JP2006249084A - 抗MadCAM抗体組成物 - Google Patents
抗MadCAM抗体組成物 Download PDFInfo
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- JP2006249084A JP2006249084A JP2006056818A JP2006056818A JP2006249084A JP 2006249084 A JP2006249084 A JP 2006249084A JP 2006056818 A JP2006056818 A JP 2006056818A JP 2006056818 A JP2006056818 A JP 2006056818A JP 2006249084 A JP2006249084 A JP 2006249084A
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Abstract
【解決手段】本発明に係る抗MadCAM組成部は、a)少なくとも1つのキレート剤と;b)配列ID番号2に示した重鎖アミノ酸配列と少なくとも90%が一致するアミノ酸配列;および配列ID番号4に示した軽鎖アミノ酸配列と少なくとも90%が一致するアミノ酸配列を含む少なくとも1つの抗体とを含み、ここで、上記抗体がヒトMadCAMに結合することを特徴とする。
【選択図】なし
Description
本出願は、2005年3月8日に出願されたアメリカ合衆国仮特許出願シリアル番号第60/752,712号;2006年1月26日に出願されたアメリカ合衆国仮特許出願シリアル番号第60/762,456号;2005年3月8日に出願されたアメリカ合衆国仮特許出願シリアル番号第60/659,766号;2005年10月19日に出願されたアメリカ合衆国仮特許出願シリアル番号第60/728,165号の恩恵を主張する。なおこれらの仮特許出願はすべて、参考としてその全体がこの明細書に組み込まれているものとする。
読者にとって以下の詳細な説明が理解しやすくなるようにするため、以下のように定義する。
本発明により、この明細書に記載した所定の抗MadCAM抗体の安定性を、溶液中でその抗MadCAM抗体を薬理学的に許容可能なキレート剤(例えばエチレンジアミン四酢酸(“EDTA”)と混合することによって向上させうることが見いだされた。
抗MadCAM抗体は、一般に、対象に非経口投与するために医薬組成物として製剤化される。一実施態様では、この医薬組成物は液体医薬組成物である。別の一実施態様では、この医薬組成物は液体組成物である。
本発明の抗体は、トランスジェニック・マウスを用いて調製することができる。このトランスジェニック・マウスは、挿入したヒト抗体産生ゲノムの重要な部分を含んでいるが、内部でマウスの抗体は産生しないようにされている。そのためこのようなマウスは、ヒトの免疫グロブリン分子と抗体を産生することができる一方で、マウスの免疫グロブリン分子と抗体は産生しない。そのための技術に関して以下に説明する。
本発明の組成物は溶液にすることができる(例えば注射用や輸液用の溶液)。好ましい形態は、予定する投与形態と何を治療するかに応じて異なる。典型的な好ましい組成物は、注射用または輸液用の溶液の形態(例えばヒトの受動免疫に用いるのと同様の組成物)になっている。好ましい投与形態は、殺菌注射液または油性懸濁液の形態での非経口投与(例えば静脈内投与、皮下投与、皮内投与、腹腔内投与、筋肉内投与、胸骨内投与)または輸液である。当業者であればわかるように、投与経路および/または形態は、どのような結果を望むかに応じて異なることになろう。好ましい一実施態様では、抗体を静脈内に輸液または注射して投与する。別の好ましい一実施態様では、抗体を筋肉内、皮下、皮内に注射する。
