JP2021152058A - 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を投与することによって内臓痛を治療するための方法 - 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を投与することによって内臓痛を治療するための方法 Download PDFInfo
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Abstract
Description
本願は、2009年8月28日に出願された米国仮特許出願第61/237,901号の優先権の利益を主張するものであり、前記出願は、参照によりその全体が本明細書に組み込まれる。
本願は電子的に出願されるものであり、電子的に提出された、テキストフォーマットの配列表を含む。テキストファイルは、2010年8月11日に作製され28KBのサイズを有する、「PC33920A_SeqList.txt」というタイトルの配列表を含有する。このテキストファイルに含有される配列表は明細書の一部であり、参照によりその全体が本明細書に組み込まれる。
本発明は、抗CGRP抗体を用いて内臓痛および/または内臓痛の症状を治療および/または予防する方法、ならびに内臓痛および/または内臓痛の症状の予防および/または治療において使用するための抗CGRP抗体に関する。
本発明の実施は、別段の指示がない限り、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採用し、これらは当分野の技術の範囲内である。このような技術は、Molecular Cloning:A Laboratory Manual、second edition(Sambrookら、1989)Cold Spring Harbor Press;Oligonucleotide Synthesis(M.J.Gait編、1984);Methods in Molecular Biology、Humana Press;Cell Biology:A Laboratory Notebook(J.E.Cellis編、1998)Academic Press;Animal Cell Culture(R.I.Freshney編、1987);Introduction to Cell and Tissue Culture(J.P.MatherおよびP.E.Roberts、1998)Plenum Press;Cell and Tissue Culture:Laboratory Procedures(A.Doyle、J.B.Griffiths、およびD.G.Newell編、1993〜1998)J.WileyおよびSons;Methods in Enzymology(Academic Press,Inc.);Handbook of Experimental Immunology(D.M.WeirおよびC.C.Blackwell編);Gene Transfer Vectors for Mammalian Cells(J.M.MillerおよびM.P.Calos編、1987);Current Protocols in Molecular Biology(F.M.Ausubelら編、1987);PCR:The Polymerase Chain Reaction(Mullisら編、1994);Current Protocols in Immunology(J.E.Coliganら編、1991);Short Protocols in Molecular Biology(WileyおよびSons、1999);Immunobiology(C.A.JanewayおよびP.Travers、1997);Antibodies(P.Finch、1997);Antibodies:a practical approach(D.Catty編、IRL Press、1988〜1989);Monoclonal antibodies:a practical approach(P.ShepherdおよびC.Dean編、Oxford University Press、2000);Using antibodies:a laboratory manual(E.HarlowおよびD.Lane(Cold Spring Harbor Laboratory Press、1999);The Antibodies(M.ZanettiおよびJ.D.Capra編、Harwood Academic Publishers、1995)などの文献において全て説明されている。
「抗体」は、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に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り、前記結合は、免疫グロブリン分子の可変領域に位置する少なくとも1つの抗原認識部位を介して行われる。本明細書において用いられる場合、この用語はインタクトなポリクローナル抗体またはモノクローナル抗体だけではなく、その断片(Fab、Fab’、F(ab’)2、Fvなど)、一本鎖(ScFv)、その突然変異体、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免疫グロブリン分子の任意の他の修飾立体構造を包含する。抗体は、IgG、IgA、またはIgM(またはそのサブクラス)などの任意のクラスの抗体を含み、抗体は何らかの特定のクラスのものである必要はない。抗体の重鎖の定常ドメインの抗体アミノ酸配列に応じて、免疫グロブリンは異なるクラスに属し得る。IgA、IgD、IgE、IgG、およびIgMという、免疫グロブリンの5つの主なクラスが存在し、これらのいくつかはさらに、サブクラス(アイソタイプ)、例えばIgG1、IgG2、IgG3、IgG4、IgA1、およびIgA2に分類され得る。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3次元立体構造は周知である。
本明細書において、内臓痛および/または内臓痛の症状を予防および/または治療するための方法と、個体における内臓痛および/または内臓痛の1つもしくは複数の症状を予防および/または治療するための医薬品が開示される。
いくつかの実施形態において、抗CGRPアンタゴニスト抗体はCGRPに結合する。好ましくは、抗CGRPアンタゴニスト抗体はCGRPに結合し、CGRPがCGRP受容体に結合する能力を阻害する。いくつかの実施形態において、抗CGRPアンタゴニスト抗体は、ヒトおよび齧歯動物のCGRPの両方、好ましくはヒトおよびラットのCGRPに結合する。より好ましくは、抗体はヒトCGRPに結合する。好ましい実施形態において、抗CGRPアンタゴニスト抗体は、ヒトα−CGRPに結合するか、またはヒトα−CGRPおよび/もしくはβ−CGRPに結合する。最も好ましくは、抗CGRPアンタゴニスト抗体は、(a)CGRPに結合すること、(b)CGRPが(1つまたは複数の)その受容体に結合することを遮断すること、(c)cAMPの活性化を含むCGRP受容体の活性化を遮断するかまたは低下させること、(d)受容体結合および/またはCGRPに対する細胞応答の誘出などの、CGRPシグナル伝達により仲介される下流の経路を含む、CGRPの生物学的活性を阻害するか、遮断するか、抑制するか、または低減させること、(e)内臓痛の任意の態様を予防、改善、または治療すること、(f)CGRPのクリアランスを増大させること、ならびに(g)CGRPの合成、産生、または放出を阻害する(低減させる)ことという機能的特徴のいずれか1つまたは複数を示す抗体である。
