JP6707445B2 - 抗Ly6E抗体及び使用方法 - Google Patents
抗Ly6E抗体及び使用方法 Download PDFInfo
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- JP6707445B2 JP6707445B2 JP2016525078A JP2016525078A JP6707445B2 JP 6707445 B2 JP6707445 B2 JP 6707445B2 JP 2016525078 A JP2016525078 A JP 2016525078A JP 2016525078 A JP2016525078 A JP 2016525078A JP 6707445 B2 JP6707445 B2 JP 6707445B2
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Description
本発明は、抗LY6E抗体及びイムノコンジュゲート並びにその使用方法に関する。
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、VLの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、A及びBのプログラムアラインメントにおいて、配列アラインメントプログラムALIGN−2によって同一であると一致したスコアのアミノ酸残基の数であり、YはBの全アミノ酸残基の全数である。アミノ酸配列Aの長さがアミノ酸配列Bの長さと一致しない場合、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一致しないと評価されるであろう。特に断らない限りは、ここで使用される全ての%アミノ酸配列同一性値は、直前のパラグラフに記載したように、ALIGN−2コンピュータプログラムを用いて得られる。
一態様において、本発明は、Ly6Eに結合する抗体及びそのような抗体を含むイムノコンジュゲートに、一部、基づいている。本発明の抗体とイムノコンジュゲートは、例えば、Ly6E陽性がんの診断又は治療のために有用である。
幾つかの実施態様において、本発明はLy6Eに結合する単離された抗体を提供する。ある実施態様において、抗Ly6E抗体は、以下の特性の少なくとも一以上を、任意の組み合わせで有する:
(a)配列番号1のアミノ酸21〜131内のエピトープに結合し;及び
(b)SPR又はスキャッチャード分析の何れかによって測定される場合、≦7nM、又は≦6nM、又は≦5nM、又は≦4nM、又は≦3nM、又は≦2nM、又は≦1nM、及び必要に応じて≧0.0001nM、又は≧0.001nM、又は≧0.01nMの親和性でLy6Eに結合する。
非限定的な例示的抗Ly6E抗体は、マウス9B12及びそのヒト化変異体、例えば、hu9B12.v12などである(例えば、配列番号4及び6並びに配列番号3及び5に示される可変領域配列を参照)。幾つかの実施態様において、Ly6EはヒトLy6Eである。幾つかの実施態様において、Ly6Eは、ヒト、カニクイザル、アカゲザル、マウス又はラットLy6Eから選択される。
非限定的な例示的抗Ly6E抗体は、図4に示されるようなウサギGEN−93−8−1及び抗体GEN−93−8−1の一又は複数のHVRを含む抗体である。幾つかの実施態様において、Ly6EはヒトLy6Eである。幾つかの実施態様において、Ly6Eは、ヒト、非ヒト霊長類、マウス又はラットLy6Eから選択される。幾つかの実施態様において、非ヒト霊長類Ly6Eは、カニクイザル又はアカゲザルLy6Eである。
抗Ly6E抗体が、配列番号1のアミノ酸21〜131内のエピトープに結合するかどうかを決定するため、N末端及びC末端の欠失を有するLy6Eポリペプチドが293細胞で発現され、切断型ポリペプチドに対する抗体の結合がFACSによって試験され、ここで、293細胞で発現された完全長Ly6Eへの結合に比較して、切断型ポリペプチドに対する抗体の結合の実質的な減少(≧70%の減少)又は消失は、抗体がその切断型ポリペプチドに結合しないことを示している。
ある実施態様において、本明細書において与えられる抗体は、≦1μM、≦100nM、≦10nM、≦1nM、≦0.1nM、≦0.01nM、又は≦0.001nM、及び任意で≧10−13M(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)の解離定数(Kd)を有する。
ある実施態様において、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、Pluckthuen, 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。
ある実施態様において、本明細書で提供される抗体は、キメラ抗体である。特定のキメラ抗体は、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。一例では、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、又はサルなど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。更なる例では、キメラ抗体は、クラス又はサブクラスが親抗体のクラス又はサブクラスから変えられている「クラス転換された」抗体である。キメラ抗体にはその抗原結合断片が含まれる。
ある特定の実施態様では、本明細書に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種々の技術を使用して産生することができる。ヒト抗体は、van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001) 及びLonberg, Curr. Opin. Immunol. 20:450-459 (2008)に一般的に記載されている。
本発明の抗体は、所望の活性又は活性(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。
ある実施態様において、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。ある実施態様において、結合特異性の一つはLy6Eに対してであり、他は、任意の他の抗原に対してである。ある実施態様において、結合特異性の一つはLy6Eに対してであり、他はCD3に対してである。例えば、米国特許第5821337号を参照。ある実施態様において、二重特異性抗体は、Ly6E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Ly6Eを発現する細胞に対して細胞傷害性薬物を局在化させ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。
ある実施態様において、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、又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。
ある実施態様において、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。置換型変異誘発の対象となる部位は、HVRとFRを含む。保存的置換は、表1の「望ましい置換」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「例示的置換」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る。
(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:Asp、Glu;
(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.
