JP5940061B2 - 抗axl抗体及び使用方法 - Google Patents
抗axl抗体及び使用方法 Download PDFInfo
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- JP5940061B2 JP5940061B2 JP2013515538A JP2013515538A JP5940061B2 JP 5940061 B2 JP5940061 B2 JP 5940061B2 JP 2013515538 A JP2013515538 A JP 2013515538A JP 2013515538 A JP2013515538 A JP 2013515538A JP 5940061 B2 JP5940061 B2 JP 5940061B2
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Description
本出願は、2010年6月18日に出願された米国仮特許出願第61/356508号に対して、米国特許法第119条の下で優先権を主張し、その内容はその全体が参照することにより援用される。
本出願は、EFS−Web経由でASCIIフォーマットで提出された配列表を含み、その全体が本明細書中で参照することにより援用される。
本発明は、抗Axl抗体及び同じものを使用する方法に関する。
Axlは受容体型チロシンキナーゼのTAM(Tyro3、Axl、及びMer)ファミリーのメンバーである(O'Bryan et al, 1991; Lai et al, 1991)。それはもともと血液系腫瘍における形質転換遺伝子として同定された(O'Bryan et al, 1991; Janssen et al, 1991)。Axl、又はそのリガンドGas6の調節不全は、種々のヒト癌の病因に関与している。Axlの過剰発現は、広範囲のヒトの癌に報告されており(Berclaz et al, 2001; Craven et al, 1995; Shieh et al, 2005; Sun et al, 2004; Ito et al, 1999)、肺癌(Shieh et al, 2005)、前立腺癌(Sainaghi et al, 2005)、乳癌(Meric et al, 2002; Zhang et al, 2008)、胃癌(Wu et al, 2002)、膵臓癌(Koorstra et al, 2009)、腎細胞癌(Chung et al, 2003)、並びに神経膠芽腫(Hutterer et al, 2008)における浸潤及び転移に関連付けられている。最近、リン酸化チロシンシグナル伝達のプロファイリングによって、活性化Axlタンパク質がNSCLCの約5%の原発性腫瘍で検出された(Rikova et al, 2007)。Axlの発現が標的薬及び化学療法薬によって誘発され、薬剤誘導性Axl発現は、急性骨髄性白血病における化学療法に対する耐性、並びに消化管間質腫瘍及び乳癌におけるイマチニブ及びラパチニブ/ハーセプチンに対する耐性をそれぞれ付与する。Axl及び抗Axl抗体に係る他の出版物としては、国際公開第2004/039955号、国際公開第2009/063965号;2009年7月27日に出願の共同所有の米国出願番号61/228,915号;国際公開第2009/062690号、国際公開第2004/008147号;5468634号が含まれる。
I.定義
本明細書における目的のための「アクセプターヒトフレームワーク」とは、下記に定義されるように、ヒト免疫グロブリンフレームワーク又はヒトコンセンサスフレームワークから得られる軽鎖可変ドメイン(VL)フレームワーク又は重鎖可変ドメイン(VH)フレームワークのアミノ酸配列を含有するフレームワークである。ヒト免疫グロブリンのフレームワーク又はヒトコンセンサスフレームワーク”に由来する”アクセプターヒトフレームワークは、その同一のアミノ酸配列を含んでもよく、又はそれはアミノ酸配列の変化を含み得る。幾つかの実施態様において、アミノ酸変化の数は、10以下、9以下、8以下、7以下、6以下、5以下、4以下、3以下、又は2以下である。幾つかの実施態様において、VLアクセプターヒトフレームワークは、Vはヒト免疫グロブリンのフレームワーク配列又はヒトコンセンサスフレームワーク配列に、配列が同一である。
分率X/Yの100倍
ここで、Xは配列アラインメントプログラムALIGN−2により、AとBのそのプログラムのアラインメントにおいて同一と一致したスコアのアミノ酸残基の数であり、YはBの全アミノ酸残基数である。アミノ酸配列Aの長さがアミノ酸配列Bの長さと異なる場合、AのBに対する%アミノ酸配列同一性は、BのAに対する%アミノ酸配列同一性とは異なることは理解されるであろう。特に断らない限り、本明細書で使用されるすべての%アミノ酸配列同一性値が、ALIGN−2コンピュータプログラムを使用し、直前の段落で説明したように、得られる。