本発明には、この明細書に記載した抗MadCAM抗体と、薬理学的に許容可能なキレート剤とを含む安定な医薬組成物が含まれる。安定な組成物は、例えば製品の外観および安定性を維持すること、あるいは製品の外観および安定性の変化(例えば物理的・化学的に分解して生物活性が低下する可能性)に対する抵抗力があることが望ましい。タンパク質の安定性を測定するためのさまざまな分析法や指標が文献に報告されており、そのような多数の方法や指標が、Vincent Lee編、『ペプチドとタンパク質のドラッグ・デリバリー』(マルセル・デッカー社、ニューヨーク、ニューヨーク州、1991年)、247-301ページと、Jones, A.、Drug Delivery Rev.、第10巻、29-90ページ、1993年にまとめられている。一般に、本発明の液体組成物は、低温である期間保管したときの安定性、および/または1回以上の凍結/解凍サイクルを経たときの安定性が向上している。
(a)組成物は、約2℃〜約8℃の温度で少なくとも12ヶ月間、好ましくは少なくとも約18ヶ月間、より好ましくは少なくとも約24ヶ月間にわたって保管したとき、キレート剤が含まれていないこと以外は同じ組成物を同じ条件下で同じ期間保管したものよりも安定である;
(b)組成物は、約25℃〜約30℃の温度で少なくとも3ヶ月間、好ましくは少なくとも約6ヶ月間、より好ましくは少なくとも約12ヶ月間にわたって保管したとき、キレート剤が含まれていないこと以外は同じ組成物を同じ条件下で同じ期間保管したものよりも安定である;
(c)組成物は、約40℃の温度で少なくとも1ヶ月間、好ましくは少なくとも約2ヶ月間、より好ましくは少なくとも約3ヶ月間にわたって保管したとき、キレート剤が含まれていないこと以外は同じ組成物を同じ条件下で同じ期間保管したものよりも安定である;
(d)組成物は、少なくとも1回の凍結/解凍サイクル、好ましくは少なくとも2回の凍結/解凍サイクル、より好ましくは少なくとも3回の凍結/解凍サイクル、さらに好ましくは少なくとも4回の凍結/解凍サイクル、より一層好ましくは少なくとも5回の凍結/解凍サイクル、それ以上に好ましくは少なくとも6回の凍結/解凍サイクルを経たとき、キレート剤が含まれていないこと以外は同じ組成物を同じ凍結/解凍条件にしたものよりも安定である。
(a)組成物を、約2℃〜約8℃の温度で少なくとも12ヶ月間、好ましくは少なくとも約18ヶ月間、より好ましくは少なくとも約24ヶ月間にわたって保管する;
(b)組成物を、約25℃〜約30℃の温度で少なくとも3ヶ月間、好ましくは少なくとも約6ヶ月間、より好ましくは少なくとも約12ヶ月間にわたって保管する;
(c)組成物を、約40℃の温度で少なくとも1ヶ月間、好ましくは少なくとも約2ヶ月間、より好ましくは少なくとも約3ヶ月間にわたって保管する;
(d)組成物に、少なくとも1回の凍結/解凍サイクル、好ましくは少なくとも2回の凍結/解凍サイクル、より好ましくは少なくとも3回の凍結/解凍サイクル、さらに好ましくは少なくとも4回の凍結/解凍サイクル、より一層好ましくは少なくとも5回の凍結/解凍サイクル、それ以上に好ましくは少なくとも6回の凍結/解凍サイクルを経験させる。次に、凝集した抗体をクロマトグラフィでモノマーから分離し(例えばHPLCを利用する)、得られたクロマトグラムから凝集の程度を明らかにする。本発明の安定な液体医薬組成物でのクロマトグラム上の凝集体のピークの面積は、一般に、クロマトグラム上の全ピーク面積の約6%未満、約5%未満、約4%未満、約3%未満、約2%未満、約1.5%未満である。凝集を測定するこの方法の特別な一例では、組成物を40℃で24週間にわたって保管した後、SE-HPLCを利用したクロマトグラフィにより分離を行ない、214ナノメートルでの紫外検出を実施する。
(a)組成物を、約2℃〜約8℃の温度で少なくとも約12ヶ月間、好ましくは少なくとも約18ヶ月間、より好ましくは少なくとも約24ヶ月間にわたって保管する;
