JP2021121615A - 第XIIa因子のモノクローナル抗体阻害剤 - Google Patents
第XIIa因子のモノクローナル抗体阻害剤 Download PDFInfo
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Abstract
Description
本出願は、2015年7月21日に出願された米国仮出願第62/194957号、2015年12月31日に出願された米国仮出願第62/273657号、および2016年3月31日に出願された米国仮出願第62/316310号の出願日の利益を主張するものである。これらの参照される出願の各内容全体が参照により本明細書に組み込まれる。
本開示は、FXIIa、例えばFXIIaの触媒ドメインに結合する抗体を提供する。そのような抗体はFXIIに結合することはできない。
[Bound]=[Free]/(Kd+[Free])
M0191−E09の重鎖可変領域配列(配列番号1):
YTE変異体の例示的な重鎖定常領域配列(配列番号120):
抗FXIIa抗体の例示的な軽鎖可変領域(配列番号40):
本明細書に記載されているFXIIaに結合することができる抗体は、当該技術分野で知られている任意の方法によって調製することができる。例えば、「HarlowおよびLane, (1998) Antibodies: A Laboratory Manual(抗体:実験書), Cold Spring Harbor Laboratory, ニューヨーク」を参照されたい。
本明細書に記載されている抗体ならびにそれをコードする核酸もしくは核酸セット、それを含むベクターまたはそのベクターを含む宿主細胞を薬学的に許容される担体(賦形剤)と混合して標的疾患を治療するのに使用される医薬組成物を形成することができる。「許容される」とは、その担体が当該組成物の有効成分と適合可能でなければならず(好ましくは有効成分を安定化することができ)、かつ治療される対象に有害でないことを意味する。薬学的に許容される賦形剤(担体)は当該技術分野において周知である緩衝液を含む。例えば、「Remington: The Science and Practice of Pharmacy 20th Ed.(レミントン:薬学の科学および実践、第20版) (2000) Lippincott Williams and Wilkins, K. E. Hoover編」を参照されたい。
本明細書に記載されている抗体のいずれかならびにそれをコードする核酸もしくは核酸セット、それを含むベクターまたはそのベクターを含む宿主細胞は、接触系活性化に関連する疾患、接触系活性化異常に関連する疾患(例えばHAE)または眼疾患などの、接触系活性化異常に関連する疾患または障害を治療するのに有用である。
本開示は、HAEなどの接触系活性化に関連する疾患/障害を軽減するのに使用されるキットも提供する。そのようなキットは、抗FXIIa抗体、例えば本明細書に記載されている抗体のいずれかを含む1つ以上の容器を含むことができる。
本発明の実施では、特に明記しない限り、分子生物学(組換え技術を含む)、微生物学、細胞生物学、生化学および免疫学の従来の技術を用い、それらは当業者の技量の範囲内である。そのような技術は、「Molecular Cloning: A Laboratory Manual(分子クローニング:実験書), 第2版 (Sambrookら, 1989) Cold Spring Harbor Press」、「Oligonucleotide Synthesis(オリゴヌクレオチドの合成) (M. J. Gait編, 1984)」、「Methods in Molecular Biology(分子生物学における方法), Hum ana Press」、「Cell Biology: A Laboratory Notebook(細胞生物学:実験ノート) (J. E. Cellis編, 1998) Academic Press」、「Animal Cell Culture(動物細胞培養) (R. I. Freshney編, 1987)」、「Introduction to Cell and Tissue Culture(細胞および組織培養の入門書) (J. P. MatherおよびP. E. Roberts, 1998) Plenum Press」、「Cell and Tissue Culture: Laboratory Procedures(細胞および組織培養:実験室法) (A. Doyle, J. B. GriffithsおよびD. G. Newell編, 1993-8) J. Wiley and Sons」、「Methods in Enzymology(酵素学における方法) (Academic Press, Inc.)」