JP7028453B2 - テネイシンに対するヒト抗体及びその結合断片 - Google Patents
テネイシンに対するヒト抗体及びその結合断片 Download PDFInfo
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Description
2.配列番号3のCDRH1、配列番号4のCDRH2、及び配列番号5、12、14、16、18、24、26、28、30、及び32から独立して選択されるCDRH3をもつVH又はそのバリアントをさらに含み、最大で5個のアミノ酸がVH及びVLのCDRにおいて変更される第1項に記載の抗体又は結合断片。
3.配列番号6、13、15、17、19、21、25、27、29、31、33、及びそのバリアントから選択されるVHを含み、その配列の最大で5個のアミノ酸が変更される第1項又は第2項に記載の抗体又は結合断片。
4.Fab又はFab’断片である第1項~第3項のいずれか一項に記載の抗体又は結合断片。
5.完全長抗体である第1項~第3項のいずれか一項に記載の抗体又は結合断片。
6.重鎖が配列番号1に示される配列を有する第5項に記載の抗体又は結合断片。
7.重鎖が配列番号2に示される配列を有する第5項又は第6項に記載の抗体又は結合断片。
8.第1項~第7項のいずれか一項に記載の抗体又は結合断片を含む医薬組成物。
9.治療に使用するための、第1項~第7項のいずれか一項に記載の抗体若しくは結合断片又は第8項に記載の医薬組成物。
10.使用が、炎症性疾患、例えば慢性炎症性疾患、例えば、関節リウマチなどの本明細書に開示の障害の治療のためである第9項に記載の使用のための抗体、結合断片、又は組成物。
11.慢性炎症反応、例えば、関節リウマチなどの本明細書に開示に障害の治療用の薬剤の製造に使用するための第1項~第7項のいずれか一項に記載の抗体又は結合断片又は第8項に記載の医薬組成物。
12.第1項~第7項のいずれか一項に記載の抗体若しくは結合断片又は第8項に記載の医薬組成物の治療有効量を投与することを含む治療の方法。
13.治療が、炎症性疾患、例えば、関節リウマチなどの慢性炎症性疾患のためである第12項に記載の方法。
14.第1項~第7項のいずれか一項に記載の抗体又は結合断片をコードするポリヌクレオチド。
15.第13項に記載のポリヌクレオチドを含むベクター。
16.第12項のポリヌクレオチド又は第13項のベクターを含む宿主細胞(例えば哺乳類細胞)。
17.第16項で定められる宿主細胞を培養して、前記抗体又は結合断片を発現させるステップを含む本開示による抗体又は結合断片を製造する(作製する)方法。
(i)本開示による抗体、又はその抗原結合断片、誘導体、若しくはバリアント、若しくは組成物
(ii)投与手段
(iii)それらを使用するための説明書
を含む部品のキットが提供される。
(iv)少なくとも1つの他の薬剤
を随意に含む。
(i)本開示による抗体、又はその抗原結合断片、誘導体、若しくはバリアント、若しくは組成物、及び
(ii)使用のための説明書
を含む、対象の慢性炎症性疾患状態を決定するのに使用するための部品のキットが提供される。
本明細書で使用される「アミノ酸変化」は、アミノ酸の置換又は欠失を指し、特にアミノ酸の置換は、配列中のアミノ酸を異なる(代替)アミノ酸で置換することを指す。
テネイシン-CのFBGドメインを含む精製可溶性タンパク質(TNC FBG)を、抗体選択における抗原として、並びにその後のスクリーニング及び特性解析アッセイにおける試薬として使用するために生成した。複数の哺乳動物種のテネイシン-Cに結合する抗体を単離するための選択方法を可能にするために、ヒト、マウス、ラット、又はイヌのいずれかのTNC FBGドメインを組み込んださまざまなDNA発現コンストラクトを合成した。また、ヒトテネイシン-R FBGコンストラクトも、このホモログへの望ましくない結合を示す抗体を同定するために調製した。以下に記載するように、C末端又はN末端FBGドメインのいずれかに結合したラットCD4又はヒトIgG1 Fcタグのいずれかを有する6Hisタグタンパク質としてコンストラクトを作製した。
