JP2018093873A - B7−h1に対する標的結合剤 - Google Patents
B7−h1に対する標的結合剤 Download PDFInfo
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- JP2018093873A JP2018093873A JP2017250880A JP2017250880A JP2018093873A JP 2018093873 A JP2018093873 A JP 2018093873A JP 2017250880 A JP2017250880 A JP 2017250880A JP 2017250880 A JP2017250880 A JP 2017250880A JP 2018093873 A JP2018093873 A JP 2018093873A
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Abstract
Description
(a)配列番号3と同一のアミノ酸配列、または配列番号3に対して1つ、2つ、または3つのアミノ酸残基置換を含むアミノ酸配列を有するVH CDR1、
(b)配列番号4と同一のアミノ酸配列、または配列番号4に対して1つ、2つ、または3つのアミノ酸残基置換を含むアミノ酸配列を有するVH CDR2、
(c)配列番号5と同一のアミノ酸配列、または配列番号5に対して1つ、2つ、または3つのアミノ酸残基置換を含むアミノ酸配列を有するVH CDR3、
(d)配列番号8のVL CDR1と同一のアミノ酸配列、または配列番号8のVL CDR1に対して1つ、2つ、または3つのアミノ酸残基置換を含むアミノ酸配列を有するVL CDR1、
(e)配列番号9と同一のアミノ酸配列、または配列番号9に対して1つ、2つ、または3つのアミノ酸残基置換を含むアミノ酸配列を有するVL CDR2、および
(f)配列番号10と同一のアミノ酸配列、または配列番号10に対して1つ、2つ、または3つのアミノ酸残基置換を含むアミノ酸配列を有するVL CDR3
を有する配列を含む、標的結合剤または抗体を含む。
(a)配列番号23と同一のアミノ酸配列、または配列番号23に対して1つ、2つ、または3つのアミノ酸残基置換を含むアミノ酸配列を有するVH CDR1、
(b)配列番号24と同一のアミノ酸配列、または配列番号24に対して1つ、2つ、または3つのアミノ酸残基置換を含むアミノ酸配列を有するVH CDR2、
(c)配列番号25と同一のアミノ酸配列、または配列番号25に対して1つ、2つ、または3つのアミノ酸残基置換を含むアミノ酸配列を有するVH CDR3、
(d)配列番号28のVL CDR1と同一のアミノ酸配列、または配列番号28のVL CDR1に対して1つ、2つ、または3つのアミノ酸残基置換を含むアミノ酸配列を有するVL CDR1、
(e)配列番号29と同一のアミノ酸配列、または配列番号29に対して1つ、2つ、または3つのアミノ酸残基置換を含むアミノ酸配列を有するVL CDR2、および
(f)配列番号30と同一のアミノ酸配列、または配列番号30に対して1つ、2つ、または3つのアミノ酸残基置換を含むアミノ酸配列を有するVL CDR3
を有する配列を含む、標的結合剤または抗体を含む。
増殖または侵入関連疾患、
新生物疾患、
非新生物疾患、
悪性腫瘍、もしくは
慢性ウイルス感染、または
B7−H1発現に関連する疾患もしくは状態
の治療は、前述の疾患または状態のいずれかを管理する、改善する、防止することを含む。
特に定義されない限り、本明細書に使用される科学的および技術的用語は、当業者によって一般的に理解される意味を有するものとする。さらに、特に文脈上必要とされない限り、単数形の用語は複数を含み、複数形の用語は単数形を含むものとする。一般に、本明細書に記載される細胞および組織の培養物、分子生物学、ならびにタンパク質およびオリゴ−もしくはポリヌクレオチド化学およびハイブリッド形成に関連して利用される命名法、およびそれらの技術は、当該分野において周知であり、一般的に使用されるものである。
