JP7184936B2 - 選択的il-6-トランス-シグナル伝達阻害剤組成物 - Google Patents
選択的il-6-トランス-シグナル伝達阻害剤組成物 Download PDFInfo
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- JP7184936B2 JP7184936B2 JP2021007075A JP2021007075A JP7184936B2 JP 7184936 B2 JP7184936 B2 JP 7184936B2 JP 2021007075 A JP2021007075 A JP 2021007075A JP 2021007075 A JP2021007075 A JP 2021007075A JP 7184936 B2 JP7184936 B2 JP 7184936B2
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Description
a.ポリペプチドダイマーは、ポリペプチド1モル当たり6%以下のガラクトース-アルファ-1,3-ガラクトース、好ましくは3モル%以下、より好ましくは1モル%以下、なおより好ましくは0.5モル%以下のガラクトース-アルファ-1,3-ガラクトースを含むか、
b.ポリペプチドダイマーは、グリカンを含み、グリカンの少なくとも52%、好ましくは少なくとも54%、より好ましくは52~65%の平均は、1若しくは複数のシアル酸残基を含むか、又は
c.両方である、ポリペプチドダイマーを提供する。
急性炎症では、IL-6は、肝臓において急性期応答を誘導し、急性期タンパク質、特にCRPのカスケードの放出をもたらすことが示されている。炎症の部位におけるアポトーシス好中球によって取り除かれるsIL-6Rと複合体を形成すること、及び得られたIL-6/sIL-6Rトランスシグナル伝達複合体の、内皮細胞上のシグナル伝達因子gp130への結合によって、IL-6は、単球走化性タンパク質(MCP)-1等のケモカインの発現を誘導し、単核細胞を攻撃する。これは、急性炎症の消散、及び適応免疫応答の開始をもたらす。したがって、急性炎症において、IL-6とsIL-6Rとの複合体は、炎症の初期の優勢に好中球性の段階と、炎症の消散も最終的にもたらす、より持続性の単核細胞流入との間での移行を支持する。
本発明の更なる一態様は、配列番号1又は配列番号2をコードする核酸分子を含むベクター、並びに前記ベクターを含む細胞を提供する。配列番号1又は配列番号2のアミノ酸配列をコードするDNAは、シグナルペプチドが抗体鎖のアミノ酸配列のアミノ末端にインフレームで連結されるように、ベクター中にクローニングされ得る。このシグナルペプチドは、免疫グロブリンシグナルペプチド又は異種シグナルペプチド(即ち、非免疫グロブリンタンパク質由来のシグナルペプチド)であり得る。
ペプチド1(その活性ダイマー化形態での配列番号1のポリペプチド)の調製及び特徴付け
CHO/dhfr-細胞におけるペプチド1のクローニング及び発現
CHO/dhfr-細胞は、European collection of cell cultures(ECACC、番号9406067)から得た。接着性CHO/dhfr-細胞は、葉酸のジヒドロ葉酸への還元、次いで、テトラヒドロ葉酸への還元を触媒する酵素、ジヒドロ葉酸レダクターゼ(DHFR)が欠損している。したがって、CHO/dhfr-細胞は、葉酸代謝拮抗薬物、メトトレキサート(MTX)に対する感受性を示す。
ペプチド1(配列番号1のポリペプチド配列)のcDNA配列は、gp130の細胞外ドメイン(IL6ST、NCBI遺伝子ID 3572、転写物バリアント1(NP_002175)、アミノ酸23~617)及びヒトIgG1のFcドメイン(IGHG1、NCBI遺伝子ID 3500、Kabat EU番号付けに従ってアミノ酸221~447)の配列を使用して、GeneArt AG社(Regensburg、Germany)が、単一のDNA断片として合成した。配列を、CHO細胞における最適なコドン使用に向けて最適化した。3つの十分に特徴付けられた点変異を、Fc部分の下部ヒンジ領域中に導入した。
ペプチド1cDNAを、以下のように、MTXを用いたトランスフェクタント選択のために、dhfr遺伝子を含むpANTVhG1発現ベクター(Antitope社)中にクローニングした(図4)。第1に、発現ベクターをMluI及びEagI制限酵素で消化して、ペプチド1のcDNAの挿入を可能にした。第2に、ペプチド1コード領域を、OL1425及びOL1426プライマー(Table 1(表1))を使用してPCR増幅し、MluI及びEagI制限酵素を用いて消化した。第3に、消化された断片をゲル精製し、一緒にライゲーションして、pFER02発現ベクターを生成した(図5)。ペプチド1cDNAを、サイトメガロウイルス(CMV)プロモーターの制御下に挿入した。