抗原発現用の合成DNAコンストラクトはすべて合成し、Genscript(ピスカタウェイ、アメリカ合衆国)によって配列を確認した。発現ドメインを、ラットCd4(ドメイン3及び4)タグ(Chappie et al, 2006)又はヒトIgG1 Fcタグ(Falk et al, 2012)のいずれかとそれぞれ融合させる哺乳動物発現ベクターpBIOCAM4又はBIOCAM5にFBGドメインをクローニングした。発現させたタンパク質の分泌を分泌させるために、ベクターを、マウスVH鎖に由来する小胞体(ER)シグナル配列を含むpCMV/myc/ERプラスミド(インビトロジェン)(Falk et al, 2012)から改変した。N末端FBG(例えば、FBG-Fc-His又はFBG-rCd4-His)を生じるコンストラクトの場合はすべて、消化したPCR産物をNcoI/NotI切断pBIOCAM4又はpBIOCAM5ベクターと連結した。C末端FBG(例えば、Fc-His-FBG又はrCd4-His-FBG)を生じるコンストラクトの場合はすべて、消化したPCR産物をBamHI/HindIII切断pBIOCAM4又はpBIOCAM5ベクターと連結した。FBGドメインを増幅するために使用したプライマーを図3に載せる。コンストラクトはすべて配列を確認した。ELISAスクリーニングを容易にするために、Hisタグをコードするインサート(プライマー2574及び2575)を、FBG-X(N末端FBG)融合を含む発現プラスミドのBamHI部位とHindIII部位の間に(His-FLAGタグを置換して)クローニングした。全長テネイシンCを、BstXI及びBamHIによる消化によってGenscriptpUC57プラスミドから直接クローニングし、BstXI/BamHI切断発現ベクターpFBG-Fc-His6にクローニングした。His-FBGコンストラクトを作り出すために、プライマーをrCd4-His-FBG発現プラスミドからPCRを設計し、His-FBGをコードするPCR産物をXhoI及びHindIIIで消化し、XhoI/HindIII消化pBIOCAM5にクローニングした。
Machery Nagel Nucleobond Xtra Midiキット(740410.50、フィッシャーサイエンティフィック、英国)を使用して、トランスフェクション品質のプラスミドDNAを調製した。抗原及び抗体発現用のHEK293F懸濁細胞及びFreestyle培地、RPMI培地はライフテクノロジーズ(Paisley、英国)から入手した。HEK293F細胞のトランスフェクションを以前に記載されているように行った(Chappie et al, 2006)。
タンパク質アフィニティー精製には、Ni-NTAアガロース又は固定化組換えプロテインA樹脂のいずれかを使用した。Hisタグタンパク質の精製では、培養上清をNi-NTAアガロース(1018240、キアゲン、クローリー、英国)と1時間混合し、樹脂を遠心分離(200×g、2分)のためにProteus1ステップミディスピンカラム(Generon、英国)に移した。非結合タンパク質を、20mMイミダゾール(pH8)を補ったリン酸緩衝化生理食塩水(PBS)で洗い流した。結合したタンパク質を、PBS(pH8)中の300mMイミダゾールを加え、カラム遠心分離(200×g、2分)することによって分画して溶出させた。プールした溶出タンパク質含有画分を、Gebaflex Midi透析チューブ(Generon D010、分子量カットオフ3.5kDa)に入れ、PBSに対して透析した。
抗体ファージディスプレイ
43名のヒトリンパ球ドナーから単離されたDNAを用いて構築したIontas Ltd専有ヒト抗体ファージディスプレイライブラリーを用いて、テネイシン-C FBGドメインに対する抗体を単離した。選択、ファージレスキュー、及びpSANGlO(Martin et al, 2006)へのサブクローニングはすべて、当該技術分野で周知の技術を用いて以前に記載されているように実施した(Schofield et al, 2007)。