ある実施態様において、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が増加又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又は欠失は、一以上のグリコシル化部位が作成又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。
ある実施態様において、1つ又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領域変異体は、1つ又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。
ある実施態様において、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、システイン操作抗体、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存在する。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、本明細書中で更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、例えば薬物部分又はリンカー−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。ある実施態様において、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。
ある実施態様において、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−トリオキサン、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に起因して製造における利点を有し得る。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ってよい。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、抗体誘導体が限定された条件下で治療に使用されるのか等を含む考慮に基づいて決定することができる。
抗体は、例えば米国特許第4,816,567号で説明したように、組換えの方法及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Ly6E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一以上のベクター(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二ベクター。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、又はリンパ系細胞(例えば、Y0、NS0、Sp20細胞)である。一実施態様において、抗Ly6E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、及び必要に応じて、宿主細胞(又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Ly6E抗体は、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同定され、スクリーニングされ、又は特徴づけることができる。
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、又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(即ち、放射性コンジュゲート)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Ly6E抗体を含むイムノコンジュゲートを提供する。
ある実施態様において、本明細書で提供される抗Ly6E抗体の何れかは、生物学的試料中のLy6Eの存在を検出するために有用である。本明細書で使用する「検出」という用語は、定量的又は定性的検出を包含する。「生物学的試料」は、例えば細胞又は組織(例えば、がん性又は潜在的にがん性の結腸、結腸直腸、子宮内膜、膵臓、又は卵巣組織を含む生検材料)を含む。
本明細書に記載の抗Ly6E抗体又はイムノコンジュゲートの薬学的製剤は、所望の程度の純度を有するその抗体又はイムノコンジュゲートと任意の薬学的に許容可能な担体(Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed.: Williams and Wilkins PA, USA (1980))とを、凍結乾燥製剤又は水性溶液の形態で混合することによって調製される。薬学的に許容可能な担体は、使用される投薬量及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、クエン酸塩及び他の有機酸のような緩衝液;アスコルビン酸及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、ブチル又はベンジルアルコール;アルキルパラベン、例えば、メチル又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;及び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、又は免疫グロブリン;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、アルギニン又はリジン;マンノサッカライド、ジサッカライド、及びグルコース、マンノース又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、トレハロース又はソルビトール;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可能な担体は、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)などの介在性薬物分散剤、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。特定の例示的sHASEGP及び使用方法は、rHuPH20を含めて、米国特許公開第2005/0260186号及び第2006/0104968号に記載されている。一態様において、sHASEGPは、コンドロイチナーゼなどの一以上の付加的なグルコサミノグリカナーゼと組み合わされる。