(a)前記抗体の断片(例えば、Fab、Fab’、F(ab’)2、Fv、Fc、ScFvなど)、
(b)前記抗体の軽鎖、
(c)前記抗体の重鎖、
(d)前記抗体の軽鎖および/もしくは重鎖の1つもしくは複数の可変領域、
(e)前記抗体の1つもしくは複数のCDR(1個、2個、3個、4個、5個、もしくは6個のCDR)、
(f)前記抗体の重鎖のCDR H3、
(g)前記抗体の軽鎖のCDR L3、
(h)前記抗体の軽鎖の3つのCDR、
(i)前記抗体の重鎖の3つのCDR、
(j)前記抗体の軽鎖の3つのCDRおよび重鎖の3つのCDR、
(k)(a)から(j)のいずれか1つまたは複数
を含むか、もしくはこれからなるものである。
いくつかの実施形態において、抗CGRPアンタゴニスト抗体は、例えば1週間に約1回から約7回、さらに好ましくは1カ月に約1回から約4回、さらに好ましくは6カ月間に約1回から約6回、さらに好ましくは1年に約1回から約12回、末梢に投与される。好ましくは、抗CGRPアンタゴニスト抗体は、1日約1回、2、3、4、5、もしくは6日ごとに1回、1週間に1回、2週間ごとに2回、3週間ごとに1回、1カ月に1回、2カ月ごとに1回、3カ月ごとに1回、4カ月ごとに1回、5カ月ごとに1回、6カ月ごとに1回、7カ月ごとに1回、8カ月ごとに1回、9カ月ごとに1回、10カ月ごとに1回、11カ月ごとに1回、または1年に1回から選択される期間内で末梢に投与される。好ましい実施形態によれば、抗CGRPアンタゴニスト抗体は、経口、舌下、口腔内、局部的、直腸内、吸入を介して、経皮、皮下、静脈内、動脈内もしくは筋肉内、心臓内投与を介して、骨内、皮内、腹腔内、経粘膜的、膣内、硝子体内、皮膚上、関節内、関節周辺、または局所的の1つまたは複数から選択される経路を介して投与される。
(i)オピオイド系鎮痛薬、例えばモルヒネ、ヘロイン、ヒドロモルホン、オキシモルホン、レボルファノール、レバロルファン、メタドン、メペリジン、フェンタニル、コカイン、コデイン、ジヒドロコデイン、オキシコドン、ヒドロコドン、プロポキシフェン、ナルメフェン、ナロルフィン、ナロキソン、ナルトレキソン、ブプレノルフィン、ブトルファノール、ナルブフィン、またはペンタゾシン、
(ii)非ステロイド系抗炎症薬(NSAID)、例えば、アスピリン、ジクロフェナク、ジフルシナル、エトドラク、フェンブフェン、フェノプロフェン、フルフェニサル、フルビプロフェン、イブプロフェン、インドメタシン、ケトプロフェン、ケトロラック、メクロフェナム酸、メフェナム酸、ナブメトン、ナプロキセン、オキサプロジン、フェニルブタゾン、ピロキシカム、スリンダク、トルメチン、またはゾメピラック、シクロオキシゲナーゼ−2(COX−2)阻害剤、セレコキシブ、ロフェコキシブ、メロキシカム、JTE−522、L−745,337、NS398、またはその薬学的に許容できる塩、
(iii)バルビツール系鎮静薬、例えば、アモバルビタール、アプロバルビタール、ブタバルビタール、ブタビタール、メフォバルビタール、メタルビタール、メトヘキシタール、ペントバルビタール、フェノバルビタール、セコバルビタール、タルブタール、チアミラール、またはチオペンタール、またはその薬学的に許容できる塩、
(iv)鎮静活性を有するベンゾジアゼピン、例えば、クロルジアゼポキシド、クロラゼプ酸、ジアゼパム、フルラゼパム、ロラゼパム、オキサゼパム、テマゼパム、またはトリアゾラム、またはその薬学的に許容できる塩、
(v)鎮静活性を有するH1アンタゴニスト、例えば、ジフェンヒドラミン、ピリラミン、プロメタジン、クロルフェニラミン、またはクロルシクリジン、またはその薬学的に許容できる塩、
(vi)グルテチミド、メプロバメート、メタカロン、またはジクロラルフェナゾン、またはその薬学的に許容できる塩などの鎮痛薬、
(vii)骨格筋弛緩薬、例えば、バクロフェン、カリソプロドール、クロルゾキサゾン、シクロベンザプリン、メトカルバモール、またはオルフェナジン、またはその薬学的に許容できる塩、
(viii)NMDA受容体アンタゴニスト、例えば、デキストロメトルファン((+)−3−ヒドロキシ−N−メチルモルフィナン)もしくはその代謝産物であるデキストロルファン((+)−3−ヒドロキシ−N−メチルモルフィナン)、ケタミン、メマンチン、ピロロキノリンキノン、またはシス−4−(ホスホノメチル)−2−ピペリジンカルボン酸、またはその薬学的に許容できる塩、
(ix)α−アドレナリン作動薬、例えば、ドキサゾシン、タムスロシン、クロニジン、または4−アミノ−6,7−ジメトキシ−2−(5−メタンスルホンアミド−1,2,3,4−テトラヒドロイソキノール−2−イル)−5−(2−ピリジル)キナゾリン、
(x)三環系抗鬱薬、例えば、デシプラミン、イミプラミン、アミトリプチリン、またはノルトリプチリン、
(xi)抗けいれん薬、例えば、カルバマゼピン、またはバルプロエート、
(xii)タキキニン(NK)アンタゴニスト、とりわけ、NK−3、NK−2、またはNK−1アンタゴニスト、例えば、(αR,9R)−7−[3,5−ビス(トリフルオロメチル)ベンジル]−8,9,10,11−テトラヒドロ−9−メチル−5−(4−メチルフェニル)−7H−[1,4]ジアゾシノ[2,1−g][1,7]ナフチリジン−6−13−ジオン(TAK−637)、5−[[(2R,3S)−2−[(1R)−1−[3,5−ビス(トリフルオロメチル)フェニル]エトキシ−3−(4−フルオロフェニル)−4−モルホリニル]メチル]−1,2−ジヒドロ−3H−1,2,4−トリアゾール−3−オン(MK−869)、ラネピタント、ダピタント、または3−[[2−メトキシ−5−(トリフルオロメトキシ)フェニル]メチルアミノ]−2−フェニル−ピペリジン(2S,3S)、
(xiii)ムスカリン性アンタゴニスト、例えば、オキシブチン、トルテロジン、プロピベリン、塩化トロスピウム、またはダリフェナシン、
(xiv)COX−2阻害剤、例えば、セレコキシブ、ロフェコキシブ、またはバルデコキシブ、
(xv)非選択的COX阻害剤(好ましくはGI保護を有する)、例えば、ニトロフルルビプロフェン(HCT−1026)、
(xvi)コールタール鎮痛薬、とりわけパラセタモール、
(xvii)ドロペリドールなどの神経遮断薬、
(xviii)バニロイド受容体アゴニスト(例えば、レジニフェラトキシン)またはアンタゴニスト(例えば、カプサゼピン)、
(xix)プロプラノロールなどのβ−アドレナリン作動薬、
(xx)メキシレチンなどの局所的麻酔薬、
(xxi)デキサメタゾンなどのコルチコステロイド、
(xxii)セロトニン受容体アゴニストまたはアンタゴニスト、
(xxiii)コリン作用性(ニコチン性)鎮痛薬、
(xxiv)tramadol、
(xxv)シルデナフィル、バルデナフィル、またはタダラフィルなどのPDEV阻害剤、
(xxvi)ガバペンチンまたはプレガバリンなどのα−2−δリガンド、
(xxvii)カンナビノイド、ならびに
(xxviii)アミトリプチリン(Elavil(登録商標))、トラゾドン(Desyrel(登録商標))、およびイミプラミン(Tofranil(登録商標))などの抗鬱剤、またはフェニトイン(Dilantin(登録商標))もしくはカルバマゼピン(Tegretol(登録商標))などの抗けいれん剤
の1つまたは複数から選択される。
本発明のさらなる態様によれば、上記に規定した医薬組成物と、内臓痛および/もしくは内臓痛の症状を予防および/もしくは治療するため、または内臓痛および/もしくは内臓痛の症状を改善するか、制御するか、その発症を低減させるか、その進展もしくは進行を遅延させるための、有効量の前記医薬組成物を個体に末梢投与するための指示とを含むキットが提供される。