ELISA結合アッセイにおいて抗原認識を確認するために、2ラウンド目の選択産物を個々のscFvクローンとして発現させた。産物集団を細菌発現ベクターpSANG10(Martin et al, 2006)にサブクローニングし、大腸菌BL21(DE3)に形質転換し、個々の形質転換体を以前に記載されているように96ウェルプレートで誘導した(Schofield et al, 2007)。大腸菌上清を集め、ユウロピウム標識抗FLAG検出抗体を用いたDELFIAベースのELISAを用いて、scFvのTNC FBGへの結合についてアッセイした。
全細胞アッセイ系におけるFBG誘発シグナル伝達の阻害剤としての抗FBG scFvの活性を評価するために、抗FBG scFvを二価scFv-Fc又は単量体Fabにいずれかとしてフォーマット(reformat)した。
テネイシン-Cは、FBGドメインと細胞TLR4との相互作用によって、炎症細胞及び線維芽細胞におけるサイトカインの産生を誘発することが示されている(Midwood et al, 2009)。TNFa、IL-8、及びIL-6などの炎症性サイトカインの産生を導く受容体シグナル伝達カスケードは、転写因子NF-κBの活性化を伴う。このプロセスは、容易に測定されるタンパク質シグナルの生成を伴うNF-κΒ活性化に応答するように改変された「レポーター」細胞系において研究することができる。THP1-Blue(商標)レポーター細胞株(インビボジェン、トゥールーズ、フランス)は、ヒトTHP-1単球細胞株に由来し、NF-κΒ誘導性分泌型アルカリホスファターゼ(SEAP)レポーターコンストラクトを安定に発現する。さらにこれらの細胞は細胞表面TLR4を恒常的に発現し、それによって、TNC FBG融合タンパク質のシグナル伝達活性を、ミディアムスループット~ハイスループットのアッセイ法で培養上清中のSEAPの比色定量又は蛍光定量を用いて容易に測定することができる。
ELISA交差反応性アッセイ
THP1-Blue(商標)機能アッセイで同定した9個のヒトFBGシグナル伝達阻害剤のパネルを、ラット、マウス、及びイヌFBGに対する交差反応性についてELISAで評価した。また、ヒトテネイシン-R FBGホモログに対する結合も決定した。アッセイウェルをヒト、ラット、マウス、及びイヌTNC FBG-rCD4、又はヒトTNR FBG-rCd4融合タンパク質でコーティングし、Fabの結合を、抗カッパ又は抗ラムダmAb、続いてユウロピウム結合抗マウスmAbを用いて検出した。ELISAの結果は、C3抗体がヒトTNF-FBGの他の哺乳類ホモログに対して良好な交差反応性を示し、ヒトTNF-FBGに対する見かけの結合がより低いことを明らかにした。これらが以下であった。
ヒト、ラット、及びマウスのTNC FBG並びにヒトTNR FBGとの結合についての、選択したFabの親和性並びに結合及び解離動態を、25℃にて表面プラズモン共鳴(SPR)で測定した。
実験は、Human Fab Capture Kit(GE、28-9583-25)で提供されたプロトコールに従ってCM5センサーチップを備えたBIAcore T100装置を用いて行った。さまざまな濃度のrCd4-FBGを、固定化Fabを含むフローセル及びリファレンスフローセルに注入した。リファレンスシグナルを差し引いた後、データを、T100 BIAevaluationソフトウェアを用いてグローバル1:1フィットに当てはめた。
阻害効力アッセイ
標的化CDR変異導入による親和性成熟
抗FBG抗体B12を親和性成熟のために選択した。標的化CDR変異導入は、Kunkel変異導入を用いて6個のアミノ酸のブロックにおけるVH及びVL CDR3残基をランダム化することによって行った(Fellouse and Sidhu, 2007; Kunkel et al., 1987; Sidhu and Weiss, 2004)。所与のクローンにおいてVH CDR3は長いため(10~16残基)、3つの重複ブロックにおいてランダム化を行い、VL CDR3(9残基)は2つの重複ブロックにおいてランダム化を行った。ランダム化は、32個のコドン組み合わせから所定の位置に20個のアミノ酸のいずれか(及び単一のアンバー終止コドンのみ)をコードしうるNNS(N=A/G/C/T及びS=G/C)縮重プライマーを用いて行った。以下のライブラリーを作り出した。
