XPBS/%1 süt kullanilarak bloke edilmistir ve oda sicakliginda en az 30 dakika inkübe edilmistir. Blok, RO suyu ile TiterTek 3 döngülü yikamasi kullanilarak yikanmistir. Daha sonra, 2 pg/mL'de 1XPBS/%l süt/lOmM Ca2+ (test seyrelticisi) içinde 50 pl/kuyucuk biyotinlenmis huOSMR-FNFH (Amgen, Seattle, WA tarafindan hazirlanmistir) yakalanmistir ve oda sicakliginda 1 saat inkübe edilmistir. Daha sonra RO suyu ile TiterTek 3 devirli yikama kullanilarak yikanmistir. Primer antikor için serumlar, 1:100 oranindan çiftler halinde 113 oranina titre edilmistir. Bu islem, 50 uL/kuyucuk test seyrelticisi içinde gerçeklestirilmis ve oda sicakliginda 1 saat inkübe edilmistir. Daha sonra RO suyu ile TiterTek 3 devirli yikama kullanilarak yikanmistir. Sekonder antikor, 50 uL/kuyucuk'ta test seyrelticisi içinde keçi anti Insan IgG FC HRP @ 400 ng/mL'dir. Bu antikor oda sicakliginda 1 saat inkübe edilmistir. Daha sonra RO suyu ile TiterTek 3 devirli yikama kullanilarak yikanmis ve kagit havlular üzerinde nazikçe kurutulmustur. Substrat için tek adimli TMB Çözeltisi (Neogen, Lexington, Kentucky) kullanilmis (50 uL/kuyucuk) ve substrat, 30 dakika boyunca oda sicakliginda gelismeye birakilmistir. Uygun titreler sergileyen hayvanlar tespit edilmistir. Bes XMG2KL hayvaninin, OSMR'ye karsi spesifik bir lgG immün yaniti verdigi tespit edilmistir. Bu hayvanlardan dalaklar ve drene olan lenf nodlari hasat edilmis ve hibridom üretimi için bir araya getirilmistir. Spesifik immün yanitlari veren bes XMG4KL hayvani, benzer sekilde hasat edilmis ve ayri bir füzyon taramasi olarak ilerletilmistir. Immün hayvanlardan elde edilen zenginlestirilmis B hücreleri, standart teknikler kullanilarak hibridomlar olusturmak için (Kohler ve dig., Nature 256, 495-7, ((Amerikan Tipi Kültür Koleksiyonu CRL-1580; Kearney ve dig., J. Hibridomlar daha sonra yüksek yogunlukta (kuyucuk basina çoklu farkli hibridom klonlari) 96 kuyucuklu doku kültür plakalarina yerlestirilmistir ve dört hafta boyunca büyütülmüstür. Hibridom hatti süpernatantlari, geçici olarak transfekte edilmis 293T hücreleri üzerinde ifade edilen tam uzunluklu insan ve sinomolgus OSMR'ye baglanma bakimindan Florometrik Mikrohacimli Test Teknolojisi (FMAT: Fluorometric Microvolume Assay Technology) (Applied Biosystems, Foster City, CA) ile taranmistir. Kisaca, 384 kuyucuklu FMAT plakalarinda, 3.000 OSMR hücreden olusan 40 ul'lik bir karisim, 15 uL'lik hibridom süpernatant ve 10 uL'lik anti-insan hafif zincir (hukappa/hulambda) Alexa etiketli sekonder antikoru (1,0 ug/mL final konsantrasyonu) ile birlestirilmistir. Plakalar daha sonra oda sicakliginda üç saat inkübe edilmis ve FMAT okuyucu kullanilarak flüoresan okunmustur. Bu taramalarda insan ve sinomolgus OSMR'ye baglanan 885 hibridom hatti tespit edilmistir. ÖRNEK 2: Insan OSMR Blogu Testleri OSMR antikorlarinin insan OSMR araciligiyla sinyallemeyi bloke etme kabiliyeti, ligand olarak insan onkostatin M (OSM) veya insan interlökin 31'in (IL-31) kullanildigi iki test kullanilarak belirlenmistir. Testler birlikte, antikorlarin OSM ve/Veya lL-3l'in baglanmasi yoluyla tetiklenen OSMR'nin sinyallemesini inhibe edip edemeyecegini belirlemek için kullanilmistir. Ilk taramada antikorlar, OSMR araciligiyla OSM'nin sinyalini bloke etme kabiliyetleri bakimindan degerlendirilmistir. Primer normal insan akciger fibroblastlarinin OSM ile uyarilmasi, STATB'ün fosforilasyonunu ve bunu takiben çekirdege translokasyonu indükler. Hücreler, Costar 384 kuyucuklu plakalarda kuyucuk basina 3000 hücrede ekilmis ve gece boyunca yapismaya birakilmistir. Hücreler, antikor süpernatanlari ile yirmi dakika boyunca ön isleme tabi tutulmustur ve daha sonra 80 pM insan OSM ile 30 dakika boyunca uyarilmistir. Hücreler, PBS içinde 3 kere yikanmis, %3,5 formaldehit çözeltisi ile sabitlenmis, yikanmis (PBST içinde 3 kere) ve %0,5 Triton X-100 çözeltisi ile geçirgen hale getirilmistir. Hücreler daha sonra bir saat boyunca bir anti-fosfoSTAT3 antikoru ile boyanmis, yikanmis ve bir AlexaFluor (tümü Cellomics'e ait HitKit içinde bulunur) ile konjüge edilmis antikor ile boyanmistir. Plakalar, bir Nükleer Yogunluk degeri ve bir Sitoplazmik Yogunluk degeri olusturmak için Cellomics tescilli algoritmasinin kullanilarak ArrayScan cihazinda okunmustur. Sonuçlar, söz konusu iki degerin arasinda fark olarak bildirilmistir ve ayrica en üst düzeyde uyarilmis hücreler ve ortam ile içeren kontrol verisine normallestirilmistir (POC). Ikinci testte antikorlar, insan lL-31RA4 ve OSMR'yi asiri ifade etmis stabil bir hücre hattinda OSMR yoluyla IL-3l'in proliferatif bir sinyalini inhibe etme kabiliyetleri bakimindan test edilmistir. BaF3 hücreleri, iki plazmid ile stabil bir sekilde transfekte edilmistir: pcDNA ve pcDNA3.l + huIL31RA4 (ZeoR). Murin IL-3'ün yoklugunda, bu hücre