この実施例は、内臓痛モデルにおける抗CGRPアンタゴニスト抗体治療の効果を例示する。
相互作用分析を、標準的なBiacoreランニングバッファー(HBS−PまたはHBS−EP)を用いて、ストレプトアビジンで被覆した(SA)センサーチップを備えたBiacore 3000(商標)システム(Biacore AB、Uppsala、Sweden)で、25℃および37℃で実施した。N−LC−ビオチニル化したヒトおよびラットのα−およびβ−CGRPを、低レベル(典型的には100応答単位)で個別のフローセル上に捕捉して反応表面を作製し、一方、修飾されていないフローセルは参照チャネルとして用いた。精製された、抗体G1およびG2のFab断片が作製された。典型的には、Fabは、0.5μMを最高濃度として用いて2倍の連続希釈として調製し、最大2時間の解離時間が可能となるよう、100μl/分で1分間注射した。表面を、G1のFabについては50%v/vのエタノールと25mMのNaOHとの混合物で、G2のFabについては2:1v/vのPierce Gentle溶出緩衝液/4MのNaClで再生した。Fabの注射は、アッセイが再現可能であることを実証するために2回行った。結合応答は二重参照され、BiaEvaluation v.4.0ソフトウェアを用いた単純モデルに全体的に適合した。親和性は、動態速度定数の商から推定した(KD=koff/kon)。
この実施例は、内臓痛モデルにおける抗CGRPアンタゴニスト抗体治療の効果を例示する。
以下の材料は、American Type Culture Collection、10801 University Boulevard、Maassas、Virginia 20110−2209、USA(ATCC)に寄託されている。
抗体G1の重鎖可変領域のアミノ酸配列(配列番号1)
GFTFSNYWIS
EIRSESDASATHYAEAVKG
YFDYGLAIQNY
KASKRVTTYVS
GASNRYL
SQSYNYPYT
NH2−ACDTATCVTHRLAGLLSRSGGVVKNNFVPTNVGSKAF−CONH2(配列番号15)
NH2−ACNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF−CONH2(配列番号16)
NH2−SCNTATCVTHRLAGLLSRSGGVVKDNFVPTNVGSEAF−CONH2(配列番号17)
NH2−SCNTATCVTHRLAGLLSRSGGVVKDNFVPTNVGSKAF−CONH2(配列番号18)
SSVMH
YINPYNDGTKYNEKFKG
GGNDGY
SASSSISSIYLH
RASNLAS
QQGSTIPFT
GFTFSNY
NYWIS
RSESDASA
GYTFTSSVMH
GYTFTSS
NPYNDG
(項目1) 治療有効量の抗CGRPアンタゴニスト抗体を、内臓痛に罹患しているかまたは内臓痛のリスクがある個体に投与することを含む、個体における内臓痛および/または内臓痛の1つもしくは複数の症状を治療する方法。
(項目2) 内臓痛が機能性腸障害(FBD)に関連する、項目1に記載の方法。
(項目3) FBDが、胃食道逆流、消化不良、過敏性腸症候群(IBS)、および機能性腹痛症候群(FAPS)からなる群から選択される、項目2に記載の方法。
(項目4) 内臓痛が炎症性腸疾患(IBD)に関連する、項目1に記載の方法。
(項目5) IBDが、クローン病、回腸炎、および潰瘍性大腸炎からなる群から選択される、項目4に記載の方法。
(項目6) 内臓痛が、腎疝痛、月経困難症、膀胱炎、月経期間、陣痛、閉経、前立腺炎、または膵炎に関連する、項目1に記載の方法。
(項目7) 内臓痛が間質性膀胱炎(IC)に関連する、項目6に記載の方法。
(項目8) 抗CGRPアンタゴニスト抗体が、50nM以下のKD(37℃で表面プラズモン共鳴によって測定される)でCGRPに結合し、かつ/または少なくとも7日間のインビボでの半減期を有する、項目1に記載の方法。
(項目9) 抗CGRPアンタゴニスト抗体が、CGRPのC末端領域に特異的に結合する、項目1に記載の方法。
(項目10) 抗CGRPアンタゴニスト抗体が、配列GSKAF(配列番号39)により規定されるエピトープを特異的に認識する、項目9に記載の方法。
(項目11) 抗CGRP抗体が、配列番号1または19に示されるアミノ酸配列を有するVHドメインを含む、項目1に記載の方法。
(項目12) 抗CGRP抗体が、配列番号2または20に示されるアミノ酸配列を有するVLドメインを含む、項目1に記載の方法。
(項目13) 抗CGRP抗体が、
(a)配列番号3、21、33、34、36、または37で示されるCDR H1、
(b)配列番号4、22、35、または38で示されるCDR H2、
(c)配列番号5または23で示されるCDR H3、
(d)配列番号6または24で示されるCDR L1、
(e)配列番号7または25で示されるCDR L2、および
(f)配列番号8または26で示されるCDR L3
からなる群から選択される少なくとも1つのCDRを含む、項目1に記載の方法。
(項目14) 抗CGRP抗体が、配列番号1に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に示されるアミノ酸配列を有するVLドメインとを含む、項目1に記載の方法。
(項目15) 抗CGRP抗体が、ATCC受託番号がPTA−6867および/またはPTA−6866の発現ベクターにより産生される、項目1に記載の方法。
(項目16) 抗CGRP抗体が、
C末端のリジンを有するかまたは有さない、配列番号11に示される、抗体G1の重鎖の完全な抗体アミノ酸配列と、
配列番号12に示される、抗体G1の軽鎖の完全な抗体アミノ酸配列とを含む、項目1に記載の方法。
(項目17) 抗CGRP抗体が、
配列番号29に示される、抗体G2の重鎖の完全な抗体アミノ酸配列と、
配列番号30に示される、抗体G2の軽鎖の完全な抗体アミノ酸配列と
を含む、項目1に記載の方法。
(項目18) 個体における内臓痛および/または内臓痛の症状を治療および/または予防するための医薬組成物であって、抗CGRPアンタゴニスト抗体および薬学的に許容できる担体を含み、末梢に投与するために調製される医薬組成物。
Claims (18)
- 治療有効量の抗CGRPアンタゴニスト抗体を含む、個体における内臓痛および/または内臓痛の1つもしくは複数の症状を治療するための医薬組成物。
- 前記内臓痛が機能性腸障害(FBD)に関連する、請求項1に記載の医薬組成物。
- 前記FBDが、胃食道逆流、消化不良、過敏性腸症候群(IBS)、および機能性腹痛症候群(FAPS)からなる群から選択される、請求項2に記載の医薬組成物。
- 前記内臓痛が炎症性腸疾患(IBD)に関連する、請求項1に記載の医薬組成物。
- 前記IBDが、クローン病、回腸炎、および潰瘍性大腸炎からなる群から選択される、請求項4に記載の医薬組成物。
- 前記内臓痛が、腎疝痛、月経困難症、膀胱炎、月経期間、陣痛、閉経、前立腺炎、または膵炎に関連する、請求項1に記載の医薬組成物。
- 前記内臓痛が間質性膀胱炎(IC)に関連する、請求項6に記載の医薬組成物。
- 前記抗CGRPアンタゴニスト抗体が、50nM以下のKD(37℃で表面プラズモン共鳴によって測定される)でCGRPに結合し、かつ/または少なくとも7日間のインビボでの半減期を有する、請求項1に記載の医薬組成物。
- 前記抗CGRPアンタゴニスト抗体が、CGRPのC末端領域に特異的に結合する、請求項1に記載の医薬組成物。
