JP4584713B2 - 神経成長因子アンタゴニストを投与することによって術後疼痛を処置するための方法および神経成長因子アンタゴニストを含有する組成物 - Google Patents
神経成長因子アンタゴニストを投与することによって術後疼痛を処置するための方法および神経成長因子アンタゴニストを含有する組成物 Download PDFInfo
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Description
本出願は、2002年10月8日に出願された米国仮特許出願第60/417,347号明細書の優先権を主張するものであり、その内容を参照によってその内容全体を本願明細書に援用したものとする。
本発明は、DARPAにより与えられた米国政府の支援の契約番号DAAD19−03−C−0006の下で作成された。米国政府は、本発明のある一定の権利を有する場合がある。
本発明は、術後疼痛を予防、緩和または処置するための神経成長因子(NGF)アンタゴニストの使用に関する。
神経成長因子(NGF)は同定された最初のニューロトロフィンであり、末梢性および中枢ニューロンの両方の発生および生存におけるその役割は十分に特徴付けられている。NGFは、末梢性交感神経性 および胚性感覚ニューロン、および基底前脳コリン作動性ニューロンの発達に不可欠な生存および維持因子であることが示されている(Smeyneら、Nature、368:246−249(1994年);Crowleyら、Cell、76:1001−1011(1994年))。NGFは、感覚ニューロンにおいて神経ペプチドの発現を上方制御し(Lindsayら、Nature 337:362−364(1989))、その活性は2つの異なる膜結合型レセプター、TrkAチロシンキナーゼレセプターおよびp75レセプターにより媒介される。これは腫瘍壊死因子レセプターファミリーの他のメンバーと構造的に関連する(Chaoら、Science、232:518−521(1986))。
本発明は、NGFのアンタゴニストが、術後疼痛の処置に有効であるという発見に基づく。処置は、本明細書中に記載されるような術後疼痛の1つ以上の局面に取り組む。
本発明は、治療有効量のNGFアンタゴニスト(例えば、抗NGFモノクローナル抗体)のインビボ投与を用いて、術後疼痛を予防および/または処置し得るという発見に基づく。術後疼痛は、以前は、高用量のオピオイド麻酔薬を用いて処置されてきた。これらの薬剤は、胃の運動性の減少、鎮静、呼吸抑制および腎疝痛のような望ましくない副作用を生じる。他の疼痛薬(例えば、NSAID)は、この型の疼痛を処置するのに、比較的成功していない。さらに、いくつかのNSAIDは、創傷治癒を阻害することが知られている。
本発明の実施は、他に説明のない限り、当業者の範囲内にある分子生物学(組換え技術を含む)、微生物学、細胞生物学、生化学、および免疫学に関する従来技術を使用するものとする。このような技術は、Molecular Cloning: A Laboratory Manual、第2版(Sambrookら、1989年)、Cold Spring Harbor Press、Oligonucleotide Synthesis(M.J.Gait編、1984年)Methods in Molecular Biology、Humana Press、Cell Biology:A Laboratory Notebook(J.E.Cellis編、1998年)Academic Press、Animal Cell Culture;(R.I.Freshney編、1987年)、Introduction to Cell and Tissue Culture(J.P.Mather、およびP.E.Roberts、1998年)Plenum Press、Cell and Tissue Culture: Laboratory Procedures (A.Doyle、J.B.Griffiths、およびD.G.Newell編集、1993−8年)J.Wiley&Sons、Methods in Enzymology(Academic Press社)、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年)、Current