(b)組成物を、約25℃〜約30℃の温度で少なくとも約3ヶ月間、好ましくは少なくとも約6ヶ月間、より好ましくは少なくとも約12ヶ月間にわたって保管する;
(c)組成物を、約40℃の温度で少なくとも約1ヶ月間、好ましくは少なくとも約2ヶ月間、より好ましくは少なくとも約3ヶ月間にわたって保管する;
(d)組成物に、少なくとも1回の凍結/解凍サイクル、好ましくは少なくとも2回の凍結/解凍サイクル、より好ましくは少なくとも3回の凍結/解凍サイクル、さらに好ましくは少なくとも4回の凍結/解凍サイクル、より一層好ましくは少なくとも5回の凍結/解凍サイクル、それ以上に好ましくは少なくとも6回の凍結/解凍サイクルを経験させる。次に、抗体フラグメントを電気泳動によって組成物から分離し(例えばSDS-PAGE)、得られた電気泳動パターンまたはゲル・パターンから断片化の程度を明らかにする。本発明の安定な液体医薬組成物でのSDS-PAGEゲル上の断片のバンドの体積は、一般に、ゲル上のバンドの全体積の約9%未満、約8%未満、約7%未満、約6%未満、約5%未満、約4.5%未満のいずれかである。断片化を測定するこの方法の特別な一例では、組成物を40℃で24週間にわたって保管した後に還元SDS-PAGE(rSDS-PAGE)を利用して分析し、モレキュラー・ダイナミクス・パーソナル・PDQC-90写真濃度計またはバイオ-ラドGS800イメージング写真濃度計で走査することによってバンドの体積を明らかにする。
この明細書に記載したどのタイプの抗体を治療に用いてもよい。好ましい一実施態様では、抗MadCAM抗体はヒト抗体である。別の好ましい一実施態様では、MadCAMはヒトのものであり、対象はヒト患者である。好ましいさらに別の一実施態様では、抗MadCAM抗体はヒトIgG2抗体である。あるいは対象は、抗MadCAM抗体が交差反応するMadCAMタンパク質を発現する哺乳動物にすることができる。獣医学のため、またはヒト疾患のモデル動物にするため、抗体は、その抗体が交差反応するMadCAMを発現する非ヒト哺乳動物(例えば霊長類)に投与するとよい。このようなモデル動物は、本発明による抗体の治療効果を評価するのに役立つ。
本発明の別の一実施態様では、製造装置が提供される。この製造装置は、キレート剤のみ、またはキレート剤と薬理学的に許容可能な他の賦形剤の組み合わせを含む組成物の中に本発明の少なくとも1つのモノクローナル抗MadCAM抗体が含まれた液体医薬組成物を収容する容器を備えている。適切な容器としては、例えば瓶、バイアル、袋、注射器などがある。容器は、いろいろな材料(ガラスやプラスチック)で作ることができる。容器の一例は、3〜20ccの使い捨てガラス製バイアルである。あるいは複数用量の組成物の場合には、容器を3〜100ccのガラス製バイアルにするとよい。容器には組成物が収容され、その容器の表面に貼り付けるかその容器に添付したラベルに使用法を記載することができる。製造装置はさらに、商品の観点、使用者の観点から望ましい他の材料(例えば他の緩衝液、希釈剤、フィルタ、針、注射器、使用法を記載したパッケージ添付物、禁忌、起こりうる副作用)も備えることができる。
抗MadCAM抗体産生ハイブリドーマの作製
本発明の抗体をこの実施例に従って調製した。PCT/US2005/000370を参照のこと。
ゼノマウス(登録商標)を免疫化するため、2つの免疫原を調製した。すなわち(i)MadCAM-IgG1 Fc融合タンパク質と、(ii)MadCAMが安定にトランスフェクトされた細胞から調製した細胞膜である。
発現ベクターの構成:
MadCAMの成熟した細胞外免疫グロブリン様ドメインをコードしているEcoRI/BgIII cDNAフラグメントをpINCYインサイト・クローン(3279276)から切り出してクローニングし、pIG1ベクターのEcoRI/BgHI部位に入れ(『発生における細胞相互作用:実践的アプローチ』、Hartley, D.A.編(オックスフォード大学出版、オックスフォード、1993年)のSimmons, D.L.による93-127ページ)、インフレームIgG1 Fc融合体を作った。得られた挿入体をEcoRI/NotIを用いて切り出し、クローニングしてpCDNA3.1+(インヴィトロジェン社)に入れた。このベクターに入れたMadCAM-IgG1 Fc cDNAの配列を確認した。MadCAM-IgG1 Fc融合タンパク質のアミノ酸配列を以下に示す。
MadCAM-IgG1 Fc融合タンパク質のcDNAを含むpCDNA3.1+ベクターをCHO-DHFR細胞にトランスフェクトし、600μg/mlのG418と100ng/mlのメトトレキセートを含むイスコフ培地の中でMadCAM-IgG1 Fc融合タンパク質を発現している安定なクローンを選択した。タンパク質を発現させるため、中空ファイバー・バイオリアクターの中に、10%低IgGウシ胎仔血清(ギブコ社)と、いろいろな非必須アミノ酸(ギブコ社)と、2mMのグルタミン(ギブコ社)と、ピルビン酸ナトリウム(ギブコ社)と、100μg/mlのG418と、100ng/mlのメトトレキセートとを含むイスコフ培地を入れてその中に安定に発現しているMadCAM-IgG1 Fc CHO細胞を植え、このバイオリアクターを用いて培地の濃縮された上清を作り出した。回収した上清からMadCAM-IgG1 Fc融合タンパク質をアフィニティ・クロマトグラフィによって精製した。簡単に説明すると、上清をハイトラップ・プロテインGセファロース(5ml、ファルマシア社)カラムに入れ(2ml/分)、25mMのトリス(pH8)と150mMのNaCl(カラム5容積分)で洗浄し、100mMのグリシン(pH2.5)で溶離し(1ml/分)、1Mのトリス(pH8)を用いて分画を直ちに中和してpHを7.5にした。MadCAM-IgG1 Fc融合タンパク質を含む分画をSDS-PAGEによって同定し、1つにまとめてプールし、セファクリルS100カラム(ファルマシア社)に入れ、35mMのビストリス(pH6.5)と150mMのNaClを用いてあらかじめ平衡させた。0.35ml/分の速度でゲル濾過し、ほぼ3×5mlの分画の中にMadCAM-IgG1 Fc融合タンパク質のピークを回収した。サンプルをプールし、リソースQ(6ml、ファルマシア社)カラムに入れ、35mMのビストリス(pH6.5)の中であらかじめ平衡させた。カラムをカラム5容積分の35mMビストリス(pH6.5)と150mMのNaCl(6ml/分)で洗浄し、35mMのビストリス(pH6.5)と400mMのNaClを用いてMadCAM-IgG1 Fc融合タンパク質を4〜6mlの分画の中に溶離させた。この段階でタンパク質の純度は90%であり、SDS-PAGEによるとそのタンパク質は約68kDの位置に単一のバンドとして移動した。免疫原として用いるため、また続くアッセイで使用するため、この材料の緩衝液を交換して25mMのヘペス(pH7.5)、1mMのEDTA、1mMのDTT、100mMのNaCl、50%グリセロールの中に入れ、アリコートとして-80℃で保管した。
公開されているMadCAM配列(Shyjan, A.M.、J. Immunol.、第156巻、2851-2857ページ、1996年)のヌクレオチド645〜1222を含むSacI/NotIフラグメントを大腸cDNAライブラリからPCRで増幅し、クローニングしてpIND-Hygroベクター(インヴィトロジェン社)のSacI/NotI部位に入れた。追加5'コード配列を含むSacIフラグメントをサブクローニングしてpCDNA3.1 MadCAM-IgG1 Fcからのこの構造体の中に入れ、完全長MadCAM cDNAを生成させた。次にMadCAM cDNAを含むKpnI/NotIフラグメントをクローニングしてpEF5FRTV5GWCATベクター(インヴィトロジェン社)の対応する部位に入れ、CATコード配列と置き換えた。