- 前記抗CGRPアンタゴニスト抗体が、配列GSKAF(配列番号39)により規定されるエピトープを特異的に認識する、請求項9に記載の医薬組成物。
- 前記抗CGRP抗体が、配列番号1または19に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に記載の医薬組成物。
- 前記抗CGRP抗体が、配列番号2または20に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に記載の医薬組成物。
- 前記抗CGRP抗体が、
(a)配列番号3、21、33、34、36、または37で示されるCDR H1、
(b)配列番号4、22、35、または38で示されるCDR H2、
(c)配列番号5または23で示されるCDR H3、
(d)配列番号6または24で示されるCDR L1、
(e)配列番号7または25で示されるCDR L2、および
(f)配列番号8または26で示されるCDR L3
からなる群から選択される少なくとも1つのCDRを含む、請求項1に記載の医薬組成物。 - 前記抗CGRP抗体が、配列番号1に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に示されるアミノ酸配列を有するVLドメインとを含む、請求項1に記載の医薬組成物。
- 前記抗CGRP抗体が、ATCC受託番号がPTA−6867および/またはPTA−6866の発現ベクターにより産生される、請求項1に記載の医薬組成物。
- 前記抗CGRP抗体が、
C末端のリジンを有するかまたは有さない、配列番号11に示される、抗体G1の重鎖の完全な抗体アミノ酸配列と、
配列番号12に示される、抗体G1の軽鎖の完全な抗体アミノ酸配列と
を含む、請求項1に記載の医薬組成物。 - 前記抗CGRP抗体が、
配列番号29に示される、抗体G2の重鎖の完全な抗体アミノ酸配列と、
配列番号30に示される、抗体G2の軽鎖の完全な抗体アミノ酸配列と
を含む、請求項1に記載の医薬組成物。 - 薬学的に許容できる担体をさらに含み、末梢に投与するために調製される、請求項1〜17のいずれか一項に記載の医薬組成物。
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Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AP2008004467A0 (en) | 2005-11-14 | 2008-06-30 | Rinat Neurosciene Corp | Antagonist antibodies directed against calcitonin generelated peptide anf methods using same |
JP5537441B2 (ja) | 2008-03-04 | 2014-07-02 | ファイザー・リミテッド | 慢性疼痛を治療する方法 |
JO3382B1 (ar) | 2008-12-23 | 2019-03-13 | Amgen Inc | أجسام مضادة ترتبط مع مستقبل cgrp بشري |
MX2012002464A (es) | 2009-08-28 | 2012-03-14 | Rinat Neuroscience Corp | El uso de anticuerpos antagonistas dirigidos contra el peptido relacionado con el gen de la calcitonina para tratar dolor visceral. |
EP2709663B1 (en) | 2011-05-20 | 2019-03-20 | AlderBio Holdings LLC | Use of anti-cgrp antibodies and antibody fragments to prevent or inhibit photophobia or light aversion in subjects in need thereof, especially migraine sufferers |
HUE054437T2 (hu) * | 2011-05-20 | 2021-09-28 | H Lundbeck As | Anti-CGRP készítmények és alkalmazásuk |
AU2012258976B8 (en) * | 2011-05-20 | 2017-07-20 | H. Lundbeck A/S | Use of anti-CGRP or anti-CGRP-R antibodies or antibody fragments to treat or prevent chronic and acute forms of diarrhea |
JP6568099B2 (ja) | 2014-03-21 | 2019-08-28 | テバ・ファーマシューティカルズ・インターナショナル・ゲーエムベーハーTeva Pharmaceuticals International GmbH | 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及びその使用方法 |
US10556945B2 (en) | 2014-03-21 | 2020-02-11 | Teva Pharmaceuticals International Gmbh | Antagonist antibodies directed against calcitonin gene-related peptide and methods using same |
MX2017003247A (es) | 2014-09-15 | 2017-11-30 | Amgen Inc | Proteina de union a antigenos, bi-especificos del receptor anti-cgrp/receptor pac1 y usos de las mismas. |
JOP20200116A1 (ar) | 2015-04-24 | 2017-06-16 | Amgen Inc | طرق لعلاج أو الوقاية من الصداع النصفي |
JP7116685B2 (ja) | 2016-04-15 | 2022-08-10 | エイチ. ルンドベック アー/エス | ヒト化抗pacap抗体及びそれらの使用 |
CA3036632A1 (en) | 2016-09-23 | 2018-03-29 | Teva Pharmaceuticals International Gmbh | Treating refractory migraine |
JP2021519790A (ja) | 2018-04-02 | 2021-08-12 | アムジェン インコーポレイテッド | エレヌマブ組成物及びその使用 |
US10899826B1 (en) | 2018-09-13 | 2021-01-26 | Teva Pharmaceuticals International Gmbh | Pharmaceutical compositions for an anti-CGRP antagonist antibody |
CN113544152A (zh) * | 2018-12-18 | 2021-10-22 | 勃林格殷格翰国际加拿大公司 | Flt3激动剂抗体及其用途 |