基本的な抗体の構造単位は、四量体を含むことが知られている。各四量体は、ポリペプチド鎖の2つの同一対から成り、各対は、1つの「軽」鎖(約25kDa)と、1つの「重」鎖(約50〜70kDa)とを有する。各鎖のアミノ末端部分は、主に抗原認識に関与する約100〜110以上のアミノ酸の可変領域を含む。各鎖のカルボキシ末端部分は、主にエフェクター機能に関与する定常領域を画定する。ヒト軽鎖は、カッパおよびラムダ軽鎖として分類される。重鎖は、ミュー、デルタ、ガンマ、アルファ、またはイプシロンとして分類され、それぞれ、IgM、IgD、IgA、およびIgEのように抗体のアイソタイプを定義する。軽鎖および重鎖内で、可変および定常領域は、約12以上のアミノ酸の「J」領域によって接合され、重鎖も、約10以上のアミノ酸の「D」領域を含む。一般的に、 Fundamental Immunology Ch.7(Paul,W.,ed.,2nd ed.Raven Press,N.Y.(1989))を参照のこと(全ての目的において、参照によりその全体が組み込まれる)。各軽鎖/重鎖対の可変領域は、抗体結合部位を形成する。
ヒト抗体は、マウスもしくはラット可変および/または定常領域を保有する抗体に関連する問題のいくつかを回避する。そのようなマウスもしくはラット由来のタンパク質の存在は、抗体の急速なクリアランスをもたらすか、または患者により抗体に対する免疫応答の生成をもたらす場合がある。マウスもしくはラット由来の抗体の利用を回避するために、ゲッ齒類、他の哺乳類、または動物が完全ヒト抗体を生産するように、機能性ヒト抗体遺伝子座をゲッ齒類、他の哺乳類、または動物の中に導入することにより、完全ヒト抗体を生成することができる。
本明細書に記載される抗体は、以下に記載するXenoMouse(登録商標)技術の利用を通して調製された。そのようなマウスは、ヒト免疫グロブリン分子および抗体を産生することができるが、マウス免疫グロブリン分子および抗体の産生に欠ける。同様のことを達成するために利用された技術は、本明細書の背景技術セクションに開示される特許、出願、および参考文献において開示される。しかしながら、特に、マウスおよびそれからの抗体の遺伝子導入産生の好ましい実施形態は、1996年12月3日に出願された米国特許出願第08/759,620号、ならびに1998年6月11日に出願された国際特許出願WO第98/24893号、および2000年12月21日に出願されたWO第00/76310号に開示されており、それらの開示は、参照により本明細書に組み込まれる。Mendez et al.Nature Genetics15:146−156(1997)も参照し、この開示は、参照により本明細書に組み込まれる。
本発明の実施形態は、以下の表1に列挙される抗体を含む。この表は、それぞれ、各抗体の識別番号と、それとともに対応する重鎖および軽鎖の遺伝子およびポリペプチドの可変ドメインの配列番号を報告する。各抗体配列には、識別番号が与えられている。
本発明の実施形態は、障害の治療に有用である抗B7−H1抗体の減菌薬学的製剤を含む。そのような製剤は、B7−H1がその同族リガンドのうちの1つ以上に結合することを阻害し、それによって、例えば、血清または組織B7−H1が異常に上昇する病的状態を治療するであろう。本発明の抗体は、好ましくは、B7−H1活性を強力に阻害する、またはB7−H1がその同族リガンドのうちの1つ以上に結合することを阻害するための十分な親和性を保有し、好ましくは、ヒトにおける低頻度投与を可能にするのに十分な作用持続を有する。作用持続の延長は、皮下または筋肉内注射等の代替の非経口経路による、頻度が低く、より簡便な投与スケジュールを可能にする。
本発明に従い、またB7−H1に関して本明細書で産生され、特徴付けされる抗体の活性に基づき、抗体部分を超えた他の治療様式の設計が容易になり、当業者に開示される。そのような様式は、二重特異性抗体、免疫毒素、放射性標識化治療薬、および単一抗体Vドメイン等の進歩した抗体治療薬、V領域足場以外に基づく抗体様結合剤、単一ドメイン抗体、ペプチド治療薬の生成、新規足場におけるB7−H1結合ドメイン、遺伝子療法、特に細胞内抗体、アンチセンス治療薬、ならびに小分子を含むが、これらに限定されない。
本明細書に定義される抗腫瘍治療は、単独療法として適用されるか、または本発明の化合物に加え、従来の手術、骨髄および抹消血幹細胞移植、または放射線療法、もしくは化学療法を含むことができる。そのような化学療法は、以下の抗腫瘍剤のカテゴリーのうちの1つ以上を含み得る:
(i)アルキル化剤(例えば、シス−プラチン、オキサリプラチン、カルボプラチン、シクロホスファミド、ナイトロジェンマスタード、メルファラン、クロラムブシル、ブスルファン、テモゾロミド、およびニトロソウレア)、代謝拮抗薬(例えば、ゲムシタビンならびに5−フルオロウラシルおよびテガフールのようなフルオロピリミジン等の葉酸代謝拮抗薬、ラルチトレキセド、メトトレキサート、シトシンアラビノシド、およびヒドロキシウレア)、抗腫瘍抗生物質(例えば、アドリアマイシン、ブレオマイシン、ドキソルビシン、ダウノマイシン、エピルビシン、イダルビシン、マイトマイシン−C、ダクチノマイシン、およびミトラマイシンのようなアントラサイクリン)、抗有糸分裂剤(例えば、ビンクリスチン、ビンブラスチン、ビンデシン、およびビノレルビンのようなビンカアルカロイド、ならびにタキソールおよびタキソテールのようなタキソイド、ならびにポロキナーゼ阻害剤)、ならびにトポイソメラーゼ阻害剤(例えば、エトポシドのようなエピポドフィロトキシンおよびテニポシド、アムサクリン、トポテカンならびにカンプトテシン)等の、医療腫瘍学で使用される他の抗増殖/抗新生物薬物およびそれらの組み合わせ、(ii)抗エストロゲン(例えば、タモキシフェン、フルベストラント、トレミフェン、ラロキシフェン、ドロロキシフェン、およびイドキシフェン)、抗アンドロゲン(例えば、ビカルタミド、フルタミド、ニルタミド、および酢酸シプロテロン)、LHRH拮抗薬もしくはLHRH作動薬(例えば、ゴセレリン、リュープロレイン、およびブセレリン)、プロゲストーゲン(例えば、酢酸メゲストロール)、アロマターゼ阻害剤(例えば、アナストロゾール、レトロゾール、ボロゾール、およびエキセメスタン)、ならびにフィナステリド等の5α−レダクターゼの阻害剤等の、細胞分裂阻害剤、
(iii)抗侵入剤(anti−invasion agents)(例えば、4−(6−クロロ−2,3−メチレンジオキシアニリノ)−7−[2−(4−メチルピペラジン−1−イル)エトキシ]−5−テトラヒドロピラン−4−イルオキシキナゾリン(AZD0530;国際特許出願WO第01/94341)およびN−(2−クロロ−6−メチルフェニル)−2−{6−[4−(2−ヒドロキシエチル)ピペラジン−1−イル]−2−メチルピリミジン−4−いイルアミノ}チアゾール−5−カルボキサミド(dasatinib,BMS−354825;J.Med.Chem.,2004,47,6658−6661)のようなc−Srcキナーゼファミリー阻害剤)、およびマリマスタットのようなメタロプロテイナーゼ阻害剤、ウロキナーゼプラスミノーゲン活性化因子レセプター機能の阻害剤、またはカテプシン活性の阻害剤、セリンプロテアーゼの阻害剤、例えば、マトリプターゼ、ヘプシン、ウロキナーゼ、およびインテグリンαvβ6機能の阻害剤、
(iv)フルダラビン、2−クロロデオキシアデノシン、クロラムブシル、またはドキソルビシン、およびフルダラビン+シクロホスファミド、CVP:シクロホスファミド+ビンクリスチン+プレドニゾン、ACVBP:ドキソルビシン+シクロホスファミド+ビンデシン+ブレオマイシン+プレドニゾン、CHOP:シクロホスファミド+ドキソルビシン+ビンクリスチン+プレドニゾン、CNOP:シクロホスファミド+ミトキサントロン+ビンクリスチン+プレドニゾン、m−BACOD:メトトレキサート+ブレオマイシン+ドキソルビシン+シクロホスファミド+ビンクリスチン+デキサメタゾン+ロイコボリン、MACOP−B:メトトレキサート+ドキソルビシン+シクロホスファミド+ビンクリスチン+プレドニゾン固定用量+ブレオマイシン+ロイコボリン、またはProMACE CytaBOM:プレドニゾン+ドキソルビシン+シクロホスファミド+エトポシド+シタラビン+ブレオマイシン+ビンクリスチン+メトトレキサート+ロイコボリンの、それらの組み合わせ等の細胞毒性剤、
(v)成長因子機能の阻害剤:例えば、そのような阻害剤は、成長因子抗体および成長因子レセプター抗体(例えば、Stern et al.Critical reviews in oncology/haematology,2005,Vol.54,pp11−29に開示される抗erbB2抗体トラスツズマブ[Herceptin(商標)]、抗EGFR抗体パニツムマブ、抗erbB1抗体セツキシマブ[Erbitux,C225]、ならびにあらゆる成長因子および成長因子レセプター抗体)を含み、そのような阻害剤は、チロシンキナーゼ阻害剤、例えば、上皮増殖因子ファミリーの阻害剤(例えば、N−(3−クロロ−4−フルオロフェニル)−7−メトキシ−6−(3−モルホリノプロポキシ)キナゾリン−4−アミン(ゲフィチニブ、ZD1839)、N−(3−エチニルフェニル)−6,7−ビス(2−メトキシエトキシ)キナゾリン−4−アミン(エルロチニブ、OSI−774)、および6−アクリルアミド−N−(3−クロロ−4−フルオロフェニル)−7−(3−モルホリノプロポキシ)−キナゾリン−4−アミン(CI1033)等のEGFRファミリーチロシンキナーゼ阻害剤、ラパチニブ等のerbB2チロシンキナーゼ阻害剤、肝細胞増殖因子ファミリーの阻害剤、イマチニブ等の血小板由来成長因子ファミリーの阻害剤、セリン/スレオニンキナーゼの阻害剤(例えば、ファルネシルトランスフェラーゼ阻害剤等のRas/Rafシグナル伝達阻害剤、例えば、ソレフェニブ(BAY43−9006))、MEKおよび/またはAKTキナーゼを通した細胞シグナル伝達の阻害剤、肝細胞増殖因子ファミリーの阻害剤、c−kit阻害剤、ablキナーゼ阻害剤、IGFレセプター(インスリン様成長因子)キナーゼ阻害剤、オーロラキナーゼ阻害剤(例えば、AZD1152、PH739358、VX−680、MLN8054、R763、MP235、MP529、VX−528、およびAX39459)、ならびにCDK2および/またはCDK4阻害剤等のサイクリン依存性キナーゼ阻害剤、ならびにBcl−2、Bcl−XL等の生存シグナル伝達タンパク質、例えば、ABT−737も含む、
(vi)血管内皮増殖因子の作用を阻害するもの[例えば、抗血管内皮細胞成長因子抗体ベバシズマブ(Avastin(商標))]、および4−(4−ブロモ−2−フルオロアニリノ)−6−メトキシ−7−(1−メチルピペリジン−4−イルメトキシ)キナゾリン(ZD6474;WO第01/32651号内の実施例2)、4−(4−フルオロ−2−メチルインドール−5−イルオキシ)−6−メトキシ−7−(3−ピロリジン−1−イルプロポキシ)キナゾリン(AZD2171;WO第00/47212号内の実施例240)、バタラニブ(PTK787;WO第98/35985号)、および第SU11248(スニチニブ;WO第01/60814号)等のVEGFレセプターチロシンキナーゼ阻害剤、国際特許出願WO第97/22596号、WO第97/30035号、WO第97/32856号、WO第98/13354号、WO第00/47212号、およびWO第01/32651号に開示されるもの等の化合物、抗KDR抗体および抗flt1抗体等の抗血管内皮増殖因子レセプター抗体)、ならびに他の機構、またはコロニー刺激因子1(CSF1)、もしくはCSF1レセプターにより機能する化合物(例えば、リノミド、インテグリンαvβ3機能の阻害剤、およびアンジオスタチン)]等の抗血管新生剤;AZD2171のさらなる詳細は、Wedge et al(2005)Cancer Research.65(10):4389−400に見出され得る。AZD6474のさらなる詳細は、Ryan&Wedge(2005)British Journal of Cancer.92 Suppl 1:S6−13に見出され得る。双方の刊行物は、参照によりそれらの全体が本明細書に組み込まれる。
(viii)アンチセンス療法、例えば、ISIS2503、抗rasアンチセンス、または抗bcl2アンチセンスであるG3139(ゲナセンス)等の、上に列挙される標的を対象とするもの、
(ix)遺伝子療法アプローチ、例えば、異常p53もしくは異常BRCA1、またはBRCA2等の異常遺伝子を置換するアプローチ、シトシンデアミナーゼ、チミジンキナーゼ、または細菌性ニトロレダクターゼ酵素を使用するもの等のGDEPT(遺伝子指向性酵素プロドラッグ療法)アプローチ、および多剤耐性遺伝子療法等の化学療法もしくは放射線療法に対する患者の耐性を増加するアプローチを含む、
(x)例えば、アレムツズマブ(campath−1H(商標))を用いた治療、CD52に向けられるモノクローナル抗体、またはCD22に向けられる抗体を用いた治療、患者の腫瘍細胞の免疫原性を増加するための生体外および生体内アプローチ、インターロイキン2、インターロイキン4、または顆粒球マクロファージコロニー刺激因子等のサイトカインを用いた形質移入、CTLA−4機能を阻害するモノクローナル抗体を用いた治療等のT細胞の反応不顕性を低下させるアプローチ、サイトカイン形質移入された樹状細胞等の形質移入された免疫細胞を使用するアプローチ、サイトカイン形質移入された腫瘍細胞系を使用するアプローチ、ならびに非特異的に活性化された、または生体内で関心の特定の抗原を標的としたT細胞を使用する養子T細胞移入である、抗イディオタイプ抗体を使用するアプローチを含む、免疫療法アプローチ、
(xi)例えば、HIVもしくはHBV等の特定のウイルス感染を対象としたワクチンを用いた治療、または特定の腫瘍抗原を対象としたワクチンを用いた治療を含む、ワクチン接種アプローチ、
(xii)Velcade(ボルテゾミブ)等のプロテアソーム阻害剤等のタンパク質分解の阻害剤、