一態様において、本発明は、様々なAxl結合剤(例えば、抗体およびその断片など)の同定に、部分的に基づいている。Axlは重要かつ有利な治療標的を提示し、本発明は、Axlへの薬剤の結合に基づく組成物及び方法を提供する。本発明のAxlの結合剤は、本明細書に記載のように、Axlのシグナル伝達経路の発現及び/又は活性に関連する病理的状態を標的にすることに使用するための、重要な治療薬および診断薬を提供する。所定の実施態様において、Axlに結合する抗体が提供される。本発明の抗体は、例えば、癌の診断又は治療のために、有用である。
一態様において、本発明は、Axlに結合する単離された抗体を提供する。所定の実施態様において、抗Axl抗体は、≦550pMの親和性でヒトAxlに結合し、及び幾つかの実施態様において、≦1nMの親和性でマウスAxlに結合する。幾つかの実施態様において、抗Axl抗体は、ヒト及びマウスAxlに結合する。
−HVR−H1(配列番号7)において:位置2,3,4,5,6,7,8,9,及び10;
−HVR−H2(配列番号8)において:位置1,2,4,6,7,8,9,及び10;
−HVR−H3(配列番号9)において:位置3,4,5,6,7,8,9,10,11,12,13,14,又は15;
−HVR−L1(配列番号10)において:位置5,6,7,8,9,及び10;
−HVR−L2(配列番号11)において:位置1,4,及び6;
−HVR−L3(配列番号12)において:位置3,4,5,6,7,及び8.
−HVR−H1(配列番号7)において.S28T;L29F又はV:S30T又はR;G31S;S32H,T又はI;W33G;I34L;
−HVR−H2(配列番号8)において:G49A;W50G;N52S,A,又はP;Y53A又はV;R54G又はS;G55S又はR;Y56S又はH;A57T又はP;
−HVR−H3(配列番号9)において:E95W;Y96R;S97N又はP;G98D又はL;W99S;G100R,A,又はS;G100aS;S100b欠失;S100cY又は欠失;V100dI又は欠失;G100e又は欠失;Y100f又は欠失,A100gE又は欠失;
−HVR−L1(配列番号10)において:D28I又はS;V29I;S30G又はR;T31I,N又はR;A32S;V33L;
−HVR−L2(配列番号11):S50A又はV;F53N又はS;Y55A;
−HVR−L3(配列番号12):S91A;Y92K又はN;T93S,Y,M,R,又はA;T94N,F,又はS;P95R;P96Y,S,又はL.
−HVR−H1(配列番号7)において.S28T;L29F又はV:S30T;G31S;S32H,T又はI;
−HVR−H2(配列番号8)において:N52S,又はA;R54G又はS;G55R;Y56S,又はH;A57T又はP;
−HVR−H3(配列番号9)において:S97N又はP;G98D;G100S;
−HVR−L3(配列番号12)において:T93S,又はY;T94N,F,又はS.
−HVR−H1(配列番号112):GFX1X2X3X4X5X6X7H,ここでX1はS又はT;X2はL,F又はV;X3はS,T,又はR;X4はG又はS;X5はS,H,T又はI;X6はW又はG;X7はI又はLである;
−HVR−H2(配列番号113)において:X1X2IX3PX4X5X6X7X8YYADSVKG,ここでX1はG又はA;X2はW又はG;X3はN,S,A又はP;X4はY,A又はV;X5はR,G,又はS;X6はG,R又はS;X7はY,S,H又はY;X8はA,T,又はPである;及び/又は(配列番号166):X1X2IX3PX4X5X6X7X8X9X10YYADSVKG,ここでX1はG又はA;X2はW又はG;X3はN,S,A又はP;X4はY,A又はV;X5はR,G,又はS;X6はG,R又はS;X7はY,S,H又はY;X8はA,T,又はP;X9は任意のアミノ酸又は欠失;X10は任意のアミノ酸又は欠失;
−HVR−H3(配列番号114)において:ARX1X2X3X4X5X6X7X8X9X10X11X12X13MDY,ここでX1はE又はW;X2はY又はR;X3はS,N又はP;X4はG,D,又はL;X5はW又はS;X6はG,R,A,又はS;X7はG又はS;X8はS又は欠失;X9はS,Y又は欠失;X10はV,I又は欠失;X11はG又は欠失;X12はY又は欠失;X13はA,E又は欠失;
−HVR−L1(配列番号115)において:RASQX1X2X3X4X5X6A,ここでX1はD,I又はS;X2はV又はI;X3はS,G又はR;X4はT,I,N又はR;X5はA又はS;X6はV又はL;
−HVR−L2(配列番号116)において:X1ASX2LX3S,ここでX1はS,A,又はV;X2はF,N又はS;X3はY又はA;
−HVR−L3(配列番号117)において:QQX1X2X3X4X5X6T,ここでX1はS又はA;X2はY,K又はN;X3はT,S,Y,M,R又はA;X4はT,N,S,又はF;X5はP又はR;X6はP,Y,S又はL.
