JP5123197B2 - カルシトニン遺伝子関連ペプチドに対するアンタゴニスト抗体およびその使用方法 - Google Patents
カルシトニン遺伝子関連ペプチドに対するアンタゴニスト抗体およびその使用方法 Download PDFInfo
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Description
本発明の実践は、他に示さない限り、当技術分野の範囲内にある(組換え技法を含めた)分子生物学、微生物学、細胞生物学、生化学および免疫学の従来の技法を利用するものとする。このような技法は、Molecular Cloning:A Laboratory Manual,second edition(Sambrook et al.,1989)Cold Spring Harbor Press;Oligonucleotide Synthesis(M.J.Gait,ed.,1984);Methods in Molecular Biology,Humana Press;Cell Biology:A Laboratory Notebook(J.E.Cellis,ed.,1998)Academic Press;Animal Cell Culture(R.I.Freshney,ed.,1987);Introduction to Cell and Tissue Culture(J.P.Mather and P.E.Roberts,1998)Plenum Press;Cell and Tissue Culture:Laboratory Procedures(A.Doyle,J.B.Griffiths,and.G.Newell,eds.,1993−1998)J.Wiley and Sons;Methods in Enzymology(Academic Press,Inc.);Handbook of Experimental Immunology(D.M.Weir and C.C.Blackwell,eds.);Gene Transfer Vectors for Mammalian Cells(J.M.Miller and M.P.Calos,eds.,1987);Current Protocols in Molecular Biology(F.M.Ausubel et al.,eds.,1987);PCR:The Polymerase Chain Reaction,(Mullis et al.,eds.,1994);Current Protocols in Immunology(J.E.Coligan et al.,eds.,1991);Short Protocols in Molecular Biology(Wiley and Sons,1999);Immunobiology(C.A.Janeway and P.Travers,1997);Antibodies(P.Finch,1997);Antibodies:a practical approach(D.Catty.,ed.,IRL Press,1988−1989);Monoclonal antibodies:a practical approach(P.Shepherd and C.Dean,eds.,Oxford University Press,2000);Using antibodies:a laboratory manual(E.Harlow and D.Lane(Cold Spring Harbor Laboratory Press,1999);The Antibodies(M.Zanetti and J.D.Capra,eds.,Harwood Academic Publishers,1995)などの文献中で完全に説明されている。
「抗体」は、免疫グロブリン分子の可変領域中に位置する少なくとも1つの抗原認識部位を介して、例えば炭水化物、ポリヌクレオチド、脂質、ポリペプチドなどの標的と特異的に結合することができる免疫グロブリン分子である。本明細書中で使用するこの用語は、完全なポリクローナルまたはモノクローナル抗体だけでなく、それらの断片(Fab、Fab’、F(ab’)2、Fvなど)、単鎖(ScFv)、それらの突然変異体、抗体部分(ドメイン抗体など)を含む融合タンパク質、および抗原認識部位を含む任意の他の修飾形状の免疫グロブリン分子も包含する。抗体はIgG、IgA、またはIgM(またはそれらのサブクラス)などの任意のクラスの抗体を含み、抗体は任意の特定クラスである必要はない。抗体の重鎖の定常ドメインのそのアミノ酸配列に応じて、免疫グロブリンを異なるクラスに割り当てることができる。5つの主なクラスの免疫グロブリン:IgA、IgD、IgE、IgG、およびIgMが存在し、これらの数個はサブクラス(イソ型)、例えばIgG1、IgG2、IgG3、IgG4、IgA1およびIgA2にさらに分けることができる。異なるクラスの免疫グロブリンに対応する重鎖の定常ドメインは、それぞれアルファ、デルタ、イプシロン、ガンマ、およびミューと呼ばれる。異なるクラスの免疫グロブリンのサブユニット構造および三次元形状はよく知られている。