Protocols in Molecular Biology(F.M.Ausubelら、編、1987年)、PCR:The Polymerase Chain Reaction(Mullisら編、1994年)、Current Protocols in Immunology(J.E.Coliganら編、1991年)、Short Protocols in Molecular Biology(Wiley&Sons、1999年)、Immunobiology(C.A.Janeway、およびP.Travers、1997年)、Antibodies(P.Finch、1997年)、Antibodies:a practical approach(D.Catty編、IRLPress、1988−1989年)、Monoclonal antibodies:a practical approach(P.Shepherd、およびC.Dean編、Oxford University Press、2000年)、Using antibodies:a laboratory manual (E.HarlowおよびD.Lane(Cold Spring Harbor Laboratory、1999年)、The Antibodies(M.Zanetti、およびJ.D.Capra編、Harwood Academic Publishers、1995年)などの文献で詳細に説明されている。
「抗体」(複数形での使用と交換可能)は、免疫グロブリン分子の可変領域に位置した少なくとも1つの抗原認識部位を介して、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可能な免疫グロブリン分子である。本明細書で使用されるこの用語は、完全な多クローン性またはモノクローナル抗体のみではなく、そのフラグメント(Fab,Fab’,F(ab’)2,Fvなど)、単鎖(ScFv)、その変異体、抗体部分を有する融合蛋白質、ヒト化抗体、キメラ抗体、ディアボディdiabodies直鎖状抗体、単鎖抗体、多重特異性抗体(例えば二重特異性抗体)、および必要な特異性の抗原認識部位を有する免疫グロブリン分子の他の任意の改質された構造も含まれる。抗体には、IgG、IgA、あるいはIgM(あるいはそのサブクラス)などの任意のクラスの抗体が含まれるが、抗体は任意の特別のクラスである必要はない。その重鎖の定常ドメインの抗体アミノ酸配列に依存して、免疫グロブリンを種々のクラスに割り当てることができる。5つの主要なクラスの免疫グロブリンが存在し:IgA、IgD、IgE、IgG、および1gM、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、IgA2に分類される。異なるクラスの免疫グロブリンに相当する重鎖定常ドメインは、それぞれα、δ、ε、γおよびμ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構造は公知である。
本明細書中に記載された全ての方法に関して、NGFアンタゴニストに対する言及がまた、これらの薬剤の1つ以上を含む組成物を含む。これらの組成物はさらに、当該分野で周知の、緩衝液を含む薬学的に受容可能な賦形剤(キャリア)のような、適切な賦形剤を含み得る。本発明は単独で、あるいは他の従来の処置方法と組み合せて使用され得る。
本発明は、全ての哺乳動物(ヒトおよび非ヒトの両方)を含む個体における術後疼痛の発生を処置、遅延、および/または、術後疼痛を予防するために有用である。さらに、本発明は、切開、穿刺または引き裂きのいずれかで、内側または外側のいずれかで、組織に切開創傷を有する個体において有用である。このような切開創傷は、外傷創傷と同様に偶然生じ得るか、または手術と同様に故意に生じ得る。