hatti, yalnizca insan lL-31'e yanit olarak çogalabilir ve bu nedenle anti-OSMR antikorlarinin bloke etme kabiliyetini degerlendirmek için spesifik olarak kullanilabilir. BaF3 hücreleri, 96 kuyucuklu plakalara kuyucuk basina 20.000 hücre yogunlugunda yerlestirilmistir. Antikorlar ve ligand (huIL-3l, Peprotech), 100 uL'lik bir son hacimde kuyucuklara ilave edilmistir ve plakalar, %5 COZ, 37C nemlendirilmis bölmede 72 saat boyunca inkübe edilmistir. Inkübasyonun ardindan her bir kuyucuga 20 uL Alamar Blue ilave edilmis ve plakalar yeniden inkübatöre koyulmustur. Plakalar, Alamar Blue ilavesinin sonrasinda bir Molecular Devices Vmax Plate reader (570-600 nm) üzerinde çesitli zaman noktalarinda okunmustur. Söz konusu iki teste ait sonuçlar asagida yer alan Tablo 4'te sunulmustur. 3000'den fazla hibridom süpernatanti bu iki testte bloklama kabiliyeti bakimindan taranmistir; en iyi 200 bloklayici, 4 noktali bir titrasyonda tekrar test edilmistir ve bunlardan 14'ü rekombinant protein üretimi ve baska testler için seçilmistir. Örnek niteligindeki üç antikor (antikor 1-3) için antikorlar, GSM ile indüklenen STAT3 translokasyonunu IL-3l ile indüklenen çogalmayi inhibe ettiginden daha fazla inhibe etmistir ve bazi antikorlarda da tam tersi görülmüstür. Ancak üç antikor` da, OSNI ve IL-3l aracili sinyallemesine karsi güçlü inhibitörlerdir. ÖRNEK 3: Sinomolgus OSMR Blogu Testleri OSMR antikorunun sinomolgus OSMR araciligiyla sinyallemeyi bloke etme kabiliyeti, ligand olarak insan OSM veya insan IL-31 kullanildigi iki test kullanilarak arastirilmistir. Ilk taramada antikorlar, bir primer bir böbrek epitelyal hücre hatti kullanilarak sinomolgus OSMR araciligiyla OSM'nin sinyalini bloke etme kabiliyetleri bakimindan degerlendirilmistir. Bu hücrelerin sinomolgus (sino) OSM ile uyarilmasi, STAT3'ün fosforilasyonunu ve bunu takiben çekirdege translokasyonu indükler. Hücreler, Costar 384 kuyucuklu plakalarda kuyucuk basina 3000 hücrede ekilmis ve gece boyunca yapismaya birakilmistir. Hücreler, antikor süpernatanlari ile yirmi dakika boyunca ön isleme tabi tutulmustur ve daha sonra 80 pM sino OSM ile 30 dakika boyunca uyarilmistir. Hücreler, PBS içinde 3 kere yikanmis, %3,5 formaldehit çözeltisi ile sabitlenmis, yikanmis (PBST içinde 3 kere) ve %0,5 Triton X-lOO çözeltisi ile geçirgen hale getirilmistir. Hücreler daha sonra bir` saat boyunca bir anti-fosfoSTAT3 antikoru ile boyanmis, yikanmis ve bir AlexaFluor (tümü Cellomics'e ait HitKit içinde bulunur) ile konjüge edilmis antikor ile boyanmistir. Plakalar, bir Nükleer Yogunluk degeri ve bir Sitoplazmik Yogunluk degeri olusturmak için Cellomics tescilli algoritmasinin kullanilarak ArrayScan cihazinda okunmustur. Sonuçlar, söz konusu iki degerin arasinda fark olarak bildirilmistir ve ayrica en üst düzeyde uyarilmis hücreler ve ortam ile içeren kontrol verisine normallestirilmistir (POC). Ikinci testte antikorlar, sino IL-3 IRA ve OSMR'yi asiri ifade etmis stabil bir hücre hattinda sinomolgus OSMR yoluyla IL-31'in proliferatif bir sinyalini inhibe etme kabiliyetleri bakimindan test edilmistir. Örnek Z'ye benzer sekilde BaF3 hücreleri, 96 kuyucuklu plakalara kuyucuk basina 20.000 hücre yogunlugunda yerlestirilmistir. Antikorlar ve ligand (sinomolgus IL-3l, kurum içi, Amgen, Seattle, WA), lOO uL'lik bir son hacimde kuyucuklara ilave edilmistir ve plakalar, %5 COZ, 37C nemlendirilmis bölmede 72 saat boyunca inkübe edilmistir. Inkübasyonun ardindan her bir kuyucuga 20 uL Alamar Blue ilave edilmis ve plakalar yeniden inkübatöre koyulmustur. Plakalar, Alamar Blue ilavesinin sonrasinda. Molecular Devices Vmax Plate reader (570-600 nm) üzerinde çesitli zaman noktalarinda okunmustur. Söz konusu iki teste ait sonuçlar, iki test için de gösterilen her bir antikor için IC50 degeri ile birlikte asagida yer alan Tablo 5'te sunulmustur. Sonuçlar, antikor` l, 2 ve 3'ün her birinin, OSM ve IL-3l aracili sinyallemesine karsi güçlü inhibitörler oldugunu dogrular. ÖRNEK 4: Anti-OSMR Antikorlarinin Epitop Gruplamasi (Binning) Anti-OSMR xenomouse antikorlarinin epitoplarini karakterize etmek üzere antikor rekabet çalismalari gerçeklestirilmistir. Birbiriyle rekabet eden antikorlarin hedef üzerinde ayni alana baglandiklari kabul edilir. Bu deneylerde OSMR veya alakasiz antikorlar, bir uygulama antikoruna (biyotinlenmis monovalent fare anti-insan IgG FC antikoru) önceden baglanmis streptavidin kapli Luminex boncuklari üzerinde yakalanmistir. OSMR antijeni veya tamponu (antijensiz) kuyucuklara ilave edilmistir ve bir prob antikoru her bir kuyucuga eklenmis ve bir PE etiketli monovalent fare anti-insan IgG FC antikoru ile tespit edilmistir. Her kuyucugun ortalama flüoresan yogunlugu ölçülmüstür. Tam referans için bkz. Jia ve dig., J. Immunol. tespit edilmesi, prob antikorunun diger