一態様では、本発明は、個体に有効量の抗CGRPアンタゴニスト抗体または抗体に由来するポリペプチドを投与することを含む、個体における、頭痛(例えば、片頭痛)または顔面紅潮などの、少なくとも1つの血管運動症状を処置または防止するための一方法を提供する。
本発明の方法は、受容体との結合および/もしくはCGRPへの細胞応答の誘発などのCGRPシグナリングによって調節される下流経路を含むCGRPの生物学的活性を、(有意にを含んで)遮断、抑制または低減させる任意の抗体分子を意味する抗CGRPアンタゴニスト抗体を使用する。
本発明は、表6に示された抗体G1およびその変異体または表6に示された抗体G1に由来するポリペプチドおよびその変異体;およびG1およびその変異体または該ポリペプチドをコードする配列を含むポリヌクレオチドを含む医薬組成物などの組成物を包含する。本明細書に用いられる組成物は、CGRPに結合する1種以上の抗体またはポリペプチド(抗体であってもなくてもよい)、および/またはCGRPに結合する1種以上の抗体またはポリペプチドをコードする配列を含む1種以上のポリヌクレオチドを含む。これらの組成物は、当業界に知られている緩衝剤など、薬学的に許容できる賦形剤などの好適な賦形剤をさらに含むことができる。
(1)非極性:ノルロイシン、Met、Ala、Leu、Ile;
(2)電荷なしの極性:Cys、Ser、Thr、Asn、Gln;
(3)酸性(負電荷):Asp、Glu;
(4)塩基性(正電荷):Lys、Arg;
(5)鎖配向性に影響を及ぼす残基:Gly、Pro;および
(6)芳香族:Trp、Tyr、Phe、His
に基づいた群に分けられる。
本発明の方法で使用される組成物は、有効量の抗CGRPアンタゴニスト抗体または本明細書に記載の抗CGRPアンタゴニスト抗体由来ポリペプチドを含む。そのような組成物の例、ならびに処方の方法は、前のセクションおよび以下にも記載されている。一実施形態では、前記組成物は、CGRPアンタゴニストをさらに含む。別の実施形態では、前記組成物は、1個または複数個の抗CGRPアンタゴニスト抗体を含む。他の実施形態では、前記抗CGRPアンタゴニスト抗体はヒトCGRPを認識する。さらに他の実施形態では、前記抗CGRPアンタゴニスト抗体はヒト化される。さらに他の実施形態では、前記抗CGRPアンタゴニスト抗体は、抗体媒介溶解またはADCCなどの、必要ではないまたは望ましくない免疫応答を始動させない定常領域を含む。他の実施形態では、前記抗CGRPアンタゴニスト抗体は、(1個、2個、3個、4個、5個、または、いくつかの実施形態では、G1由来の6個すべてのCDRなどの)抗体G1の1個または複数個のCDRを含む。いくつかの実施形態では、前記抗CGRPアンタゴニスト抗体はヒトである。
本発明は、即時法で使用するためのキットも提供する。本発明のキットには、本明細書に記載する(ヒト化抗体などの)抗CGRPアンタゴニスト抗体またはポリペプチドを含む1個または複数個の容器、および本明細書に記載する本発明の方法のいずれかに従って使用するための説明書が含まれる。一般的に、これらの説明書には、本明細書に記載する方法のいずれかに従って(片頭痛などの)頭痛を治療し、寛解し、または予防するための前記抗CGRPアンタゴニスト抗体の投与についての説明文が含まれる。前記キットは、個体が頭痛がするのかどうか、または個体が頭痛に見舞われる危険性があるかどうかを確認することに基づいて治療に適した個体を選択する説明文をさらに含んでいてよい。さらに他の実施形態では、前記説明書は、(片頭痛などの)頭痛に見舞われる危険性がある個体に抗CGRPアンタゴニスト抗体を投与する説明文を含む。
抗CGRPモノクローナル抗体の生成および性状解析