このcDNA挿入体の配列を確認してトランスフェクションを行ない、製造者の指示に従ってFlpリコンビナーゼ技術によってFlpn NIH 3T3細胞(インヴィトロジェン社)の中で安定して発現する単一のクローンを作った。安定に発現しているクローンの選択を、そのクローンがα4β7+JYヒトBリンパ芽球細胞系(Chan, B.M.他、J. Biol. Chem.、第267巻、8366-8370ページ、1992年)の結合をサポートする能力を基準にして行なった。その概略を以下に説明する。MadCAMを発現するCHO細胞の安定なクローンを、Flpln CHO細胞(インヴィトロジェン社)を用いて同様にして調製した。
精製した組み換えMadCAM-IgG1 Fc融合タンパク質(マウス1頭につき1回に10μg)か、安定に発現しているMadCAM-CHO細胞またはNIH 3T3細胞(マウス1頭につき1回に10×106個の細胞)から調製した細胞膜
用い、年齢が8〜10週のゼノマウス(登録商標)の腹腔または後肢に免疫化を行なった。この量の投与を3〜8週間の期間にわたって5〜7回繰り返した。融合の4日前、マウスに対し、ヒトMadCAMの細胞外ドメインを含むPBSの最終回の注射を行なった。免疫化したマウスからの脾臓とリンパ節のリンパ球を、非分泌性骨髄腫P3-X63-Ag8.653細胞系と融合させ、以前に報告されているようにしてHAT選択した(GalfreとMilstein、Methods Enzymol.、第73巻、3-46ページ、1981年)。MadCAM特異的ヒトIgG2κを分泌する一群のハイブリドーマを回収し、サブクローニングした。
抗体組成物
以下の実施例では以下の組成物に言及する。
異なるいくつかの緩衝液が抗MadCAM抗体7.16.6の凝集に及ぼす効果を調べる実験を行なった。
緩衝液の調製:
まず最初に、ある量の緩衝用の化学物質を水に溶かすことによって緩衝液を調製した(標的の約90%)。次に十分な量の酸溶液または塩基溶液を添加することによって各緩衝液のpHを5.5にした。pHを調節した後、水をさらに添加して緩衝液の最終濃度を20mMにした。緩衝液の濃度を20mMにしたのは、選択したpH5.5でpHが十分に安定するようにするためである。次に、緩衝液を殺菌濾過し(ポアのサイズ0.22ミクロン)、殺菌済みの容器に入れ、あとで使用した。
以下のようにして抗体組成物を調製した。バルクの抗体溶液を20mMの酢酸ナトリウム緩衝液(pH5.5)+140mMの塩化ナトリウムを含む10.5mg/mlの溶液として得た。分子量カットオフ膜(例えば30kD)を用いて4500×gで遠心分離することにより、このバルク溶液の緩衝液を交換して組成物溶液にした。約8容積分を交換し、濃度が約10mg/mlの抗体溶液を調製した。抗体の濃度は、紫外-可視光分光(UV-Vis)法により、280nmでの消衰係数が1.56(mg/ml)-1cm-1という値を利用して決定した。次にすべての成分が含まれた組成物を0.22ミクロンの膜フィルタで濾過して殺菌した。次に濾過された組成物を洗浄し、蒸気滅菌したバイアルに充填し、大協精工777-1フルロテック(登録商標)でコーティングした栓をし、クリンプ・シールし、安定チェンバーの中に入れた。
抗体組成物を40℃で保管した。6週間目の時点でサイズ排除クロマトグラフィ(SEC)を利用して各組成物の凝集を分析した。サイズ排除クロマトグラフィは、TSKゲルG3000SWXL-G2000SWXLカラムと、0.2Mのリン酸ナトリウム(pH7)移動相を利用して流速0.7ml/分で実施し、214nmでUV検出した。各組成物のクロマトグラムについてピークよりも下の面積を積分することによって凝集のレベルを計算し、高分子量種のピークよりも下にある面積の積分値を全ピーク面積に対するパーセントとして表現した。表3に示してあるように、緩衝液がEDTAである組成物で凝集レベルが最も低く、凝集の相対的増加が最も少なかった。