(xiii)生物学的療法治療アプローチ、例えば、レセプターリガンドを捕捉する、リガンドがレセプターに結合するのを阻害する、またはレセプターのシグナル伝達を低下させる(例えば、レセプター分解の強化、または発現レベルの低下)かのいずれかである、ペプチドまたはタンパク質(抗体、もしくは可溶性外部レセプタードメイン構築物)を使用するもの。
ヒトB7−H1 cDNA(Dong,H.et al.,1999,Nat.Med.5:1365−1369)を、ポリメラーゼ連鎖反応(PCR)を使用して、Imageクローン7262208(ATCC)から増幅した後、pcr3.1BidベクターのNhe1およびEcoR1部位の中にクローン化した。この構築物をCHO細胞(American Type Tissue Collection、カタログ番号#CCL−61)の中にリポフェクション導入(lipofected)し、細胞表面上の発現を蛍光活性化細胞分類(FACS)分析により確認した。
免疫化
ヒトB7−H1に対するモノクローナル抗体を、順次、XenoMouse(登録商標)マウス(XenoMouse株:XMG2(IgG2カッパ/ラムダ)およびXMG4(IgG4カッパ/ラムダ)Amgen,Inc.Vancouver,British Columbia,Canada)5〜10μgのB7−H1/Fcキメラタンパク質もしくは実施例1に記載する組み換えヒトB7−H1を発現する1−2x10(6)CHO細胞のいずれかで免疫化することにより開発した。
免疫化されたマウスからの血清中の抗体の滴定量をELISAアッセイにおいて決定した。プレート(Corning Costar、カタログ#3368)をヒトB7−H1/Fcタンパク質(R&D Systems Inc.、カタログ#156−B7−100)でコーティングした。B7−H1特異的抗体を西洋わさびペルオキシダーゼに共役されたマウス抗ヒトIgG抗体およびヤギ抗マウスIgG Fc抗体を用いて検出した。通常、各免疫化コホート内で最も滴定量が高い5匹の動物が、リンパ球単離、およびハイブリドーマの生成ために選択された。
免疫化マウスを頚部脱臼により屠殺し、所属リンパ腺を、各コホートから採取し、プールした。DMEM中で粉砕することによりリンパ球細胞を解離し、組織から細胞を開放し、細胞をDMEMに懸濁した。細胞を数え、1億のリンパ細胞当り0.9mlのDMEMを細胞ペレットに添加し、細胞を穏やかに、しかし完全に再懸濁した。1億の細胞当り100μlのCD90+磁気ビーズを使用して、15分間4℃で、磁気ビーズを用いて細胞をインキュベートすることにより、細胞を標識した。最大108の陽性細胞(または最大2×109の総細胞)を含有する磁気的に標識された細胞懸濁液をLS+カラム上に装填し、カラムをDMEMで洗浄した。全流出物をCD90陰性画分(これらの細胞の大半は、B細胞であると予想された)として収集した。
・膜切断:電圧:3000V、時間:30μ秒
・融合後保持時間:3秒
ECF後、細胞懸濁液を減菌条件下で融合チャンバから慎重に取り出し、L−グルタミン、pen/strep、OPI(オキサロ酢酸、ピルビン酸、ウシインスリン)(全てSigma)、およびIL−6(Boehringer Mannheim)で補充された、同容量のハイブリドーマ培養培地(DMEM,JRH Biosciences)、15%のFBS(Hyclone)を含有する減菌管中に移した。細胞を37℃で15〜30分間インキュベートした後、5分間、400xg(1000rpm)で遠心分離した。細胞を小容量のハイブリドーマ選択培地(0.5xHA(Sigma、カタログ#A9666)で補充されたハイブリドーマ培養培地)に穏やかに再懸濁し、総量が96ウェルプレート当り5x106B細胞の最終平板培養およびウェル当り200μlに基づき、容量をさらなるハイブリドーマ選択培地で適切に調節した。細胞を穏やかに混合し、96ウェルプレート中にピペット注入し、成長させた。7日目および10日目に、培地の半分を取り除き、ハイブリドーマ選択培地を細胞に再供給した。
ハイブリドーマ細胞から収集した上清を検査して、分泌された抗体が、完全長ヒトまたはカニクイザルのいずれかのB7−H1を一過的に発現する293T細胞に結合する能力を評価した。疑似形質移入された293T細胞系を陰性対照として使用した。2%のFBSを含有するPBSに希釈した細胞を、384ウェルプレート(Corning Costar、カタログ#3712)に40μl/ウェルで、2500〜3000の発現および15000〜17500の疑似形質移入された細胞の濃度で播種した。平板培養直後、10μl/ウェルのハイブリドーマ上清を添加し、プレートを室温で1.5時間インキュベートした。次に、10μl/ウェルのCy5共役ヤギ抗ヒトIgG Fc(700ng/ml、Jackson Immunoresearch、カタログ#109−175−098)を添加し、FMAT8200装置(Applied Biosystems)で蛍光シグナルを読み取る前に、プレートを室温で3時間インキュベートした。6つのハイブリドーマ上清の結果を表3に示す。