ストレプトアビジンダイナビーズでのファージ-抗体選択は、以前に記載されているように行った(Dyson et al, 2011)。複数ラウンドの溶液相選択をビオチン化rCd4-His-FBGに対して行って、親和性が向上したクローンを富化させた。各ラウンドの至適抗原濃度は、さまざまな抗原濃度に対して選択すること及び成果物の数を非抗原対照と比較することによって経験的に決定した。選択のストリンジェンシーは、各ラウンドで使用する抗原の量を減らすことによって増加させた。選択ウィンドウ(selection window)(選択産物と非抗原対照との間のファージ力価の倍数差(fold difference))が10を下回った後は、さらなるラウンドの選択は行わなかった。したがって、3ラウンド目で観察された選択ウィンドウが大きかったために4ラウンド目の選択に供したB12を除く全てのライブラリーについて、3ラウンドの選択をビオチン化ヒトrCd4-His-FBGに対して行った。全てのライブラリーを、各選択ラウンドにおいてストレプトアビジンビーズおよびテネイシン-R(1~3ラウンド目は100nM、4ラウンド目は1nM)に対する除外の対象として、ストレプトアビジンまたはテネイシン-Rに対する望まれない交差反応性を回避した。くわえて、ヒト抗原およびマウス抗原を選択ラウンド間で交代させたハイブリッド選択戦略をB12ランダム化ライブラリーのみに対して行った。B12ライブラリーに対してこの追加選択を行った理由は、ヒトおよびマウスrCd4-his-FBGに結合するB12親抗体において観察された、親和性の大きな違いのためであった。さらに、優れたオフレートをもつ抗体クローンを選択するために、追加ラウンドの選択を行った。オフレート選択では、ファージをビオチン化抗原(この場合1nM)に結合させ、その後、大過剰な非ビオチン化抗原(500nM)を反応に加え、20時間または40時間インキュベーションした。非ビオチン化抗原は、競合物としての役目を果たし、ビオチン化抗原から解離したファージ抗体を捕捉し、すなわち、より長いオフレートをもつ抗体のみが選択の終わりに回収されることになる(Hawkins et al., 1992; Zahnd et al., 2010)。各選択ラウンドの結果のファージ力価を、計算した選択ウィンドウと共に、下記表3~5に示す。
抗FLAG捕捉ELISAを行って、親抗体と比較してマウスFBG結合について親和性が向上したクローンをスクリーニングした。
HTRFに基づく競合アッセイを開発し、ヒトTNC FBGへの結合が向上した抗体バリアントをスクリーニングした。
31個の対象となるscFvを、ヒンジ安定化突然変異(S241P、Angal et al, 1993)をもつヒトIgG4としての抗体の生成のために、ヒトIgG4発現ベクターにサブクローニングした。IgG4抗体をHEK-293F細胞中で一過性で発現させ、ヒト及びマウスのTNC FBG並びにヒトTNR FBGへの結合に関するそれらのオフレートをランク付けするために、培養上清を表面プラズモン共鳴分光法を用いてスクリーニングした。簡潔に説明すると、表面プラズモン共鳴(SPR)実験は、BIAcore T100装置を用いて行い、ヒト抗体捕捉キットプロトコール(GE、BR-1008-39)によるプロトコールに従った。オフレートスクリーニングでは、10,000レスポンスユニット(RU)の抗ヒトFc IgG(GE、BR-1008-39)を、アミンカップリングキットプロトコール(GE、BR-1000-50)に従ってEDC/NHS架橋結合化学を用いて、Series5 CM5デキストランセンサーチップ(BR-1005-30)のフローセル(FC1及びFC2)に固定化した。発現したIgG4を含有する培養上清を2×PBS-Tで1:2に希釈し、FC2(流速5μl/分、60秒添加時間)に注入して25℃での抗体捕捉を可能にした。抗体捕捉レベルは、上清中の抗体の発現レベルに依存して308~1975RUの範囲であった。