抗CGRP抗体の生成。ラットおよびヒトCGRPに対し種間活性を有する抗CGRP抗体を生成するため、マウスは,アジュバントを添加した(1足蹠当たり50μl、1匹当たり計100μl)25〜100μgのKLHと結合したヒトα−CGRPまたはβ−CGRPを用いて様々な間隔でを感作された。感作は概して、Geerligs HJ et al.,1989,J.Immunol.Methods 124:95−102;Kenney JS et al.,1989,J.Immunol.Methods 121:157−166;and Wicher K et al.,1989,Int.Arch.Allergy Appl.Immunol.89:128−135に記述されている方法で行われた。最初にマウスはCFA(完全フロイントアジュバント)を添加した50μgのKLHと結合したヒトα−CGRPまたはβ−CGRPでマウスで感作された。21日後、マウスは、IFA(不完全フロイントアジュバント)を添加した25μgのKLHと結合したヒトβ−CGRP(最初にヒトα−CGRPで感作されたマウスに対して)またはα−CGRP(最初にヒトβ−CGRPで感作されたマウスに対して)で2回目の感作を受けた。2回目の感作23日後、IFAを添加した25μgのKLHと結合したラットα−CGRPで3回目の感作が行われた。その10日後、抗体価ga,ELISAを用いて測定された。3回目の感作34日後、IFAを添加した25μgのペプチド(ラットα−CGRP−KLH)で4回目の感作が行われた。4回目の感作32日後、最終追加抗原刺激が,100μgの可溶性ペプチド(ラットα−CGRP)で行われた。
IN VITRO試験で使用される抗CGRPアンタゴニスト抗体のスクリーニング。
マウス抗CGRP抗体は、細胞ベースのcAMP活性試験および結合試験を用いて、in vitroでのアンタゴニスト活性の有無に関してさらにスクリーニングされた。
ラットの伏在神経刺激により誘発された皮膚血管拡張に対する抗CGRPアンタゴニスト抗体の効果
抗CGRP抗体のアンタゴニスト活性を試験するために、ラットの伏在神経刺激による皮膚血管拡張に対する抗体の効果が、既述のラットモデルを用いて試験された。Escott et al.,Br.J.Pharmacol.110:772−776,1993。このラットモデルでは、伏在神経の電気刺激が神経終末からのCGRPの放出を誘導し、皮膚血流の増加が起きる。雄のSprague Dwaleyラット(170〜300g、Charles River Hollisterより)の足の皮膚の血流が、伏在神経刺激後測定された。ラットは2%のイソフルランにより、麻酔下で維持された。ブレチリウムトシラート(30mG/kg、静脈投与)が、伏在神経の交感神経線維の付随する刺激による血管収縮を最小限にするため、実験の開始時に投与された。体温は、温度調整ヒーティングパッドにサーモスタットで接続した直腸プローブの使用により、37℃に維持された。抗体、陽性対照(CGRP8〜37)および媒体(0.01%Tween20加PBS)などの物質が、右大腿静脈から静脈内に投与された。図3に示された実験では被検物質および対照は尾静脈から投与された。図2Aおよび2Bに示された実験では抗体4901および7D11は腹腔内に(IP)投与された。陽性対照物質CGRP8〜37(血管拡張アンタゴニスト)は、半減期が短いので、神経刺激3〜5分前に400nmol/kg(200ml)投与された。Tan et al.,Clin.Sci.89:656−73,1995。抗体は、異なる用量(1 MG/KG、2.5mg/kg、5mg/kg、10mg/kgおよび25mg/kg)で投与された。
抗CGRP抗体G1およびその変異体の性状解析
抗CGRP抗体G1のH鎖可変領域およびL鎖可変部のためのアミノ酸配列と(ギャップ1)のは、図5に示される。以下の方法が、抗体G1およびその変異体の発現と性状解析に使用された。
ラットの伏在神経刺激により誘発された皮膚血管拡張に対する抗CGRPアンタゴニスト抗体の効果
抗CGRP抗体G1のアンタゴニスト活性を試験するために、ラットの伏在神経刺激による皮膚血管拡張に対する抗体の効果が、実施例3で記述されたラットモデルを用いて試験された。短時間、ラットは2%のイソフルランにより、麻酔下で維持された。ブレチリウムトシラート(30mg/kg、静脈に投与された)が、伏在神経の交感神経線維の付随する刺激による血管収縮を最小限にするため、実験の開始時に投与された。体温は、温度調整ヒーティングパッドにサーモスタットで接続した直腸プローブの使用により、37℃に維持された。抗体または媒体対照投与後、右後肢の伏在神経は、外科的に露出され、近位側が切断され、乾燥を防ぐためにラップで覆われた。レーザードップラープローブは、伏在神経によって神経の分布を受ける領域である後足の背側正中の皮膚に設置された。血液細胞の流束として測定される皮膚血流は、レーザードップラーフローメーターでモニターされた。