、「Handbook of Experimental Immunology(実験免疫学のハンドブック) (D. M. WeirおよびC. C. Blackwell編)」、「Gene Transfer Vectors for Mammalian Cells(哺乳類細胞のための遺伝子導入ベクター) (J. M. MillerおよびM. P. Calos編, 1987)」、「Current Protocols in Molecular Biology(分子生物学における現在の手順) (F. M. Ausubelら編, 1987)」、「PCR: The Polymerase Chain Reaction(PCR:ポリメラーゼ連鎖反応) (Mullisら編, 1994)」、「Current Protocols in Immunology(免疫学における現在の手順) (J. E. Coliganら編, 1991)」、「Short Protocols in Molecular Biology(分子生物学における短いプロトコル) (Wiley and Sons, 1999)」、「Immunobiology(免疫生物学) (C. A. JanewayおよびP. Travers, 1997)」、「Antibodies(抗体) (P. Finch, 1997)」、「Antibodies: a practical approach(抗体:実践的なアプローチ) (D. Catty.編, IRL Press, 1988-1989)」、「Monoclonal antibodies: a practical approach(モノクローナル抗体:実践的なアプローチ) (P. ShepherdおよびC. Dean編, Oxford University Press, 2000)」、「Using antibodies: a laboratory manual(抗体の使用、実験書) (E. HarlowおよびD. Lane (Cold Spring Harbor Laboratory Press, 1999)」、「The Antibodies(抗体) (M. ZanettiおよびJ. D. Capra編, Harwood Academic Publishers, 1995)」などの文献に十分に説明されている。
活性化部分トロンボプラスチン時間(APTT)アッセイ
阻害剤(または対照希釈緩衝液=25mMのHEPES(pH7.5)、125mMのNaCl)を純血漿に添加して1:1の混合物にし、37℃で5分間予め平衡化させた。2×50μlのこの混合物を2つの別個のKC4デルタアッセイキュベット(金属球を有する)に分注した。60秒後に、50μlのAPTT試薬(活性化剤、Pacific Hemostasis APTT-XL)を回転キュベットに添加し、かつAPTT添加(t=0秒)から180秒後に、50μlのCaCl2を添加した。KC4デルタ機器で凝固時間(秒)を記録した。
阻害剤(または対照希釈緩衝液=25mMのHEPES(pH7.5)、125mMのNaCl)を純血漿に添加して1:1の混合物にし、37℃で5分間予め平衡化させた。2×50μlのこの混合物を2つの別個のKC4デルタアッセイキュベット(金属球を有する)に分注した。4分後、PT活性化剤(Pacific Hemostasis Thromboplastin D)を添加した(t=0秒)。凝固時間をKC4デルタ機器で自動的に記録した。
精製した成分の阻害アッセイが図3に示されている(パネル1)。96ウェルマイクロプレートにおいて20pMのFXIIaを様々な濃度の阻害剤と共に30℃で1時間インキュベートした。10nMのプレカリクレインを30℃で20分間添加した後、100nMのコーントリプシン阻害剤(CTI)と共に5分間インキュベートした。次いで、10μMの最終蛍光発生ペプチド基質(PFR−AMC)の添加によってタンパク質分解を経時的に評価し、その際、基質タンパク質分解の初速度(y軸)を阻害剤濃度(x軸)に対してプロットし、得られたデータを強結合阻害剤のために修正されたモリソン式(式1)に当てはめた。全ての試薬をアッセイ緩衝液(=20mMのTris−HCl(pH7.5)、150mMのNaCl、1mMのEDTA、0.1%のPEG−8000および0.1%のTriton X-100)で希釈した。
血漿阻害アッセイが図3に示されている(パネル2)。貯蔵した正常なヒトの血漿をアッセイ緩衝液(上記)で1:40に希釈し、阻害剤を様々な濃度で96ウェルマイクロプレートに室温で添加した。次いで、25%(2.5%の最終)エラグ酸を添加して接触活性化を開始させ、マイクロプレートを穏やかに振盪させて混合し、そのまま室温で2分間反応を進行させ、その後に100nMのCTIを添加した。次いで、10μlのこの混合物を取り出して、30℃で予め平衡化させた80μlのアッセイ緩衝液を含む反復マイクロプレートに入れた。次いで、この希釈プレートを30℃でさらに5分間インキュベートし、標準的なIC50の式への曲線当てはめのためにX軸に阻害剤の逆算した濃度を使用したこと以外は(最終のアッセイ読み取りでは血漿を1:400に希釈した)、PFR−AMCのタンパク質分解を上記のとおり評価した。
抗FXIIa抗体の結合優先を決定するために、各抗体をFXII酵素前駆体(接触/凝固系の他の関連するプロテアーゼ)と共にインキュベートした。次いで、結合親和性をBiacoreバイオセンサーを用いて表面プラズモン共鳴(SPR)分析によって評価した。図3のパネル3を参照されたい。