OSMR antikorunun varliginda bile OSMR'ye baglanabildigini ve bunlarin ayri epitoplara baglandiklarini göstermistir. Asagida Tablo 6'da gösterildigi gibi en az üç kutu bulunmustur. ÖRNEK 5: Anti-OSMR Antikorlarinin Afinite Tayini Anti-OSMR antikorlarinin afiniteleri belirlenmistir. Antikorlar 1-3'ün (Ab 1-3) insan OSMR ile etkilesimini arastirmak için kinetik hiz sabitleri belirlenmistir. Biyosensör analizi, 25°C'de bir HBS-EP+ (1x) tampon sisteminde P20) bir CM5 sensör çipi içeren bir Biacore 3000 optik biyosensörü ile gerçeklestirilmistir. Tüm ayiraçlar, enjeksiyondan önce 8°C'de muhafaza edilmistir. Keçi anti-insan 2'ye standart amin kenetleme yoluyla sensör çipine immobilize edilmistir (~ ve etanolamin ile bloke edilmistir. hOSMR.FH, 150 nM'de yürütme tamponu içinde hazirlanmistir ve 0,617 nM'ye 3 kat seyreltilmistir. Antikorlar 1-3, yürütme tamponunda seyreltilmistir (0,25 ila 0,5 üg/mL). Antikorlar, 10 uL/dk'lik bir akis hizinda Akis Hücresi 2 üzerinden enjekte edilmistir (15 uL). Yaklasik 50 RU antikor yakalanmistir. Yüzey, stabilize olmaya birakilmistir (90 sn) ve daha sonra hOSMR'nin birlesme (5 dk) ve ayrismayi (5 dk) gözlemlemek için 50 uL/dk'lik bir akis hizinda Akis Hücre l xwe 2 üzerinden geçirilmistir. Numuneler, ikili halinde ve rastgele sirayla yürütülmüstür. Tampon analit boslari (0 nM hOSMR) numune enjeksiyonlarindan önce, enjeksiyonlarin arasinda ve enjeksiyonlardan sonra enjekte edilmistir. Antikorlar, 10 uL/dk'lik bir akis hizinda Akis Hücresi 2 üzerinden enjekte edilmistir (15 uL). Yaklasik 50 RU antikor yakalanmistir. Yüzey, stabilize olmaya birakilmistir (90 sn) ve daha sonra hOSMR'nin her bir konsantrasyonu (150), birlesme (5 dk) ve ayrismayi (1-2 saat) gözlemlemek için 50 uL/dk'lik bir akis hizinda Akis Hücre 1 ve 2 üzerinden geçirilmistir. Numuneler üçlü halinde yürütülmüstür. Tampon analit boslari (0 nM hOSMR) numune enjeksiyonlarindan önce ve enjeksiyonlardan sonra enjekte edilmistir. Yüzey, iki 10 mM glisin (pH 1,5, 50 uL) enjeksiyonu ile birlikte 50 uL/dk'lik bir akis hizinda rejenere edilmistir. Ardindan bir tampon bos enjeksiyon (15 sn) gerçeklestirilmistir. Veriler, Scrubber 2.0 ile asagidaki gibi analiz edilmistir. Akis Hücresi Z'den elde edilen veriler, Akis Hücresi 1'den (bos referans) elde edilen veriler çikarilmistir. Çikarilan referans veriler (2-1), daha sonra en yakin 0 nM konsantrasyon verisinden çikarilmistir (çift referansli). Çift referansli uzun ayrisma verileri, ayrisma hizi sabitini (kd) belirlemek için bir 1:1 oraninda baglanma modeline uydurulmustur. Bu ayrisma hizi sabiti, ayrisma hizi sabitini (ka) ve denge ayrisma sabitini (Kd) belirlemek için çift referansli kisa ayrisma verisinin bir 121 oraninda baglanma modeline uydurulmasi için bir uydurulmus parametre olarak kullanilmistir. Ayiraçlar, deney kosullari altinda iyi bir sekilde davranmistir ve veriler (bkz. asagida yer alan Tablo 7), bir lzl oraninda baglanma modelinde iyi bir sekilde uyum saglamistir. Antikor Antijen kd (1/Ms) Kd (1/s) Kd (pM) Ab2 huOSMR Ab2 huOSMR Insan OSMR'ye karsi yönlendirilmis tamamen insan antikorlar, asagida Örnek tarif edilen XENOMOUSE® teknolojisi kullanilarak üretilmistir. Antikor 1, 2 ve 3'ün her birinin, OSM ve/Veya lL-3l aracili sinyallemenin güçlü inhibitörleri oldugu görülmüstür. Antikor l, 2 ve 3'ün sekanslari (örn. Abl, Ab2, ve Ab3), belirlenmistir ve asagida Tablo 8'de belirtilmistir. Açiklama Sekans Abl-Agir Zincir nükleotidi caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggc ctcagtgaaggtctcctgcaaggcttctggatacaccttcaccagtt atgatatcaactgggtgcgacaggccactggacaggggcttgagtgg atgggatggatgaaccctaatagtggtaacacagactatgcacagaa gttccagggcagagtcaccatgaccaggaacatttccataagcacgg cctacattgagctgagcagcctgagatctgaggacacggccgtttat tactgtgcgagagatatggtggctgcgaatacggattactacttcta ctacggtatggacgtctggggccaagggaccacggtcaccgtctcct cagctagcaccaagggcccatcggtcttccocctggcgccctgctcc aggagcacctccgagagcacagcggccctgggctgcctggtcaagga ctacttccccgaaccgqtgacggtgtcgtggaathaggcgctctga ccagcggcgtgcacaccttcccagctgtcctacagtcctcaggactc tactccctcagcagcgtggtgaccgtgccctccagcaacttcggcac ccagacctacacctgcaacgtagatcacaagcccagcaacaccaagg tggacaagacagttgagcgcaaatgttgtgtcgagtgcccaccgtgc ccagcaccacctgtggcaggaccgtcagtcttcctcttccccccaaa acccaaggacaccctcatgatctcccggacccctgaggtcacgtgcg tggtggtggacgtgagccacgaagaccccgaggtccagttcaactgg tacgtggacggcgtggaggtgcataatgccaagacaaagccacggga ggagcagttcaacagcacgttccgtgtggtcagcgtcctcaccgttg tgcaccaggactggctgaacggcaaggagtacaagtgcaaggtctcc aacaaaggcctcccagcccccatcgagaaaaccatctccaaaaccaa agggcagccccgagaaccacaggtgtacaocctgcccccatcccggg aggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggc ttctaccccagcgacatcgccgtggagtgggagagcaatgggcagcc ggagaacaactacaagaccacacctcccatgctggactccgacggct ccttcttcctctacagcaagotcaccgtggacaagagcaggtggcag caggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaa AbZ-Agir Zincir nükleotidi âlüd±&`"ââ`LQQßLJCܱüaJgIIgüLUJiCdÂQQUCLLÜdqLUU ata "âîüiuIC"'&NVaÇLgqLLLClßiüüüLjLJJJ?Lgli JL * ÇJ .im qt '&LüdîîdqqiiüiîîlûüilâdûîgCJÇ tt.