チリウムトシラート投与30〜45分後に、投与後2時間以内の抗体の効果を決定するための実験では、ブレ安定したベースライン流束(5%未満の変動)が少なくとも5分間確立されたとき、神経はプラチナ双極電極上に置かれ、電気的に刺激され(2Hz、10V、1mS、30秒間)、20分後に再度刺激された。これらの2つの刺激に対する血流流束反応の平均は、電気刺激に対するベースラインの反応(時間0)を確立するのに用いられた。次に、G1(1mg/kgまたは10mg/kg)もしくは媒体(0.01%のTween20加PBS)が、静脈内に投与された(i.v.)。続いて、神経が、抗体投与30分、60分、90分および120分後に刺激された(2Hz、10V、1mSで30秒間)。動物は、約3時間麻酔下に維持された。皮膚血流の累積的な変化は、電気パルス刺激に対する各流束の反応において、血中濃度時間曲線下面積(AUC、流束の変化×時間の変化と等しい)によって推定された。
硬膜動脈(閉塞頭窓)試験閉塞頭窓モデルにおける、抗CGRPアンタゴニスト抗体G1の急性効果
この実験の目的は、抗CGRPアンタゴニスト抗体の急性効果を決定し、それをCGRPレセプターアンタゴニストBIBN4096BSの急性効果と比較することであった。実験は、前述の通りに((Williamson et al.,Cephalalgia 17(4):518−24(1997))、次のような改変を伴って行われた。Sprague Dawleyラット(300〜400g)は、70mg/kgの腹腔内ペントバルビタールで麻酔された。麻酔は、20mg/kg/時の静脈投与のペントバルビタールで維持された。ラットは、すべての薬の送達のために、頸静脈を通してカニューレを挿入された。血圧は、腹腔動脈に大腿動脈を通して装着されたプローブ(マイクロチップカテーテル、Millar Instruments)でモニターされた。ラットは気管切開術を施され、呼吸速度は、容量3.5mlで、1分当たり75回の呼吸数に維持された。定位装置で頭部を固定させて、頭皮を取り除いた後に、歯科用ドリルで骨を薄くすることによって、矢状縫合外側の左頭頂部に、2×6mMの窓を作成した。マイクロマニピュレーターを使用して、プラチナ双極電極が表面に降ろされ、重い鉱油で覆われた。電極窓の外側には、5×6mmの別の窓が作られ、重い鉱油で満たされた。その窓を通して、中硬膜動脈(MMA)の枝分かれ血管の直径が、CCDカメラおよびビデオ直径分析機(Living Systems)で継続的にモニターされた。ラットは、準備後45分間以上休息した。電気刺激に対するベースライン反応は確立され(15V、10Hz、0.5mSのパルス、30秒)、その後、ラットは静脈内に実験物質(10mg/kg mu7E9、300g/kg BIBN4096BS、またはTween20加PBS 0.01%)を投与された。追加の電気刺激は、投与5(BIBN4096BS)、30、60、90と120分後に行われた。すべてのデータは、チャートソフトウェア(ADInstruments)を使用して記録された。
硬膜動脈(閉塞頭窓)試験における抗CGRPアンタゴニスト抗体G1の慢性効果
この実験の目的は、抗CGRP抗体が、電気的に刺激されたMMA拡張を投与7日後に依然として阻止できるかどうかを決定することである。ラットの準備は、次のような例外を除いて、上記の急性実験(図6)と同じである。ラットは、閉塞頭窓作成の準備および刺激の7日前に静脈内に投与された(10mg/kg、3mg/kgまたは1mg/kgの G1)。投与前に電気パルス刺激に対するベースラインの拡張反応を確立することは、急性実験のように不可能だったので、抗体群は媒体(0.01%Tween20加PBS)投与対象群におけるMMAの拡張と比較された。ラットが45分以上の休息が許された後、硬膜は30分間隔で電気的に刺激された。刺激は、2.5V、5V、10V、15Vおよび20Vで、全例10Hz、0.5mSのパルスで30秒間行った。
モルヒネ離脱によるほてりのモデル