本明細書で提供される抗Ly6E抗体又はイムノコンジュゲートの何れかを、例えば治療方法などの方法で使用することができる。
本発明の別の態様において、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、容器とラベル又は容器上にある又は容器に付属する添付文書を含む。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、単独で、又は別の組成物と組み合わせて、障害を治療、予防及び/若しくは診断するのに有効な組成物を収容し、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って貫通可能なストッパーを有する静脈輸液バッグ又はバイアルでもよい)。組成物中の少なくとも一の活性剤は本発明の抗体又はイムノコンジュゲートである。ラベル又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又はイムノコンジュゲートを包含する組成物を含む第一の容器;及び(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二の容器を含み得る。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更に含んでいてもよい。あるいは、又は更に、製造品は、薬学的に許容可能な緩衝液、例えば注射用静菌水(BWFI)、リン酸緩衝食塩水、リンガー液又はデキストロース溶液を含む第2(又は第3)の容器を更に含むことができる。他の緩衝液、希釈剤、濾過器、針及び注射器を含めた、商業的及び使用者の観点から望ましい他の材料を更に含んでいてもよい。
本発明の別の態様において、上述した障害の治療、予防、及び/又は診断に有用な以下の配列が提供される。
以下は本発明の方法及び組成物の例である。上記提供される一般的な説明を前提として、他の様々な実施態様が実施され得ることが理解される。
GeneLogicプロファイル:複数のヒト腫瘍及び正常な生検試料におけるLy6E mRNA発現の解析のために、Affymetrixデータをジーンロジック社から入手した。プローブセットID202145_atについて示される解析は、3879の正常なヒト組織試料(緑の記号)、1605のヒトがん組織試料(赤の記号:1291は原発性及び314は転移性)、並びに3872ヒトの非がん疾患組織試料(青の記号)に関してHGU133 Plus v2遺伝子チップを使用して実施された。マイクロアレイデータをAffymetrix MAS(Microarray Analysis Suite)5.0版ソフトウェアを使用して標準化し、試料発現値を500のトリム平均にスケーリングした。
Origene、Rockville、MD(HMRT 102)の48正常組織のパネル由来の第1鎖DNAを含むヒト主要組織のqPCRアレイを、Ly6ERNAの発現についてアッセイした。選択したがん細胞系統及び組織(***及び膵臓)のパネル中のLy6Eの発現を同時にアッセイした。Taqmanアッセイを、Applied Biosystems(ABI、Foster City、CA)の試薬、機器及びソフトウェアを使用してセットアップした。プライマー−プローブセットは、レポーター色素FAM及びクエンチャー色素TAMRAにより二重に標識された蛍光発生プローブに隣接するプライマーを考慮して設計された。
フォワードプライマー −5’AGA AGG CGT CAA TGT TGG T(配列番号51);リバースプライマー −5’CAC TGA AAT TGC ACA GAA AGC(配列番号52)及びプローブ −5’TTC CAT GGG CAT CAG CTG CTG(配列番号53)。
3匹のウサギは、細菌(大腸菌)が生成したHisタグ付きLy6E(YenZym,South San Francisco,CA)を用いて免疫化された。試験採血を用いたLy6Eに対する血清力価は、標準的なプロトコルを用いて評価された。1匹のウサギが良好な免疫応答を有することが判明し、脾臓摘出及びモノクローナル融合のための候補として選択された。
免疫組織化学(IHC)はVentana Discovery XT自動染色装置(Ventana Medical Systems;Tucson,AZ)で行われた。ホルマリン固定パラフィン包埋全組織及び組織マイクロアレイ切片を脱パラフィンし、60分間CC1溶液(Ventana Medical Systems)で前処理し、続いて0.2μg/mLの抗Ly6E抗体クローンGEN−93−8−1又はナイーブウサギIgG(Clone DA1E,Cell Signaling Technologies;Danvers,MA)の何れかとともに37℃で60分間インキュベートした。検出は、32分間のOmniMap抗ウサギ西洋ワサビペルオキシダーゼ(HRP)インキュベーション及びジアミノベンジジン(DAB)(Ventana Medical Systems)により行われ、続いてヘマトキシリンII(Ventana Medical Systems)によるカウンター染色を行った。