-ii-iri It--«jJS~JJJJJJU-~-;TçtüâhiJ--tuüî ±:_t_ _1w__;_J:g:;uu;.tuggt-ttcuuci qjcjurstgctui ---i "tt--';;J- çujgtq-u;jtgîc-îjjJJ-îü-_ -I--~t11 UUJSCJJC'-W-;Q---CIÇÇ--I I_Ituu-J:UjtCÇîUJUQ_C-Ç tJ.îCCÇIuJ_I--Iljtjjt:u .qîiuuutriJ;r Ab3-Agir Zincir nükleotidi caggttcatctggtgcagtctggagctgaggtgaagaagcctggggc ctcagtgaaggtctcctgcaaggcttctggttacacctttaccagct atggtatcagctgggtgcgacaggcccctggacaagggcttgagtgg atgggatggctcagcacttacagtggtaacacaaactatgcacagaa gctccagggcagagtcaccatgaccacagacacatccacgagcacag cctacatggagctgaggagcctgagatctgacgacacggccgtgtat tactgtgcgagagggaacttCtactactacggtatggacgtctgggg ccaggggaccacggtcaccgtctcctcagctagcaccaagggcccat cggtcttccccctggcgccctgctccaggagcacctccgagagcaca gcggccctgggctgcctggtcaaggactacttccccgaaccggtgac ggtgtcgtggaactcaggcgctctgaccagcggcgtqcacaccttcc cagctgtcctacagtcctcaggactctactccctcagcagcgtggtg accgtgccctccagcaacttcggcacccagacctacacctgcaacgt agatcacaagcccagcaacaccaaggtggacaagacagttgagcgca aatgttgtgtcgagtgcccaccgtgcccagcaccacctgtggcagga ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgat ctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccacg aagaccccgaggtccagttcaactggtacgtggacggcgtggaggtg cataatgccaagacaaagccacgggaggagcagttcaacagcacgtt ccgtgtggtcagcgtcctcaccgttgtgcaccaggactggctgaacg gcaaggagtacaagtgcaaggtctccaacaaaggcctcccagccccc atcgagaaaaccatctccaaaaccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccagg tcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgcc gtggagtgggagagcaatgggcagccggagaacaactacaagaccac acctcccatgctggactccgacggctccttcttcctctacagcaagc tcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgc Abl-Agir Zincir proteini QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDINWVRQATGQGLEW MGWMNPNSGNTDYAQKFQGRVTMTRNISISTAYIELSSLRSEDTAVY YCARDMVAANTDYYFYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPC PAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNW YVDGVEVHNÃKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVS NKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTOKSLSLSPGK AbZ-Agir Zincir proteini QVQLVQSGAEVKKPGASVKVSCKÄSGYTFTSYEINWVRQÄTGQGLEW MGWMNPNSGYTGYAQKFQGRVTMTRNTSISTAYMEMSSLRSEDTAVY YCARDIVAANTDYYFYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPC PAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNW YVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVS NKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK Ab3-Agir Zincir proteini QVHLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEW MGWLSTYSGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVY YCARGNFYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSEST AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV TVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEV HNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAP VEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGK Abl-Agir Zincir Degisken Bölgesi QVQLVQSGABVKKPGASVKVSCKASGYTFTSYDINWVRQATGQGLEW MGWMNPNSGNTDYAQKFQGRVTMTRNISISTAYIELSSLRSEDTAVY YCARDMVAANTDYYFYYGMDVWGQGTTVTVSS AbZ-Agir Zincir Degisken Bölgesi QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYEINWVRQATGQGLEW MGWMNPNSGYTGYAQKFQGRVTMTRNTSISTAYMEMSSLRSEDTAVY YCARDIVAANTDYYFYYGMDVWGQGTTVTVSS Ab3-Agir Zincir Degisken Bölgesi QVHLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEW MGWLSTYSGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVY YCARGNFYYYGMDVWGQGTTVTVSS Abl-Agir ZincirlZ SYDIN AbZ-Agir Zincir13 SYEIN Ab3-Agir Zincirl4 SYGIS Abi-Agir ZincirlS WMNPNSGNTDYAQKFQG AbZ-Agir Zincir16 WMGWMNPNSGYTGYAQKFQG Ab3-Agir Zincirl7 WLSTYSGNTNYAQKLQG Abl-Agir Zincirl8 DMVAANTDYYFYYGMDV AbZ-Agir Zincir19 DIVAANTDYYFYYGMDV Abl-Hafif 21 cagtctgtgctgactcagccaccctcagcatctgggacccccgggca nükleotidi ctcatctatactaataatcggcggccctccggggtccctgaccgatt ctctggctccaagtctggcacctcagcctccctggccatcagtgggc tccagtctgaggatgaggctgattatttctgtgcagcgttagatgac agtctgaatggtgtggtattcggcggagggaccaaactgaccgtcct aggccaaccgaaagcggcgccctcggtcactctgttcccgccctcct ctgaggagcttcaagccaacaaggccacactggtgtgtctcataagt gacttctacccgggagccgtgacagtggcctggaagqcagatagcag ccccgtcaaggcgggagtggagaccaccacaccctccaaacaaagca acaacaagtacgcggccagcagctatctgagcctgacgcctgagcag tggaagtcccacagaagctacagctgccaggtcacgcatgaagggag caccgtggagaagacagtggcccctacagaatgttca Ab2-Hafif nükleotidi cagtctgtgctgactcagccaccctcagcgtctgggacccccgggca gagggtcaccatctcttgttctggaagcaactccaacatcggaagta atactgtcaactggtaccaccagctcccaggaacggcccccaaactc ctcatctataatattaataagcggccctcaggggtccctgaccgatt ctctggctccaagtctggctcctcagcctccctggccatcagtgggc tccagtctgaggatgaggctgattattactgttcaacatgggatgac agcctggatggtgtggtattcggcggagggaccaagctgaccgtcct aggccaaccgaaagcggcgccctcggtcactctgttcccgccctcct