JP6126652B2 - Il−4および/またはil−13に結合する抗体およびそれらの使用 - Google Patents
Il−4および/またはil−13に結合する抗体およびそれらの使用 Download PDFInfo
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Description
。この受容体は、考えられる細胞型に従って変動し得る数で種々の細胞型の表面に存在する。IL−13およびIL−4受容体の比較分布は、A.J.Minty(非特許文献18)によって示されている。
13に結合する。IL−4および/またはIL−13に結合する受容体および受容体複合体の主成分は、IL−4Rα、IL−13RαlおよびIL−13Rα2である。これらの鎖は、単量体またはIL− 4Rα/IL−13Rαl(II型 IL−4R)またはIL−4Rα/c(I型 IL−4R)のヘテロ二量体として細胞の表面上に発現される。IL−4Rα単量体およびIL−4R/cヘテロ二量体はIL−4に結合するが、IL−13には結合しない。IL−13Rα1およびIL−13Rα2単量体はIL−13に結合するが、IL−4には結合しない。IL−4Rα/IL−13Rα1ヘテロ二量体はIL−4およびIL−13の両方に結合する(非特許文献19)。
本発明は、IL−4および/またはIL−13に特異的に結合する、新規なヒト化モノクローナル抗体および二重特異性抗体、ならびにそれらのフラグメントおよび誘導体を提供する。抗−IL−4および/またはIL−13の単一特異性または二重特異性抗体、およびそれらのフラグメントのいくつかは、インビボでの製造および使用の間、安定な分子をもたらす鎖内のジスルフィド結合形成を防ぐように改変され得る。本発明の抗体は、本明細書中に記載される生物学的アッセイにおいて、IL−4および/またはIL−13活性を中和させる。
本発明は、本発明の精神および範囲から逸脱することなく変更され得るので、本明細書中に記載される特定の方法論、プロトコル、細胞株、ベクター、または試薬に限定されない。さらに、本明細書中で使用される専門用語は、特定の実施形態を例示する目的のためだけであり、本発明の範囲を限定することを意図しない。他に定義されない限り、全ての技術用語および科学用語ならびに本明細書中で使用される任意の頭字語は、本発明の分野の当業者により一般に理解されるのと同じ意味を有する。本明細書中に記載されるものと類似または同等の任意の方法および材料が本発明の実施において使用され得、典型的な方法、デバイス、および材料のみが本明細書中に記載される。
13タンパク質および天然もしくは対応する内因性哺乳動物IL−13タンパク質と同じアミノ酸配列を有するタンパク質(例えば、組換えタンパク質、合成タンパク質(すなわち、有機合成化学の方法を使用して生産される))をいう。従って、本明細書中で定義される場合、用語は、成熟IL−13タンパク質、多型変異体もしくは対立遺伝子多型、およびIL−13の他のアイソフォーム(例えば、選択的スプライシングまたは他の細胞過程により生産される)、ならびに前述の修飾もしくは未修飾形態(例えば、脂質化(Hpidated)、グリコシル化)を含む。天然または内因性IL−13は、成熟IL−13のような野生型タンパク質、哺乳動物(例えば、ヒト、非ヒト霊長類)中に天然に存在する多型変異体もしくは対立遺伝子多型ならびに他のアイソフォームおよび突然変異型を含む。例えば、本明細書中で使用される場合、IL−13は成熟ヒトIL−13の位置110のArgが喘息(アトピー性および非アトピー性喘息)に関連するGinで置き換えられているヒトIL−13変異体(成熟IL−13の位置110は前躯体タンパク質の位置130に対応する)および他のIL−13の変異体を含む。(Heinzmann el al,Hum MoI Genet.9:549−559(2000))。このようなタンパク質は、例えば、IL−13を自然に生産する供給源から回収または単離され得る。これらのタンパク質および天然または対応する内因性IL−13と同じアミノ酸配列を有するタンパク質は、対応する哺乳動物の名称で呼ばれる。例えば、対応する哺乳動物がヒトである場合、タンパク質はヒトIL−13と呼ばれる。WO03/035847に開示されるもののようないくつかの突然変異IL−13タンパク質が、当該分野で公知である。
に連結していることを意味する。「欠失」変異体は、天然アミノ酸配列の1つまたはそれ以上のアミノ酸が除去されているものである。通常、欠失変異体は、分子の特定領域において1つまたは2つのアミノ酸が欠失している。
IgG2、IgG2a、IgG3、IgG4、IgA1、IgA2など)(「タイプ」および「
クラス」、ならびに「サブタイプ」および「サブクラス」は、本明細書中で交互に用いられる)のものであり得る。天然または野生型(すなわち、人工的に操作されていない集団のメンバーから得られる)の抗体および免疫グロブリンは、通常、約150,000ダルトンのヘテロ四量体糖タンパク質であり、2つの同一軽(L)鎖および2つの同一重(H)鎖からなる。各重鎖は一方の末端に多数の定常領域が続く可変領域(VH)を有する。
各軽鎖は一方の末端に可変領域(VL)、そして他方の末端に定常領域を有する。「人工
的に操作されていない」とは、異質の抗原結合分子を含むか、または発現するように処理されていないことを意味する。野生型とは、集団において見られる最も一般的な対立遺伝子もしくは種、または対立遺伝子もしくは多型体、または抗原結合分子のアミノ酸を変化させるための突然変異生成のような操作の形態、組換え方法の使用などにより得られる変異体もしくは誘導体と比較して、操作されていない動物から得られる抗体をいうことができる。
位の形成に寄与する(Kabat et al.Sequences of Proteins of Immunological Interest,National Institute of Health,Bethesda,MD(1987)を参照のこと)。本明細書中で使用される場合、免疫グロブリンアミノ酸残基の番号付けは、他に示されない限りKabat et al.の免疫グロブリンアミノ酸残基番号付けシステムに従って行なわれる。1つのCDRは、同種エピトープに特異的に結合する能力を有し得る。
Fv」フラグメントは、非共有結合(VH−VL二量体)中の1つの重鎖可変領域と1つの
軽鎖可変領域の二量体からなる。この立体配置において、インタクトな抗体においてみられるように、各可変領域の3つのCDRがVH−VL二量体の表面上の標的結合部位を定義するために相互作用する。集合的に、6つのCDRが、インタクトな抗体に標的結合特異性を与える。しかし、単一の可変領域(または標的に特異的な3つのCDRのみを含むFvの半分)でさえ、標的を認識し、そして結合する能力を有し得る。
びVL領域を含み、これらの領域は、単一のポリペプチド鎖中に存在する。一般的に、Fvポリペプチドは、さらにVH領域とVL領域との間に、sFvが標的結合のための所望の構造を形成し得るポリペプチドリンカー、多くの場合、柔軟性分子を含む。
)に連結した重鎖可変領域(VH)を含み得る。同一鎖上にある2つの可変領域間で対合
するには短過ぎるリンカーを用いることにより、ディアボディー領域は、別の鎖の結合領域と強制的に対合させられ、2つの抗原結合部位を生成する。
ンジ領域由来の1つまたはそれ以上のシステインを含むようにいくつかの残基が付加されている点でFabフラグメントと異なる。Fab'フラグメントは、F(ab')2ペプシン消化産