正常なヒト組織マイクロアレイ(TMA)は、ウサギ抗Ly6E抗体GEN9381で染色された。弱い(1+)陽性染色は、脾臓、***、副腎、唾液腺、子宮頸部、及び子宮の子宮内膜で観察され、中程度(2+)の陽性染色は、大脳皮質及び小脳で観察された。同じ抗Ly6E抗体で染色された正常カニクイザル組織は、正常な***組織において弱い(1+)発現、及び及び脾臓、子宮の子宮内膜、及び膀胱上皮において中程度(2+)の染色を明らかにした。表5を参照。
大規模な抗体産生のために、抗体hu9B12.v12 waは、CHO細胞において産生された。VL及びVHをコードするベクターは、CHO細胞にトランスフェクトされ、IgGはプロテインAアフィニティークロマトグラフィーによって細胞培養培地から精製された。
乳がん細胞株HCC1569(CRL−2330)及び膵臓がん細胞株SU.86.86(CRL−1837)は、アメリカン・タイプ・カルチャー・コレクション(ATCC,Manassas,VA)から入手した。CHO−K1Sは、CHO−K1の懸濁細胞株誘導体である。HCC1569 X2細胞株は、インビボでの増殖のために最適化された親HCC1569細胞株(ATCC、CRL−2330)の誘導体である。親のHCC1569細胞は、の右脇腹に皮下注射され、一つの腫瘍が回収され、刻まれ、インビトロで増殖され、HCC1569 X1細胞株を生じた。HCC1569 X1株は、細胞株の成長を改善する目的で、メスのTaconic NCrヌードマウスの右脇腹に再び皮下注射された。この研究からの腫瘍を回収し、HCC1569 X2細胞株を生成するためにインビトロでの増殖に再び適応させた。この株から由来する腫瘍はLy6Eを発現する。
Claims (35)
- (a)配列番号32のアミノ酸配列を含むHVR−H1、(b)配列番号33のアミノ酸配列を含むHVR−H2、(c)配列番号34のアミノ酸配列を含むHVR−H3、(d)配列番号29のアミノ酸配列を含むHVR−L1、(e)配列番号30のアミノ酸配列を含むHVR−L2、及び(f)配列番号31のアミノ酸配列を含むHVR−L3を含む、Ly6Eに結合する単離された抗体。
- (a)配列番号28のアミノ酸配列に少なくとも95%の配列同一性を有するVH配列;(b)配列番号27のアミノ酸配列に少なくとも95%の配列同一性を有するVL配列;又は(c)(a)のVH配列及び(b)のVL配列を含む、請求項1に記載の抗体。
- 配列番号28のVH配列を含む、請求項1又は2に記載の抗体。
- 配列番号27のVL配列を含む、請求項1から3の何れか一項に記載の抗体。
- 配列番号28のVH配列及び配列番号27のVL配列を含む、Ly6Eに結合する単離された抗体。
- 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。
- マウス、ウサギ、ヒト、ヒト化、又はキメラ抗体である、請求項6に記載の抗体。
- IgG1、IgG2a、IgG2b、IgG3、及びIgG4から選択されるIgG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。
- 抗体が産生されるように、請求項10に記載の宿主細胞を培養することを含む、抗体を産生する方法。
- 請求項1から8の何れか一項に記載の抗体及び細胞傷害性薬物を含む、イムノコンジュゲート。
- 請求項12に記載のイムノコンジュゲート及び薬学的に許容可能な担体を含む薬学的製剤。
- 標識にコンジュゲートした、請求項1から8の何れか一項に記載の抗体。
- 標識が陽電子放出体である、請求項14に記載の抗体。
- 陽電子放出体が89Zrである、請求項15に記載の抗体。
- 天然に生じるヒトLy6Eに対する抗Ly6E抗体の結合を許容する条件下で、生物学的試料を請求項1から8及び14から16の何れか一項に記載の抗Ly6E抗体と接触させること、及び生物学的試料中で抗Ly6E抗体と天然に生じるヒトLy6Eとの間に複合体が形成されるかを検出することを含む、生物学的試料中のヒトLy6Eを検出するインビトロ方法。
- 抗Ly6E抗体が請求項5に記載の抗体である、請求項17に記載のインビトロ方法。
- 生物学的試料が乳がん試料、膵臓がん試料、結腸がん試料、結腸直腸がん試料、黒色腫がん試料、卵巣がん試料、非小細胞肺がん試料、食道がん試料、頭頸部がん試料、腎臓がん試料、軟組織がん試料、子宮内膜がん試料、又は胃がん試料である、請求項17又は請求項18に記載のインビトロ方法。
- 被験体においてLy6E陽性がんを検出するためのキットであって、請求項1から8の何れか一項に記載の抗Ly6E抗体を含む標識抗Ly6E抗体を含み、(i)該標識抗Ly6E抗体がLy6E陽性がんを有するか又は有することが疑われる被験体に投与され、及び(ii)被験体において標識抗Ly6E抗体が検出され、標識抗Ly6E抗体の検出が、被験体のLy6E陽性がんを示す、キット。
- 標識抗Ly6E抗体が標識された請求項5に記載の抗体である、請求項20に記載のキット。
- 標識抗Ly6E抗体が陽電子放出体にコンジュゲートした抗Ly6E抗体を含む、請求項20又は21に記載のキット。
- 陽電子放出体が89Zrである、請求項22に記載のキット。
- Ly6E陽性がんを有するとしてがん患者を同定するためのキットであって、請求項1から8及び14から16の何れか一項に記載の抗Ly6E抗体を含み、天然に生じるヒトLy6Eに対する抗Ly6E抗体の結合を許容する条件下で、患者からのがん試料が抗Ly6E抗体と接触させられ、及びがん試料中で抗Ly6E抗体と天然に生じるヒトLy6Eとの間に複合体が形成されるかが検出される、キット。
- がん生検試料中で抗Ly6E抗体と天然に存在するヒトLy6Eとの間の複合体が検出される場合、がん患者はLy6E陽性がんを有するとして同定される、請求項24に記載のキット。