ctgaggagcttcaagccaacaaggccacactggtgtgtctcataagt gacttctacccgggagccgtgacagtqgcctggaaggcagatagcag ccccgtcaaggcgggagtggagaccaccacaccctccaaacaaagca acaacaagtacgcggccagcagctatctgagcctgacgcctgagcag tggaagtcccacagaagctacagctgccaggtcacgcatgaagggag caccgtggagaagacagtggcccctacagaatgttca Ab3-Hafif nükleotidi gaaattgtgttgacgcagtctccaggcaccctgtctttgtctccagg ggaaagagccaccctctcctgcagggccagtcagagtgttagcagca gctacttagcctggtaccagcagaaacctggccaggthccaggctc ctcatctttggtgcttccagcagggccactggcatcccagacaggtt cagtggcagtgggtctgggacagacttcactctcaccatcagcagac tggagcctgaagattttgcagtgtattactgtcagcagtatggtagc tcgcctccgatcaccttcggccaagggacacgactggagattaaacg tacgqtggctgcaccatctgtcttcatcttcccgccatctgatgagc agttgaaatctggaactgcctctgttgtgtgcctgctgaataacttc tatcccagagaggccaaagtacagtggaaggtggataacgccctcca atcgggtaactcccaggagagtgtcacagagcaggacagcaaggaca gcacctacagcctcagcagcaccctgacgctgagcaaagcagactac gagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgag ctcgcccgtcacaaagagcttcaacaggggagagtgt Abl-Hafif Zincir proteini QSVLTQPPSASGTPGQRVTISCSGSSSNVGSNTVSWYQQLPGTAPKL LIYTNNRRPSGVPDRFSGSKSGTSASLAISGLQSEDEADYFCAALDD SLNGVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLIS DFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAÂSSYLSLTPEQ WKSHRSYSCQVTHEGSTVEKTVAPTECS AbZ-Hafif Zincir proteini QSVLTQPPSASGTPGQRVTISCSGSNSNIGSNTVNWYHQLPGTAPKL LIYNINKRPSGVPDRFSGSKSGSSASLAISGLQSEDEADYYCSTWDD SLDGVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLIS DFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQ WKSHRSYSCQVTHEGSTVEKTVAPTECS Ab3-Hafif Zincir proteini EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRL LIFGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGS SPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLSSPVTKSFNRGEC Abl-Hafif Zincir Degisken QSVLTQPPSASGTPGQRVTISCSGSSSNVGSNTVSWYQQLPGTAPKL LIYTNNRRPSGVPDRFSGSKSGTSASLAISGLQSEDEADYFCAALDD SLNGVVFGGGTKLTVLG AbZ-Hafif Zincir Degisken QSVLTQPPSASGTPGQRVTISCSGSNSNIGSNTVNWYHQLPGTAPKL LIYNINKRPSGVPDRFSGSKSGSSASLAISGLQSEDEADYYCSTWDD SLDGVVFGGGTKLTVLG Ab3-Hafif Zincir Degisken EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRL LIFGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGS SPPITFGQGTRLEIKR Abl-Hafif Zincir CDRl AbZ-Hafif 31 SGSNSNIGSNTVN Zincir CDRl Ab3-Hafif 32 RASQSVSSSYLA Zincir CDRl Abl-Hafif 33 TNNRRPS Zincir CDR2 AbZ-Hafif 34 NINKRPS Zincir CDR2 Ab3-Hafif 35 GASSRAT Zincir CDR2 Abl-Hafif 36 AALDDSLNGVV Zincir CDR3 AbZ-Hafif 37 STWDDSLDGVV Zincir CDR3 Ab3-Hafif 38 QQYGSSPPIT Zincir CDR3 ÖRNEK 7: Modifiye Edilmis Anti-OSMR Antikorlari Abl, Ab2 ve Ab3'ün modifiye edilmis versiyonlari olusturulmustur. Antikorlarin modifiye edilmis üç formu için de agir zincir C ucundaki lizin kaldirilmistir. Abl ve Ab2 için pozisyon 73'teki glikozilasyon alani, pozisyon 73'teki asparaginin bir aspartik asit ile ornatilarak kaldirilmistir. Bu varyantlar, Abl-N73D ve Ab2-N73D olarak adlandirilir. Modifiye edilmis sekanslar, asagida Tablo 9'da yer alir (modifiye edilmis nükleotitler ve amino asitlerin alti çizilmistir). Açiklama SEQ ID Sekans bl versiyon 2- Agir Zincir nükleotidi (N73D / C ucu silinmis) .1.Lm4tviigciun.: t; hacq: ..:".n:x atüdî_zt"5 55:'q~ç Ç]dejgîatjjtfjß-j-jsgi_ ua! Mifîî'i'üg n -îu1qi 'rateraa Ab2 versiyon 2- Agir Zincir nükleotidi (N73D / C ucu silinmis) caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggc ctcagtgaaggtctcctgcaaggcttctggatacaccttcaccagtt atgaaatcaactgggtgcgacaggccactggacaagggcttgagtgg atgggatggatgaaccctaacagtggttacacaggctatgcacagaa gttccagggcagagtcaccatgaccagggacacctccataagcacag cctacatggaaatgagcagcctgagatctgaggacacggccgtgtat tactgtgcgagagatatagtggctgcgaatacggattactacttcta ttatggtatggacgtctggggccaagggaccacggtcaccgtctcct cagctagcaccaagggcccatcggtcttccccctggcgccctgctcc aggagcacctccgagagcacagcggccctgggctgcctggtcaagga ctacttccccgaaccggtgacggtgtcgtggaactcaggcgctctga ccagcggcgtgcacaccttcccagctgtcctacagtcctcaggactc tactccctcagcagcgtggtgaccgtgccctccagcaacttcggcac ccagacctacacctgcaacgtagatcacaagcccagcaacaccaagg tggacaagacagttgagcgcaaatgttgtgtcgagtgcccaccgtgc ccagcaccacctgtggcaggaccgtcagtcttcctcttccccccaaa acccaaggacaccctcatgatctcccggacccctgaggtcacgtgcg tggtggtggacgtgagccacgaagaccccgaggtccagttcaactgg tacgtggacggcgtggaggtgcataatgccaagacaaagccacggga ggagcagttcaacagcacgttccgtgtggtcagcgtcctcaccgttg tgcaccaggactggctgaacggcaaggagtacaagtgcaaggtctcc aacaaaggcctcccagcccccatcgagaaaaccatctccaaaaccaa agggcagccccgagaaccacaggtgtacaccctgcccccatcccggg aggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggc ttctaccccagcgacatcgccgtggagtgggagagcaatgggcagcc ggagaacaactacaagaccacacctcccatgctggactccgacggct ccttcttcctctacagcaagctcaccgtggacaagagcaggtggcag caggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaa ccactacacgcagaagagcctctccctgtctccgggt Ab3-Agir Zincir nükleotidi (C silinmis) ir'wî`1'34 .JJUIJfÜuVQJJ"CÜIUJACJJJJd'IrHJJIWU