緩衝液の濃度と他の賦形剤の存在/不在が抗MadCAM抗体7.16.6の断片化に及ぼす効果を調べる実験を行なった。
液体抗MadCAM抗体組成物の中に含まれるEDTAが凝集と断片化に及ぼす効果を調べる実験を行なった。
緩衝液を実施例3に記載した方法で調製した。抗体組成物を以下のようにして調製した。バルクの抗体溶液を、20mMの酢酸ナトリウム緩衝液(pH5.5)を含む9.6mg/mlの溶液として得た。分子量カットオフ膜(例えば30kD)を用いて5000×gで遠心分離することにより、このバルク溶液の緩衝液を交換して組成物溶液にした。約8容積分を交換し、タンパク質の濃度が約8mg/mlまたは約30mg/mlの抗体溶液を調製した。抗体の濃度は、紫外-可視光分光(UV-Vis)法により、280nmでの消衰係数が1.56(mg/ml)-1cm-1という値を利用して決定した。ポリソルベート80(PS80)を適切な緩衝液を用いて希釈し溶解させることによってPS80の濃縮溶液(一般に20mg/ml)を調製した。次にこのPS80濃縮溶液を抗体溶液に添加し、最終組成物を得た。次にすべての成分が含まれた組成物を0.22ミクロンの膜フィルタで濾過して殺菌した。次に濾過された組成物を洗浄し、蒸気滅菌したバイアルに充填し、大協精工777-1フルロテック(登録商標)でコーティングした栓をし、クリンプ・シールし、安定チェンバーの中に入れた。
酢酸塩緩衝液とヒスチジン緩衝液が抗MadCAM抗体7.16.6の凝集と断片化に及ぼす効果を調べる実験を行なった。表7と表8に示した組成物は、実施例5に記載した方法で調製した。表7の組成物を40℃で26週間にわたって保管し、実施例3に記載したSEC法で分析した。
抗体の濃度がさまざまである組成物の中で抗MadCAM抗体7.16.6が凝集する傾向を調べる実験を行なった。この実験では、表9の組成物を実施例5に記載した方法で調製した。表9の組成物を5℃、25℃、40℃で26週間にわたって保管した後、実施例3に記載したSEC法で分析した。
さまざまなレベルのEDTAが含まれた組成物中で抗MadCAM抗体7.16.6が凝集する傾向を調べる実験を行なった。組成物は実施例5に記載したようにして調製したが、抗体の最終濃度を80±10mg/mlに調節した点が異なっている。表10の組成物を5℃または25℃で26週間にわたって保管した後、上記のようにSECで分析した。
さまざまなレベルのポリソルベート80を含む抗MadCAM抗体7.16.6の組成物の安定性を調べる実験を行なった。組成物は上記のようにして調製したが、抗体の最終濃度は80±10mg/mlに調節した。表11の組成物を25℃または40℃で26週間にわたって保管した後、上記のようにSECで分析した。
さまざまな緩衝液を含む組成物中で抗MadCAM抗体7.16.6が凝集する傾向を調べる実験を行なった。組成物を上記のようにして調製し、抗体の最終濃度を80±10mg/mlに調節した。表13の組成物を25℃または40℃で26週間にわたって保管した。
さまざまな糖とポリオールを含む組成物中で抗MadCAM抗体7.16.6が凝集する傾向を調べる実験を行なった。組成物を上記のようにして調製し、抗体の最終濃度を80±10mg/mlに調節した。表14の組成物を40℃で26週間にわたって保管した。
さまざまな界面活性剤とPEGを含む組成物中で抗MadCAM抗体7.16.6が凝集する傾向を調べる実験を行なった。組成物を上記のようにして調製し、抗体の最終濃度を80±10mg/mlに調節した。抗体組成物中の界面活性剤またはPEGの最終濃度は、界面活性剤とPEGの濃縮貯蔵溶液から適量を添加することによって実現した。表15の組成物を40℃で26週間にわたって保管した。