−HVR−H1(配列番号118)において.GFX1X2X3GX4WIH,ここでX1はT又はS,X2はF又はL,X3はT又はS,X4はH,S又はT;
−HVR−H2(配列番号119)において:GWIX1PYX2X3X4X5YYADSVKG,ここでX1はS,N又はA;X2はG,R又はS;X3はG又はR;X4はS,Y又はH;X5はT,A又はP;
−HVR−H3(配列番号120)において:AREYX1X2WX3X4SX5X6GYX7MDY,ここでX1はS,N又はP;X2はG又はD;X3はG,R,又はA;X4はG又はS;X5はS又はY;X6はV又はI;X7はA又はE;
−HVR−L3(配列番号121)において:QQSYX1X2X3X4T,ここでX1はT,S又はY;X2はT,N,S又はF;X3はP又はR;X4はP,Y又はS.
所定の実施態様において、本明細書において与えられる抗体は、解離定数(Kd)が、≦1μM、≦100nM、≦10nM、≦1nM、≦0.1nM、≦0.01nM、又は≦0.001nM(例えば、10−8M未満、例えば、10−8Mから10−13M、例えば、10−9Mから10−13M)。
所定の実施態様において、本明細書で提供される抗体は、抗体断片である。抗体断片は、限定されないが、Fab,Fab’,Fab’−SH,F(ab’)2,Fv,及びscFv断片、及び下記の他の断片を含む。所定の抗体断片の総説については、Hudson et al. Nat. Med. 9:129-134 (2003)を参照。scFv断片の総説については、例えば、Pluckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994)を参照;また、国際公開第93/16185号;及び米国特許第5571894号及び第5587458号も参照。サルベージ受容体結合エピトープ残基を含み、かつインビボ半減期を増加させたFab及びF(ab’)2断片の議論については、米国特許第5869046号を参照のこと。
所定の実施態様において、本明細書で提供される抗体は、キメラ抗体である。所定のキメラ抗体は、例えば、米国特許第4816567号、及びMorrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984))に記載されている。一例において、キメラ抗体は、非ヒト可変領域(例えば、マウス、ラット、ハムスター、ウサギ、又はサル等の非ヒト霊長類由来の可変領域)及びヒト定常領域を含む。更なる例において、キメラ抗体は、クラスまたはサブクラスが親抗体のものから変更された「クラススイッチ」抗体である。キメラ抗体は、その抗原結合断片を含む。
所定の実施態様において、本明細書で提供される抗体は、ヒト抗体である。ヒト抗体は、当技術分野で公知の様々な技術を用いて生産することができる。ヒト抗体は一般的にvan Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001) 及びLonberg, Curr. Opin. Immunol. 20:450-459 (2008)に記載されている。
本発明の抗体は、所望の活性または活性(複数)を有する抗体についてコンビナトリアルライブラリーをスクリーニングすることによって単離することができる。例えば、様々な方法が、ファージディスプレイライブラリーを生成し、所望の結合特性を有する抗体についてのライブラリーをスクリーニングするために、当該技術分野で知られている。そのような方法は、例えば、Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O’Brien et al., ed., Human Press, Totowa, NJ, 2001)に総説され、更に、例えば、McCafferty et al., Nature 348:552-554; Clackson et al., Nature 352: 624-628 (1991); Marks et al., J. Mol. Biol. 222: 581-597 (1992); Marks and Bradbury, in Methods in Molecular Biology 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003); Sidhu et al., J. Mol. Biol. 338(2): 299-310 (2004); Lee et al., J. Mol. Biol. 340(5): 1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34): 12467-12472 (2004); 及びLee et al., J. Immunol. Methods 284(1-2): 119-132(2004)に記載されている。