物のヒンジシステインでのジスルフィド結合の切断により生産され得る。抗体のさらなる酵素処理および化学的処理により、目的の他の機能的フラグメントを得ることができる。
性である。
al.(1994)J.Biol.Chem.269:199−206)。BsAbは、ロイシンジッパーのような二量化官能性を介する2つのscFvを遺伝学的に融合することによって構築される(Kostelny et al.(1992)J.Immunol.148:1547−53;de Kruif et al.(1996)J.Biol.Chem.271:7630−4)。
tl.Acad.Sci.USA.90:6444−6448)。ディアボディーは、Fabフラグメントと同じくらいの大きさである。3〜12のアミノ酸のリンカーと結合したVH領域およびVL領域のポリペプチド鎖は、主に二量体(ディアボディー)を形成するが、0〜2アミノ酸残基のリンカーでは三量体(トリアボディー)および四量体(テトラボディー)が支持される。リンカーの長さに加えて、オリゴマー化の正確なパターンは、組成さらにV領域の方向に依存しているようである(Hudson et al.(1999),J Immunol Methods 231:177−189)。ディアボディー分子の最終構造の予測可能性は非常に低い。
head)抗体フラグメントは、2つのポリペプチド鎖をコードする二シストロン性ベクターを発現させることによって得られ、一方のポリペプチド鎖は、ペプチドリンカー(VH1−リンカー−VH2)による連続する二倍のVHを有し、そして他方のポリペプチド鎖はペプチドリンカー(VL1−リンカー−VL2)による連続して連結した相補的VL領域からなる。各リンカーは、少なくとも10のアミノ酸残基を含むべきであると米国特許第5,989,830号に記載されていた。
ブタイプ)に属する抗体における対応する配列と同一かまたは相同であり、鎖の残りが、別の種に由来する抗体、または別の抗体のクラスまたはサブクラスに属する抗体における対応する配列と同一かまたは相同である「キメラ」抗体、さらにIL−4および/またはIL−13に結合するか、またはIL−4および/またはIL−13の活性または代謝に影響を与える所望の生物活性を示す限り、このような抗体のフラグメントを含む(米国特許第4,816,567号;およびMorrison et al.,Proc Natl Acad Sci USA 81:6851(1984))。従って、あるクラスの抗体由来のCDRは、異なるクラスまたはサブクラスの抗体のFRに埋め込まれ得る。
993)、WO2006/042333および米国特許第5,869,619号を参照のこと。
Soc;2000;122(51):12898−12900を参照のとこ)がMDシミュレーションを可能にする。
くとも約98%同一である重鎖および軽鎖可変領域フレームワーク表面露出位置を得る;(2)重鎖および軽鎖可変領域フレームワーク表面露出アミノ酸残基のセットを非ヒト(例えば、齧歯動物)抗体(またはそれらのフラグメント)について定義する;(3)齧歯動物表面露出アミノ酸残基のセットに最も厳密に一致する重鎖および軽鎖可変領域フレームワーク表面露出アミノ酸残基のセットを同定する;そして(4)齧歯動物抗体のCDRのあらゆる残基のあらゆる原子の5Å以内にあるアミノ酸残基を除いて、工程(2)で定義した重鎖および軽鎖可変領域フレームワーク表面露出アミノ酸残基のセットを工程(3)で同定した重鎖および軽鎖可変領域フレームワーク表面露出アミノ酸残基のセットで置換し、結合特異性を保持したヒト化、例えば、齧歯動物抗体を得る。
519 596号;Padlan,1991,Molec Imm 28(4/5):489−498;Studnicka et al.,1994,Prot Eng 7(6):805−814;およびRoguska et al.,1994,PNAS 91:969−973)および鎖シャフリング(chain shuffling)(米国特許第5,565,332号)を含む他の様々な技術により、抗体はヒト化され得る。ヒト抗体は、当該分野で公知の様々な方法によりなされ得、この方法としては、トランスジェニック動物(例えば、齧歯動物)を使用し、キメラ細胞などを使用するファージディスプレイ法が挙げられるが、これらに限定されない、米国特許第4,444,887号、同第4,716,111号、同第5,545,806号および同第5,814,318;ならびにWO98/46645、WO98/50433、WO98/24893、WO98/16654、WO96/34096、WO96/33735およびWO91/10741を参照のこと。
などを含む。ホモログのアミノ酸配列は、天然の抗体のものに対する同一性を必要としないが、改善された特性または他の有益な特性を有するポリペプチドを得るために、置換アミノ酸、挿入アミノ酸、欠失アミノ酸、タンパク質中に通常見出される20以外のアミノ酸などを保有するように改変または修飾され得る。
、Morrison,1985,Science 229:1202;Oi et al.,1986,BioTechniques 4:214;Gillies et al.,1989,J Immunol Methods 125:191−202;ならびに米国特許第5,807,715号、同第4,816,567号および同第4,816,397号を参照のこと。
換)が抗体中に導入され得、それによりIL−4および/またはIL−13に対する抗体突然変異体の結合親和性が改善される。修飾され得るフレームワーク領域残基の例としては、抗原に直接的に非共有結合するもの(Amit et al.Science 233:747−753(1986));CDRの立体配座に相互作用/影響するもの(Chothia et al.J.Mol.Biol.196:901−917(1987));および/またはVL−VH界面に関与するもの(欧州特許第239 400号)が挙げられる。特定の実施形態において、1つまたはそれ以上のこのようなフレームワーク領域残基の修飾により、同種抗原に対する抗体の結合親和性が増大する。本発明の実施形態において、例えば、約1〜約5のフレームワーク残基が改変され得る。時折、超可変領域残基が全く改変されていない場合でさえ、これは前臨床試験に使用するのに適切な抗体突然変異体を得るのに十分であり得る。しかし、通常、抗体突然変異体は、1つまたはそれ以上の超可変領域改変を含み得る。定常領域はまた、所望の、またはより所望のエフェクター特性を得るために改変され得る。
(1)疎水性:メチオニン(Mまたはmet)、アラニン(Aまたはala)、バリン(Vまたはval)、ロイシン(Lまたはleu)およびイソロイソン(Iまたはile);
(2)中性、親水性:システイン(Cまたはcys)、セリン(Sまたはser)、スレオニン(Tまたはthr)、アスパラギン(Nまたはasn)およびグルタミン(Qまたはgln);
(3)酸性:アスパラギン酸(Dまたはasp)およびグルタミン酸(Eまたはglu)(4)塩基性:ヒスチジン(Hまたはhis)、リシン(Kまたはlys)およびアルギニン(Rまたはarg);
(5)鎖の方向に影響を与える残基:グリシン(Gまたはgly)およびプロリン(Pまたはpro)、および
(6)芳香族:トリプトファン(Wまたはtrp)、チロシン(Yまたはtyr)およびフェニルアラニン(Fまたはphe)。