シトルリン化FBGに対する抗体B12の結合親和力を表面プラズモン共鳴(SPR)によって測定した。B12を、QMCF発現技術(Icosagen、エストニア)を用いて、ヒンジ安定化するS241P変異を有するヒトIgG4として発現させ、プロテインAアフィニティークロマトグラフィー(MabSelect Sure、GEヘルスケア)で精製した。
供給業者の取扱説明書に従って、ペプチジルアルギニンデイミナーゼ2(PAD2;MQ-16.201-2.5、Modiquest、オランダ)又はペプチジルアルギニンデイミナーゼ4(PAD4;MQ-16.203-2.5、Modiquest、オランダ)のいずれかを用いて、精製ヒトHis-FBGをシトルリン化した。簡潔に説明すると、His-FBGを、供給された脱イミノ化バッファー(0.1Mトリス-HCl pH7.5、10mM CaCl2、5mMジチオスレイトール)中で1mg/mlに希釈し、250μlを125mUのPAD2又はPAD4酵素と混ぜた後に37℃で2時間インキュベーションした。シトルリン化は、酵素処理した試料のアミノ酸分析によって確認した。非シトルリン化対照タンパク質として使用するために、脱イミノ化バッファー中のHis-FBGの分割量をPAD酵素の非存在下において37℃で2時間インキュベーションした。シトルリン化His-FBGタンパク質及び非修飾His-FBGタンパク質を以下に記載するようにSPR実験に使用した。
SPR実験はBIAcore 3000装置で行った。抗ヒトIgG(GEヘルスケア)をアミノカップリング化学を用いてCM5センサーチップの表面に共有結合させた。RU単位で表した結合抗ヒトIgGの量は6500~7000(6.5~7.0ng/mm2)の間で変動した。HBS-EPバッファー(10mM Hepes、0.15M NaCl、2.5mM EDTA、及び0.005%ツイーン20)中で25℃にて、B12-hIgG4(1~13nM)を固定化した抗ヒトIgGに結合させた。His-FBGバリアントの固定化B12-hIgG4への結合もまた、25℃でHBS-EPバッファー中で測定した。流速は、固定化実験では5μl/分であり、動態解析では20μl/分であった。センサーチップ表面は3M MgCl2を用いて再生した。BIAevaluationプログラム4.1(GEヘルスケア)を用いてデータを解析した。
抗FBG抗体が、ヒト組織におけるヒトTNC FBGタンパク質の内在性形態を効果的に認識するかどうかを決定するために、免疫組織化学研究を行った。テネイシン-Cは慢性炎症の部位で発現し、関節リウマチをもつ個人の炎症を起こした関節滑膜内に局在することは、市販の抗体を用いた免疫組織化学によって以前に示されている(Goh et al, 2010、Salter DM, 1993)。B12抗体を、QMCF発現技術(Icosagen、エストニア)を用いてマウスIgG2aフォーマットとして発現させ、プロテインGアフィニティークロマトグラフィーで精製し、続いてSuperdex 200ゲルろ過を行った。完全長ヒトテネイシン-CのEGFドメインを認識する対照マウスIgG1抗テネイシン-C抗体(クローン4F10TT;タカラクローンテック)を陽性対照コンパレーター(comparator)として使用した。関連がない細菌抗原に対するマウスIgG1(ダコ X0931)又はIgG2a(ダコ X0943)を対照一次抗体として使用して、これらのアイソタイプによる非特異的バックグラウンド染色のレベルを測定した。診断が確定したRAをもつドナーからのヒト膝関節滑膜の凍結切片(Asterand、英国)を室温に平衡化し、1:1体積/体積のアセトン/メタノール中で固定し(10分間)、洗浄バッファーに移した。免疫染色は、製造者のプロトコールに従ってDako AutostainerをEnvision Flex試薬(ダコ K8010)と共に用いて行った。簡潔に説明すると、固定した組織スライドを自動染色装置上に置き、ブロック(ペルオキシダーゼブロック、5分間;タンパク質ブロック、10分間、ダコ X0909)した後に、一次抗体(B12又はクローン4F10TT;1、2、又は4μg/ ml)を30分間加えた。いくつかの対照では、スライドを一次抗体に曝露しなかった。洗浄後、HRP標識ヤギ抗マウス二次抗体を加え(20分)、スライドを再度洗浄した後、DAB+クロモゲンを10分間加えた。スライドを洗浄し、ヘマトキシリンで対比染色し、染色を顕微鏡での可視化のためにカバーガラスを被せた。