モルヒネ離脱のラットモデルは、閉経期のほてりのメカニズムの確立された齧歯類モデルである(Sipe et al.,Brain Res.1028(2):191−202(2004);Merchenthaler et al.,Maturitas 30:307−316(1998);Katovich et al.,Brain Res.494:85−94(1989);Simpkins et al.,Life Sciences 32:1957−1966(1983))。基本的に、ラットは皮下にモルヒネペレットを挿入することによって、モルヒネの中毒になる。中毒時には、動物は直ちに離脱させるナロキソンが注射される。この離脱は、皮膚温上昇、中核体温の低下、心拍数の増加および血清黄体ホルモンの増加を伴う。これらすべて、程度および時期という点で、ヒトでほてりが発生するときと同じである(Simpkins et al.,Life Sciences 32:1957−1966(1983))。さらに、もしラットが離脱を誘導する前にエストラジオールで治療されていたら、ほてりの症状は軽減される(Merchenthaler et al.,Maturitas 30:307−316(1998))。これが、モルヒネの離脱モデルが、偽の臨床的ほてりであると信じられているかの理由である。
以下の材料は、the American Type Culture Collection,10801 University Boulevard,Manassas,Virginia 20110−2209,USA(ATCC)に寄託された:
材料 抗体番号 ATCC登録番号 寄託の日付
pDb.CGRP.hFcGI G1H鎖 PTA−6867 2005年7月15日
pEb.CGRP.hKGI G1L鎖 PTA−6866 2005年7月15日
G1重鎖可変領域アミノ酸配列(配列番号1)
EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWISWVRQAPGKGLEWVAEIRSESDASATHYAEAVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCLAYFDYGLAIQNYWGQGTLVTVSS
G1軽鎖可変領域アミノ酸配列(配列番号2)
EIVLTQSPATLSLSPGERATLSCKASKRVTTYVSWYQQKPGQAPRLLIYGASNRYLGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCSQSYNYPYTFGQGTKLEIK
G1 CDR H1(伸長CDR)(配列番号3)
GFTFSNYWIS
G1 CDR H2(伸長CDR)(配列番号4)
EIRSESDASATHYAEAVKG
G1 CDR H3(配列番号5)
YFDYGLAIQNY
G1 CDR L1(配列番号6)
KASKRVTTYVS
G1 CDR L2(配列番号7)
GASNRYL
G1 CDR L3(配列番号8)
SQSYNYPYT
G1重鎖可変領域ヌクレオチド配列(配列番号9)
GAAGTTCAGCTGGTTGAATCCGGTGGTGGTCTGGTTCAGCCAGGTGGTTCCCTGCGTCTGTCCTGCGCTGCTTCCGGTTTCACCTTCTCCAACTACTGGATCTCCTGGGTTCGTCAGGCTCCTGGTAAAGGTCTGGAATGGGTTGCTGAAATCCGTTCCGAATCCGACGCGTCCGCTACCCATTACGCTGAAGCTGTTAAAGGTCGTTTCACCATCTCCCGTGACAACGCTAAGAACTCCCTGTACCTGCAGATGAACTCCCTGCGTGCTGAAGACACCGCTGTTTACTACTGCCTGGCTTACTTTGACTACGGTCTGGCTATCCAGAACTACTGGGGTCAGGGTACCCTGGTTACCGTTTCCTCC
G1軽鎖可変領域ヌクレオチド配列(配列番号10)
GAAATCGTTCTGACCCAGTCCCCGGCTACCCTGTCCCTGTCCCCAGGTGAACGTGCTACCCTGTCCTGCAAAGCTTCCAAACGGGTTACCACCTACGTTTCCTGGTACCAGCAGAAACCCGGTCAGGCTCCTCGTCTGCTGATCTACGGTGCTTCCAACCGTTACCTCGGTATCCCAGCTCGTTTCTCCGGTTCCGGTTCCGGTACCGACTTCACCCTGACCATCTCCTCCCTGGAACCCGAAGACTTCGCTGTTTACTACTGCAGTCAGTCCTACAACTACCCCTACACCTTCGGTCAGGGTACCAAACTGGAAATCAAA
G1重鎖完全抗体アミノ酸配列(本明細書に記載の改変IgG2を含む)(配列番号11)
EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWISWVRQAPGKGLEWVAEIRSESDASATHYAEAVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCLAYFDYGLAIQNYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