Structure(Branden & Tooze,eds.,Garland Publishing,New York,N.Y.(1991));およびThornton et al.Nature 354:105(1991)。
抗体突然変異体は生成され得る。抗体突然変異体を生成するための別の手順は、ファージディスプレイを使用する親和性成熟の使用を含む(Hawkins et al.,J Mol Biol 254:889−896(1992)およびLowman et al.,Biochemistry 30(45):10832−10838(1991))。バクテリオファージコートタンパク質融合(Smith,Science 228:1315(1985);Scott & Smith,Science 249:386(1990);Cwirla et al.Proc Natl Acad Sci USA 8:309(1990);Devlin et al.Science 249:
404(1990);Wells & Lowman,Curr Opin Struct Biol 2:597(1992);および米国特許第5,223,409号)は、それらをコードするバクテリオファージ粒子の遺伝子型に提示されたタンパク質またはペプチドの表現型を関連付けるのに有用であることが公知である。抗体のFab領域もまた、ファージ上に提示される(McCafferty et al.,Nature 348:552(1990);Barbas et al.Proc Natl Acad Sci USA 88:7978(1991);およびGarrard et al.Biotechnol 9:1373(1991))。
ク質変異体のライブラリーは、各々が特定のタンパク質変異体をコードするDNAを含むバクテリオファージ粒子上で構築され得る。親和性精製のサイクル後、固定化抗原を使用して個々のバクテリオファージクローンを単離し、そして提示されたタンパク質のアミノ酸配列をDNAから推定する。
めに抗体に付加され得る。
、アスパラギン側鎖への炭水化物部分の酵素的結合(enzymatic attachment)のための一般的な認識配列である。例えば、N−アセチルガラクトサミン、ガラクトース、フコース、またはキシロースは、ヒドロキシアミノ酸に結合され、最も一般的にはセリンまたはスレオニンであるが、5−ヒドロキシプロリンまたは5−ヒドロキシリシンもまた使用され得る。元の抗体の配列への1つまたはそれ以上のセリンまたはスレオニン残基の付加または置換は、O結合グリコシル化の可能性を増し得る。
の領域における鎖間ジスルフィド結合形成を可能にし得る。このように生成されたホモ二量体抗体は、内在性機能(internalization capability)が改善され、そして/または補体仲介性細胞死滅および抗体依存性細胞毒性 (ADCC)が向上され得る、Caron etal.,J Exp Med 176:1191−1195(1992)およびShopes,Immunol 148:29182922(1993)を参照のこと。あるいは、二重のFc領域を有する抗体が設計され得、それに
より、補体溶解(complement lysis)およびADCC機能が向上され得る、Stevenson et al.,Anti−Cancer Drug Design 3:219 230(1989)を参照のこと。
& Wriston,CRC Crit Rev Biochem,pp.259−306(1981)に記載される。
ポリマーの1つ、例えば、ポリエチレングリコール、ポリプロピレングリコールまたはポリオキシルアルキレンに連結することを含む。
al.,1995,J Mol Biol 254:392−403;Rader et al.,1998,Proc Natl Acad Sci USA 95:8910−8915;およびVaughan etal.,1998,Nature Biotechnology 16,535−539)。
合体、巨大分子、小分子を含む化合物をいう。リガンドにより活性化される細胞のマイトジェンとして作用することにより、および/または細胞不活性化または受容体へのリガンド結合後のシグナル変換阻害を妨害することにより、アゴニストはリガンドへの受容体の結合と相互作用し得る(逆の場合もまた同じ)。アゴニストによる介入のこのような全ての点が、本発明の目的の等価物とみなされるべきである。
、当業者に周知の方法に従って、そして、例えば以下を参照して、プラスミドまたは他の発現ベクター中でクローニングされ、そしてかなり多数の発現系中で発現され得る。
により制御されたDNAを用いて形質転換される。外来DNAの導入後、操作された細胞は富化培地で1〜2日間増殖され得、次いで選択培地に移される。組換えプラスミド中のの選択可能マーカーにより、選択に耐性が与えられ、そして細胞がプラスミドを染色体に安定して組み込むことを可能にし、そして細胞株に拡大される。このように操作された細胞株は、抗体生産に有用なだけでなく、抗体分子と直接または間接的に相互作用する化合物のスクリーニングおよび評価に有用である。
e 322:52(1986);およびKohler,Proc Natl Acad Sci USA 77:2197(1980))。重鎖および軽鎖のコード配列はcDNAまたはゲノムDNAを含み得る。
−MEM)またはRPMI−1640培地が挙げられる。さらに、ハイブリドーマ細胞は、動物の腹水腫瘍としてインビボで増殖され得る。
Protocols.A Guide to Methods and Applications,Academic(1990),およびSanger et al.,Proc Natl Acad Sci 74:5463(1977))。ハイブリドーマ細胞は、このようなDNAの供給源として役立つ。一旦単離されると、DNAは発現ベクター内に配置され、次いで、これは宿主細胞、例えば、大腸菌細胞、NS0細胞、COS細胞、チャイニーズハムスター卵巣(CHO)細胞または別法で免疫グロブリンタンパク質を生産しない骨髄腫細胞にトランスフェクトされ、組換え宿主細胞においてモノクローナル抗体の合成を得る。例えば、相同なマウス配列の代わりに、ヒト重鎖および軽鎖定常領域のコード配列を置換することにより(米国特許第4,816,567号;およびMorrison et al.,Proc Natl Acad Sci USA 81:6851(1984))、または非免疫グロブリンポリペプチドのコード配列の全てまたは一部を、免疫グロブリンコード配列に共有結合することにより、DNAはまた修飾され得る。このような非免疫グロブリンポリペプチドは、本発明の抗体の定常領域と置換されるか、または本発明の抗体の1つのIL−4またはL−13結合部位の可変ドメインと置換され、キメラ二価抗体を作製し得る。
、関連するシステイン残基が別のアミノ酸残基と置換されるか、または欠失される。
から単離され得る。あるいは、F(ab')2−SHフラグメントが、大腸菌から直接回収され、そして化学的に結合され、F(ab')2フラグメントを形成し得る(Carter et al.,,Bio/Technology 10:163 (1992))。別法に従って、F(ab')2フラグメントは、組換え宿主細胞培養物から直接単離され得る。抗体フラグメントを生産するための他の技術は、当業者に明らかである。他の実施形態において、最適な抗体は、単鎖Fvフラグメント(Fv)である(WO93/16185)。