r I'ÃJ *jiiî' J-'qa'î' "'-VJ'II'Ã' -'~"'"I"-"Jf'L-"ÄI'I'J I|._i›.i r [î ' *:i: :117._1 1:" î i" 1:" .Jrf ~j*'IIiII..I' ;Ja-'zit * [|-' ' ii ,wr'i :iziig f i-'i'îziiçîi'vgi 11|i;._ii"I._i<'fî:^ i" i._i._i:'i'i;i[î i._iv' ii Mr i 1J i fr i.i'iw "Tîhif iii l i i it i Ü pwnw i iîF'îi`JPq Wfq af 'i i i ° f 'iîi tiqtqf wttu wîit'nnhn:i~1ûiuzi HHJJild'rf J'I'YISJlH'I' -:'a:eqq wl'›° fvvalit'fv.)]1t Abl versiyon 2- Agir Zincir proteini (N73D / C ucu lizini silinmis) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDINWVRQATGQGLEW MGWMNPNSGNTDYAQKFQGRVTMTRQISISTAYIELSSLRSEDTAVY YCARDMVAANTDYYFYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPC PAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNW YVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVS NKGLPAPIEKTISKTKGQPREPQVYTLFPSREEMTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPG Ab2 versiyon 2- Agir Zincir proteini (N73D / C ucu lizini silinmis) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYEINWVRQATGQGLEW MGWMNPNSGYTGYAQKFQGRVTMTRETSISTAYMEMSSLRSEDTAVY YCARDIVAANTDYYFYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPC PAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNW YVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVS NKGLPAPIBKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG FYPSDIAVEWBSNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPG Ab3 versiyon 2- Agir Zincir proteini QVHLVQSGAEVKKPGASVKVSCKÃSGYTFTSYGISWVRQAPGQGLEW MGWLSTYSGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTÄVY (C ucu lizini silinmis) YCARGNFYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSEST AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV TVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEV Abl versiyon 2- 53 Agir Zincir Degisken Bölgesi QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDINWVRQATGQGLEW MGWMNPNSGNTDYAQKFQGRVTMTREISISTAYIELSSLRSEDTAVY YCARDMVAANTDYYFYYGMDVWGQGTTVTVSS Ab2 versiyon 2- 54 Agir Zincir Degisken Rölnpqi QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYEINWVRQATGQGLEW MGWMNPNSGYTGYAQKFQGRVTMTRETSISTAYMEMSSLRSEDTAVY YCARDIVAANTDYYFYYGMDVWGQGTTVTVSS ELISA deneyleri, degisken bölgelerini içeren antikorlar farkli FC bölgelerine sahip Abl veya Ab2 (veya Abl veya Ab2'nin N73D varyanti) kullanilarak çesitli formatlarda (düsük aviditeli format için Yakalamali (capture) ELISA; çözelti fazi formati için Sandviç ELISA ve kati hal avidite formati için Direkt ELISA) gerçeklestirilmistir. Abl ve Ab2'nin her biri, insan IgG2 kökenli CHl, CH2, CH3 domenlerini içerir. Burada kullanildigi sekliyle "Abl" ve "Abl IgGZ WT" terimleri ayni antikoru ifade eder. Benzer sekilde "AbZ" ve "Ab2 IgG2 WT" terimleri ayni antikoru ifade eder. CHl domenine, karmayi azaltmak için (pozisyon 228'de bulunan) bir Ser'den Pro'ya mutasyona sahip insan IgG4'ten mentese, N baglantili glikozilasyon alani elimine etmek için (pozisyon 297'de bulunan) lgG4'ten CH2 Asn'den Gln'ye mutasyona sahip insan domeni ve insan IgGl'den CH3 domenine kaynastirilmistir Abl veya Ab2'nin (veya Abl veya Ab2'nin N73D varyantinin) degisken bölgelerini içerir. "IgG4P agly / IgGl" çerçevesi, US yayinlanmis patent basvurusu numarasi US ELISA sonuçlari, çikarilmasinin, N73D ornatmasi yoluyla glikozilasyon alaninin modifiye edilmis antikorlarin OSMR'ye baglanmasini etkilemedigini göstermistir. Bkz. Tablo lO. Yakalamali Sandviç (EC50) Antikor Direkt (EC50) nM Abl N73D IgG4P agly / IgGl Ab2 N73D IgG4P agly / IgGl Baglanma çalismalari, BIAcore yöntemi kullanilarak gerçeklestirilmistir. Farkli Fc bölgelerine sahip Abl veya Ab2'nin (Abl veya Ab2'nin N73D varyantinin) degisken bölgelerini içeren antikorlar, üreticinin protokollerine göre bir CM4 çipi (GE lifesciences) üzerinde immobilize edilmistir. Çözünebilir OSMR, analit olarak kullanilmistir. N73D ornatmasi yoluyla Abl ve Ab2'de glikosilasyon alaninin kaldirilmasi, baglanma afinitelerini gelistirmistir. Abl için ornatma, Kon hizini gelistirirken, Ab2 için Koff hizini gelistirmistir. Bkz. Tablo Antikor Kon (M-ls-l) Koff(1/s) KD (M) Fab fragmanlarinin stabilitesi, antikorlarin termal açiliminin degerlendirilmesiyle belirlenmistir. Fab fragmanlarinin yüksek erime sicakligi, artan stabilite ile dogrudan iliskilidir. Diferansiyel taramali flüorimetri deneyleri ile degerlendirildigi üzere, Ab2 üzerindeki glikozilasyon alanlarinin N73D ornatilmasiyla kaldirilmasi, Fab fragmanlarinin termal stabilitesini etkilememistir ve Abl üzerinde küçük etkiler göstermistir. Bkz. Tablo 12. Fab Tm Standart Hata Antikor (Santigrat) (Santrigat) Ab2 N73D Modifiye edilmis anti-OSMR antikorlarinin insan OSMR araciligiyla sinyallemeyi bloke etme kabiliyeti degerlendirilmistir. Modifiye edilmis antikorlar, IL31, OSM veya hattinda çogalmayi inhibe etme kabiliyetleri bakimindan