VH及びVL配列のCDRを囲み枠で示した。
モノクローナル抗体C3(165_13_C3)が、TNC-FBGのその受容体TLR4への結合を乱すことによって作用することを確認するために、まずインビトロ結合アッセイをTLR4及びFc-His-FBGについて開発し、次にFc-His-FBGとC3とのをプレインキュベーションの効果を決定した。
抗TNC-FBG抗体B12及びC3(165_13_C3)は、生体系において抗炎症効果を有することが確認された。これを行うために、ヒト単球をフィコール勾配及び向流遠心分離によって末梢血(London blood bank)から単離した。次いで単球を100ng/mlのM-CSF(ペプロテック)で5日間分化させてM2マクロファージを得た。
滑膜線維芽細胞は、RAにおいて炎症誘発性サイトカイン放出の重要な源でありうることが報告されている(R Bucala et al. (1991) Constitutive Production of Mitogenic and Inflammatory Cytokines by Rheumatoid Synovial Fibroblasts. J. Exp. Med. 173:569-574)ので、C3抗体がやはり、FBG誘導サイトカイン放出に対してマクロファージにおける効果と同様の効果を示すかどうかを試験した。
マウスCIA(コラーゲン誘導関節炎)モデル及びラットCIAモデルの両方におけるテネイシン-Cの発現が確認され、疾患活性が臨床スコアと相関することが示された。
IgG4 C3(165_13_C3)を標準的なラットコラーゲン誘導関節炎モデルにおける治療活性(therapeutic activity)について試験した。成体雄Lewisラットを無作為に実験群に割り当て、1週間順化させた。0日目に、動物に下背部での皮内注射によって、不完全フロイントアジュバント(CII/IFA)中のII型ウシコラーゲンの1mg/mlエマルションを500μl投与した。7日目に、動物はCII/IFAの2回目の注射を受けた。注射はガス(イソフルラン)麻酔下で行った。表12で下記に示す投与スケジュールに従って治療を施した。
結果
0日目から実験終了まで、毎日、異常な姿勢(背中を丸くして前かがみになった姿勢)、異常な被毛の状態(立毛)、及び異常な活動レベル(活動の減少又は増加)を含む非特異的な臨床徴候について動物をチェックした。第6群の1匹の動物(ID#6.9、抗体10mg/kg治療)は、21日目のイソフルラン麻酔から回復しなかった。動物は、異常な姿勢、異常な被毛の状態、及び異常な活動レベルなどのいかなる非特異的な臨床徴候も示さなかった。関節炎の臨床症状が重症であったために、第1群の1匹の動物(ID#1.10、媒体治療)を実験終了に先立ち、22日目に処分した。
7日目から実験終了まで、週に3回、前肢及び後肢の腫脹を含む関節炎の臨床徴候について動物を点数化した。
実験者には治療の内容をわからないようにした。各肢を5段階で点数化した:(0)腫脹がない、(1)わずかな腫脹及び/又は紅斑、(2)軽度の腫脹、(3)中等度の腫脹、並びに(4)重度の腫脹及び/又は関節硬直。各肢のスコアを足すことによって各動物の臨床的スコアを計算した。図6に示されるデータをグラフ化し(各実験群の平均±SEM)、二元配置ANOVA、続いて実験群間の多重比較のためのダネットの事後検定により分析した。媒体治療動物#1.10の最後に記録したスコアは22日目の後に使用した。動物#6.9から記録したデータは解析から除外した。媒体治療群の臨床スコアは、7日目に測定した臨床スコアと比較して、17日目から28日目の実験終了まで、有意に増加した(p<0.0001)。対照IgG4及びIgG4 C3 1mg/mL投与群は、7日目と28日目の実験終了の間、媒体治療群と比較した場合に、いかなる有意差も誘導しなかった。3mg/kgで投与したIgG4 C3は、24日目において、媒体治療群と比較した場合に、臨床スコアの有意な減少を引き起こした(p<0.01)。10mg/kgで投与したIgG4 C3は、22日目から28日目の実験終了まで、媒体治療群と比較した場合に、臨床スコアの有意な減少を引き起こした(p<0.01)。