重鎖を含む分子の結合に影響を与えるヒンジ領域中のアミノ酸を含む。IgG1分子中のこのようなアミノ酸としては、約233〜約237(GluLeu−Leu−Gly−Gly);(配列番号49)、約252〜約256(Met−Ile−Ser−Arg−Thr)(配列番号50)および約318(Glu)〜約331(Pro)(例えば、Lys320、Lys322およびPro329が挙げられる)の残基が挙げられる。
bodies and Cancer Therapy,Alan R.Liss(1985);およびBoerner et al.,JImmunol 147:86(1991))。
、または培地中に直接分泌され得る。抗体変異体が細胞内で生産される場合、第一段階として、宿主細胞または溶解したフラグメントいずれかの微粒子状破片を、例えば、遠心分離または限外ろ過により除去し得る。Carter et al.,Bio/Technology 10:163(1992)は、大腸菌のペリプラズム空間に分泌された抗体を単離する手順を記載する。簡潔に、細胞ペーストを酢酸ナトリウム(pH3.5)およびEDTAに暴露する。細胞片を遠心により除去し得る。抗体変異体が培地中に分泌される場合は、このような発現系由来の上清を、一般に、始めに、市販のタンパク質濃縮フィルター、例えばAmiconまたはMillipore Pellicon限外ろ過装置を使用して濃縮する。タンパク分解を防止するために、PMSFのようなプロテアーゼ阻害剤を含んでもよく、そして外因性汚染物質の増殖を防止するために抗生物質を含んでもよい。
テインAを使用して、ヒトIgG1、IgG2またはIgG4重鎖に基づく抗体を精製し得る(Lindmark et al.,J.Immunol Meth.62:1(1983))。プロテインGは、マウスアイソタイプおよびヒトIgG3に使用され得る(Guss et al.,EMBO J.5:1567(1986))。アフィニティーリガンドを結合させているマトリックスは、ほとんどの場合アガロースであるが、他のマトリックスも利用可能である。制御されたポアガラスまたはポリ(スチレンジビニル)ベンゼンのような機械的に安定なマトリックスは、アガロースを用いて達成され得るよりも流速を速め、そして処理時間を短縮することが可能となる。抗体変異体がCH3領域を含む場合、Bakerbond ABXTM樹脂(J.T.Baker,Phillipsburg,N.J.)が精製に有用である。回収される抗体または変異体に依存して、タンパク質精製のための他の技術、例えば、イオン交換カラムでの分画、エタノール沈殿、逆相HPLC、シリカでのクロマトグラフィー、ヘパリンアガロースでのクロマトグラフィー、アニオンまたはカチオン交換樹脂(例えば、ポリアスパラギン酸カラム)でのクロマトグラフィー、等電点電気泳動、SDS−PAGEおよび硫酸アンモニウム沈殿も利用可能である。
されている。他の二重特異性抗体の作製方法が、例えば、Kufer et al.,Trends Biotech 22:238−244,2004に提供される。
フラグメントを連結することにより形成され、単鎖ポリペプチドがもたらされる。大腸菌における機能的Fvフラグメントのアセンブリ技術もまた使用され得る(Skerra
et al.,Science 242:1038(1988))。
体(「scFv」)およびそれらの構築方法は、例えば、米国特許第4,946,778
号に記載されている。あるいは、同様の手段によりFabを構築し、そして発現し得る。全ての完全および部分的ヒト抗体が、完全マウスモノクローナル抗体よりも免疫原性を低くし得、そしてフラグメントおよび単鎖抗体もまた免疫原性を低くし得る。
348:552(1990)に記載の技術を使用して生成された抗体ファージライブラリーから単離され得る。Clarkson et al.,Nature 352:624(1991)およびMarks et al.,J Mol Biol 222:581(1991)は、ファージライブラリーを使用して、それぞれマウス抗体およびヒト抗体の単離を記載する。続く公報は、鎖シャフリングによる高親和性(nM範囲)ヒト抗体の生産(Marks et al.,Bio/Technology 10:779(1992))、さらに非常に大きなファージライブラリーを構築するためのストラテジーとしての組合せ感染(combinatorial infection)およびインビボ組換え(Waterhouse et al.,Nucl Acids Res 21:2265(1993))を記載する。従って、これらの技術は、モノクローナル抗体の単離のための伝統的なモノクローナル抗体ハイブリドーマ技術に対する実行可能な代替法である。
とも80%、少なくとも75%、少なくとも70%、少なくとも65%、少なくとも60%、少なくとも55%、および少なくとも50%の同一性を有する、IL−4および/またはIL−13 ポリペプチドを結合する抗体もまた、本発明に包含される。
平衡解離定数またはKDを有するものような、目的の抗体におけるより高い結合親和性が
有益であり得る。本発明はまた、競合的結合を決定するための当該分野で公知の任意の方法、例えば、本明細書中に記載される免疫測定法により決定されるような、本発明のエピトープへの抗体の結合を競合的に阻害する抗体を提供する。好ましい実施形態おいにて、抗体は、少なくとも95%、少なくとも90%、少なくとも85%、少なくとも80%、少なくとも75%、少なくとも70%、少なくとも60%、または少なくとも50%でエピトープへの結合を競合的に阻害する。
の反応により調製される);(2)C−14アルコキシメチル(デメトキシ/CH2OR
)(米国特許第4,331,598号);(3)C−14ヒドロキシメチルまたはアシルオキシメチル(CH2OHまたはCH2OAc)(米国特許第4,450,254号)(ノカルジアから調製される);(4)C−15ヒドロキシ/アシルオキシ(米国特許第4,364,866号)(ストレプトマイセスによるメイタンシノールの変換により調製される);(5)C−15メトキシ(米国特許第4,313,946号および同第4,315,929号)(トレビア ヌーディフロラ(Trewia nudiflora)から単離される);(6)C−18−Nデメチル(米国特許第4,362,663号および同第4,322,348号)(ストレプトマイセスによるメイタンシノールの脱メチル反応により調製される);および(7)4,5−デオキシ(米国特許第4,371,533号)(メイタンシノールの三塩化チタン/LAH還元により調製される)が挙げられる。
レオチド配列(例えば哺乳動物、微生物、ウイルスまたは昆虫遺伝子由来のもの)に操作可能に連結されたヌクレオチド配列を含む。さらなる制御配列の例としては、オペレーター、mRNAリボソーム結合部位、および/または転写および翻訳(例えば、これらの開始および終止)を制御する他の適切な配列が挙げられる。ヌクレオチド配列は、制御配列が適切なポリペプチドのヌクレオチド配列と機能的に関連する場合「操作可能に連結」される。従って、プロモーターヌクレオチド配列がヌクレオチド配列の転写を制御する場合、プロモーターヌクレオチド配列は、例えば、抗体重鎖配列に操作可能に連結される。