所定の実施態様において、本明細書で提供される抗体は、多重特異性抗体、例えば二重特異性抗体である。多重特異性抗体は、少なくとも二つの異なる部位に対して結合特異性を有するモノクローナル抗体である。所定の実施態様において、結合特異性の一つはAxlに対してであり、他は、任意の他の抗原に対してである。所定の実施態様において、二重特異性抗体は、Axlの2つの異なるエピトープに結合することができる。二重特異性抗体はまたAxlを発現する細胞に細胞傷害性薬物を局在化するために用いることができる。二重特異性抗体は、全長抗体又は抗体断片として調製することができる。
所定の実施態様において、本明細書で提供される抗体のアミノ酸配列変異体が企図される。例えば、抗体の結合親和性及び/又は他の生物学的特性を改善することが望まれ得る。抗体のアミノ酸配列変異体は、抗体をコードするヌクレオチド配列に適切な改変を導入することにより、またはペプチド合成によって調製することができる。このような改変は、例えば、抗体のアミノ酸配列内における、残基の欠失、及び/又は挿入及び/又は置換を含む。最終コンストラクトが所望の特性、例えば、抗原結合を有していることを条件として、欠失、挿入、及び置換の任意の組み合わせが、最終コンストラクトに到達させるために作成され得る。
所定の実施態様において、一つ以上のアミノ酸置換を有する抗体変異体が提供される。置換突然変異の対象となる部位は、HVRとFRを含む。保存的置換は、表1の「保存的置換」の見出しの下に示されている。より実質的な変更が、表1の「典型的な置換」の見出しの下に与えられ、アミノ酸側鎖のクラスを参照して以下に更に説明される。アミノ酸置換は、目的の抗体に導入することができ、その産物は、所望の活性、例えば、抗原結合の保持/改善、免疫原性の減少、又はADCC又はCDCの改善についてスクリーニングされた。
(1)疎水性:ノルロイシン,Met,Ala,Val,Leu,Ile;
(2)中性の親水性:Cys,Ser,Thr,Asn,Gln;
(3)酸性:His,Lys,Arg;
(4)塩基性:His,Lys,Arg;
(5)鎖配向に影響する残基:Gly,Pro;
(6)芳香族:Trp,Tyr,Phe.
所定の実施態様において、本明細書で提供される抗体は抗体がグリコシル化される程度を増加または減少するように改変される。抗体へのグリコシル化部位の付加または欠失は、一以上のグリコシル化部位が作成または削除されるようにアミノ酸配列を変えることによって簡便に達成することができる。
所定の実施態様において、1つまたは複数のアミノ酸改変を、本明細書で提供される抗体のFc領域に導入することができ、それによってFc領域変異体を生成する。Fc領域の変異体は、1つまたは複数のアミノ酸位置においてアミノ酸修飾(例えば置換)を含むヒトFc領域の配列(例えば、ヒトIgG1、IgG2、IgG3又はIgG4のFc領域)を含んでもよい。
所定の実施態様において、抗体の1つ以上の残基がシステイン残基で置換されている、システイン改変抗体、例えば、「thioMAbs」を作成することが望まれ得る。特定の実施態様において、置換された残基は、抗体のアクセス可能な部位で起きる。それらの残基をシステインで置換することにより、反応性チオール基は、それによって抗体のアクセス可能な部位に配置され、本明細書中でさらに記載されるように、イムノコンジュゲーを作成するために、例えば薬物部分またはリンカー−薬剤部分などの他の部分に抗体をコンジュゲートするために使用することができる。所定の実施態様において、一以上の以下の残基がシステインで置換され得る:軽鎖のV205(Kabatの番号付け);重鎖のA118(EU番号付け);及び重鎖Fc領域のS400(EU番号付け)。システイン改変抗体は、例えば、米国特許第7521541号に記載のように生成され得る。