本発明の方法ではNGFアンタゴニストを使用するが、これはレセプター結合および/またはNGFに対する細胞反応の誘発などのNGFシグナル伝達により媒介された下流経路を含むNGF生物活性をブロックし、抑制し、または減少させる(有意にを含む)任意の分子を指す。用語「アンタゴニスト」は、生物学的作用の特定の機序をまったく意味しておらず、NGFによる全ての可能性のある薬理学的、生理的、および生化学的相互作用、ならびに多様な種々の、化学的に多岐にわたる組成物により達成することができるその結果を明らかに含むと考えられる。代表的なNGFアンタゴニストは、抗NGF抗体、NGFに向けたアンチセンス分子(NGFをコードする核酸に向けたアンチセンス分子を含む)、NGFレセプター(TrkAレセプターおよび/またはp75レセプターなど)に向けたアンチセンス分子、(TrkAおよび/またはp75を符号化する核酸に向けたアンチセンス分子を含む)、NGF阻害化合物、NGF構造アナログ、NGFと結合するTrkAレセプターのドミナントネガティブ突然変異体、TrkA免疫付着因子、抗−TrkA抗体、抗−p75抗体、およびリン酸化酵素阻害薬などがあるが、これに限定されない。本発明の目的において、用語「アンタゴニスト」は、全ての事前に特定された用語、表題、およびNGF自体、NGF生物活性(術後疼痛の任意の局面を仲介する能力を含むが、これに限定されない)、または生物活性の結果による機能的状態および特性は、任意の意味のある程度に実質的に無効にされ、減少され、中和されていることを含むことが明示的に理解される。いくつかの実施形態において、NGFアンタゴニスト(例えば、抗体)は、NGFと結合し(物理的に相互作用し)、NGFレセプター(TrkAレセプターおよび/またはp75レセプターなどの)に結合し、下流のNGFレセプターシグナル伝達を減少させる(妨害および/またはブロックさせる)。したがって、いくつかの実施形態では、NGFアンタゴニストはNGFと結合する(物理的に相互作用する)。他の実施形態において、NGFアンタゴニストは、NGFレセプター(trkAレセプターあるいはp75など)に結合する。他の実施形態では、NGFアンタゴニストは下流のNGFレセプターシグナル伝達を減少させる(妨害および/またはブロックする)(例えば、リン酸化酵素シグナル伝達インヒビター)。他の実施形態では、NGFアンタゴニストはNGF合成および/または遊離を阻害する(減少させる)。別の実施形態では、NGFアンタゴニストはTrkA免疫付着因子でないNGF抗体である(すなわち、TrkA免疫付着因子以外である)。別の実施形態では、NGFアンタゴニストは抗NGF抗体以外である。他の実施形態において、NGFアンタゴニストは、TrkA免疫付着因子でも、抗NGF抗体でもない。いくつかの実施形態において、NGFアンタゴニストはNGF(hNGFなど)と結合し、NT−3、NT4/5、および/またはBDNFなどの関連したニューロトロフィンには有意に結合しない。いくつかの実施形態において、NGFアンタゴニストは、有害な免疫応答を伴わない。他の実施形態では、NGFアンタゴニストは抗NGF抗体である。さらに他の実施形態において、抗NGF抗体はヒト化されている(本明細書に記載された抗体E3など)。いくつかの実施形態において、抗NGF抗体は(本明細書で述べたように)抗体E3である。他の実施形態において、抗NGF抗体は、抗体E3の1つ以上のCDR(いくつかの実施形態において、E3由来の1つ、2つ、3つ、4つ、5つ、あるいは全ての6つのCDRなど)を含む。他の実施形態では、抗体はヒトである。さらに他の実施形態では、抗NGF抗体は、表1(配列番号:1)に示す重鎖可変領域のアミノ酸配列、および表2(配列番号:2)に示す軽鎖可変領域のアミノ酸配列を含む。さらに他の実施形態において、抗体は、免疫学的に不活性な、例えば、補体媒介性溶解を引き起こさない、あるいは抗体依存性細胞媒介性細胞障害性(ADCC)を刺激しない定常領域などの改質された定常領域を備える。他の実施形態において、Eur.J.Immunol.(1999年)29:2613−2624、PCT出願番号PCT/GB99/01441号明細書、および/または英国特許出願第9809951.8号明細書で記載されるように定常領域は改質される。
本発明のいくつかの実施形態において、NGFアンタゴニストは抗NGF抗体を含む。抗NGF抗体は、(a)NGFへの結合、(b)NGF生物活性、あるいはNGFシグナル伝達作用により媒介された下流経路を阻害する、(c)術後疼痛の任意の局面が処置、改善または予防されること、(d)NGFレセプター活性化(TrkAレセプター二量体化および/または自己リン酸化を含む)をブロックあるいは減少させること、(e)NGFクリアランスの増加、(f)NGF合成、産生、または遊離を阻害する(減少させる)、(g)手術、創傷または外傷からの回復を増強する特性のうち任意の1つ以上の特性を示す必要がある。
QVQLQESGPGLVKPSETLSLTCTVSGFSLIGYDLNWIRQPPGKGLEWIGIIWGDGTTDYNSAVKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCARGGYWYATSYYFDYWGQGTLVTVS(配列番号:1)。
DIQMTQSPSSLSASVGDRVTITCRASQSISNNLNWYQQKPGKAPKLLIYYTSRFHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQEHTLPYTFGQGTKLEIKRT(配列番号:2)。
抗NGF抗体以外のNGFアンタゴニストを使用してもよい。本発明のいくつかの実施形態において、NGFアンタゴニストは、機能的NGFの発現をブロッキングまたは減少させることが可能な少なくとも1つのアンチセンス分子を含む。NGFのヌクレオチド配列は公知であり、公的に利用できるデータベースから容易に入手可能である。例えば、Borsaniら、Nuc.Acids Res.1990年,18,4020、登録番号NM002506、Ullrichら、Nature 303:821−825(1983年)参照。他のポリヌクレオチドと交差反応せずに特異的にNGFmRNAと結合すると予想されるアンチセンスオリゴヌクレオチド分子を調製することが一般的である。ターゲティングの代表的な部位は、開始コドン、5’制御領域、コード配列、および3’未翻訳領域などがあるがこれらに限定されない。いくつかの実施形態において、オリゴヌクレオチドは、長さ約10〜100ヌクレオチド、長さ約15〜50ヌクレオチド、長さ約18〜25ヌクレオチドあるいはそれ以上である。例えば当該分野において公知のホスホロチオネート結合および2’−O糖改質などのバックボーン改質を含むことができる。代表的なアンチセンス分子は、米国特許出願公開第20010046959号明細書に記載されたNGFアンチセンス分子などがある。http://www.rna−tec.com/repair.htmも参照。
http://www.macalester.edu/〜montgomery/RNAi.html;
http://pub32.ezboard.com/fmorpholinosfrm19.showMessage?topicID=6.topic;
http://www.highveld.com/ribozyme.html
を参照。
VR 1249、ATCC VR−532)、およびアデノ随伴ウイルス(AAV)ベクター(例えば、PCT特許出願公開第94/12649号パンフレット、国際公開第93/03769号パンフレット、国際公開第93/19191号パンフレット、国際公開第94/28938号パンフレット、国際公開第95/11984号パンフレット、および国際公開第95/00655号パンフレット参照)などがあるが、これらに限定されない。Curiel,Hum.Gene Ther.(1992)3:147で述べたように、不活化アデノウイルスに結合したDNAの投与も使用することができる。
抗NGF抗体および他のNGFアンタゴニストは、当該分野において公知の方法を使用して、同定しまたは特徴付けることができ、これによりNGF生物活性の減少、改善、あるいは中和が検出、および/または測定される。例えば、米国特許第5,766,863号明細書および同第5,891,650号明細書に記載されたリン酸化酵素レセプター活性化(KIRA)分析を使用して、NGFアンタゴニストを同定することができる。このELISA型分析は、レセプタープロテインチロシンキナーゼ(以後「rPTK」)(例えば、TrkAレセプター)のリン酸化酵素ドメインの自己リン酸化の測定により、リン酸化酵素活性化の定性的あるいは定量的測定、ならびに選択されたrPTK、例えばTrkAの潜在的アンタゴニストの同定および特徴付けに適している。この分析の第1ステージは、リン酸化酵素レセプター、例えばTrkAレセプターのリン酸化酵素ドメインのリン酸化を含み、このレセプターは、真核細胞の細胞膜の中に存在する。レセプターは内因性レセプターあるいはレセプターをコードする核酸、すなわち細胞内で形質転換されるレセプター構築物でもよい。