Biol 219:37(1991);およびSchoepfer,Gene 124:83(1993))が挙げられる。組換え原核宿主細胞発現ベクターに一般的に使用されるプロモーター配列としては、T7(Rosenberg et al.,Gene 56:125(1987))、β−ラクタマーゼ(ペニシリナーゼ)、ラクトースプロモーター系(Chang et al.,Nature 275:615(1978);およびGoeddel et al.,Nature 281:544(1979))、トリプトファン(trp)プロモーター系(Goeddel et al.,Nucl Acids Res 8:4057(1980))、およびtacプロモーター(Sambrook et al.,Molecular Cloning,A Laboratory Manual,第2編,Cold Spring Harbor Laboratory(1990))が挙げられる。
et al.,Gene 107:285(1991)に記載される。酵母および酵母形質転換プロトコルに適切な他のプロモーターおよびベクターが当該分野で周知である。酵母形質転換プロトコルは周知である。このようなプロトコルの1つは、Hinnen et al.,Proc Natl Acad Sci 75:1929(1978)に記載され、これは、選択培地におけるTrp+形質転換体を選択する。
トランスフェクションのための種々のウイルス株(例えば、AcNPVのL−1変異体およびカイコNPVのBm−5株)が公的に入手可能である。さらに、綿、トウモロコシ、ジャガイモ、大豆、ペチュニア、トマト、およびタバコの植物細胞培養もまた、当該分野で公知の宿主として利用される。
くつかの実施形態において、標識は放射性標識、フルオロフォア、発色団、造影剤または金属イオンである。
tocols in Immunology,vol.12,Coligen et al.,ed.,Wiley−Interscience,New York(1991)に記載される技術を使用して、放射性同位体で標識され得、そしてシンチレーションカウンターを使用して放射性活性を測定し得る);(b)蛍光標識、例えば、希土類キレート(ユーロピウムキレート)、フルオレセインおよびその誘導体、ローダミンおよびその誘導体、ダンシル、リサミン、フィコエリトリンおよびテキサスレッド、蛍光光度計を使用して蛍光を定量化し得る場合、蛍光標識は、例えば、Current Protocols in Immunology、前出に開示される技術を使用して抗体に抱合され得る;および(c)種々の酵素基質標識が利用可能であり(米国特許第4,275,149号はレビューを提供する)、一般に、酵素は、種々の技術を使用して測定され得る発色性基質の化学的変化を触媒し、例えば、酵素は、分光光度法で測定され得る基質における色素変化を触媒し得るか、または酵素は基質の蛍光または化学発光を改変し得る。例えば、照度計を使用する蛍光の変化を定量化するための技術が公知であるか、または標識は蛍光アクセプターにエネルギーを放出する。酵素標識の例としては、ルシフェラーゼ(例えば蛍ルシフェラーゼおよび細菌ルシフェラーゼ;米国特許第4,737,456号)、ルシフェリン、2,3−ジヒドロフタラジンジオン、リンゴ酸デヒドロゲナーゼ、ウレアーゼ、ペルオキシダーゼ(例えば、西洋ワサビペルオキシダーゼ(HRPO))、アルカリホスファターゼ、β−ガラクトシダーゼ、グルコアミラーゼ、リゾチーム、サッカリドオキシダーゼ(例えば、グルコースオキシダーゼ、ガラクトースオキシダーゼ、およびグルコース−6−リン酸デヒドロゲナーゼ)、複素環オキシダーゼ(例えば、ウリカーゼおよびキサンチンオキシダーゼ)、ラクトペルオキシダーゼ、マイクロペルオキシダーゼなどが挙げられる。抗体に酵素を抱合する技術は、O’Sullivan et al.,Meth Enz,ed.Langone & Van Vunakis,Academic Press,New York,73(1981)に記載される。
ベンジジン塩酸塩(TMB));(ii)発色基質としてp−ニトロフェニルリン酸塩を用いるアルカリホスファターゼ(AP);および(iii)発色基質(例えば、p−ニトロフェニル−β−D−ガラクトシダーゼ)または蛍光発生基質(例えば、4−メチルウンベリフェリル(methylumbelliferyl)−β−D−ガラクトシダーゼを用いるβ−D−ガラクトシダーゼ(β−D−Gal)。
用のための、例えば、診断アッセイを実施する治療上の使用のための指示書と共に所定量の試薬の包装された組み合わせが検討される。抗体が、例えば、酵素で標識される場合、キットは、酵素が必要とする基質および補因子(例えば、検出可能な発色団またはフルオロフォアを提供する基質前駆体)を含み得る。さらに、他の添加物、例えば、安定剤、緩衝剤(例えば、ブロック緩衝剤または溶解緩衝剤)などを含み得る。種々の試薬の相対量は、試薬溶液濃度を提供するように変化し得、これは使用者の柔軟性、空間の節約、試薬の節約などを提供する。溶解の際に、適切な濃度を有する試薬溶液を提供する添加剤を含み、通常、凍結乾燥された乾燥粉末として、試薬は提供され得る。
疫疾患、感染、心疾患、呼吸器疾患、神経疾患および代謝性疾患が挙げられる。
Tリンパ球により調節される。Th2−型免疫応答は、特定のサイトカイン(例えば、IL−4、IL−13)および特定のクラスの抗体(例えば、IgE)の生産に関連し、そして液性免疫に関連する。Th2−仲介性疾患は、高レベルのTh2サイトカイン(例えば、IL−4、IL−13)および/または特定のクラスの抗体(例えば、IgE)の存在により特徴付けられ、そしてこれらとしては、例えば、アレルギー性疾患(例えば、アレルギー性鼻炎、アトピー性皮膚炎、喘息(例えば、アトピー性喘息)、アレルギー性気道疾患(AAD)、アナフィラキシーショック、結膜炎)、高レベルのIL−4および/またはIL−13に関連する自己免疫疾患(例えば、リウマチ性関節炎、移植片対宿主病、腎疾患(例えば、腎炎症候群、ループス腎炎)、および高レベルのIL−4および/またはIL−13に関連する感染(例えば、ウイルス感染、寄生虫感染、真菌(例えば、カンジダアルビカンス)感染)が挙げられる。特定のがん(例えば、B細胞リンパ腫、T細胞リンパ腫、多発性骨髄腫、頭頸部がん、乳がんおよび卵巣がん)が、高レベルのIL−4および/またはIL−13に関連するか、またはIL−4−誘発性および/またはIL−13−誘発性がん細胞増殖に関連する。これらのがんは本発明のリガンド(Iigaud)を使用して、治療、抑制または予防され得る。
えば、サルメテロール/フルチカゾン、およびホルモテロール(formolerol)/ブデソニド)および粘液溶解剤(例えば、エルドステイン、アセチルシステイン、ブロムヘキシン(bromheksin)、カルボシステイン(carbocyslcine)、グアイフェネシン(guiafencsin)およびヨウ素化グリセリン)。
学合成した場合、化学前駆体もしくは他の化学物質を実質的に含まない。専門用語「細胞物質を実質的に含まない」は、ポリペプチド/タンパク質が、それが単離されたか組換えにより生産された細胞の細胞成分から分離される抗体の調製物を含む。従って、細胞物質を実質的に含まない抗体は、約30%、20%、10%、5%、2.5%または1%(乾燥重量で)未満の夾雑タンパク質を有する抗体の調製物を含む。抗体を組換え的に生産する場合、培地もまた実質的に含まない、すなわち、培地がタンパク質調製物の約20%、10%、5%、2.5%または1%未満の量を示すことが好ましい。抗体を化学合成により生産する場合、化学前駆体または他の化学物質および試薬を実質的に含まない、すなわち、目的の抗体がタンパク質合成に関する化学前駆体または他の化学物質から分離されていることが好ましい。従って、抗体のこのような調製物は、約30%、20%、10%、5%または1%(乾燥重量で)未満の化学前駆体または目的の抗体以外の化合物を有する。本発明の好ましい実施形態において、抗体は単離または精製される。