所定の実施態様において、本明細書で提供される抗体は、当技術分野で知られ、容易に入手されている追加の非タンパク質部分を含むように更に改変することができる。抗体の誘導体化に適した部分としては、限定されないが、水溶性ポリマーを含む。水溶性ポリマーの非限定的な例は、限定されないが、ポリエチレングリコール(PEG)、エチレングリコール/プロピレングリコールの共重合体、カルボキシメチルセルロース、デキストラン、ポリビニルアルコール、ポリビニルピロリドン、ポリ−1,3−ジオキソラン、ポリ−1,3,6−トリオキソラン、エチレン/無水マレイン酸共重合体、ポリアミノ酸(単独重合体又はランダム共重合体の何れか)及びデキストラン又はポリ(n−ビニルピロリドン)ポリエチレングリコール、プロピレングリコール単独重合体、プロピレンオキシド/エチレンオキシド共重合体、ポリオキシエチル化ポリオール(例えばグリセロール)、ポリビニルアルコール及びこれらの混合物を包含する。ポリエチレングリコールプロピオンアルデヒドはその水中での安定性のために製造上の利点を有し得る。ポリマーは何れかの分子量のものであってよく、そして分枝鎖又は未分枝鎖であってよい。抗体に結合するポリマーの数は変動してよく、そして、一以上の重合体が結合する場合は、それらは同じか又は異なる分子であることができる。一般的に、誘導体化に使用するポリマーの数及び/又は種類は、限定されないが、向上させるべき抗体の特定の特性又は機能、抗体誘導体が特定の条件下で治療に使用されるのか等を考慮しながら決定することができる。
抗体は、例えば米国特許第4816567号で説明したように、組換えの方法および組成物を用いて製造することができる。一実施態様において、本明細書に記載される抗Axl抗体をコードする単離された核酸が提供される。このような核酸は、抗体のVLを含むアミノ酸配列、及び/又は抗体のVHを含むアミノ酸配列(例えば、抗体の軽鎖及び/又は重鎖)をコードし得る。更なる実施態様において、そのような核酸を含む1つ以上のベクター(例えば、発現ベクター)が提供される。更なる実施態様において、そのような核酸を含む宿主細胞が提供される。一実施態様において、宿主細胞は以下を含む(例えば、以下で形質転換される):(1)抗体のVLを含むアミノ酸配列、及び抗体のVHを含むアミノ酸配列をコードする核酸を含むベクター、又は(2)抗体のVLを含むアミノ酸配列をコードする核酸を含む第一ベクター、及び抗体のVHを含むアミノ酸配列をコードする核酸を含む第ニベクター。一実施態様において、宿主細胞は、真核生物、例えばチャイニーズハムスター卵巣(CHO)細胞、またはリンパ系細胞(例えば、Y0、NS0、Sp20細胞)である。一実施態様において、抗Axl抗体を作る方法が提供され、その方法は、上記のように、抗体の発現に適した条件下で、抗体をコードする核酸を含む宿主細胞を培養することを含み、および必要に応じて、宿主細胞(または宿主細胞培養培地)から抗体を回収することを含む。
本明細書で提供される抗Axl抗体は、同定され、当技術分野で公知の様々なアッセイによってその物理的/化学的性質及び/又は生物学的活性についてスクリーニングされ、または特徴づけることができる。
一態様において、本発明の抗体は、例えばELISA、ウエスタンブロット法など公知の方法により、その抗原結合活性について試験される。
一態様において、アッセイは、生物学的活性を有するそれらの抗Axl抗体を同定するために与えられる。生物学的活性は、例えば、AxlへのGas6結合の阻害、Axl活性化の阻害、Axl下流分子シグナル伝達の阻害、Axl発現(例えば、Axlの細胞表面の発現、又は腫瘍細胞などの細胞内の全Axl発現)の阻害、炎症性サイトカイン分泌の阻害、アポトーシスの促進(例えば、Gas6媒介性アポトーシス阻害を阻害することによる)、腫瘍内血管系の抑制、腫瘍間質性Axl活性及び/又は発現の阻害、及び/又は転移の阻害を含み得る。インビボ及び/又はインビトロでこのような生物学的活性を有する抗体もまた提供される。
本発明はまた、化学療法剤又は薬物、成長抑制剤、毒素(例えば、タンパク質毒素、細菌、真菌、植物、または動物起源の酵素活性毒素、又はそれらの断片)、又は放射性同位元素など、1つ以上の細胞傷害性薬物にコンジュゲートした本明細書中の抗Axl抗体を含むイムノコンジュゲートを提供する。
所定の実施態様において、本明細書で提供される抗LRP6抗体の何れかは、生物学的サンプル中のAxlの存在を検出するのに有用である。本明細書で使用する「検出」という用語は、定量的または定性的検出を包含する。所定の実施態様において、生物学的サンプルは、乳房、膵臓、食道、肺及び/又は脳などの細胞または組織を含む。