G1軽鎖完全抗体アミノ酸配列(配列番号12)
EIVLTQSPATLSLSPGERATLSCKASKRVTTYVSWYQQKPGQAPRLLIYGASNRYLGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCSQSYNYPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
G1重鎖完全抗体ヌクレオチド配列(本明細書に記載の改変IgG2を含む)(配列番号13)
GAAGTTCAGCTGGTTGAATCCGGTGGTGGTCTGGTTCAGCCAGGTGGTTCCCTGCGTCTGTCCTGCGCTGCTTCCGGTTTCACCTTCTCCAACTACTGGATCTCCTGGGTTCGTCAGGCTCCTGGTAAAGGTCTGGAATGGGTTGCTGAAATCCGTTCCGAATCCGACGCGTCCGCTACCCATTACGCTGAAGCTGTTAAAGGTCGTTTCACCATCTCCCGTGACAACGCTAAGAACTCCCTGTACCTGCAGATGAACTCCCTGCGTGCTGAAGACACCGCTGTTTACTACTGCCTGGCTTACTTTGACTACGGTCTGGCTATCCAGAACTACTGGGGTCAGGGTACCCTGGTTACCGTTTCCTCCGCCTCCACCAAGGGCCCATCTGTCTTCCCACTGGCCCCATGCTCCCGCAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCAGAACCTGTGACCGTGTCCTGGAACTCTGGCGCTCTGACCAGCGGCGTGCACACCTTCCCAGCTGTCCTGCAGTCCTCAGGTCTCTACTCCCTCAGCAGCGTGGTGACCGTGCCATCCAGCAACTTCGGCACCCAGACCTACACCTGCAACGTAGATCACAAGCCAAGCAACACCAAGGTCGACAAGACCGTGGAGAGAAAGTGTTGTGTGGAGTGTCCACCTTGTCCAGCCCCTCCAGTGGCCGGACCATCCGTGTTCCTGTTCCCTCCAAAGCCAAAGGACACCCTGATGATCTCCAGAACCCCAGAGGTGACCTGTGTGGTGGTGGACGTGTCCCACGAGGACCCAGAGGTGCAGTTCAACTGGTATGTGGACGGAGTGGAGGTGCACAACGCCAAGACCAAGCCAAGAGAGGAGCAGTTCAACTCCACCTTCAGAGTGGTGAGCGTGCTGACCGTGGTGCACCAGGACTGGCTGAACGGAAAGGAGTATAAGTGTAAGGTGTCCAACAAGGGACTGCCATCCAGCATCGAGAAGACCATCTCCAAGACCAAGGGACAGCCAAGAGAGCCACAGGTGTATACCCTGCCCCCATCCAGAGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGATTCTATCCATCCGACATCGCCGTGGAGTGGGAGTCCAACGGACAGCCAGAGAACAACTATAAGACCACCCCTCCAATGCTGGACTCCGACGGATCCTTCTTCCTGTATTCCAAGCTGACCGTGGACAAGTCCAGATGGCAGCAGGGAAACGTGTTCTCTTGTTCCGTGATGCACGAGGCCCTGCACAACCACTATACCCAGAAGAGCCTGTCCCTGTCTCCAGGAAAGTAA
G1軽鎖完全抗体ヌクレオチド配列(配列番号14)
GAAATCGTTCTGACCCAGTCCCCGGCTACCCTGTCCCTGTCCCCAGGTGAACGTGCTACCCTGTCCTGCAAAGCTTCCAAACGGGTTACCACCTACGTTTCCTGGTACCAGCAGAAACCCGGTCAGGCTCCTCGTCTGCTGATCTACGGTGCTTCCAACCGTTACCTCGGTATCCCAGCTCGTTTCTCCGGTTCCGGTTCCGGTACCGACTTCACCCTGACCATCTCCTCCCTGGAACCCGAAGACTTCGCTGTTTACTACTGCAGTCAGTCCTACAACTACCCCTACACCTTCGGTCAGGGTACCAAACTGGAAATCAAACGCACTGTGGCTGCACCATCTGTCTTCATCTTCCCTCCATCTGATGAGCAGTTGAAATCCGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCGCGCGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCCGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACCCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGTTCTCCAGTCACAAAGAGCTTCAACCGCGGTGAGTGCTAA
ヒトおよびラットCGRP(ヒトα−CGRP(配列番号15);ヒトβ−CGRP(配列番号43);ラットα−CGRP(配列番号41);およびラットβ−CGRP(配列番号44))のアミノ酸配列比較:
NH2−ACDTATCVTHRLAGLLSRSGGVVKNNFVPTNVGSKAF−CONH2(ヒトα−CGRP)
NH2−ACNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF−CONH2(ヒトβ−CGRP)
NH2−SCNTATCVTHRLAGLLSRSGGVVKDNFVPTNVGSEAF−CONH2(ラットα−CGRP)
NH2−SCNTATCVTHRLAGLLSRSGGVVKDNFVPTNVGSKAF−CONH2(ラットβ−CGRP)
Claims (12)
- 37℃で表面プラズモン共鳴によって測定される、ヒトα−CGRPに対する結合親和性(KD)が50nM以下である抗体であって、
a.配列番号3で示されるアミノ酸配列を有するCDR H1、
b.配列番号4で示されるアミノ酸配列を有するCDR H2、または表6で示されるアミノ酸の変異を有するCDR H2の変異体、
c.配列番号5で示されるアミノ酸配列を有するCDR H3、
d.配列番号6で示されるアミノ酸配列を有するCDR L1、または表6で示されるアミノ酸の変異を有するCDR L1の変異体、
e.配列番号7で示されるアミノ酸配列を有するCDR L2、または表6で示されるアミノ酸の変異を有するCDR L2の変異体、および
f.配列番号8で示されるアミノ酸配列を有するCDR L3
を含む抗体。 - 配列番号1で示されるアミノ酸配列を有するV H ドメインを含む請求項1に記載の抗体であり、ここで、配列番号1の99位のアミノ酸残基がLであり、またはA、N、S、T、VもしくはRによって置換され、配列番号1の100位のアミノ酸残基がAであり、またはL、R、S、V、Y、C、G、T、KもしくはPによって置換されている、抗体。
- 配列番号1で示されるアミノ酸配列を有するVHドメインを含む、請求項1に記載の抗体。
- 配列番号2で示されるアミノ酸配列を有するVLドメインを含む、請求項1に記載の抗体。
- 配列番号1で示されるアミノ酸配列を有するVHドメインと、配列番号2で示されるアミノ酸配列を有するVLドメインとを含む抗体。
- 抗体がIgG、IgM、IgE、IgA、もしくはIgD分子であり、またはそれに由来する、請求項5に記載の抗体。
- ATCCアクセッション番号PTA−6867の発現ベクターによって産生される重鎖を含む、請求項5に記載の抗体。
- ATCCアクセッション番号PTA−6866の発現ベクターによって産生される軽鎖を含む、請求項5に記載の抗体。
- 請求項1から8のいずれか一項に記載の抗体と、薬学的に許容できる添加剤とを含む医薬組成物。
- 個体中の少なくとも1つの血管運動症状を予防または治療するための、請求項9に記載の医薬組成物。
- 前記血管運動症状が、前兆を伴うもしくは伴わない片頭痛、片麻痺性片頭痛、群発性頭痛、片頭痛性神経痛、慢性頭痛、または緊張性頭痛である、請求項10に記載の医薬組成物。
- 前記血管運動症状が顔面紅潮である、請求項10に記載の医薬組成物。
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SI (3) | SI1957106T2 (ja) |
SV (1) | SV2008002905A (ja) |
TN (1) | TNSN08213A1 (ja) |
UA (1) | UA94244C2 (ja) |
WO (1) | WO2007054809A2 (ja) |
ZA (1) | ZA200803484B (ja) |
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