り得る。組成物は、伝統的なバインダーおよび担体、例えば、トリグリセリドを用いて坐薬として製剤され得る。経口製剤は、標準的な担体、例えば、医薬等級のマンニトール、ラクトース、デンプン、ステアリン酸マグネシウム、サッカリンナトリウム、セルロース、炭酸マグネシウムなどを含み得る。適切な担体の例は、「Remington’s Pharmaceutical Sciences」Martinに記載されている。このような組成物は、患者への適切な投与のための形態を提供するように適切な量の担体と共に、好ましくは精製形態の有効量の抗体を含む。当該分野で公知なように、製剤は、投与様式に適合するように構成される。
ルビトール、キシリトール、リビトール、ミオイニシトール、ガラクチトール、グリセリンなど、イノシトールのようなシクリトールを含む;ポリエチレングリコール;アミノ酸ポリマー;イオウ含有還元剤、例えば、尿素、グルタチオン、チオクト酸、チオグリコール酸ナトリウム、チオグリセリン、α−モノチオグリセリンおよびチオ硫酸ナトリウム;低分子量ポリペプチド(すなわち<約10残基);タンパク質、例えば、ヒト血清アルブミン、ウシ血清アルブミン、ゼラチンまたは免疫グロブリン;親水性ポリマー、例えば、ポリビニルピロリドン、サッカリド、単糖、例えば、キシロース、マンノース、フルクトース、グルコース;二糖、例えば、ラクトース、マルトースおよびスクロース;三糖、例えば、ラフィノース;多糖、例えば、デキストランなどであり得る。安定剤は、1活性タンパク質あたり0.1〜10,000w/wの範囲で存在する。
/ml〜約1.0mg/ml、好ましくは、約0.07mg/ml〜約0.2mg/mlの範囲で存在し得る。
複合され得る。細胞毒または細胞毒性薬は、細胞に有毒な任意の薬剤を含む。例としては、パクリタキソール、サイトカラシンB、グラミシジンD、臭化エチジウム、エメチン、マイトマイシン、エトポシド、テノポシド(tenoposide)、ビンクリスチン、ビンブラスチン、コルヒチン、ドキソルビシン、ダウノルビシン、ジヒドロキシアントラセンジオン(dihydroxy anthracindione)、ミトキサントロン、ミトラマイシン、アクチノマイシンD、1−デヒドロテストステロン、グルココルチコイド、プロカイン、テトラカイン、リドカイン、プロプラノロールおよびピューロマイシン、ならびにそれらのアナログまたはホモログが挙げられる。治療薬としては、代謝拮抗剤(例えば、メトトレキサート、6−メルカプトプリン、6−チオグアニン、シタラビン、5−フルオロウラシルおよびダカルバジン(decarbazine))、アルキル化剤(例えば、メクロレタミン、クロラムブシル、メルファラン、カルムスチン(BSNU)およびロムスチン(CCNU)、シクロホスファミド(cyclothosphamide)、ブスルファン、ジブロモマンニトール、ストレプトゾトシン、マイトマイシンC、およびシス−ジクロロジアミン白金(II)(DDP)シスプラチン)、アントラサイクリン(例えば、ダウノルビシン、ダウノマイシンおよびドキソルビシン)、抗生物質(例えば、ダクチノマイシン、アクチノマイシン、ブレオマイシン、ミトラマイシンおよびアントラマイシン(AMC))、ならびに抗有糸分裂剤(例えば、ビンクリスチンおよびビンブラスチン)が挙げられるが、これらに限定されない。
lan R.Liss(1985);Hellstrom et al.,Controlled Drug Delivery,第2編,Robinson et al.,eds.,p.623−53,Marcel Dekker(1987);Thorpe,Monoclonal Antibodies ’84:Biological And
Clinical Applications,Pinchera et al.,eds.,p.475−506(1985);Monoclonal Antibodies For Cancer Detection and Therapy,Baldwin et al.,eds.,p.303−16,Academic Press(1985);およびThorpe,et al.,Immunol Rev 62:119(1982)を参照のこと。あるいは、抗体は、抗体ヘテロ複合体、例えば、二重特異性抗体を形成するために、第二の抗体に複合され得る、例えば、米国特許第4,676,980号を参照のこと。
et al.,Int Immunol,6:1567(1994))、VEGF(WO99/23105);抗血栓剤;抗血管新生薬、例えば、アンギオスタチンもしくはエンドスタチン));または生物学的応答修飾因子、例えば、リンホカイン、インターロイキン−1(IL−1)、インターロイキン−2(IL−2)、インターロイキン−6(IL−6)、顆粒球マクロファージコロニー刺激因子(GM−CSF)、顆粒球コロニー刺激因子(GCSF)または他の成長因子が挙げられ得る。
致する様式で、製剤し、投薬し、そして投与する。これに関連し、考慮される因子として
は、治療される特定の障害、治療される特定の哺乳動物またはヒト、個々の患者の臨床症状、障害の原因、薬剤の送達部位、投与方法、投与の計画、および医師に公知の他の因子が挙げられる。投与される抗体または変異体の「治療有効量」は、このような考慮により調節され、そしてIL−4および/またはIL−13仲介性疾患、状態または障害を予防、改善または治療するのに必要な最小量であり得る。
更され得る。
ント(例えば、FeまたはヒンジFe領域フラグメント)に導入することにより生成され得る、例えば、WO98/23289;WO97/34631;および米国特許第6,277,375号を参照のこと。
g/ml、250mg/ml、または300mg/mlのIL−4および/またはIL−13抗体を有する密閉容器で供給され得る。
以下の方法に使用した試薬は、Cell Sciences,Inc.(Canton,MA,USA)から購入したマウス抗−IL−13モノクローナル抗体クローンB−B13であった。Cell SciencesはDiaclone(Besancon,F
rance)の米国販売業者であり、抗体B−B13を製造する。
ドマンN末端配列決定および画分のLC/MS/MS分析。
試薬のマウス抗−IL−4モノクローナル抗体クローン8D4−8を、Biozol diagnostica Vertrieb GmbH(Eching,Germany)から購入した。BiozolはBioLegend(San Diego,CA,USA)のドイツ販売業社であり、抗体8D4−8を製造する。
本明細書で上述したヒト化プロトコルを使用して、B−B13クローンをヒト化した。問題のある残基(脱アミド部位、溶媒露出メチオニン、酸に不安定な(acide labile)部位)に対処するために、CDR中に突然変異を含む6つのヒト化バージョンを提案した。