pFER02ベクターを、ベータ-ラクタマーゼ遺伝子中に位置する単一の認識部位を有する平滑末端制限酵素SspIを用いて直鎖化した。直鎖化したプラスミドを、脂質媒介性トランスフェクションを使用して、5×106のCHO/dhfr-細胞中にトランスフェクトした。トランスフェクション後の24時間に、トランスフェクトされた細胞を、5%透析済胎仔ウシ血清(FCS)及び100nMメトトレキサート(MTX)を補充した培地中で選択した。トランスフェクトされた細胞を、種々の密度でこの培地中に希釈し、96ウェル平底組織培養プレート中に分配した。次いで、細胞を、5% CO2及び37℃で加湿雰囲気中でインキュベートした。新鮮なMTX選択培地を、インキュベーション時間の間一定の間隔で添加して、MTXレベル及び栄養素レベルが一定のままであることを確実にした。
トランスフェクション後数週間にわたって、組織培養プレートを、Genetix CloneSelect(登録商標)Imagerを使用して試験し、>2,000のウェルが、活発に成長しているコロニーを有することが観察された。これらのウェルからの上清をサンプリングし、ELISAによってペプチド1の力価についてアッセイした。このアッセイの結果に基づいて、合計105の最良の発現ウェルを、48ウェルプレート中に拡大増殖させた。合計83の細胞株を、6ウェルプレート又はT-25フラスコ中への拡大増殖のために選択し、これらの細胞株の各々からの上清をサンプリングし、ペプチド1の力価についてアッセイした(ELISA)。これらの結果に基づいて、54の、最適な成長特徴を有する最良の発現細胞株を、T-75又はT-175フラスコ中への拡大増殖のために選択し、コンフルエントなフラスコからの上清をサンプリングし、ペプチド1の力価を定量した(ELISA)。細胞株間の発現レベルの比較により、生産性分析のために選択された38の最良の細胞株の同定が可能になった。生産性を以下のように評価した。
生産性(pg/細胞/日)=((Th-Ti)/((Vh+Vi)/2))/時間
式中、
Thは、回収力価[μg/mL]であり、
Tiは、初期力価[μg/mL]であり、
Vhは、回収時の生存細胞数[×106細胞/mL]であり、
Viは、初期生存細胞数[×106細胞/mL]であり、
時間は、TiとThとの間の経過時間(日)である。
13の選択された細胞株を、漸増濃度のMTX(0.1~50M)の下での選択圧による第1ラウンドの遺伝子増幅のために選択した。7~10日後、13の細胞株の各々由来の各ウェルからの上清をサンプリングし、ペプチド1の力価についてアッセイした(ELISA)。高いペプチド1発現レベルを有する各細胞株由来のウェルを、生産性(pg/細胞/日)について評価した。第2ラウンドの遺伝子増幅を、生産性における顕著な増加を示した細胞株由来の合計16のウェルで開始した。
限界希釈クローニングを、ペプチド1発現を実証している5つの細胞株に対して実施した。1週間のインキュベーション後、Genetix CloneSelect(登録商標)Imagerを使用してプレートを試験し、シングルコロニーを同定した。希釈クローニングの間の2つの細胞株の成長速度は、特に緩徐であることが注目されたので、これらの細胞株は中断した。合計して、3つの残りの細胞株から、58のクローン性コロニーを、最初に48ウェルプレート中への拡大増殖のために選択し、次いで、MTXの非存在下で、12ウェルプレート、T-25フラスコ及びT-75フラスコを通じて連続的に拡大増殖させた。次いで、58の選択されたクローンの各々を、生産性(pg/細胞/日)について評価し、16のクローンを、懸濁適応及び既知組成培地における成長への適応のために選択した。
これら16の細胞株を、以下のように、既知組成培地中での懸濁培養に適応させた。接着培養物中の選択された細胞株を、CHO懸濁成長培地(L-グルタミン及びピルビン酸ナトリウム、5%透析済FCS、20mg/L L-プロリン、1×ペニシリン/ストレプトマイシン、1% pluronic F68を含むDMEM高グルコース)中での懸濁、次いで、既知組成懸濁成長培地(Life Technologies Ltd.社(Paisley、UK)からのCD Opti-CHO(登録商標)、2.5%透析済FCS、0.1×ペニシリン/ストレプトマイシン、8mM Glutamax(登録商標))中での懸濁の両方に、最初に適応させた。
ペプチド1 DS製造プロセスの簡潔な説明は以下のとおりである。WCBバイアルからの細胞を生き返らせ、産生バイオリアクター中への接種の前に、無タンパク質培地を使用して進行性に拡大増殖させた。細胞培養の完了の際に、細胞及び細胞デブリを、培養物の濾過によって除去する。