0日目、14日目、21日目、及び28日目に、プレチスモメーター(水置換装置)を用いて後肢容積を測定した。測定はガス(イソフルラン)麻酔下で行った。
実験者には治療の内容をわからないようにした。各実験日の各動物の右及び左後肢容積を平均した。図7はグラフ化したデータを示す(各実験群の平均±SEM)。データを、二元配置ANOVA、続いて実験群間の多重比較のためのダネットの事後検定によって分析した。媒体治療動物#1.10の最後に記録した値は28日目に使用した。動物#6.9から記録したデータは分析から除外した。媒体治療群で測定された足容積は、0日目に測定された足容積と比較して、14日目から28日目の実験終了まで、有意に増加した(14日目でp<0.01、21日目及び28日目でp<0.0001)。対照IgG4及び1mg/kg IgG4 C3投与群は、0日目と28日目の間、媒体治療群と比較した場合に、後肢容積にいかなる有意差も誘導しなかった。3mg/kgで投与したIgG4 C3は、28日目において、媒体治療群と比較した場合に、後肢容積の有意な減少を引き起こした(p<0.01)。10mg/kgで投与したIgG4 C3は、21日目(p<0.05)及び28日目(p<0.01)において、媒体治療群と比較した場合に、後肢体積の有意な減少を引き起こした。
試験抗体、IgG4 C3(165_13_C3)は、3mg/kg又は10mg/kgで投与した場合に、臨床徴候の重症度を有意に減少させた。
無作為に実験群に割り当て、1週間順化させた成体雄Lewisラットを使用する。0日目に、動物に下背部での皮内注射によって、不完全フロイントアジュバント(CII/IFA)中のII型ウシコラーゲンの1mg/mlエマルションを500μl投与する。7日目に、動物はCII/IFAの2回目の注射を受ける。注射はガス(イソフルラン)麻酔下で行う。下記の投与スケジュールに従って治療を施す。0日目から実験の終了まで、週に3回、動物を体重測定することになる。7日目から実験の終了まで、週に3回、治療の内容を知らされていない実験者が関節炎の臨床徴候について動物を点数化する。0日目、14日目、21日目、及び28日目には、治療の内容を知らされていない実験者がプレチスモメーターを用いて足容積を測定する。
治療群及び投与量を表13にまとめる。試験化合物用媒体は0.9%塩化ナトリウム溶液(生理食塩水)であった。静脈内注射の投与量は5ml/kgであった。群はすべてn=10である。
7日目から実験終了まで、週に3回、前肢及び後肢の腫脹を含む関節炎の臨床徴候について動物を点数化する。
実験者には治療の内容をわからないようにする。各肢を5段階で点数化する:(0)腫脹がない、(1)わずかな腫脹及び/又は紅斑、(2)軽度の腫脹、(3)中等度の腫脹、並びに(4)重度の腫脹及び/又は関節硬直。各肢のスコアを足すことによって各動物の臨床的スコアを計算する。
動態アッセイ:ヒト及びマウスTNC rCd4-His-FBG並びにヒトTNR rCd4-His-FBGのNSCT抗体に対する結合の特性評価
KD、平衡定数(M);T Rmax、レスポンスユニット(RU)におけるリガンドの理論的最大結合レベル;SA、パーセント(%)単位の界面活性(surface activity);ka、結合定数(1/Ms);kd、解離定数(1/s);Chi2、値はあてはまりの近さ(closeness of fit)の統計的尺度である(典型的には<2)。U値はパラメーターの有意性のさらなる指標である。これは、選択された変数間の相関性のある変化に対するあてはめの依存性を検定することによって決定される、計算された速度定数とRmaxの一意性を表すパラメーターである。値が低いほど、結果の信頼度が高いことを示す。高い値(約10超)は、報告された動態定数が有用な情報を含まないことを示す。
165_13_C3及び165_13_C3*を、ヒンジ改変IgG4重鎖定常領域をもつGS-CHO発現ベクターにクローニングした。