本抗体を生体外流れモデルで試験し、ここでは本抗体を添加したヒトの血液をコラーゲン被覆した毛細管に異なる流速で通す。蛍光によって血小板およびフィブリン沈着を評価する。この系では、酵素前駆体である第XI因子または第XII因子に結合する抗体によって血小板およびフィブリン沈着は阻害される。典型的な実験では、血液の流れを開始する前に本抗体をそれらの標的に結合させる。
塩化第二鉄によって誘発される頸動脈血栓症のマウスモデルにおいて本抗体を試験する。このモデルに、C57Bl/6マウスにおいて一貫して血栓形成を誘発する最も低い濃度(3.5%)で開始する異なるFeCl3濃度を組み入れる。本抗体が低いFeCl3濃度で抗血栓効果を示す場合、本抗体の抗血栓効果が他の濃度を凌ぐまで徐々により高い濃度を試験する。
39種の抗FXIIa抗体単離物を各種生体外活性アッセイで試験して、以下の特性:見かけのKi、IC50、FXII酵素前駆体への結合などの結合優先、接触/凝固系における他の関連するプロテアーゼとの交差反応性、近縁である配列相同体との交差反応性、血漿カリクレイン(pKal)産生に対する効果、ヒトの血漿における活性、部分トロンボプラスチン時間(PT)、活性化部分トロンボプラスチン時間(APTT)およびトロンビン産生に対する遅れ時間を決定した。
559C−X211−A01_HV(CDRは下線および太字で示されている)
559C−X211−A01は、1μMで試験したプロテアーゼ、すなわちウロキナーゼプラスミノーゲン活性化因子、ヒト増殖因子活性化因子、活性化タンパク質C、カテプシンG、C1s、エラスターゼ、第VIIa因子、第Xa因子、第XIa因子、プラスミン、トロンビンα、トリプシン、ウロキナーゼおよび血漿カリクレインに対して交差反応性を示さなかった。
阻害剤(または対照希釈緩衝液=25mMのHEPES(pH7.5)、125mMのNaCl)をマウスおよびヒトの純血漿の両方に添加して1:1の混合物にし、37℃で5分間予め平衡化させた。2×50μlのこの混合物を2つの別個のKC4デルタアッセイキュベット(金属球を有する)に分注した。60秒後、50μlのAPTT試薬(活性化剤、Pacific Hemostasis APTT-XL)を回転キュベットに添加し、この(t=0秒)180秒後に、50μlのCaCl2を添加した。KC4デルタ機器で凝固時間(秒)を記録した。
96ウェルマイクロプレートにおいて、20pMのFXIIaを様々な濃度の阻害剤と共に30℃で1時間インキュベートした。次いで、10nMのプレカリクレインを30℃で20分間添加し、その後、100nMのコーントリプシン阻害剤(CTI)と共に5分間インキュベートした。次いで、10μMの最終蛍光発生ペプチド基質(PFR−AMC)を添加してタンパク質分解を経時的に評価し、その際、基質タンパク質分解(y軸)の初速度を阻害剤濃度(x軸)に対してプロットし、得られたデータを強結合阻害剤について修正されたモリソン式に当てはめた。全ての試薬をアッセイ緩衝液(=20mMのTris−HCl(pH7.5)、150mMのNaCl、1mMのEDTA、0.1%のPEG−8000および0.1%のTriton X-100)で希釈した。
貯蔵したヒトの正常血漿をアッセイ緩衝液(上記)で1:40に希釈し、様々な濃度の阻害剤を96ウェルマイクロプレートに室温で添加した。次いで、25%(2.5%の最終)APTT−XL試薬(希釈エラグ酸、Pacific Hemostasis)を添加して接触活性化を開始させ、マイクロプレートを穏やかに振盪させて混合し、そのまま室温で2分間反応を進行させ、その後に100nMのCTIを添加した。次いで、10μlのこの混合物を取り出して、30℃で予め平衡化させた80μlのアッセイ緩衝液を含む反復マイクロプレートに入れた。次いで、この希釈プレートを30℃でさらに5分間インキュベートし、標準的なIC50の式および/または修正されたモリソン式への曲線当てはめのためにX軸に阻害剤の逆算した濃度を使用したこと以外は(最終のアッセイ読み取りでは血漿を1:400に希釈した)、上記のとおりPFR−AMCのタンパク質分解を評価した。
循環系中の本抗体の存在の薬力学的マーカーとして、健康なヒヒにおいて単回投与のDX−4012の抗凝固効果を評価した。これらの動物を穏やかに鎮静させ、ベースライン凝固値のために肘前の静脈から血液を採取した。次いで、本抗体を飽和用量で投与した。単回投与の本抗体を静脈内に送達させ、ベースラインに対してAPTTアッセイで抗凝固を確認することができる限り各時点で血液試料を採取した。また、さらなる試験のために血漿試料を凍結した。
抗凝固の前および間に急性血栓症および止血実験を行って、陽性および陰性対照と比較して単回飽和用量における本抗体の有効性および安全性を決定した。血管グラフトセグメントを慢性の表在化大腿AVシャントの中に展開させることで、訓練したヒヒにおいて血栓症実験を行った。研究の各日に、連続的な出血時間、体積測定および抗凝固アッセイのために、1mLのクエン酸塩添加血液をシャントループから各時点で採取した。試料採取時間は、薬物前(動物がエノキサパリンまたはDX−4012を接種する日であってエノキサパリンまたはDX−4012の投与前)、研究前(研究開始の5分前)および研究後(シャントループを除去するときである研究終了の5分前)を含む。血栓症および止血実験の前に、ヒヒに111Inで放射性標識した自己由来の血小板および125Iで放射性標識したフィブリノーゲンを投与した。DX−4012の抗血栓活性をエノキサパリン(低分子ヘパリン)の活性と比較した。