グリカン構造分析を、Procognia Limited社(Ashdod、Israel)において実施した。N-グリカンを、PNGase Fを使用してサンプルから放出させ、次いで、2-アミノベンズアミドで標識した。放出されたグリカンを、異なるグリカン形態を生成するために、一連のエキソグリコシダーゼで処理した又は処理しなかった。グリカンを、二次元HPLC分析(NP-HPLC及びWAX)によって分離し、同じ二次元HPLC分析によって分離及び分析した社内調製標準を使用して構築した保持時間データベースとの比較によって同定した。
超高圧液体クロマトグラフィー(UPLC)を使用して、シアル酸含量を決定し、ペプチドの同一性を確認した。この方法は、Acquity UPLC BEH C18 1.7μm 2.1×50カラム及び以下の移動相:9:7:84/アセトニトリル:メタノール:水、流速0.3mL/分を使用して実施した。シアル酸を、シアリダーゼによる酵素的切断によって試験サンプルから放出させ、その後、蛍光標識(1,2ジアミノ4,5メチレンジオキシベンゼン二塩酸塩(DMB))を用いて誘導体化した。標識した試験サンプルを、イソクラティック溶出(isocratic elution)を用いたUPLC並びに373nmの励起波長及び448nmの発光波長を用いた蛍光検出によって分離した。試験サンプル中のシアル酸含量を、検量線として実行したN-グリコリルノイラミン酸(NGNA)及びN-アセチルノイラミン酸(NANA)標準と比較して定量した。NGNA及びNANAシアル酸含量を、pmolシアル酸/pmolタンパク質として報告する。
弱アニオン交換(WAX)-HPLCを、中性、モノ-、ジ-、トリ-及びテトラ-シアル化グリカンの%の決定に使用した。この方法には、PNGaseを用いた薬物物質からのN-グリカンの酵素的放出、2-アミノベンズアミド(2-AB)を用いた蛍光標識化、Ludger D1カートリッジを使用した脱塩が関与する。シアル酸化グリカンの分離を、20%アセトニトリル/0.5Mアンモニウム形式の勾配を用いて40℃でGlyco Sep Cカラムを使用して、WAX-HPLCによって実施した。蛍光検出を、330nmの励起及び420nmの発光に設定した。参照標準の試験を並行して実施した。中性、モノ-、ジ-、トリ-及びテトラ-シアル化グリカンの%を、WAX-HPLCクロマトグラムから決定し、報告した。
サイズ排除HPLC(SEC)を使用して、SGF及びオリゴマー形態(活性ダイマーのダイマーから主に構成される)からインタクトな活性ダイマーを分離することによって、薬物物質純度を決定した。インタクトな活性ダイマー分子は、2つの同一のグリコシル化されたタンパク質サブユニット(ヒトIgG1重鎖のFc部分に融合したgp130細胞外ドメイン)からなる。サンプルを、1mL/分の流速及び0.2Mリン酸ナトリウムpH7.0の移動相を用いて、ゲル浸透カラム(TSK G3000SWXL)を使用して分子量に基づいて分離した。カラム溶出物を、280nmでモニタリングした。インタクトな種を、その特徴的な保持時間によって同定し;活性ダイマーの%純度を、総積分ピーク面積の百分率として表す。
オリゴマー形態の百分率を、上に示したSEC法を使用して決定する。オリゴマー形態の百分率を、総積分ピーク面積の百分率として表す。
SGFの百分率を、上に示したSEC法を使用して決定した。SGFの百分率を、総積分ピーク面積の百分率として表す。
DPは、i.v.注入によって投与される無菌溶液である。DPは、25mM L-ヒスチジン、200mMスクロース及び0.1mgポリソルベート20/mLを含有するpH7.6の等張溶液中15mg/mLの濃度のペプチド1からなる。バイアルは、酸化に対する保護のために窒素でオーバーレイする。製品は、単回使用のために意図され、臨床的投与のための解凍まで、-20℃で貯蔵される。
薬物製品のためのバッチ配合物を、Table 4(表4)に示す。
臨床試験000067(単回用量)
設計
これは、単回用量、プラセボ対照、単盲検、用量無作為化、並行群用量漸増試験であった。試験は2つのパートで実施し、パート1は健康な対象を含み、パート2は、臨床的寛解状態にあるCDを有する患者を含んでいた。その目的は、安全性及び忍容性を試験すること、並びに可能な場合には、ペプチド1の単回投与後の薬理学的効果の徴候を得ることであった。
ペプチド1のi.v.投与後のPK評価により、0.75mgから750mgの範囲において、AUC及びCmaxの両方について用量比例性が示され、血漿中のCmax濃度は、0.2μg/mLから170μg/mLまでの範囲であった(図3)。クリアランスはおよそ0.13L/時間であり、平均終末相半減期はおよそ4.5日であり、分布容積はおよそ20Lであり、後者は、いくらかの血管外分布を示した。60mgのペプチド1のs.c.投与は、2.3日で1.1μg/mLのCmaxを示し、5.0日の半減期を示した。ペプチド1のs.c.投与後のバイオアベイラビリティは、およそ50%であると計算された。
臨床試験000115(複数の漸増用量)
設計