検索のために保持された。マウスB−B13抗体可変領域柔軟性残基を置き換えるために、CDRが5.0Å以内である位置を特に考慮して、最も一致する柔軟性残基を有するヒト抗体可変領域を選択した。問題のある残基を避けるために、CDR中の多数の突然変異がまた、提案されたバージョンに含まれた。以下の配列モチーフを考察した:Asp−Pro(酸に不安定な(acide labile)結合)、Asn−X−Ser/Thr(グリコシル化)、Asn−Gly/Ser/Thr(露出範囲における脱アミド部位)、Met(露出範囲における酸化)。得られたヒト化配列を、配列類似性について合理的仮定がなされていると確信を得るUniProtKB/Swiss−Protデータベースに対してブラストした。全ての配列が多数のヒト抗体に対して高い程度で類似性を示すことが見出された。さらに、配列はImmune Epitope Database and Analysis Resource(IEDBデータベース)に列挙される既知のB−またはT−細胞エピトープを全く含んでいなかった。
本明細書中に上記されるヒト化(再表面形成)技術を使用して、8D4−8クローンをヒト化した。2つのヒト化バージョンを提案した。1つバージョンは、問題のある残基(露出した酸に不安定な(acide labile)位置)に対処すると考えられた重鎖のCDR中に1つの突然変異を含む。
ed Born陰溶媒中、1.7ナノ秒間実施した。次いで、MD軌道から得られた1,700のスナップショットを使用して、参照メドイド位置と比較して、各8D4アミノ酸について、その標準偏差(rmsd)の分布を計算した。最終的に、各アミノ酸のrmsd分布と全体的なrmsd分布を比較する統計的検定を使用して、MDの間に見られるように、アミノ酸が十分に柔軟である場合、B−細胞受容体と相互作用し、そして免疫応答の活性化の原因となる可能性があると決定される。マウス8D4−8可変領域の柔軟な位置を、局所的にダウンロードしたImMunoGeneTics Databaseの2007年1月バージョンのヒト抗体配列の対応する位置と比較した。これらの柔軟性残基の3D構造を保存する平均残基および数個の隣接残基よりも3倍大きい柔軟性を示す残基のみが、検索のために保持された。マウス8D4−8抗体可変領域柔軟性残基を置き換えるために、CDRが5.0Å以内である位置を特に考慮して、最も同一な柔軟性残基を有するヒト抗体可変領域を選択した。最終的に、問題のある残基を避けるために、いくつかのさらなる突然変異がまたなされた。以下の配列モチーフを考察した:Asp−Pro(酸に不安定な(acide labile)結合)、Asn−X−Ser/Thr(グリコシル化)、Asn−Gly/Ser/Thr(露出範囲における脱アミド)、Met(露出範囲における酸化)。唯一見出された問題のある残基は、重鎖のCDR2中のDP部位であった。得られたヒト化配列を、配列類似性について合理的仮定がなされていると確信を得るUniProtKB/Swiss−Protデータベースに対してブラストした。全ての配列が多数のヒト抗体に対して高い程度で類似性を示した。さらに、配列はIEDBデータベースに列挙される既知のB−またはT−細胞エピトープを全く含んでいなかった。
抗−IL−13クローンB−B13および抗−IL−4クローン8D4−8の可変重鎖および軽鎖のアミノ酸配列をそれぞれ、Young L.and Dong Q.(Nucl.Acids Res.(2004),32(7),e59)により記載されるオーバーラップ伸長PCR(OE−PCR)の改良プロトコルを使用してヌクレオチド配列に逆翻訳し、そして生成した。PCR産物をInvitrogen TOPO TAクローニングキット(Cat # 45−0641)を使用して、pCR(R)4−TOPO中で
クローニングし、そしてM13順方向およびM13逆方向プライマーを使用して配列決定した。可変領域をそれぞれ、定常重鎖(IGHG1、Genebank 受託番号 Q569F4)または軽鎖(IGKC、Genebank 受託番号 Q502W4)と共に融合し、NheIおよびHindIIIで消化し、そしてキメラB−B13−重鎖および軽鎖ならびにキメラ8D4−8重鎖および軽鎖の哺乳動物発現のためのプラスミドを作製するエピソーム発現ベクターpXL(Durocher et al.(2002),Nucl.Acids Res.30(2),E9により記載されるpTTベクターのアナログ)のNheI/HindIII部位に各々ライゲーションした。
オーバーラップ伸長PCR(OE−PCR)により合成的に生成した。
O2の湿気のある環境で、110rpmのオービタルシェーカープラットホーム回転(o
rbital shaker platform rotating)上、37℃のインキュベーター中で培養した。
e System GmbH)で決定した。トランスフェクションのために、90%以上の生存率を有する細胞を1〜1.5×106 細胞/mLの細胞密度で使用した。製造業者により記載された条件で、DNA:FugeneHD 2:7の比率でFugeneHD(Roche)を使用して、重鎖および軽鎖の発現プラスミドの混合物(5×10-7μgDNA/細胞)を含む500mL振とうフラスコ中で、細胞(100mL)をトランスフェクトした。トラスフェクト細胞を、110rpmのオービタルシェーカープラットホーム回転上37℃のインキュベーター(8% CO2)中で7日間培養した。
炭酸ナトリウム pH 9.6)中10μg/mlまで希釈し、そして1ウェルあたり50μLで分注した。プレートを粘着テープで密閉し、そして4℃で一晩保存した。プレートを洗浄緩衝液(PBS pH.4 0.1% Tween20)で3回洗浄した。ブロッキング溶液(1% BSA/PBS)(150μL)を各ウェルに分注し、プレートをカバーした。RTで1時間後、プレートを洗浄緩衝液で3回洗浄した。サンプルまたは標準物質(1500ng/ml〜120ng/mlの範囲)(100μL)を添加し、そしてRTで1時間そのままにしておいた。プレートを洗浄緩衝液で3回洗浄した。インキュベート溶液(0.1%BSA、PBS pH7.4、0.05% Tween20)を使用して1:10.000に希釈したヤギ抗−ヒトIgG−FC−HRP複合体[NatuTec A80−104P−60](100μL)を添加した。RTで1時間インキュベートした後、プレートを洗浄緩衝液で3回洗浄した。ABTS基質(0.1M Na2
HPO4、0.05M クエン酸溶液、pH5.0中10mg ABTS タブレット(
Pierce 34026)、使用前に30% H2O2(10μL)/基質溶液(10ml)を添加)(100μL)を各ウェルに分注し、発色させた。発色した後(約10〜15分)、1% SDS溶液(50μL)を添加し、反応を停止した。プレートをA405で読んだ。
。
試薬の組換えヒトIL−13およびIL−4をChemicon(USA)から購入した。Biacore動力学的分析を以下のように実施した。
−CSFを含まない完全培地中に播種した。細胞を添加する前に、対応するサイトカインを含む抗体の連続希釈を、37℃で30分間プレインキュベートした。細胞を72時間培養した(37℃、5% CO2)。cellTiter96 AqueousのMTS/
PMS溶液を添加した。次いで、細胞を3時間インキュベートした。その期間後、プレートリーダーを使用して、490 nmでの吸光度を読み取った。Speedソフトウェアを使用してIC50値を計算した。
二重特異性抗体(BsAb)の発現に使用される形式は、米国特許第5,989,830号に記載される二重領域ダブルヘッド形式(dual domain double head format)のIgG変異体である。この形式において、第二の抗体のさらなる可変領域により、対応する重鎖および軽鎖上のそのN末端で、IgG分子を伸張する。従って、得られたIgG分子は、2つの重鎖および2つの軽鎖からなるヘテロ四量体である。重鎖は、10のアミノ酸(G4S)2からなるリンカーにより結合され、そしてI