代表的に、第1の固相(例えば、最初のアッセイプレートのウェル)は、細胞が固相に付着する細胞(通常、哺乳動物細胞株)の本質的に均質な集団で被覆される。多くの場合、この細胞は粘着性で、このため自然に第1の固相に接着する。「レセプター構築物」が使用される場合、これは、通常リン酸化酵素レセプターおよびflagポリペプチドの融合を含む。分析のELISA部分において、flagポリペプチドは、捕捉薬、時に捕捉抗体により認識される。続いて、抗NGF抗体候補、あるいは他のNGFアンタゴニストなどの分析物は、チロシンキナーゼレセプター(例えば、TrkAレセプター)が、NGFおよび分析物に曝露される(あるいは接触する)ように、接着細胞を含むウェルにNGFと一緒に加えられる。この分析により、そのリガンドNGFによるTrkAの活性化を阻害する抗体(あるいは他のNGFアンタゴニスト)の同定が可能となる。NGFおよび分析物への曝露に続いて、溶解緩衝液(可溶化する界面活性剤を含有する)および穏やかな攪拌を使用してこの接着細胞が可溶化され、これにより細胞可溶化物の濃縮または清澄化の必要なしに、分析のELISA部分に直接供することができる細胞可溶化物が遊離される。
本発明の方法において使用される組成物は、NGFアンタゴニスト(例えば、抗NGF抗体)の有効量を含み、いくつかの実施形態においては、さらに、薬学的に受容可能な賦形剤を含む。いくつかの実施形態において、この組成物は、本明細書中に記載される方法のいずれかにおいて使用するためのものである。このような組成物の例、ならびに、その処方方法はまた、これより前の節および以下に記載される。1つの実施形態において、組成物は、1種のNGFアンタゴニストを含む。別の実施形態において、組成物は、1種以上のNGFアンタゴニストを含む。別の実施形態において、組成物は、以下のいずれかの1種以上から選択される1種以上のNGFアンタゴニストを含む:NGFと結合する(物理的に相互作用する)アンタゴニスト(例えば、抗体)、NGFレセプター(例えば、TrkAおよび/またはp75レセプター)に結合するアンタゴニスト、ならびに、下流NGFレセプターシグナル伝達を減少する(妨害および/または遮断する)アンタゴニスト。なお別の実施形態において、組成物は、TrkA免疫付着因子ではない(すなわち、TrkA免疫付着因子以外のものである)任意のNGFアンタゴニストを含む。他の実施形態において、組成物は、抗NGF抗体以外のものである、任意のNGFアンタゴニストを含む。なお他の実施形態において、組成物は、TrkA免疫付着因子および抗NGF抗体以外の任意のNGFアンタゴニストを含む。他の実施形態において、NGFアンタゴニストは、NGFの合成、生成または放出を阻害(減少)する。いくつかの実施形態において、NGFアンタゴニストは、NGFに結合し、そして、関連するニューロトロフィン(例えば、NT3、NT4/5および/またはBDNF)に有意に交差反応しない。いくつかの実施形態において、NGFアンタゴニストは、有害な免疫応答を伴わない。いくつかの実施形態において、NGFアンタゴニストは、抗NGF抗体、NGFに対するアンチセンス分子(NGFをコードする核酸に対するアンチセンス分子を含む)、NGFレセプターに対するアンチセンス分子(例えば、TrkAおよび/またはp75)、NGF阻害化合物、NGF構造アナログ、NGFに結合するTrkAレセプターのドミナントネガティブ変異体、TrkA免疫付着因子、抗TrkA抗体、抗p75抗体およびキナーゼインヒビターからなる群から選択される。別の実施形態において、NGFアンタゴニストは、抗NGF抗体である。他の実施形態において、抗NGF抗体は、ヒトNGFを認識する。いくつかの実施形態において、抗NGF抗体はヒト抗体である。なお他の実施形態において、抗NGF抗体は、ヒト化抗体(例えば、本明細書中に記載される抗体E3)である。なお他の実施形態において、抗NGF抗体は、望ましくないか、または所望でない免疫応答(例えば、抗体媒介性溶解またはADCC)を引き起こさない定常領域を含む。他の実施形態において、抗NGF抗体は、抗体E3の1つ以上のCDR(例えば、1、2、3、4、5、または、いくつかの実施形態においては、E3由来の6つ全てのCDR)を含む。