これは、ペプチド1の複数の漸増用量の安全性、忍容性及び薬物動態を調査することを目的とした、プラセボ対照、二重盲検、用量群内無作為化、並行群試験であった。調査した用量は、30分間(75mg)又は1時間(300mg及び600mg)にわたってi.v.注入によって4週間にわたって1週間に1回投与した、75、300及び600mgのペプチド1であった。
PK評価により、1回目の処置日及び最後の処置日に、単回用量研究における結果と類似した、非常に近い特徴が示された。AUC及びCmaxは、1回目の用量後に19、78及び148μg/mLのCmax濃度、並びに4回目の用量後に19、79及び142μg/mLのCmax濃度で、1回目及び4回目の投薬後に、用量比例的であった(健康な対象では、単回用量について16、77及び161μg/mL;図5)。対応するトラフ値は、3つの用量レベルについて、0.66、2.68、4.56μg/mL並びに0.98、3.95及び7.67μg/mLであった。最後の用量後に計算された平均終末相半減期は、およそ5.5日であった。
配列番号1
Glu Leu Leu Asp Pro Cys Gly Tyr Ile Ser Pro Glu Ser Pro Val Val
1 5 10 15
Gln Leu His Ser Asn Phe Thr Ala Val Cys Val Leu Lys Glu Lys Cys
20 25 30
Met Asp Tyr Phe His Val Asn Ala Asn Tyr Ile Val Trp Lys Thr Asn
35 40 45
His Phe Thr Ile Pro Lys Glu Gln Tyr Thr Ile Ile Asn Arg Thr Ala
50 55 60
Ser Ser Val Thr Phe Thr Asp Ile Ala Ser Leu Asn Ile Gln Leu Thr
65 70 75 80
Cys Asn Ile Leu Thr Phe Gly Gln Leu Glu Gln Asn Val Tyr Gly Ile
85 90 95
Thr Ile Ile Ser Gly Leu Pro Pro Glu Lys Pro Lys Asn Leu Ser Cys
100 105 110
Ile Val Asn Glu Gly Lys Lys Met Arg Cys Glu Trp Asp Gly Gly Arg
115 120 125
Glu Thr His Leu Glu Thr Asn Phe Thr Leu Lys Ser Glu Trp Ala Thr
130 135 140
His Lys Phe Ala Asp Cys Lys Ala Lys Arg Asp Thr Pro Thr Ser Cys
145 150 155 160
Thr Val Asp Tyr Ser Thr Val Tyr Phe Val Asn Ile Glu Val Trp Val
165 170 175
Glu Ala Glu Asn Ala Leu Gly Lys Val Thr Ser Asp His Ile Asn Phe
180 185 190
Asp Pro Val Tyr Lys Val Lys Pro Asn Pro Pro His Asn Leu Ser Val
195 200 205
Ile Asn Ser Glu Glu Leu Ser Ser Ile Leu Lys Leu Thr Trp Thr Asn
210 215 220
Pro Ser Ile Lys Ser Val Ile Ile Leu Lys Tyr Asn Ile Gln Tyr Arg
225 230 235 240
Thr Lys Asp Ala Ser Thr Trp Ser Gln Ile Pro Pro Glu Asp Thr Ala
245 250 255
Ser Thr Arg Ser Ser Phe Thr Val Gln Asp Leu Lys Pro Phe Thr Glu
260 265 270
Tyr Val Phe Arg Ile Arg Cys Met Lys Glu Asp Gly Lys Gly Tyr Trp
275 280 285
Ser Asp Trp Ser Glu Glu Ala Ser Gly Ile Thr Tyr Glu Asp Arg Pro
290 295 300
Ser Lys Ala Pro Ser Phe Trp Tyr Lys Ile Asp Pro Ser His Thr Gln
305 310 315 320
Gly Tyr Arg Thr Val Gln Leu Val Trp Lys Thr Leu Pro Pro Phe Glu
325 330 335
Ala Asn Gly Lys Ile Leu Asp Tyr Glu Val Thr Leu Thr Arg Trp Lys
340 345 350