gG4定常領域に融合した2つの異なる抗体に由来する2つの可変重鎖領域(VH1−VH2)からなる。軽鎖は、10のアミノ酸(G4S)2からなるリンカーにより結合され
、そして定常κ領域に融合した2つの異なる抗体に由来する2つの可変軽鎖領域(VL1−VL2)からなる。
C)−8D4−8の一部をコードするそれぞれの5’末端にBamHI 制限酵素認識部位(GGA TCC)を導入するPCRにより生成した。8D4−8ヒト化変異体のVHの3’配列は、IGHG4配列(Q569F4、末端のLysの欠失ならびに2つの突然変異S241PおよびL248Eを有する)に後で融合するために、ApaI制限酵素認識部位(CH1領域の始めのアミノ酸をコードする)を用いて終結した。VL8D4−8の3’末端は、IGKC(Gene Bank 受託番号 Q502W4)に後で融合するために、定常κ鎖の始めの2つのアミノ酸をコードするBsiWI制限酵素認識部位を用いて終結した。
−(GGA GGC GGA GGG TCC GGA GGC GGA GGA TCC(配列番号7))の一部をコードするそれぞれの3’末端にBamHI制限酵素認識部位を導入するPCRにより生成させた。B−B13変異体のVHおよびVLの両方の配列を、それぞれの5’末端にNheI制限酵素認識部位、次いで、ATG開始コドンおよびリーダーペプチドコード配列を用いて生成させた。
部位を介して融合した。B−B13および8D4−8のVLを、(G4S)2リンカー内
でそれらのBamHI部位を介して互いに融合した。従って、生成された重鎖および軽鎖のタンデムは、以下の組成を有した。
−VH8D4−8−ApaI。
−VL8D4−8−BsiWI。
グし、そしてM13順方向およびM13逆方向プライマーを使用して配列決定した。
結合および中和活性アッセイを、前の実施例に記載されるように実施した。
Claims (21)
- IL−4に特異的に結合する単離された抗体またはそのフラグメントであって、当該抗体またはそのフラグメントが、
(a)配列番号3のアミノ酸配列を含む可変軽鎖領域および配列番号4のアミノ酸配列を含む可変重鎖領域;
(b)配列番号3のアミノ酸配列を含む可変軽鎖領域および配列番号5のアミノ酸配列を含む可変重鎖領域;
(c)HASQNIDVWLS(CDR1;配列番号14)、KASNLHTG(CDR2;配列番号15)およびQQAHSYPFT(CDR3;配列番号16)のアミノ酸配列を含む可変軽鎖領域およびGYSFTSYWIH(CDR1;配列番号17)、IDPSDGETR(CDR2;配列番号18)およびLKEYGNYDSFYFDV(CDR3;配列番号19)のアミノ酸配列を含む可変重鎖領域;または、(d)HASQNIDVWLS(CDR1;配列番号14)、KASNLHTG(CDR2;配列番号15)およびQQAHSYPFT(CDR3;配列番号16)のアミノ酸配列を含む可変軽鎖領域およびGYSFTSYWIH(CDR1;配列番号20)、IDASDGETR(CDR2;配列番号21)およびLKEYGNYDSFYFDV(CDR3;配列番号22)のアミノ酸配列を含む可変重鎖領域を含む、
上記抗体またはそのフラグメント。 - IL−4に特異的に結合する単離された抗体またはそのフラグメントであって、当該抗体またはそのフラグメントが、
(a)配列番号3のアミノ酸配列と少なくとも95%同一であり、かつHASQNIDVWLS(CDR1;配列番号14)、KASNLHTG(CDR2;配列番号15)およびQQAHSYPFT(CDR3;配列番号16)のアミノ酸配列を含んでいるアミノ酸配列を含む可変軽鎖領域、並びに、配列番号4のアミノ酸配列と少なくとも95%同一であり、かつGYSFTSYWIH(CDR1;配列番号17)、IDPSDGETR(CDR2;配列番号18)およびLKEYGNYDSFYFDV(CDR3;配列番号19)のアミノ酸配列を含んでいるアミノ酸配列を含む可変重鎖領域;または、
(b)配列番号3のアミノ酸配列と少なくとも95%同一であり、かつHASQNIDVWLS(CDR1;配列番号14)、KASNLHTG(CDR2;配列番号15)およびQQAHSYPFT(CDR3;配列番号16)のアミノ酸配列を含んでいるアミノ酸配列を含む可変軽鎖領域、並びに、配列番号5のアミノ酸配列と少なくとも95%同一であり、かつGYSFTSYWIH(CD
R1;配列番号20)、IDASDGETR(CDR2;配列番号21)およびLKEYGNYDSFYFDV(CDR3;配列番号22)のアミノ酸配列を含んでいるアミノ酸配列を含む可変重鎖領域を含む、
上記抗体またはそのフラグメント。 - 二重特異性抗体である、請求項1または2に記載の抗体またはそのフラグメント。
- 二重特異性抗体がIL−4およびIL−13に特異的に結合する、請求項3に記載の抗体またはそのフラグメント。
- 定常領域の領域を含む、請求項1〜4のいずれか1項に記載の抗体またはそのフラグメント。
- 定常領域の領域がCH1、CH2、CH3およびCLからなる群から選択される、請求項5に記載の抗体またはそのフラグメント。
- IgG抗体又はそのフラグメントである、請求項1〜6のいずれか1項に記載の抗体またはそのフラグメント。
- IgG抗体又はそのフラグメントがIgG4抗体又はそのフラグメントである、請求項7に記載の抗体またはそのフラグメント。
- さらにエフェクター分子に複合している、請求項1〜8のいずれか1項に記載の抗体またはそのフラグメント。
- エフェクター分子が異種ポリペプチド、薬物、放射性ヌクレオチドまたは毒素である、請求項9に記載の抗体またはそのフラグメント。
- 請求項1〜10のいずれか1項に記載の抗体またはそのフラグメント、および薬学的に受容可能な担体を含む医薬組成物。
- さらに標識を含む、請求項1〜8のいずれか一項に記載の抗体またはそのフラグメントであって、標識が放射標識、フルオロフォア、発色団、造影剤または金属イオンである、抗体またはそのフラグメント。
- 抗体またはそのフラグメントがIL−4仲介性疾患を治療するために有用な医薬を調製するのに役立つ、治療的に有効な量の請求項1〜8のいずれか1項に記載の抗体またはそのフラグメントの使用。
- IL−4仲介性疾患がアレルギー性疾患、がん、喘息、IL−4の異常生産に関連する疾患、自己免疫疾患、強皮症または突発性肺線維症である、請求項13に記載の使用。
- 哺乳動物のIL−4仲介性疾患の治療、抑制または予防において使用するための医薬を製造するための、請求項1〜8のいずれか1項に記載の抗体またはそのフラグメント。
- IL−4仲介性疾患がアレルギー性疾患、喘息、がん、自己免疫疾患、IL−4の異常生産に関連する疾患、強皮症または突発性肺線維症から選択される、請求項15に記載の抗体またはそのフラグメント。
- 抗体またはそのフラグメントがTH−2仲介反応を抑制するために有用な医薬を調製す
るのに役立つ、治療的に有効な量の請求項1〜8のいずれか1項に記載の抗体またはそのフラグメントの使用。 - 哺乳動物のTH−2仲介反応を抑制するのに使用するための、請求項1〜8のいずれか1項に記載の抗体またはそのフラグメント。
- 請求項1〜8のいずれか1項に記載の抗体またはそのフラグメントをコードする、単離された核酸分子。
- 請求項19に記載の核酸分子を含むベクター。
- 請求項20に記載のベクターを含む単離された宿主細胞。
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