本発明は、簡易法において使用されるキットも提供する。本発明のキットは、NGFアンタゴニスト(本明細書に記載されたヒト化抗体E3などの抗体など)を含む1つ以上の容器を含み、またいくつかの実施形態において、本明細書に記載された方法のうちの任意の方法に従った使用説明書をさらに備える。いくつかの実施形態において、NGFアンタゴニストは、本明細書中に記載される任意のNGFアンタゴニストである。なお他の実施形態において、キットは、TrkA免疫付着因子ではない(すなわち、TrkA免疫付着因子以外の)NGFアンタゴニストを含む。他の実施形態において、キットは、抗NGF抗体以外のNGFアンタゴニストを含む。なお他の実施形態において、キットは、TrkA免疫付着因子でも抗NGF抗体でもない任意のNGFアンタゴニストを含む。いくつかの実施形態において、キットは抗NGF抗体(本明細書に記載された抗体E3などの)を有する。他の実施形態では、キットは、抗体E3(いくつかの実施形態において、E3由来の1つ、2つ、3つ、4つ、5つ、あるいは全ての6つのCDRなど)の1つ以上のCDRを含む抗NGF抗体を有する。いくつかの実施形態において、説明書は、本明細書中に記載される方法のいずれかにしたがって、術後疼痛を処置、緩和、または予防するためのNGFアンタゴニストの投与の説明を含む。このキットは、その個体が術後疼痛を有するかどうか、またはその個体が術後疼痛のリスクを有するかどうかを同定することに基づいた処置に適した個体の選択に関する記載をさらに備える。なお他の実施形態において、説明書は、術後疼痛を処置し、予防し、および/または緩和するために、NGFアンタゴニストを投与する説明書を含む。なお他の実施形態において、説明書は、術後疼痛の危険のある個体にNGFアンタゴニストを投与する説明書を含む。
NGFアンタゴニストは、任意の適切な経路を介して個体に投与することができる。例えば、NGFアンタゴニストは共にまたは別々に、経口的に、静脈内に、舌下に、皮下に、動脈内に、滑液包内に、膀胱内に(例えば、膀胱を介して)、直腸に、筋肉内に、胸郭内に、脊髄内に、腹腔内に、脳室内に、舌下に、吸入により、座剤により、および経皮的に投与することができる。それらは、当業者により認知された手順により調製された錠剤、トローチ、カプセル、エリキシル剤、懸濁剤、シロップ剤、オブラート、ロリオポップス(lollyopops)、またはチューインガムなどの形態で経口的に投与することができる。本明細書に記載された実施例は、制限のためではなく利用可能な技術の例示のためであることは当該分野において明白であろう。
本発明者らは、抗NGF抗体911(マウスモノクローナル抗体、Hongoら、Hybridoma 19:215−227(2000)を参照のこと)を用いる処置の有効性を評価するために、術後疼痛を模倣する疼痛モデルを使用した。各実験には、16匹の動物(群あたりn=8)を含んだ。抗NGF抗体を、実験あたり、種々の濃度(35mg/kgまたは7mg/kg)で、切開の15時間前に、腹腔内(i.p.)注射した。対照群には、抗体は与えなかったが、生理緩衝溶液をi.p.注射した。
術後疼痛に対するE3と名付けられたヒト化抗NGF抗体の効果を、実施例1に記載されるような、術後疼痛の動物モデルにおいて試験した。E3抗体は、ヒト重鎖IgG2α定常領域(A330P331からS330S331(野生型のIgG2α配列に関するアミノ酸番号付け;Eur.J.Immunol.(1999)29:2613−2624を参照のこと)の変異を含む);ヒト軽鎖κ定常領域;ならびに、表1および2に示される重鎖および軽鎖の可変領域を含む。
切開後に投与された場合の術後疼痛の減少における抗NGF抗体の有効性を、Harlan(Wisconsin)から購入した雄性のSprague Dawleyラットを使用して、実施例1に記載した術後疼痛動物モデルにおいて試験した。ヒト化抗NGF抗体E3(0.5mg/kg)を、切開後2時間で、静脈内(i.v.)注射した。対照群には、抗体は与えなかったが、生理食塩溶液をi.v.注射した。手術を行い、実施例1に記載したように、術後24時間後に、累積性の疼痛スコアとして表現した安静時疼痛を評価した。図5に示されるように、抗NGF抗体による処置は、抗体が、術後2時間で投与される場合、切開後24時間において、安静時疼痛を有意に(p<0.05)減少した。これらの結果は、抗NGFが、術後に投与される場合に、術後疼痛を効果的に緩和したことを示した。