トレハロースまたはスクロースを含む組成物中のメチオニン256の酸化を調べる実験を行なった。組成物を上記のようにして調製し、抗体の最終濃度を80±10mg/mlに調節した。表16の組成物を5℃または40℃で26週間にわたって保管した。リシル・エンドプロテイナーゼという酵素を用いてタンパク質を消化させ、得られたペプチド断片を逆相HPLCで分離して214nmの吸光度を測定することによってメチオニンの酸化を調べた。メチオニンまたはその酸化形態を含むペプチド断片をモニターした。酸化の割合(%)を、親メチオニンのピークの面積に対する酸化メチオニンのピーク面積として計算した。
抗体の濃度が大きい組成物の化学的安定性を調べる実験を行なった。表17と表18の組成物を上記のようにして調製し、抗体の最終濃度を80±10mg/mlに調節した。表17の組成物を5℃で26週間にわたって保管した。化学的安定性をiCEで調べた。pIマーカー、メチルセルロース、ファーマライトと、タンパク質との混合物を調製し、タンパク質の最終濃度を約0.22μg/μlにして測定を行なった。フォーカス時間6分、3000ボルトで電気泳動を実施し、280nmで吸光度を調べた。帯電したさまざまな種の相対的な割合を、ピークよりも下のそれぞれの面積から決定した。
凍結-解凍ストレスに対する高濃度組成物の性能を調べる実験を行なった。
表19の組成物を上記のようにして調製し、抗体の最終濃度を50±10mg/mlに調節した。表19の組成物に対して-70℃/5℃または-20℃/5℃という凍結-解凍サイクルを3回経験させた。この実験は、2mlのガラス製バイアルに組成物を1ml入れて実施した。SE HPLC測定を実施した。その条件は、0.2Mのリン酸ナトリウム(pH7)移動相とTSKゲルG3000SWXLカラムを利用して流速0.7ml/分で実施し、214nmでUV検出するというものである。抗体モノマーよりも前に溶離した抗体関連のピークを合計することにより、凝集体の量を明らかにした。
凍結保管している間の高濃度組成物の安定性を調べる実験を行なった。表21の組成物を上記のようにして調製し、抗体の最終濃度を約75mg/mlに調節した。表21の組成物を-20℃で13週間にわたって保管し、実施例15に記載したようにして凝集を評価した。
高濃度組成物の粘性率を調べる実験を行なった。表22の組成物を上記のようにして調製し、抗体の最終濃度を約75mg/mlに調節した。流量計のプレートの上に載せた組成物に対して平均剪断速度300/秒で粘性率を測定した。
Claims (24)
- a)少なくとも1つのキレート剤と;
b)配列ID番号2に示した重鎖アミノ酸配列と少なくとも90%が一致するアミノ酸配列;および
配列ID番号4に示した軽鎖アミノ酸配列と少なくとも90%が一致するアミノ酸配列を含む少なくとも1つの抗体とを含み、
ここで、上記抗体がヒトMadCAMに結合することを特徴とする組成物。 - 前記組成物が液体組成物であり、上記抗体がヒトIgG2抗体であってシグナル配列を含まない、請求項1に記載の組成物。
- 前記抗体が、配列ID番号2と配列が少なくとも99%一致する重鎖アミノ酸配列と;配列ID番号4と配列が少なくとも99%一致する軽鎖アミノ酸配列とを含む、請求項1に記載の組成物。
- 前記抗体が、配列ID番号2を含む重鎖アミノ酸配列と、配列ID番号4を含む軽鎖アミノ酸配列とを含む、請求項1に記載の組成物。
- 少なくとも1つのキレート剤としてEDTAを含む、請求項1に記載の組成物。
- 緩衝液をさらに含む、請求項1に記載の組成物。
- 少なくとも1つのキレート剤としてEDTAを含み、さらにヒスチジンを含む、請求項1に記載の組成物。
- 緩衝液と界面活性剤をさらに含む、請求項1に記載の組成物。
- 緩衝液と、界面活性剤と、張性剤をさらに含む、請求項1に記載の組成物。
- 少なくとも1つのキレート剤としてEDTAを含み、さらに緩衝液と、界面活性剤と、張性剤とを含む、請求項1に記載の組成物。
- 少なくとも1つのキレート剤としてEDTAを含み、さらにヒスチジンと、界面活性剤と、張性剤とを含む、請求項1に記載の組成物。