Ser His Leu Gln Asn Tyr Thr Val Asn Ala Thr Lys Leu Thr Val Asn
355 360 365
Leu Thr Asn Asp Arg Tyr Leu Ala Thr Leu Thr Val Arg Asn Leu Val
370 375 380
Gly Lys Ser Asp Ala Ala Val Leu Thr Ile Pro Ala Cys Asp Phe Gln
385 390 395 400
Ala Thr His Pro Val Met Asp Leu Lys Ala Phe Pro Lys Asp Asn Met
405 410 415
Leu Trp Val Glu Trp Thr Thr Pro Arg Glu Ser Val Lys Lys Tyr Ile
420 425 430
Leu Glu Trp Cys Val Leu Ser Asp Lys Ala Pro Cys Ile Thr Asp Trp
435 440 445
Gln Gln Glu Asp Gly Thr Val His Arg Thr Tyr Leu Arg Gly Asn Leu
450 455 460
Ala Glu Ser Lys Cys Tyr Leu Ile Thr Val Thr Pro Val Tyr Ala Asp
465 470 475 480
Gly Pro Gly Ser Pro Glu Ser Ile Lys Ala Tyr Leu Lys Gln Ala Pro
485 490 495
Pro Ser Lys Gly Pro Thr Val Arg Thr Lys Lys Val Gly Lys Asn Glu
500 505 510
Ala Val Leu Glu Trp Asp Gln Leu Pro Val Asp Val Gln Asn Gly Phe
515 520 525
Ile Arg Asn Tyr Thr Ile Phe Tyr Arg Thr Ile Ile Gly Asn Glu Thr
530 535 540
Ala Val Asn Val Asp Ser Ser His Thr Glu Tyr Thr Leu Ser Ser Leu
545 550 555 560
Thr Ser Asp Thr Leu Tyr Met Val Arg Met Ala Ala Tyr Thr Asp Glu
565 570 575
Gly Gly Lys Asp Gly Pro Glu Phe Thr Phe Thr Thr Pro Lys Phe Ala
580 585 590
Gln Gly Glu Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
595 600 605
Ala Glu Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
610 615 620
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
625 630 635 640
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
645 650 655
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
660 665 670
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
675 680 685
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
690 695 700
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
705 710 715 720
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
725 730 735
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
740 745 750
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
755 760 765
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
770 775 780
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
785 790 795 800
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
805 810 815
Ser Leu Ser Pro Gly Lys
820
配列番号2