実施例2および3に記載されているようにAPTTおよびPTアッセイを行った。APTTはクエン酸塩添加血漿、SynthA Sil(登録商標)(Instrumentation Laboratories)試薬およびKC−4凝固計を用いて測定した。PTはクエン酸塩添加血漿、Dade(登録商標)Innovin(登録商標)試薬(Siemens社)およびKC−4凝固計を用いて測定した。血液採取および血小板の少ない血漿を生成するための血液試料の遠心分離の直後に、APTTおよびPTの両方を測定した。DX−4012の投与の1時間後に測定したAPTTの倍数変化は2.2倍(>2.2倍と予測)であった。24〜48時間後に測定したAPTTの倍数変化は1.8倍(1.8〜2.0倍と予測)であり、1週間後に測定したAPTTの倍数変化は1.3倍(1.3〜1.5倍と予測)であった。PTについては変化が全く観察されなかった。
血栓症研究のために、動物に10mg/kgの抗体DX−4012を投与し、抗体投与から1時間、24時間、48時間、168時間および192時間後に本研究を行った。分析のために、24時間および48時間の時点からのデータを1つにまとめ、168時間および192時間の時点からのデータを1つにまとめた。予期したとおりに、対照動物はコラーゲンで惹起されたベースラインの血栓頭部を形成した。エノキサパリンを摂取した動物では血栓頭部は有意に減少した。抗体投与から最大48時間の時点で、対照動物に対して血栓頭部のサイズは減少し、エノキサパリンを摂取した動物のサイズに匹敵していた。抗体投与から1週間(168〜192時間)後に、血栓頭部のサイズは対照動物のサイズに匹敵していた(図11A)。抗体投与から最大48時間の時点で、血栓尾部はほぼ消失しており、エノキサパリンを摂取した動物の状態に匹敵していた。抗体投与から1週間(168〜192時間)後に、血栓尾部は減少したままであったがエノキサパリン治療後よりも少ない程度の減少であった(図11B)。
一般に血栓サイズは、コラーゲン被覆したシャントと比較して組織因子被覆したシャントにおいて非常に大きく変化しやすい。記載されている実験では大きなばらつきが観察された(7.4、14.0および2.3億個の血小板)。予期したとおりに、対照動物は組織因子で惹起されたベースラインの血栓頭部を形成した。エノキサパリンを摂取した動物において血栓頭部は有意に減少した。抗体投与から最大48時間後の時点で、血栓頭部のサイズは対照動物のサイズに匹敵していた(図15A)。抗体投与から1週間(168〜192時間)後に、血栓頭部のサイズは大きく変化した。エノキサパリン治療により組織因子で惹起された血栓尾部の形成はほぼ消失した。抗体治療を受けた動物において有意な血栓尾部の減少は認められなかったが、そのデータは血栓尾部の僅かな減少傾向が認められることを示唆した(図15B)。
実験の終了時に、シャントを生理食塩水で洗い流し、画像を取得して最終血小板数を評価した。血栓頭部および尾部のフィブリン含有量分析のためにループも保存した。
FDAによって認可されているSurgicutt(商標)出血時間装置およびプロトコルを用いて止血を測定した。血液体積も測定した。研究日ごとに1回の出血時間および出血体積測定を行った。図22Aおよび図22Bに示すように、DX−4012は、エノキサパリンと比較した場合に出血時間および出血体積の減少において有効であった。
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- 第XIIa因子(FXIIa)に結合し、かつ第XII因子(FXII)に結合しないモノクローナル抗体。
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MX2023006511A (es) | 2023-06-21 |
EP3325516B1 (en) | 2021-12-15 |
CA2993026A1 (en) | 2017-01-26 |
US10913802B2 (en) | 2021-02-09 |
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AU2016297018B9 (en) | 2022-12-01 |
JP7317891B2 (ja) | 2023-07-31 |
CN116333144A (zh) | 2023-06-27 |
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AU2016297018A1 (en) | 2018-02-08 |
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IL257047A (en) | 2018-03-29 |
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