EP3908606A4 (en) | 2019-01-08 | 2022-11-23 | H. Lundbeck A/S | ACUTE AND RAPID TREATMENT OF HEADACHES USING ANTI-CGRP ANTIBODIES |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009515942A (ja) * | 2005-11-14 | 2009-04-16 | ライナット ニューロサイエンス コーポレイション | 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 |
Family Cites Families (95)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
JPS62129297A (ja) | 1985-08-09 | 1987-06-11 | Toyo Jozo Co Ltd | カルシトニン遺伝子関連ペプチド誘導体 |
IL85035A0 (en) | 1987-01-08 | 1988-06-30 | Int Genetic Eng | Polynucleotide molecule,a chimeric antibody with specificity for human b cell surface antigen,a process for the preparation and methods utilizing the same |
GB8823869D0 (en) | 1988-10-12 | 1988-11-16 | Medical Res Council | Production of antibodies |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5116964A (en) * | 1989-02-23 | 1992-05-26 | Genentech, Inc. | Hybrid immunoglobulins |
CA2020786A1 (en) | 1989-07-10 | 1991-01-11 | Amylin Pharmaceuticals, Inc. | Treatment of obesity and essential hypertension and related disorders |
US5633425A (en) | 1990-08-29 | 1997-05-27 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US5625126A (en) | 1990-08-29 | 1997-04-29 | Genpharm International, Inc. | Transgenic non-human animals for producing heterologous antibodies |
US5545806A (en) | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
US5661016A (en) | 1990-08-29 | 1997-08-26 | Genpharm International Inc. | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
KR100272077B1 (ko) | 1990-08-29 | 2000-11-15 | 젠팜인터내셔날,인코포레이티드 | 이종 항체를 생산할 수 있는 전이유전자를 가진 인간이외의 동물 |
CA2405246A1 (en) | 1990-12-03 | 1992-06-11 | Genentech, Inc. | Enrichment method for variant proteins with alterred binding properties |
CA2103059C (en) | 1991-06-14 | 2005-03-22 | Paul J. Carter | Method for making humanized antibodies |
AU6524794A (en) | 1993-03-24 | 1994-10-11 | Amylin Pharmaceuticals, Inc. | Cloned receptors and methods for screening |
GB9316989D0 (en) | 1993-08-16 | 1993-09-29 | Lynxvale Ltd | Binding molecules |
WO1996005221A1 (en) | 1994-08-16 | 1996-02-22 | Human Genome Sciences, Inc. | Calcitonin receptor |
FR2732221B1 (fr) | 1995-03-28 | 1997-04-25 | Oreal | Utilisation d'un antagoniste de cgrp pour traiter les rougeurs cutanees d'origine neurogene et composition obtenue |
FR2732222B1 (fr) | 1995-03-28 | 1997-04-25 | Oreal | Utilisation d'un antagoniste de cgrp pour le traitement des prurits et des dysesthesies oculaires et palpebraux |
FR2732220B1 (fr) | 1995-03-28 | 1997-04-25 | Oreal | Utilisation d'un antagoniste de cgrp pour traiter les lichens et les prurits et composition obtenue |
EP0737471A3 (fr) | 1995-04-10 | 2000-12-06 | L'oreal | Utilisation d'un sel d'une métal alcalino-terreux comme inhibiteur de TNF-alpha dans une composition unique et composition obtenue |
FR2732598B1 (fr) | 1995-04-10 | 1997-05-09 | Oreal | Utilisation de sel de metaux alcalino-terreux pour le traitement des prurits et des dysesthesies oculaires ou palpebraux |
KR20050085971A (ko) | 1995-04-27 | 2005-08-29 | 아브게닉스, 인크. | 면역화된 제노마우스 유래의 인간 항체 |
EP0851759A4 (en) | 1995-09-05 | 2000-12-06 | Smithkline Beecham Corp | COMPOUNDS AND RELATED METHODS |
AU2731797A (en) | 1996-04-15 | 1997-11-19 | University Of Miami | Molecular clone of cgrp receptor component protein and uses thereof |