Met Leu Thr Leu Gln Thr Trp Leu Val Gln Ala Leu Phe Ile Phe Leu
1 5 10 15
Thr Thr Glu Ser Thr Gly Glu Leu Leu Asp Pro Cys Gly Tyr Ile Ser
20 25 30
Pro Glu Ser Pro Val Val Gln Leu His Ser Asn Phe Thr Ala Val Cys
35 40 45
Val Leu Lys Glu Lys Cys Met Asp Tyr Phe His Val Asn Ala Asn Tyr
50 55 60
Ile Val Trp Lys Thr Asn His Phe Thr Ile Pro Lys Glu Gln Tyr Thr
65 70 75 80
Ile Ile Asn Arg Thr Ala Ser Ser Val Thr Phe Thr Asp Ile Ala Ser
85 90 95
Leu Asn Ile Gln Leu Thr Cys Asn Ile Leu Thr Phe Gly Gln Leu Glu
100 105 110
Gln Asn Val Tyr Gly Ile Thr Ile Ile Ser Gly Leu Pro Pro Glu Lys
115 120 125
Pro Lys Asn Leu Ser Cys Ile Val Asn Glu Gly Lys Lys Met Arg Cys
130 135 140
Glu Trp Asp Gly Gly Arg Glu Thr His Leu Glu Thr Asn Phe Thr Leu
145 150 155 160
Lys Ser Glu Trp Ala Thr His Lys Phe Ala Asp Cys Lys Ala Lys Arg
165 170 175
Asp Thr Pro Thr Ser Cys Thr Val Asp Tyr Ser Thr Val Tyr Phe Val
180 185 190
Asn Ile Glu Val Trp Val Glu Ala Glu Asn Ala Leu Gly Lys Val Thr
195 200 205
Ser Asp His Ile Asn Phe Asp Pro Val Tyr Lys Val Lys Pro Asn Pro
210 215 220
Pro His Asn Leu Ser Val Ile Asn Ser Glu Glu Leu Ser Ser Ile Leu
225 230 235 240
Lys Leu Thr Trp Thr Asn Pro Ser Ile Lys Ser Val Ile Ile Leu Lys
245 250 255
Tyr Asn Ile Gln Tyr Arg Thr Lys Asp Ala Ser Thr Trp Ser Gln Ile
260 265 270
Pro Pro Glu Asp Thr Ala Ser Thr Arg Ser Ser Phe Thr Val Gln Asp
275 280 285
Leu Lys Pro Phe Thr Glu Tyr Val Phe Arg Ile Arg Cys Met Lys Glu
290 295 300
Asp Gly Lys Gly Tyr Trp Ser Asp Trp Ser Glu Glu Ala Ser Gly Ile
305 310 315 320
Thr Tyr Glu Asp Arg Pro Ser Lys Ala Pro Ser Phe Trp Tyr Lys Ile
325 330 335
Asp Pro Ser His Thr Gln Gly Tyr Arg Thr Val Gln Leu Val Trp Lys
340 345 350
Thr Leu Pro Pro Phe Glu Ala Asn Gly Lys Ile Leu Asp Tyr Glu Val
355 360 365
Thr Leu Thr Arg Trp Lys Ser His Leu Gln Asn Tyr Thr Val Asn Ala
370 375 380
Thr Lys Leu Thr Val Asn Leu Thr Asn Asp Arg Tyr Leu Ala Thr Leu
385 390 395 400
Thr Val Arg Asn Leu Val Gly Lys Ser Asp Ala Ala Val Leu Thr Ile
405 410 415
Pro Ala Cys Asp Phe Gln Ala Thr His Pro Val Met Asp Leu Lys Ala
420 425 430
Phe Pro Lys Asp Asn Met Leu Trp Val Glu Trp Thr Thr Pro Arg Glu
435 440 445
Ser Val Lys Lys Tyr Ile Leu Glu Trp Cys Val Leu Ser Asp Lys Ala
450 455 460
Pro Cys Ile Thr Asp Trp Gln Gln Glu Asp Gly Thr Val His Arg Thr
465 470 475 480
Tyr Leu Arg Gly Asn Leu Ala Glu Ser Lys Cys Tyr Leu Ile Thr Val
485 490 495
Thr Pro Val Tyr Ala Asp Gly Pro Gly Ser Pro Glu Ser Ile Lys Ala
500 505 510
Tyr Leu Lys Gln Ala Pro Pro Ser Lys Gly Pro Thr Val Arg Thr Lys
515 520 525
Lys Val Gly Lys Asn Glu Ala Val Leu Glu Trp Asp Gln Leu Pro Val
530 535 540
Asp Val Gln Asn Gly Phe Ile Arg Asn Tyr Thr Ile Phe Tyr Arg Thr
545 550 555 560
Ile Ile Gly Asn Glu Thr Ala Val Asn Val Asp Ser Ser His Thr Glu
565 570 575
Tyr Thr Leu Ser Ser Leu Thr Ser Asp Thr Leu Tyr Met Val Arg Met
580 585 590
Ala Ala Tyr Thr Asp Glu Gly Gly Lys Asp Gly Pro Glu Phe Thr Phe
595 600 605
Thr Thr Pro Lys Phe Ala Gln Gly Glu Asp Lys Thr His Thr Cys Pro
610 615 620
Pro Cys Pro Ala Pro Glu Ala Glu Gly Ala Pro Ser Val Phe Leu Phe
625 630 635 640
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
645 650 655
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
660 665 670
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
675 680 685
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
690 695 700
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
705 710 715 720
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
725 730 735
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
740 745 750
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
755 760 765
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
770 775 780
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
785 790 795 800
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
805 810 815
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
820 825 830
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
835 840
Claims (23)
- 配列番号1に対して少なくとも90%の配列同一性を有し、1又は複数のジスルフィド架橋によって連結された2つのgp130-Fcモノマーを含むポリペプチドダイマーであって、前記ポリペプチドダイマーは、IL-6/sIL-6R複合体を標的化及び中和し、
a.前記ポリペプチドダイマーは、ポリペプチド1モル当たり6モル%以下のガラクトース-アルファ-1,3-ガラクトースを含むか、
b.前記ポリペプチドダイマーは、グリカンを含み、前記グリカンの少なくとも52%の平均は、1若しくは複数のシアル酸残基を含むか、又は
c.両方である、ポリペプチドダイマー。 - 前記モノマーが、配列番号1を有する、請求項1に記載のポリペプチドダイマー。
- 前記モノマーが、配列番号2を有する、請求項1に記載のポリペプチドダイマー。