実施例14に記載したように、細胞株を生成し、材料を発現させ、精製した。濃縮及びアフィニティー精製前の細胞培養上清の抗体価データを表15に示す。IgG4 165_13_C3*の発現は、IgG4 165_13_C3と比べて3倍を超えて高かった。
Claims (20)
- 配列番号23に示されるVL配列を含むテネイシンCのFBGドメインに特異的なヒト抗体又は結合断片であって、前記抗体が、配列番号3のCDRH1、配列番号4のCDRH2、並びに配列番号5、12、14、16、18、20、24、26、28、30、又は32のCDRH3をもつVHを含むヒト抗体又は結合断片。
- 軽鎖が配列番号22に示される配列を含み、配列番号3のCDRH1、配列番号4のCDRH2、及び配列番号18のCDRH3をもつVHを含む請求項1に記載のテネイシンに特異的な(例えばテネイシンCに特異的な)抗体又は結合断片。
- 配列番号6、13、15、17、19、25、27、29、31、33、又は35から選択されるVHを含む、請求項1に記載の抗体又は結合断片。
- 配列番号19のVHを含む請求項3に記載の抗体又は結合断片。
- Fab又はFab’断片である請求項1~4のいずれか一項に記載の抗体又は結合断片。
- 完全長抗体である請求項1~4のいずれか一項に記載の抗体又は結合断片。
- 前記軽鎖が配列番号1に示される配列を有する請求項6に記載の抗体又は結合断片。
- 前記重鎖が配列番号2に示される配列を有する請求項6又は7に記載の抗体又は結合断片。
- 前記重鎖が配列番号34に示される配列を有する請求項1~7に記載の抗体又は結合断片。
- 請求項1~8のいずれか一項に記載の抗体又は結合断片及び薬理学的に許容可能な賦形剤、希釈剤、又は担体を含む医薬組成物。
- 治療に使用するための、請求項1~9のいずれか一項に記載の抗体又は結合断片又は請求項10に記載の医薬組成物。
- 前記使用が、炎症性疾患、例えば慢性炎症性疾患の前記治療のためのものである請求項11に記載の使用のための抗体、結合断片、又は組成物。
- 前記炎症性疾患が、関節リウマチなどの関節炎である請求項12に記載の使用のための抗体、結合断片、又は組成物。
- 前記炎症性疾患が関節リウマチである請求項13に記載の使用のための抗体、結合断片、又は組成物。
- 炎症性疾患、例えば慢性炎症性疾患の前記治療用の薬剤の製造のための、請求項1~9のいずれか一項に記載の抗体、結合断片又は請求項10に記載の組成物の使用。
- 前記炎症性疾患は、関節リウマチなどの関節炎である請求項15に記載の使用。
- 前記炎症性疾患が関節リウマチである請求項16に記載の使用。
- 請求項1~9のいずれか一項に記載の抗体又は結合断片をコードするポリヌクレオチド。
- 請求項18に記載のポリヌクレオチドを含むベクター。
- 請求項18のポリヌクレオチド又は請求項19のベクターを含む宿主細胞。
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KR20180133388A (ko) | 2018-12-14 |
GB201602414D0 (en) | 2016-03-23 |
AU2017218535B2 (en) | 2022-03-31 |
IL261033A (en) | 2018-10-31 |
US20200223910A1 (en) | 2020-07-16 |
WO2017137542A1 (en) | 2017-08-17 |
CN109152833B (zh) | 2022-07-01 |
EP3413911A1 (en) | 2018-12-19 |
US11332520B2 (en) | 2022-05-17 |
CN109152833A (zh) | 2019-01-04 |
SG11201806455PA (en) | 2018-08-30 |
IL261033B1 (en) | 2024-06-01 |
CA3013168A1 (en) | 2017-08-17 |
AU2017218535A1 (en) | 2018-08-30 |
JP2019507744A (ja) | 2019-03-22 |
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