degerlendirilmistir. Sonuçlar, her bir antikor için ICSO degeri ile birlikte asagida Tablo 13 ve 14'te sunulmustur. Sonuçlar, modifiye edilmis Abl ve Ab2 versiyonlarinin, OSM ve IL-3l aracili sinyallemesine karsi güçlü inhibitörler oldugunu dogrular. Antikor Abl N73D IgG4P agly / IgGl Antikor Ab2 N73D <110 SEKANS LISTESI BIOGEN IDEC MA INC. Arnett V.d.. <120 ONKOSTATIN M RESEPTÖRÜ ANTIJENI BAGLAYICI PROTEINLER <130 <160 <210 <21l <212 <213 <220 <221 <223 <400 Patentln versiyon 3.5 Homo sapiens MISC_FEATURE Insan OSMR <210 2 <211 <212 <213 <220 <22l <223 <400 2 MISC_FEATURE Macaca fascicularis Sinomolgus maymunu OSMR <210 3 <211 <212 <213 <220 <221 <223 <400 3 Homo sapiens misc_feature Abi Agir zinciri <210 4 <21l <212 <213 <220 <221 <223 <400 4 Homo sapiens misc_feature Ab2 Agir zinciri <210 5 <211 <212 <213 <220 <221 <223 <400 5 Homo sapiens misc_feature Ab3 Agir zinciri <210 6 <211 <212 <213 <220 <221 <223 <400 6 9939CCt939 99309909t9 Homo sapiens MISC_FEATURE Abl Agir zinciri <210 <211 <212 <213 <220 <221 <223 <400 Met Leu Asp Ser Asp Gly Ser Phe Phe Asp Lys Ser Arg Trp Gln Gln Gly Asn Homo sapiens MISC_FEATURE Ab2 Agir zinciri Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 <210 <21l <212 <213 <220 <221 <223 <400 Homo sapiens MISC_FEATURE Ab3 Agir zinciri Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys <210 9 <211 126 <212 PRT <213 Homo sapiens <220 <221 MISC_FEATURE <223 Abl Agir zinciri degisken bölgesi <400 9 <210 10 <2ll 12 <212 <213 <220 <221 <223 <400 10 Homo sapiens MISC_FEATURE Ab2 Agir zinciri degisken bölgesi Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 25 30 Glu Ile Asn Trp Val Arg Gln Ala Thr Gly Gln Gly Lev Glu Trp Met 40 45 Gly Trp Met Asn Pro Asn Ser Gly Tyr Thr Gly Tyr Ala Gln Lys Phe 50 55 60 Gln Giy Arg Val Thr Met Thr Arg Asn Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Met Ser Ser Lev Arg Ser Glu Asp Thr Ala Vai Tyr Tyr Cys 85 90 95 Ala Arg Asp Ile Val Ala Ala Asn Thr Asp Tyr Tyr Phe Tyr Tyr Gly 100 105 110 Met Asp Val Trp Gly Gln Gly Thr Thr Vai Thr Vai Ser Ser 115 120 125 <210 11 <211 119 <212 PRT <213 Homo sapiens <220 <221 MISC_FEATURE <223 Ab3 Agir zinciri degisken bölgesi <400 11 Gln Val His Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 40 45 Gly Trp Leu Ser Thr Tyr Ser Gly Asn Thr Asn Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Arg Gly Asn Phe Tyr Tyr Tyr Gly Met Asp 100 105 <210 <211 <212 <213 <220 <221 <223 <400 Homo sapiens MISC_FEATURE Abl Agir zinciri CDRl <210 <211 <212 <213 <220 <221 <223 <400 Homo sapiens MISC_FEATURE Ab2 Agir zinciri CDRl <210 <2ll <212 <213 <220 <221 <223 <400 Homo sapiens MISCIFEATURE Ab3 Agir zinciri CDRl <210 <211 <212 <213 <220 <221 <223 <400 Trp Met Asn Pro Asn Ser Giy Asn Thr Asp Tyr Ala Gln Lys Phe Gln <210 <211 <212 <213 <220 <221 <223 <400 Homo sapiens MISC_FEATURE Abl Agir zinciri CDR2 Homo sapiens MISC_FEATURE Ab2 Agir zinciri CDR2 Trp Met Gly Trp Met Asn Pro Asn Ser Gly Tyr Thr Gly Tyr Ala Gln 1 5 10 15 <210 17 <211 17 <212 PRT <213 Homo sapiens <220 <221 MISC_FEATURE <223 Ab3 Agir zinciri CDR2 <400 17 Trp Leu Ser Thr Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Leu Gln 1 5 10 15 <2lO 18 <211 17 <212 PRT <213 Homo sapiens <220 <221 MISC_FEATURE <223 Abl Agir zinciri CD3 <400 18 Asp Met Val Ala Ala Asn Thr Asp Tyr Tyr Phe Tyr Tyr Gly Met Asp 1 5 10 15 <210 19 <211 17 <212 PRT <213 Homo sapiens <220 <221 <223 <400 Asp Ile Val Ala Ala Asn Thr Asp Tyr Tyr Phe Tyr Tyr Gly Met Asp <210 <211 <212 <213 <220 <221 <223 <400 Gly Asn Phe Tyr Tyr Tyr Gly Met Asp Val <210 <211 <212 <213 <220 <221 <223 <400 MISC_FEATURE Ab2 Agir zinciri CDR3 Homo sapiens MISC_FEATURE Ab3 Agir zinciri CDR3 Homo sapiens misc_feature Abl Hafif Zinciri <210 22 <211 648 <212 <213 <220 <221 <223 <400 22 <210 23 <211 648 Homo sapiens misc_feature Ab2 Hafif Zinciri <212 <213 <220 <221 <223 <400 23 <210 24 <21l <212 <213 <220 <221 <223 <400 24 Homo sapiens misc_feature Homo sapiens MISC_FEATURE Ab3 Hafif Zinciri Abl Hafif Zinciri <210 25 <211 216 <212 PRT <213 Homo sapiens <220 <221 MISC_FEATURE <223 Ab2 Hafif Zinciri <400 25 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Asn Ser Asn Ile Gly Ser Asn 25 30 Thr Val Asn Trp Tyr His Gin Leu Pro Gly Thr Ala Pro Lys Leu Leu 40 45 <210 <21l <212 <213 <220 <221 <223 <400 Homo sapiens MISC_FEATURE Ab3 Hafif Zinciri Gln Ile Vai Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 40 45 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Pro Ile Thr Phe Gly Gln Giy Thr Arg Leu Glu Ile Lys Arg Thr Val 100 105 110 Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys 115 120 125 Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg 130 135 140 Glu Ala Lys Val Gln Trp Lys Vai Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Giu Ser Vai Thr Giu Gln Asp Ser Lys Asp Ser