- 前記ポリペプチドダイマーは、ポリペプチド1モル当たり1モル%以下のガラクトース-アルファ-1,3-ガラクトースを含む、請求項1から3のいずれか一項に記載のポリペプチドダイマー。
- 前記ポリペプチドダイマーは、ポリペプチド1モル当たり0.5モル%以下のガラクトース-アルファ-1,3-ガラクトースを含む、請求項1から4のいずれか一項に記載のポリペプチドダイマー。
- 前記グリカンの少なくとも54%の平均は、1若しくは複数のシアル酸残基を含む、請求項1から5のいずれか一項に記載のポリペプチドダイマー。
- 配列番号1を、細胞中で発現させる工程、培養培地中で前記細胞を培養する工程、並びに前記細胞及び/又は細胞培養培地から前記ポリペプチドダイマーを収集する工程によって取得可能である、請求項1から6のいずれか一項に記載のポリペプチドダイマー。
- 請求項1から7のいずれか一項に記載のポリペプチドダイマーを含む組成物であって、
a.前記ポリペプチドダイマーの5%以下が、オリゴマー性凝集体として存在するか、
b.前記組成物が、4.0質量%以下の、配列番号1のポリペプチドに関して配列番号1のポリペプチドのトランケート型であるポリペプチドを含むか、又は
c.両方である、組成物。 - 1.5質量%以下の、配列番号1のポリペプチドに関して配列番号1のポリペプチドのトランケート型であるポリペプチドを含む、請求項8に記載の組成物。
- 界面活性剤を更に含む、請求項1から7のいずれか一項に記載のポリペプチドダイマーを含む組成物又は請求項8若しくは9に記載の組成物。
- 前記界面活性剤が非イオン性界面活性剤である、請求項10に記載の組成物。
- 請求項1から7のいずれか一項に記載のポリペプチドダイマーを含む組成物又は請求項8から11のいずれか一項に記載の組成物であって、緩衝剤及び糖を更に含む、組成物。
- ヒトにおける炎症性疾患又はIL-6媒介性状態の処置における使用のための、請求項1から7のいずれか一項に記載のポリペプチドダイマー又は請求項8から12のいずれか一項に記載の組成物。
- 前記炎症性疾患又はIL-6媒介性状態が、炎症性腸疾患である、請求項13に記載の使用のためのポリペプチドダイマー又は組成物。
- 前記炎症性腸疾患が、クローン病又は潰瘍性大腸炎である、請求項14に記載の使用のためのポリペプチドダイマー又は組成物。
- 前記処置が、炎症性腸疾患の寛解を維持する、請求項15に記載の使用のためのポリペプチドダイマー又は組成物。
- 前記炎症性疾患若しくはIL-6媒介性状態が、関節リウマチ、乾癬、ブドウ膜炎若しくはアテローム性動脈硬化症である;又は前記炎症性疾患若しくはIL-6媒介性状態が、炎症性腸疾患と関連しない大腸炎である、請求項13に記載の使用のためのポリペプチドダイマー又は組成物。
- 前記大腸炎が、放射線大腸炎、憩室性大腸炎、虚血性大腸炎、感染性大腸炎、セリアック病、自己免疫性大腸炎、若しくは結腸に影響を与えるアレルギーに起因する大腸炎である、請求項17に記載の使用のためのポリペプチドダイマー又は組成物。
- 非経口投与される、請求項13から18のいずれか一項に記載の使用のためのポリペプチドダイマー又は組成物。
- 静脈内投与又は皮下投与される、請求項19に記載の使用のためのポリペプチドダイマー又は組成物。
- 配列番号1に対して少なくとも90%の配列同一性を有するアミノ酸配列を、チャイニーズハムスター卵巣(CHO)細胞中で発現させる工程、培養培地中で前記細胞を培養する工程、並びに前記細胞及び/又は細胞培養培地から前記ポリペプチドダイマーを収集する工程を含む、請求項1又は2に記載のポリペプチドダイマーを産生するための方法。
- 配列番号1に対して少なくとも90%の配列同一性を有するアミノ酸配列を、チャイニーズハムスター卵巣(CHO)細胞中で発現させる工程、ポリペプチド1モル当たり6モル%以下のガラクトース-アルファ-1,3-ガラクトースを含むポリペプチドダイマーを生産する細胞株を選択する工程、培養培地中で前記細胞株由来の前記細胞を培養する工程、並びに前記細胞及び/又は細胞培養培地から前記ポリペプチドダイマーを収集する工程を含む、請求項21に記載の方法。
- 前記ダイマーが、精製及び/又は濃縮される、請求項21又は22に記載の方法。
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CA3083971A1 (en) * | 2017-11-30 | 2019-06-06 | Bio-Thera Solutions, Ltd. | Liquid formulation of humanized antibody for treating il-6 related diseases |
JP7287611B2 (ja) * | 2018-02-07 | 2023-06-06 | 学校法人日本医科大学 | 改良型アデノ随伴ウイルスベクター |
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