本明細書に記載の抗Axl抗体の薬学的製剤は、所望の程度の純度を有するその抗体と任意の薬学的に許容される担体(Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed.: Williams and Wilkins PA, USA (1980))とを、凍結乾燥製剤または水性溶液の形態で混合することによって調製される。薬学的に許容される担体は、使用される投薬量および濃度でレシピエントに毒性でなく、そしてこれには、限定しないが、リン酸塩、クエン酸塩および他の有機酸のような緩衝液;アスコルビン酸およびメチオニンを含む抗酸化剤;防腐剤(例えば、オクタデシルジメチオルベンジルアンモニウムクロライド;ヘキサメトニウムクロライド;塩化ベンザルコニウム、塩化ベンゼトニウム、フェノール、ブチルまたはベンジルアルコール;アルキルパラベン、例えば、メチルまたはプロピルパラベン;カテコール;レゾルシノール;シクロヘキサノール;3−ペンタノール;およびm−クレゾール);低分子量(約10残基未満)ポリペプチド;タンパク質、例えば、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;アミノ酸、例えば、グリシン、グルタミン、アスパラギン、ヒスチジン、アルギニンまたはリジン;マンノサッカライド、ジサッカライド、およびグルコース、マンノースまたはデキストリンを含む他の炭水化物;キレート剤、例えば、EDTA;糖、例えば、スクロース、マンニトール、トレハロースまたはソルビトール;塩形成対イオン、例えば、ナトリウム、金属錯体(例えば、Zn−タンパク質錯体);及び/又はポリエチレングリコール(PEG)等の非イオン性界面活性剤が挙げられる。本明細書における典型的な薬学的に許容される担体は、介在性薬物分散剤、例えば、水溶性の中性アクティブヒアルロニダーゼ糖タンパク質(sHASEGP)、例えば、rHuPH20(HYLENEX(登録商標)、Baxter International,Inc.)などのヒト可溶性PH−20ヒアルロニダーゼ糖タンパク質を更に含む。所定の典型的なsHASEGP及び使用法は、rHuPH20を含み、米国特許出願公開第2005/0260186号及び第2006/0104968に開示されている。一態様において、sHASEGPは、コンドロイチナーゼなどの1つまたは複数の追加のグルコサミノグリカンと組み合わされる。
本明細書で提供される抗Axl抗体のいずれかを、治療方法で使用することができる。
本発明の他の実施態様において、上述した障害の治療、予防、及び/又は診断に有用な物質を含む製造品が提供される。製造品は、容器とラベルまたは容器上にあるまたは容器に付属するパッケージ挿入物を含む。好適な容器は、例としてボトル、バイアル、シリンジ、IV輸液バッグ 等を含む。容器はガラス又はプラスチックなどの様々な物質から形成されうる。容器は、疾患の治療、予防、及び/又は診断に有効である、それ自体か、又はその他の組成物と併用される化合物を収容し、無菌のアクセスポートを有し得る(例えば、容器は皮下注射針による穴あきストッパーを有する静脈内溶液バッグ又はバイアルであってよい)。組成物中の少なくとも一の活性剤は本発明の抗体である。ラベルまたはパッケージ挿入物は、組成物が特定の症状の治療のために使用されることを示している。更に、製造品は、(a)組成物が本発明の抗体を包含する組成物を含む第一の容器;および(b)組成物が更なる細胞障害性又はその他の治療的薬剤を包含する組成物を含む第2の容器を含み得る。本発明の本実施態様における製造品は、組成物が特定の疾患を治療することに用いることができることを示すパッケージ挿入物をさらに含んでいてもよい。別法として、または加えて、製造品は、薬学的に許容されるバッファー、例えば注射用静菌水(BWFI)、リン酸緩衝化塩水、リンガー溶液およびデキストロース溶液を含む第二(または第三)の容器をさらに含んでもよい。これは、他のバッファー、希釈剤、フィルター、針、およびシリンジを含む、商業的およびユーザーの立場から望まれる他の物質のさらに含んでもよい。
抗体と細胞株。抗体は次の供給者から得られた:ヒトAxlに対するマウスモノクローナル抗体(mAb)(Abnova,Taiwan)、リン酸化AktマウスmAb及びAktポリクローナル抗体(Cell Signaling)。マウス換えGAS6及びリン酸化Axl用ELISAキットは、R&Dシステムから購入した。ヒト癌細胞株は、ATCCから入手し、10%FBSを添加したPRMI1640培地で培養した。ハイブリドーマ抗ヒトAxlモノクローナル抗体の12A11及び3G9はジェネンテックにより提供された(Li(2009)を参照)。