US5746694A (en) | 1996-05-16 | 1998-05-05 | Wilk; Peter J. | Endoscope biopsy channel liner and associated method |
WO1998003534A1 (en) | 1996-07-23 | 1998-01-29 | Smithkline Beecham Corporation | Calcitonin gene-related peptide receptor component factor (houdc44) |
US6586458B1 (en) | 1996-08-16 | 2003-07-01 | Pozen Inc. | Methods of treating headaches using 5-HT agonists in combination with long-acting NSAIDs |
JP3734315B2 (ja) | 1996-08-26 | 2006-01-11 | 株式会社小松製作所 | 曲げ加工方法および曲げ加工装置 |
AU4261697A (en) | 1996-09-09 | 1998-03-26 | Smithkline Beecham Corporation | Compounds and methods |
CA2262818A1 (en) | 1996-09-10 | 1998-03-19 | Dr. Karl Thomae Gesellschaft Mit Beschrankter Haftung | Modified amino acids, pharmaceuticals containing these compounds and methods for their production |
WO1998056779A1 (en) | 1997-06-13 | 1998-12-17 | Smithkline Beecham Corporation | 4-sulfinyl benzamides as calcitonin gene-related peptide receptor antagonists |
US6063768A (en) | 1997-09-04 | 2000-05-16 | First; Eric R. | Application of botulinum toxin to the management of neurogenic inflammatory disorders |
US20030069231A1 (en) | 1999-10-12 | 2003-04-10 | Klaus Rudolf | Modified aminoacids, pharmaceuticals containing these compounds and method for their production |
GB9809951D0 (en) | 1998-05-08 | 1998-07-08 | Univ Cambridge Tech | Binding molecules |
GB9809839D0 (en) | 1998-05-09 | 1998-07-08 | Glaxo Group Ltd | Antibody |
JP2002525371A (ja) | 1998-09-30 | 2002-08-13 | メルク シャープ エンド ドーム リミテッド | Cgrpリガンドとしてのベンゾイミダゾリニルピペリジン |
US6737056B1 (en) | 1999-01-15 | 2004-05-18 | Genentech, Inc. | Polypeptide variants with altered effector function |
EP1031350A1 (en) * | 1999-02-23 | 2000-08-30 | Warner-Lambert Company | Use of a gabapentin-analog for the manufacture of a medicament for preventing and treating visceral pain |
US6313097B1 (en) | 1999-03-02 | 2001-11-06 | Boehringer Ingelheim Pharma Kg | Antagonists of calcitonin gene-related peptide |
US6521609B1 (en) | 1999-08-10 | 2003-02-18 | Boehringer Ingelheim Pharma Kg | Use of CGRP antagonists and CGRP release inhibitors for combating menopausal hot flushes |
US6849425B1 (en) | 1999-10-14 | 2005-02-01 | Ixsys, Inc. | Methods of optimizing antibody variable region binding affinity |
FR2807660A1 (fr) | 2000-04-13 | 2001-10-19 | Warner Lambert Co | Utilisation d'antagonistes du ngf pour la prevention ou le traitement de douleurs viscerales chroniques |
US20020162125A1 (en) | 2001-03-06 | 2002-10-31 | Anne-Marie Salmon | Methods and compositions for the modulation of neurogenic inflammatory pain and physical opiate withdrawal |
CA2461917C (en) | 2001-09-27 | 2012-01-17 | Merck & Co., Inc. | Isolated dna molecules encoding humanized calcitonin gene-related peptide receptor, related non-human transgenic animals and assay methods |
US6767056B2 (en) | 2002-01-14 | 2004-07-27 | Shin Yeh Enterprise Co., Ltd. | Settee with a foldable tray-support unit |
US7026312B2 (en) | 2002-03-14 | 2006-04-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Substituted piperidines, pharmaceutical compositions containing these compounds, their use and processes for the preparation thereof |
MXPA04009418A (es) | 2002-03-29 | 2005-06-08 | Schering Corp | Anticuerpos monoclonales humanos par interleucina-5, y metodos y composiciones que comprenden los mismos. |
US7879991B2 (en) | 2002-05-06 | 2011-02-01 | Noxxon Pharma Ag | CGRP binding nucleic acids |