- 少なくとも1つのキレート剤としてEDTAを含み、さらにヒスチジンと、ポリソルベート80と、張性剤とを含む、請求項1に記載の組成物。
- 少なくとも1つのキレート剤としてEDTAを含み、さらにヒスチジンと、ポリソルベート80と、トレハロースとを含む、請求項1に記載の組成物。
- 約1mg/ml〜約200mg/mlの抗体と;
約0.01ミリモル〜約5.0ミリモルのキレート剤と;
約1mM〜約100mMのヒスチジンとを含む、請求項1に記載の組成物。 - 約1mg/ml〜約200mg/mlの抗体と;
約0.01ミリモル〜約5.0ミリモルのEDTAと;
約1mM〜約100mMのヒスチジンとを含む、請求項1に記載の組成物。 - 約1mg/ml〜約200mg/mlの抗体と;
約0.01ミリモル〜約5.0ミリモルのキレート剤と;
約1mM〜約100mMの緩衝液と;
約0.005ミリモル〜約10ミリモルの界面活性剤と;
約100ミリモル〜約400ミリモルの張性剤とを含む、請求項1に記載の組成物。 - 約1mg/ml〜約200mg/mlの抗体と;
約0.01ミリモル〜約5.0ミリモルのEDTAと;
約1mM〜約100mMのヒスチジンと;
約0.005ミリモル〜約10ミリモルのポリソルベート80と;
約100ミリモル〜約400ミリモルの張性剤とを含む、請求項1に記載の組成物。 - 約1mg/ml〜約200mg/mlの抗体と;
約0.01ミリモル〜約5.0ミリモルのEDTAと;
約1mM〜約100mMのヒスチジンと;
約0.005ミリモル〜約10ミリモルのポリソルベート80と;
約100ミリモル〜約400ミリモルのトレハロースとを含む、請求項1に記載の組成物。 - 約0.1mg/ml〜約100mg/mlの抗体と;
約0.001ミリモル〜約1.0ミリモルのEDTAと;
約1mM〜約50mMのヒスチジンと;
約0.01mg/ml〜約10mg/mlのポリソルベート80と;
約10mg/ml〜約100mg/mlのトレハロースとを含む、請求項1に記載の組成物。 - 少なくとも1つのモノクローナル抗MadCAM抗体と、キレート剤とを含む組成物であって、この組成物が、少なくとも約26週間の期間にわたって約40℃の温度で維持したときに安定であるのに十分な量のキレート剤を含む組成物。
- 少なくとも1つのモノクローナル抗MadCAM抗体と、薬理学的に許容可能なキレート剤とを含む液体医薬組成物であって、抗体のモル濃度の範囲が約0.0006ミリモル〜約1.35ミリモルであり、キレート剤のモル濃度の範囲が約0.003ミリモル〜約50ミリモルであり、キレート剤に対する抗体のモル比の範囲が約0.00001〜約450である液体医薬組成物。
- 配列ID番号2に示した重鎖アミノ酸配列と少なくとも95%が一致するアミノ酸配列に加え、配列ID番号4に示した軽鎖アミノ酸配列と少なくとも95%が一致するアミノ酸配列をさらに含んでいて、ヒトMadCAMと結合する少なくとも1つの抗体と;
薬理学的に許容可能な賦形剤とを含み、ここで、抗体の濃度が少なくとも約50mg/mlである液体医薬組成物。 - 配列ID番号2の重鎖アミノ酸配列と、配列ID番号4の軽鎖アミノ酸配列とを有する少なくとも1つの抗MadCAM抗体を、溶液中で少なくとも1つのキレート剤と混合する操作を含む、液体医薬組成物の製造方法。
- 対象における炎症性疾患の治療方法であって、その対象に、
a)治療に有効な量の少なくとも1つの抗MadCAM抗体と;
b)薬理学的に許容可能なキレート剤とを含む液体医薬組成物を投与することを含む前記方法。
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JP7142200B2 (ja) | 2015-01-09 | 2022-09-27 | ファイザー・インク | MAdCAMアンタゴニストの投与レジメン |
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