抗体を含有する上清の相対的な効力を決定するために、ヒトPD−1/Fcタンパク質のCHO細胞の表面上に発現するヒトB7−H1への結合を阻害するそれらの能力を評価した。25000細胞/ウェルを384ウェル組織培養プレート(Corning Costar、カタログ#3712)のウェル中で50μlの培地にて平板培養した。翌日、50μl/ウェルの希釈した(1:5)ハイブリドーマ上清を添加し、プレートを4℃で1時間、振蘯器上でインキュベートした。ビオチン化ヒトPD−1/Fcタンパク質(R&D Systems、カタログ#1086−PD)を添加して、1.25μg/mlの最終濃度にし、プレートを4℃で1時間、振蘯器上でインキュベートした。細胞を洗浄し、3.7%のホルムアルデヒドと3%のウシ血清アルブミンを含有する100μlのPBSに、室温で20分間固定した。細胞を洗浄し、0.6%のH2O2と3%のウシ血清アルブミンを含有する100μlのPBSに、室温で10分間固定した。細胞を洗浄し、1:4000で希釈された50μlの西洋わさびペルオキシダーゼ共役されたストレプトアビジン中で、4℃で30分間インキュベートした。シグナル検出前に細胞を洗浄した。(ODmax−ODmin)の比率(%)としてデータを表示するが、ここで、ODmaxは、ビオチン共役されたヒトPD−1/Fcタンパク質の存在下、無関係のハイブリドーマ上清を用いてインキュベートされた細胞より得た平均値であり、ODminは、ビオチン共役されたヒトPD−1/Fcタンパク質の不在下で無関係のハイブリドーマ上清を用いてインキュベートされた細胞より得た平均値である。0%の最大応答は、ハイブリドーマ上清によるB7−H1/PD−1結合の100%阻害を示す(表4)。
精製された抗体がヒトB7−H1、B7−DC、マウスB7H1、およびカニクイザルB7−H1に結合する能力をFACS分析によって決定した。簡潔には、リポフェクタミン2000(Invitrogen、カタログ#11668)を使用して、ヒトB7−H1またはヒトB7−DCのいずれかで、293T細胞を疑似形質移入するか、または一過的に形質移入するかのいずれかを行った。マウスB7−H1を発現するマウスJ558細胞をATCC(カタログ#TIB−6)より得た。2%のFBS(FACS緩衝剤)を含有するPBSに細胞を再懸濁し、50000細胞/ウェルで、V字底プレート中に播種した。FACS緩衝液に希釈した抗B7−H1およびアイソタイプ対照抗体を5μg/mlの最終濃度で添加し、プレートを4℃で1時間インキュベートした。FACS緩衝液で洗浄した後、ヤギ抗ヒトFc Cy5(5μg/ml、Jackson Immunoresearch、カタログ#109−175−098)および7−AAD(5μg/ml)を添加し、プレートを4℃で15分間インキュベートした後FACS緩衝液で再度洗浄し、FACSCalibur装置で読み取った。表5は、精製された抗体(5μg/ml)がヒトB7−H1を形質移入された293T細胞を結合する能力を示す。選択された抗体のいずれも、ヒトB7−H1を形質移入された293T細胞、またはマウスB7−H1を発現するJ558細胞に結合しなかった。マウス抗ヒトB7−DC(PD−L2)抗体(R&D systems、カタログ#MAB1224、ヤギ抗マウスFc Cy5で検出、Jackson Immunoresearch)をB7−DC発現の陽性対照として使用した。PE共役されたラット抗マウスB7−H1抗体(eBioscience、クローンM1H5、ヤギ抗ラットFc Cy5で検出、Jackson Immunoresearch)をマウスB7−H1発現の陽性対照として使用した。