US20040110170A1 (en) | 2002-05-18 | 2004-06-10 | The Regents Of The University Of California | Cloning and characterization of calcitonin gene related peptide receptors |
US7345065B2 (en) * | 2002-05-21 | 2008-03-18 | Allergan, Inc. | Methods and compositions for alleviating pain |
US20040063735A1 (en) | 2002-06-05 | 2004-04-01 | Chaturvedula Prasad V. | Calcitonin gene related peptide receptor antagonists |
DE60305919T2 (de) | 2002-06-28 | 2007-01-18 | Domantis Limited, Cambridge | Dual-specifische liganden mit erhöhter halbwertszeit |
CN1674919A (zh) | 2002-08-12 | 2005-09-28 | 比克尔·斯韦恩森 | Cgrp拮抗剂化合物在治疗牛皮癣中的应用 |
DE10250082A1 (de) | 2002-10-25 | 2004-05-13 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
WO2004050683A2 (en) | 2002-12-02 | 2004-06-17 | Abgenix, Inc. | Antibodies directed to tumor necrosis factor and uses thereof |
US7569364B2 (en) | 2002-12-24 | 2009-08-04 | Pfizer Inc. | Anti-NGF antibodies and methods using same |
AU2004222328B2 (en) | 2003-03-14 | 2009-10-08 | Merck Sharp & Dohme Corp. | Aryl spirohydantoin CGRP receptor antagonists |
US7205293B2 (en) | 2003-03-14 | 2007-04-17 | Merck & Co., Inc. | Benodiazepine spirohydantoin CGRP receptor antagonists |
US7192954B2 (en) | 2003-03-14 | 2007-03-20 | Merck & Co., Inc. | Monocyclic anilide spirohydantoin CGRP receptor antagonists |
AU2004222378B2 (en) | 2003-03-14 | 2008-08-14 | Merck Sharp & Dohme Corp. | Carboxamide spirohydantoin CGRP receptor antagonists |
AU2004222383B2 (en) | 2003-03-14 | 2009-10-01 | Merck Sharp & Dohme Corp. | Bicyclic anilide spirohydantoin CGRP receptor antagonists |
JP4705908B2 (ja) | 2003-04-15 | 2011-06-22 | メルク・シャープ・エンド・ドーム・コーポレイション | Cgrp受容体拮抗薬 |
JO2355B1 (en) | 2003-04-15 | 2006-12-12 | ميرك شارب اند دوم كوربوريشن | Hereditary calcitonin polypeptide receptor antagonists |
WO2004097421A2 (en) | 2003-04-29 | 2004-11-11 | Bayer Healthcare Ag | Diagnostics and therapeutics for diseases associated with calcitonin receptor-like receptor (calcrl) |
CA2532064A1 (en) | 2003-07-15 | 2005-02-03 | Merck & Co., Inc. | Hydroxypyridine cgrp receptor antagonists |
US20080070239A1 (en) | 2003-10-29 | 2008-03-20 | University Of Rochester | Detection of neureopeptides associated with pelvic pain disorders and uses thereof |
DE102004008261B3 (de) | 2004-02-20 | 2005-09-29 | Mtu Friedrichshafen Gmbh | Verfahren zur Steuerung und Regelung einer Brennkraftmaschinen-Generator-Einheit |
EP1722792A1 (de) | 2004-03-03 | 2006-11-22 | Boehringer Ingelheim International GmbH | Ausgewählte cgrp-antagonisten, verfahren zu deren herstellung sowie deren verwendung als arzneimittel |
DE102004015723A1 (de) | 2004-03-29 | 2005-10-20 | Boehringer Ingelheim Pharma | Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
DE102004018794A1 (de) | 2004-04-15 | 2005-10-27 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
US7279471B2 (en) | 2004-04-15 | 2007-10-09 | Boehringer Ingelheim International Gmbh | Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions |
WO2005102322A1 (de) | 2004-04-20 | 2005-11-03 | Boehringer Ingelheim International Gmbh | Verwendung eines cgrp-antagonisten in kombination mit einem serotonin-wiederaufnahme-hemmer zur behandlung von migräne |
DE102004027912A1 (de) | 2004-06-09 | 2005-12-29 | Grünenthal GmbH | Substituierte Cyclopenten-Verbindungen |