Axl−2(PRK HuAxl(1−134Aa)/HuIgG1Fc),Axl−3(PRK HuAxl(1−221Aa)/HuIgG1Fc),Axl−4(PRK HuAxl(1−324Aa)/HuIgG1Fc),及びAxl−5(PRK HuAxl(1−435Aa)/HuIgG1Fc)プラスミドコンストラクトが、標準的な分子的技術により作成された。全てのプラスミドは、直接配列決定および/または制限酵素消化により確認した。Axlの細胞外ドメインの様々な部分(aa1−134,aa1−221,aa1−324,aa1−435)をコードするプラスミドを、インビトロで転写し、プロメガL2080 TNT SP6クイック転写/翻訳系キットを使用して翻訳し、ELISAにて抗原として使用した。これらの実験において使用されたAxlタンパク質:ヒトAxlのアミノ酸1−134(AxlのIg1を含む):MAWRCPRMGRVPLAWCLALCGWACMAPRGTQAEESPFVGNPGNITGARGLTGTLRCQLQVQGEPPEVHWLRDGQILELADSTQTQVPLGEDEQDDWIVVSQLRITSLQLSDTGQYQCLVFLGHQTFVSQPGYVG(配列番号111),及びヒトAxlのアミノ酸221−324(Axlのフィブロネクチンドメインを含む):ITVLPQQPRNLHLVSRQPTELEVAWTPGLSGIYPLTHCTLQAVLSDDGMGIQAGEPDPPEEPLTSQASVPPHQLRLGSLHPHTPYHIRVACTSSQGPSSWTHWL(配列番号130)。
Axlの機能をブロックするファージ由来のモノクローナル抗体の産生。マウス及びヒトのAxlと交差反応する抗体を同定するために、我々は、ヒトIgG抗体の天然の多様性を模倣し(Lee et al, 2004)、選択された相補性決定領域における合成の多様性を持つファージディスプレイ抗体ライブラリーを用いた。ヒト及びマウスAxl ECDに結合するファージ抗体がELISAにより同定され、DNA配列が決定され、全長IgGを発現するため、抗体クローンが再フォーマットされた(Liang et al, 2007)。次いで、全長IgGのパネルが、Baf3Axl細胞のGas6依存性増殖を阻害するそれらの能力についてスクリーニングされ(Li et al, 2009)、クローンの一つ、YW327.6が親和性成熟され精製された。
我々は、異種反応性及び腫瘍形成におけるAxlの様々な機能をブロックするヒト抗Axlモノクローナル抗体(YW327.6S2)を開発し、特徴づけてきた。最初に報告された、Axlに対する完全ヒト化遮断抗体であることに加えて、YW327.6S2は、癌の発生と進行の複数の側面において、Axl活性化/シグナル伝達の影響を調査するための強力なツールとして役割を果たすばかりでなく、様々な癌の治療のための潜在的治療を表わしている。
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前述の発明は、理解を明確にする目的のために例示および実施例によってある程度詳細に説明してきたが、説明や例は、本発明の範囲を限定するものとして解釈されるべきではない。すべての特許および本明細書に引用される科学文献の開示は、参照によりその全体が援用される。
Claims (27)
- Axlに結合する単離された抗体であって、(a)配列番号7のアミノ酸配列を含むHVR−H1、(b)配列番号8のアミノ酸配列を含むHVR−H2、(c)配列番号9のアミノ酸配列を含むHVR−H3、(d)配列番号10のアミノ酸配列を含むHVR−L1、(e)配列番号11のアミノ酸配列を含むHVR−L2、及び(f)配列番号12のアミノ酸配列を含むHVR−L3を含む、抗体。
- (a)配列番号103のアミノ酸配列に対して少なくとも95%の配列同一性を有するVH配列;(b)配列番号104のアミノ酸配列に対して少なくとも95%の配列同一性を有するVL配列;又は(c)(a)のVH配列と(b)のVL配列を含む、請求項1に記載の抗体。
- 配列番号103のVH配列、及び/又は配列番号104のVL配列を含む、請求項2に記載の抗体。
- Axl受容体の下方制御を促進し、及び/又は構成的Axl活性化を阻害する、請求項1から3の何れか一項に記載の抗体。
- 抗体が、次の配列番号111を含むか、本質的に配列番号111からなるか又は配列番号111からなるポリペプチドに結合する、請求項1から4の何れか一項に記載の抗体。
- モノクローナル抗体である、請求項1から5の何れか一項に記載の抗体。
- 全長IgG1抗体である、請求項1から6の何れか一項に記載の抗体。
- ヒト抗体、ヒト化抗体、キメラ抗体、又はAxlに結合する抗体断片である、請求項1から7の何れか一項に記載の抗体。
- 請求項1から8の何れか一項に記載の抗体をコードする単離された核酸。