過剰のNGFを用いる処置が、糖尿病の動物(Matsudaら(1998)J Exp Med 187(3):297−30)、ならびに角膜潰瘍および皮膚(Lambiaseら(2003)Arch Ital Biol.141(2−3):141−8)において創傷治癒を促進し得ることが、科学文献において示唆されている。抗NGF抗体の使用が創傷治癒を妨害するか否かを決定するために、抗NGF抗体処置の創傷治癒に対する効果を、ラットにおいて試験した。
術後疼痛の処置における、NGFアンタゴニストK252aの有効性を、実施例1で記述された切開モデルでテストした。K252aの25mg/mlの溶液をDMSO中で作製した。この溶液の250μlに、45%のシクロデキストリンの溶液3500μlを加え、そして十分に混ぜた。次いで、生理食塩水3750μlを0.8333mg/mlのK252aの最終濃度まで加えた。実施例1に記載されるように、切開を受けた動物(実施例2において記載されるように得た)と安静時疼痛を評価した。「ベースライン」の累積的な安静時疼痛は、切開後の24時間に決定した。次いで、K252aを試験動物に4mg/kgでi.p.注射し、対照動物に、ビヒクル溶液(K252a溶液のK252a以外の全ての成分を含む溶液)を注射した。累積低な安静時疼痛のスコアを、この処置に盲目的な実験者によってK252a処置またはビヒクル処置の1時間後(図中で「1H−P−tmt」と記す)およびK252処置またはビヒクル処置の3時間後(図中で「3H−P−Tmt」と記す)を決定した。図9に示されるように、K252aによる処置は、投薬後3時間において安静時疼痛を有意に減少した(p<0.005)が、ビヒクルでの処置は、減少しなかった。これらの結果は、K252a処置が、同じ実験での抗NGF抗体を用いる処置と同じ程度、安静時疼痛を減少させたことを証明した。
NGFの阻害に必要とされる抗NGF抗体の鎮痛効果を示すために、術後疼痛の処置における抗NGFマウス抗体911の効果を、ショウジョウバエの健忘症(amnesiac)タンパク質と免疫反応性である、同じ用量のアイソタイプ適合性の対照マウス抗体のの効果と比較した。Sprague DawleyラットをHarlan(Wisconsin)から購入したこと以外は、実施例1のように実験を行った。ラットを、手術の15時間に、1mg/kgの抗NGF抗体911(図中で「911」と記す)または1mg/kgのアイソタイプ適合性の抗健忘症抗体(図中で「amn ab」と記す)のいずれかのを用いてIP処置した。術後24時間において、安静時疼痛(累積的な疼痛スコア)を、動物の処置に盲目的な観察者によって評価した。図10に示すように、抗NGF抗体911での処置は、健忘症抗体で処置した動物と比較して、有意に安静時疼痛を減少した(p<0.005)。これらの結果は、抗NGF抗体での処置の鎮痛効果が特異的であることを示した。
Claims (5)
- 個体における術後疼痛を処置するための組成物であって、該組成物は、有効量の神経成長因子(NGF)アンタゴニストを含有し、ここで、該NGFアンタゴニストが、重鎖可変領域が配列番号1に示される配列を含み軽鎖可変領域が配列番号2に示される配列を含む抗NGF抗体である、組成物。
- 安静時疼痛が抑制または緩和される、請求項1に記載の組成物。
- 機械的に誘発された疼痛が抑制または緩和される、請求項1に記載の組成物。
- 術後疼痛を処置するための薬学的組成物であって、該薬学的組成物は、薬学的有効量のNGFアンタゴニストおよび薬学的に受容可能なキャリアを含み、ここで該NGFアンタゴニストが、重鎖可変領域が配列番号1に示される配列を含み軽鎖可変領域が配列番号2に示される配列を含む抗NGF抗体である、薬学的組成物。
- NGFアンタゴニストと、該NGFアンタゴニストを用いて術後疼痛を処置するための説明書とを含む、術後疼痛を治療するためのキットであって、ここで、該NGFアンタゴニストが、重鎖可変領域が配列番号1に示される配列を含み軽鎖可変領域が配列番号2に示される配列を含む抗NGF抗体である、キット。
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