US7384930B2 (en) | 2004-11-03 | 2008-06-10 | Bristol-Myers Squibb Company | Constrained compounds as CGRP-receptor antagonists |
TWI432196B (zh) | 2005-01-18 | 2014-04-01 | Euro Celtique Sa | 內臟痛的治療 |
EP1770091A1 (de) | 2005-09-29 | 2007-04-04 | Boehringer Ingelheim Pharma GmbH & Co. KG | CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
CA2619856A1 (en) * | 2005-08-25 | 2007-03-01 | Wex Pharmaceuticals Inc. | Use of sodium channel blockers for the treatment of visceral pain or pain caused by cancer treatment |
JP2009506076A (ja) | 2005-08-26 | 2009-02-12 | ザ・ボード・オブ・トラスティーズ・オブ・ザ・レランド・スタンフォード・ジュニア・ユニバーシティ | 三叉神経疼痛のための薬物送達のための治療手順 |
EP1933714B1 (en) | 2005-09-21 | 2020-03-18 | The Regents of The University of California | Systems and compositions for local imaging and treatment of pain |
US8168592B2 (en) | 2005-10-21 | 2012-05-01 | Amgen Inc. | CGRP peptide antagonists and conjugates |
US20070108378A1 (en) | 2005-11-14 | 2007-05-17 | Toru Terabayashi | High pressure optical cell for a downhole optical fluid analyzer |
US8071770B2 (en) | 2005-11-18 | 2011-12-06 | Merck Sharp & Dohme Corp. | Spirohydantoin aryl CGRP receptor antagonists |
WO2007076336A1 (en) | 2005-12-22 | 2007-07-05 | Eli Lilly And Company | Treatment of migraine with anti-cgrp antibodies |
US7834000B2 (en) | 2006-06-13 | 2010-11-16 | Vertex Pharmaceuticals Incorporated | CGRP receptor antagonists |
JP5511379B2 (ja) | 2006-07-21 | 2014-06-04 | バーテックス ファーマシューティカルズ インコーポレイテッド | Cgrpレセプターアンタゴニスト |
US8945505B2 (en) | 2007-02-02 | 2015-02-03 | Panaphix, Inc. | Use of arsenic compounds for treatment of pain and inflammation |
CN101903035A (zh) | 2007-10-23 | 2010-12-01 | 阿勒根公司 | 使用经修饰的梭菌毒素治疗慢性神经源性炎症的方法 |
JP5537441B2 (ja) | 2008-03-04 | 2014-07-02 | ファイザー・リミテッド | 慢性疼痛を治療する方法 |
RU2467765C2 (ru) | 2008-03-04 | 2012-11-27 | Пфайзер Лимитед | Способы лечения воспалительной боли |
WO2010006168A2 (en) | 2008-07-09 | 2010-01-14 | University Of Rochester | Methods of treating cancer using and agent that modulates activity of the calcitonin-gene related peptide ("cgrp") receptor |
JO3382B1 (ar) | 2008-12-23 | 2019-03-13 | Amgen Inc | أجسام مضادة ترتبط مع مستقبل cgrp بشري |
MX2012002464A (es) | 2009-08-28 | 2012-03-14 | Rinat Neuroscience Corp | El uso de anticuerpos antagonistas dirigidos contra el peptido relacionado con el gen de la calcitonina para tratar dolor visceral. |
JO3330B1 (ar) | 2010-06-10 | 2019-03-13 | Lilly Co Eli | الأجسام المضادة cgrp |
US8669368B2 (en) | 2010-10-12 | 2014-03-11 | Bristol-Myers Squibb Company | Process for the preparation of cycloheptapyridine CGRP receptor antagonists |
-
2010
- 2010-08-23 MX MX2012002464A patent/MX2012002464A/es active IP Right Grant
- 2010-08-23 US US13/392,860 patent/US8623366B2/en active Active
- 2010-08-23 ES ES16202020T patent/ES2912569T3/es active Active
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009515942A (ja) * | 2005-11-14 | 2009-04-16 | ライナット ニューロサイエンス コーポレイション | 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 |
Non-Patent Citations (3)
Title |
---|
EXPERIMENTAL NEUROLOGY, vol. 204, no. 2, JPN6018020040, 2007, pages 667 - 679, ISSN: 0005037430 * |
GUT, vol. 55, no. 7, JPN6016030895, 2006, pages 940 - 945, ISSN: 0005037431 * |
JOURNAL OF UROLOGY, vol. 175, no. 3, JPN6018020042, 2006, pages 1138 - 1142, ISSN: 0005037432 * |
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