96ウェルの高結合プレートをPBS(OKT3クローン、eBioscience、カタログ#160037)中に1μg/mlで希釈した100μl/ウェルの抗CD3抗体と、一晩、4℃でインキュベートした。T細胞富化キット(StemCell Technologies、カタログ#19051)を使用して、ヒトT細胞を凍結したロイコパック(leukopack)から単離した。抗CD3mAbコーティングされたプレートをPBSで洗浄し、精製されたT細胞を360000細胞/ウェルで200μlのICM培地に添加し、72時間培養した。次いで、T細胞を採取し、FACS緩衝液中で洗浄し、96ウェルのV字底アッセイプレート(50μl/ウェル)中、1μg/mlの最終濃度で、希釈した精製された抗B7−H1抗体、または無関係のヒトIgG2もしくはIgG4抗体と混合した。4℃で2時間インキュベーションした後、T細胞をFACS緩衝液中で2度洗浄した後、Cy5共役されたヤギ抗ヒトIgG Fc抗体(5μg/ml、Jackson Immunoresearch、カタログ#109−175−098)および7−AAD(10μg/ml)で染色した。細胞を4℃で30分間インキュベートした後FACS緩衝液で再度洗浄し、FACSCalibur装置で読み取った。順方向および側面分散ならびに7−AADの陰性染色に基づき、生リンパ球集団を分析のために選択した。
精製されたヒト抗B7−H1抗体が、ヒトPD−1/Fcタンパク質のES−2細胞(ATCC、カタログ#CRL−1978)の表面上で発現したヒトB7−H1への結合を阻害する能力を評価した。簡潔には、50000細胞/ウェルを384ウェル組織培養プレート(Corning Costar、カタログ#3712)のウェル中で50μlのPBSにて平板培養した。次に、50μl/ウェルの希釈したモノクローナル抗体を2.5、0.5、0.1、0.02、0.004、0.008、0.00016nMの最終濃度で添加し、プレートを4℃で1時間インキュベートした。細胞を2度洗浄し、100μl/ウェルのビオチン化ヒトPD−1/Fcタンパク質(10μg/ml、R&D Systems、カタログ#1086−PD)を添加し、プレートを4℃で1時間インキュベートした。細胞を一度洗浄し、100μl/ウェルのCy5共役されたストレプトアビジンを添加し、2%のFCSを含有するPBSで再度洗浄し、FACSCalibur装置で読み取る前に、プレートを4℃で15分間インキュベートした。最小(0%)および最大(100%)レベルのB7−H1/PD−1結合阻害を設定するために、いくつかのウェルをビオチン共役されたヒトPD−1/Fcを含む、または含まない無関係のヒトIgG2およびIgG4モノクローナル抗体とインキュベートした。抗体濃度に対する阻害の比率(%)を曲線適合ツール(GraphPad Prismソフトウェア)を使用して分析し、各抗体のIC50値を計算し、これを表7に示す。
ビーズ上に抗CD3抗体と同時に提示されるB7−H1タンパク質が、CD3媒介細胞活性化を阻害することが示されている(Freeman et al.,J.Exp.Med.,2000,192(7):1027−1034、Bennet et al.,The Journal of Immunology,2003,170:711−718)。精製されたヒトモノクローナル抗B7−H1抗体の、T細胞活性化のB7−H1媒介抑制に干渉する能力を以下のように決定した。
B7−H1を対象とする抗体によるT細胞活性化の強化は、樹状細胞−T細胞混合リンパ球(DCMLR)アッセイにより決定された。以前に記載されたように樹状細胞を単球前駆体より生成した(Curr Protoc Immunol.2001 May;Chapter7:Unit7.32)。Ficoll−Paque Plus(GE Healthcare17−1440−03)密度勾配遠心分離を使用して、抹消血単球を白血球除去バックから単離し、無血清RPMI1640(Gibco 22400−089)に再懸濁し、T150細胞培養フラスコ(Corning 430825)に付着させた。37℃で1時間後、付着しなかった細胞を取り除き、細胞を5%のヒト血清(Invitrogen 34005100)で補充したRPMI中で培養した。サイトカインを2ng/mlのGM−CSF(BD Biosciences 550068)および10ng/mlのIL−4(BD Biosciences 554605)の最終濃度で添加した。サイトカインを含む新しい培地を2〜3日おきに添加した。培養6日目に、細胞を20ng/mlのTNF−α(BD Biosciences 554618)で成熟させ、24時間インキュベートした。成熟した樹状細胞を採取し、表現型化し、後に使用するために凍結した。
抗体の重鎖可変ドメイン配列および軽鎖可変ドメイン配列が、それらのDNA配列を決定するために配列決定された。抗B7−H1抗体の完全な配列情報は、各ガンマおよびカッパまたはラムダ鎖の組み合わせにおけるヌクレオチドおよびアミノ酸配列と共に列挙される配列で提供される。可変重鎖配列は、VHファミリーおよびJ領域配列を決定するために分析された。次いで、配列は、一次アミノ酸配列を決定するために翻訳され、体細胞超変異を評価するために、生殖系列VHおよびJ領域配列と比較された。