Thr Tyr Ser 165 170 175 Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys 180 185 190 Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr 195 200 205 Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210 27 <211 <212 <213 <220 <221 <223 <400 Homo sapiens MISC_FEATURE Abi Hafif Zinciri variable Gln Ser Val Leu Thr Gln Pro Pro Ser Arg Vai Thr Ile Ser Cys Ser Gly Ser Thr Val Ser Trp Tyr Gln Gln Leu Pro Gly Ser Lys Ser Giy Thr Ser Ala Ser Ser Glu Asp Glu Ala Asp Tyr Phe Cys Asn Gly Val Val Phe Gly Gly Gly Thr <210 <21l <212 <213 <220 <221 <223 <400 100 105 Homo sapiens MISC_FEATURE Ab2 Hafif Zinciri variable Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Arg Vai Thr Ile Ser Cys Ser Giy Ser Asn Thr Val Asn Trp Tyr His Gln Leu Pro Gly Gly Ser Lys Ser Gly Ser Ser Ala Ser Leu ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Asp Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val <210 <211 <212 <2l3 <220 <221 <223 <400 100 105 Homo sapiens MISC_FEATURE Ab3 Hafif Zinciri variable Glu Ile Val Leu Thr Gin Ser Pro Gly Thr Leu Ser Leu Ser Pro Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser 25 30 Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu 40 45 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gin Tyr Gly Ser Ser 85 90 95 Pro Ile Thr Phe Gly Gin Gly Thr Arg Leu Glu Ile Lys Arg 100 105 110 <210 30 <211 13 <212 PRT <213 Homo sapiens <220 <221 MISC_FEATURE <223 Abi Hafif Zinciri CDRl <400 30 Ser Gly Ser Ser Ser Asn Val Gly Ser Asn Thr Val Ser <210 31 <211 13 <212 PRT <213 Homo sapiens <220 <221 MISCIFEATURE <223 Ab2 Hafif Zinciri CDRl <400 31 Ser Gly Ser Asn Ser Asn Ile Gly Ser Asn Thr Val Asn <210 32 <211 12 <212 PRT <213 Homo sapiens <220 <221 MISC_FEATURE <223 Ab3 Hafif Zinciri CDRl <400 32 Arg Ala Ser Gin Ser Val Ser Ser Ser Tyr Leu Ala <210 33 <211 7 <212 PRT <213 Homo sapiens <220 <221 MISC_FEATURE <223 Abl Hafif Zinciri CDR2 <400 33 <210 34 <211 7 <212 PRT <213 Homo sapiens <220 <221 MISCIFEATURE <223 Ab2 Hafif Zinciri CDR2 <400 34 <210 35 <211 7 <212 PRT <213 Homo sapiens <220 <221 MISC_FEATURE <223 Ab3 Hafif Zinciri CDR2 <400 35 <210 36 <211 11 <212 PRT <213 Homo sapiens <220 <221 MISC_FEATURE <223 Abl Hafif Zinciri CDR3 <400 36 Ala Ala Leu Asp Asp Ser Leu Asn Gly Val Val <210 37 <211 11 <212 PRT <213 Homo sapiens <220 <221 MISCIFEATURE <223 Ab2 Hafif Zinciri CDR3 <400 37 Ser Thr Trp Asp Asp Ser Leu Asp Gly Val Val <210 38 <211 10 <212 PRT <213 Homo sapiens <220 <221 MISC_FEATURE <223 Ab3 Hafif Zinciri CDR3 <400 38 Gln Gln Tyr Gly Ser Ser Pro Pro Ile Thr <210 39 <211 252 <212 PRT <213 Homo sapiens <220 <221 MISC_FEATURE <223 Insan OSM <400 39 Phe Ser Lys Trp Gly Glu Ser Pro Asn Arg Ser Arg Arg His Ser Pro 210 215 220 His Gln Ala Leu Arg Lys Gly Val Arq Arg Thr Arg Pro Ser Arg Lys Giy Lys Arg Leu Met Thr Arg Gly Gln Leu Pro Arg 245 250 <210 40 <211 196 <212 PRT <2l3 Macaca fascicularis <220 <221 MISC_FEATURE <223 Sinomolgus maymunu OSM proteini <400 40 Gln Arg Lys Leu Glu Gly Cys Ser Phe Leu Arg Gly Tyr His Arg Phe Met His Ser Val Gly Arg Val Phe Ser Lys Trp Gly Glu Ser Pro Asn <210 41 <211 164 <212 PRT <213 Homo sapiens <220 <221 MISC_FEATURE <223 Insan IL-31 <400 41 <210 42 <211 138 <212 PRT <213 Macaca fascicularis <220 <221 MISC_FEATURE <400 42 <210 43 <211 662 <212 PRT <213 Homo sapiens <220 <22l <223 <400 MISC_FEATURE Insan IL-31RA Leu Lys Arg Lys Thr Ser Tyr Ile Val Gln Vai Met Ala Ser Thr Ser 500 505 510 Ala Gly Gly Thr Asn Gly Thr Ser Ile Asn Phe Lys Thr Leu Ser Phe 515 520 525 Ser Val Phe Glu Ile Ile Leu Ile Thr Ser Leu Ile Gly Gly Gly Leu 530 535 540 Leu Ile Leu Ile Ile Leu Thr Val Ala Tyr Gly Leu Lys Lys Pro Asn Lys Leu Thr His Leu Cys Trp Pro Thr Val Pro Asn Pro Ala Glu Ser 565 570 575 Ser Ile Ala Thr Trp His Giy Asp Asp Phe Lys Asp Lys Leu Asn Leu 580 585 590 Lys Glu Ser Asp Asp Ser Val Asn Thr Glu Asp Arg Ile Leu Lys Pro 595 600 605 Cys Ser Thr Pro Ser Asp Lys Leu Val Ile Asp Lys Leu Val Val Asn 610 615 620 Phe Gly Asn Val Leu Gln Glu Ile Phe Thr Asp Glu Ala Arg Thr Gly Gln Glu Asn Asn Leu Gly Gly Glu Lys Asn Gly Thr Arg Ile Leu Ser 645 650 655 <210 44 <21l 649 <212 PRT <213 Macaca fascicularis <220 <221 misc_feature <223 Sinomolgus maymunu IL-ZlRA <400 44 Met Met Trp Thr Trp Ala Leu Trp Met Phe Pro Leu Leu Cys Lys Phe 1 5 10 15 Gly Leu Ala Ala Leu Pro Ala Lys Pro Glu Asn Ile Ser Cys Val Tyr <210 45 <211 918 <212 PRT <213 Homo sapiens <220 <221 MISC_FEATURE <223 Insan gp130 <400 45 Arg Ser Lys Gln Val Ser Ser Val 835 840 Lys Gln Gln Ile Ser Asp His Ile 850 855 Met Lys Met Phe Gln Glu Val Ser Thr Glu Gly Gln Val Glu Arg Phe Thr Asp Giu Gly Met Pro Lys Ser <210 <211 <212 <213 <220 <221 <223 <400 Macaca fascicularis MISC_FEATURE Sinomolgus maymunu gplBO Gly Gly Ty:: Met 875 880 TR
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