- 請求項9に記載の核酸を含む宿主細胞。
- 請求項10の記載の宿主細胞を、抗体が産生されるように培養することを含む、抗体を産生する方法。
- 宿主細胞から抗体を回収することを更に含む、請求項11に記載の方法。
- 請求項1から8の何れか一項に記載の抗体と細胞傷害性薬物を含むイムノコンジュゲート。
- 請求項1から8の何れか一項に記載の抗体と薬学的に許容される担体を含む薬学的製剤。
- 付加的治療薬を更に含む請求項14に記載の薬学的製剤。
- 付加的治療薬が、VEGFアンタゴニスト、EGFRアンタゴニスト、及び化学療法剤から選択される、請求項15に記載の薬学的製剤。
- 医薬としての使用のための、請求項1から8の何れか一項に記載の抗体。
- 癌の治療に使用される、請求項1から8の何れか一項に記載の抗体。
- 細胞増殖阻害、Axl下方制御の促進、転移の阻害、及び/又は血管新生の阻害における使用のための、請求項1から8の何れか一項に記載の抗体。
- 医薬の製造における、請求項1から8の何れか一項に記載の抗体の使用。
- 医薬が、癌を治療するためである、請求項20の使用。
- 医薬が、細胞増殖の阻害、血管新生の阻害、Axl下方制御の促進、及び/又は転移の阻害のためである、請求項20に記載の使用。
- 請求項1から8の何れか一項に記載の抗体の有効量を含む、癌を有する個体を治療するための医薬。
- 付加的治療薬を更に含む、請求項23に記載の医薬。
- 付加的治療薬が、VEGFアンタゴニスト、EGFRアンタゴニスト、及び化学療法剤からなる群から選択される、請求項24の記載の医薬。
- 血管新生を阻害し、細胞増殖を阻害し、Axl受容体の下方制御を促進し、又は転移を阻害するために、請求項1から8の何れか一項に記載の抗体の有効量を含む、個体において、血管新生を阻害し、細胞増殖を阻害し、Axl受容体の下方制御を促進し又は転移を阻害するための薬剤。
- 構成的Axlを阻害するために、請求項1から8の何れか一項に記載の抗体の有効量を含む、構成的Axl活性化を阻害するための薬剤。
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US9644717B2 (en) | 2011-03-22 | 2017-05-09 | Bombardier Recreational Products Inc. | Continuously variable transmission driving pulley |
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HK1179636A1 (zh) | 2013-10-04 |
BR112012027995A2 (pt) | 2017-01-10 |
EP2582729A1 (en) | 2013-04-24 |
USRE47761E1 (en) | 2019-12-10 |
TW201204388A (en) | 2012-02-01 |
EP2582729A4 (en) | 2014-05-28 |
CA2794731C (en) | 2019-03-19 |
CN103080136A (zh) | 2013-05-01 |
CN103080136B (zh) | 2015-08-12 |
US8853369B2 (en) | 2014-10-07 |
EP3098240A3 (en) | 2017-04-05 |
RU2013102225A (ru) | 2014-07-27 |
RU2577986C2 (ru) | 2016-03-20 |
KR20130032896A (ko) | 2013-04-02 |
EP3098240A2 (en) | 2016-11-30 |
JP2013538553A (ja) | 2013-10-17 |
US20130243753A1 (en) | 2013-09-19 |
WO2011159980A1 (en) | 2011-12-22 |
EP3098240B1 (en) | 2021-04-07 |
KR101885388B1 (ko) | 2018-08-03 |
MX2012014535A (es) | 2013-01-29 |
MX336001B (es) | 2016-01-07 |
CA2794731A1 (en) | 2011-12-22 |
AR082017A1 (es) | 2012-11-07 |
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