- 抗Ly6E抗体を含むイムノコンジュゲートによる治療のためのLy6E陽性がんを有するがん患者を選択するためのキットであって、請求項1から8及び14から16の何れか一項に記載の抗Ly6E抗体を含み、天然に生じるヒトLy6Eに対する抗Ly6E抗体の結合を許容する条件下で、患者からのがん試料が抗Ly6E抗体と接触させられ、及びがん試料中で抗Ly6E抗体と天然に生じるヒトLy6Eとの間に複合体が形成されるかが検出される、キット。
- がん生検試料中で抗Ly6E抗体と天然に存在するヒトLy6Eとの間の複合体が検出される場合、上記がん患者が選択される、請求項26に記載のキット。
- イムノコンジュゲートが、(a)配列番号10のアミノ酸配列を含むHVR−H1、(b)配列番号11のアミノ酸配列を含むHVR−H2、(c)配列番号12のアミノ酸配列を含むHVR−H3、(d)配列番号7のアミノ酸配列を含むHVR−L1、(e)配列番号8のアミノ酸配列を含むHVR−L2;及び(f)配列番号9のアミノ酸配列を含むHVR−L3を含む抗Ly6E抗体を含む、請求項26又は請求項27に記載のキット。
- 抗Ly6E抗体が配列番号5のVH配列及び配列番号3のVL配列を含む、請求項28に記載のキット。
- イムノコンジュゲートが細胞傷害性薬物にコンジュゲートした抗Ly6E抗体を含む、請求項26から29の何れか一項に記載のキット。
- Ly6E陽性がんを有するがん患者からのがん試料が、乳がん試料、膵臓がん試料、結腸がん試料、結腸直腸がん試料、黒色腫がん試料、卵巣がん試料、非小細胞肺がん試料、食道がん試料、頭頸部がん試料、腎臓がん試料、軟組織がん試料、子宮内膜がん試料、又は胃がん試料である、請求項26から30の何れか一項に記載のキット。
- 乳がん試料が、Her2陽性乳がん、Her2陰性乳がん、Her2陰性/ホルモン受容体陽性(Her2−/ER+/PR+)乳がん、又は三種陰性(Her2−/ER−/PR−)乳がんからのものである、請求項19に記載の方法。
- 胃がん試料がHer2陽性胃がん又はHer2陰性胃がんからのものである、請求項19に記載の方法。
- 乳がん試料が、Her2陽性乳がん、Her2陰性乳がん、Her2陰性/ホルモン受容体陽性(Her2−/ER+/PR+)乳がん、又は三種陰性(Her2−/ER−/PR−)乳がんからのものである、請求項31に記載のキット。
- 胃がん試料がHer2陽性胃がん又はHer2陰性胃がんからのものである、請求項31に記載のキット。
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AR080243A1 (es) | 2010-02-23 | 2012-03-21 | Genentech Inc | Composiciones y metodos para el diagnostico y tratamiento de tumores |
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AU2014340378A1 (en) * | 2013-10-21 | 2016-04-21 | Genentech, Inc. | Anti-Ly6E antibodies and methods of use |
AR101844A1 (es) * | 2014-09-12 | 2017-01-18 | Genentech Inc | Anticuerpos y conjugados modificados genéticamente con cisteína |
CN108064246A (zh) * | 2015-06-15 | 2018-05-22 | 基因泰克公司 | 抗体和免疫结合物 |
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US9290578B2 (en) | 2016-03-22 |
CA2924697A1 (en) | 2015-04-30 |
US20190085089A1 (en) | 2019-03-21 |
AU2014340378A1 (en) | 2016-04-21 |
RU2016118573A3 (ja) | 2018-05-24 |
BR112016008146A2 (pt) | 2017-10-03 |
WO2015061209A1 (en) | 2015-04-30 |
US10889651B2 (en) | 2021-01-12 |
IL244643A0 (en) | 2016-04-21 |
AR098126A1 (es) | 2016-05-04 |
HK1225612A1 (zh) | 2017-09-15 |
CN105658237A (zh) | 2016-06-08 |
CN105658237B (zh) | 2021-03-09 |
EP3060253B1 (en) | 2018-12-19 |
MX2016004853A (es) | 2016-07-19 |
SG11201603125SA (en) | 2016-05-30 |
US10066022B2 (en) | 2018-09-04 |
KR20160068963A (ko) | 2016-06-15 |
EP3060253A4 (en) | 2017-05-17 |
US20150132218A1 (en) | 2015-05-14 |
RU2016118573A (ru) | 2017-11-28 |
US20170058042A1 (en) | 2017-03-02 |
JP2017500007A (ja) | 2017-01-05 |
EP3060253A1 (en) | 2016-08-31 |
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