非生殖系列化(NG)抗B7−H1抗体2.7A4、2.14H9、および2.9D10のVHおよびVLドメインのアミノ酸配列をVBASEデータベース(Tomlinson,1997;http://vbase.mrc−cpe.cam.ac.uk/)の既知のヒト生殖系列配列と整列させ、配列の類似性により最も近い生殖系列を特定した。抗B7−H1抗体の最も近い生殖系列の一致を表16および17に記載する。バーニヤ残基(Foote&Winter,J Mol Biol.Mar20:224(2):487−99,1992)を考慮せず変更しないままにし、変更されるべき位置を表18に記載する。
VHおよびVLドメインをそれぞれ全抗体の重鎖および軽鎖を発現するベクターにサブクローン化することにより、クローンをscFvからIgG形式に変換した。VHドメインをIgG1を発現するようにベクターpEU15.1、またはIgG1−TM抗体を発現するようにベクターpEU15.1−TM中にクローン化した。双方のベクターは、哺乳類細胞で全IgG重鎖を発現するように、ヒト重鎖定常ドメインおよび調節エレメントを含有する。ベクターpEU15.1−TMは、修飾されたpEU15.1ヒトIgG1ベクターである。それは、抗体依存細胞媒介細胞毒性および補体依存細胞毒性を作動させるその能力を排除するために、ヒンジのL234FおよびL235EならびにIgG分子のCH2ドメインのP331Sの3つの変異体を導入するように操作された(Oganesyan V.et al.(2008),Acta Cryst.,D64:700−704)。ベクターの操作は、適切な変異原性プライマーを用いた標準的な部位指向性変異誘発技術を使用して実施された。
記載されるアッセイは、洗浄ステップを必要としないHTRF(登録商標)アッセイ技術を使用した、同種TR−FRETアッセイであった。Costar3676マイクロタイタープレートに、5μl/ウェルのPBS中に希釈した8nMのビオチン化B7−1/Fcを添加した。この後、5μl/ウェルのアッセイ緩衝液(PBS+0.1%のBSA+0.8MのKF)中に希釈した20nMのストレプトアビジンXLent(CisBio)を添加した。5μl/ウェルのPBSに希釈した試料材料の滴定を適切なウェルに添加した。総結合を定義するために、ウェル当り5μlのPBSもしくは適切な試料緩衝液を添加した。非特異的結合を定義するために、過剰(200nM)の非標識化B7H1/FcもしくはB7−1/Fcを使用した。アッセイ緩衝液中に1:100に希釈した5μl/ウェルのクリプテート標識化B7H1/Fc(クリプテート標識−CisBio,B7H1/Fc−RnD Systems)の添加が最終プロセスであった。一晩4℃でアッセイプレートを放置した後、室温に戻し、HTRF(登録商標)適合プレート読み取り装置で読み取った。
他の免疫共調節性分子に対する抗B7−H1 IgG1−TM抗体の交差反応性を決定するために、ELISAを実施した。ELISAは、4℃で一晩、ウェル当り250ngのヒトB7−H1(R&D Systems,156−B7)、ヒトPD−L2(R&D Systems,1224−PL)、ヒトB7−H2(R&D Systems,165−B7)、ヒトB7−H3(R&D Systems,1027−B3)、ヒトCD28(R&D Systems,342−CD)、ヒトCTLA−4(R&D Systems,325−CT)、およびヒトPD1(R&D Systems,1086−PD)の細胞外ドメイン(ECD)でMaxiSorpプレート(NUNC)をコーティングした後、室温で1時間、3%の乾燥粉乳を含有するPBSでプレートを遮断することから成った。マウスB7−H1(R&D Systems,1019−B7)のECDをコーティングすることにより、マウス交差反応性も検証した。3%の乾燥粉乳を含有するPBSに100nMの希釈されたビオチン化抗B7−H1 IgG1−TMを室温で2時間インキュベートし、結合させた。結合したビオチン化IgGsを0.2μg/mLでユーロピウムN1標識化ストレプトアビジン(Perkin Elmer,1244−360)で検出した。市販の抗体であるマウスIgG2a抗ヒトB7−H1(R&D Systems,MAB156)、マウスIgG2b抗ヒトPD−L2(R&D Systems,MAB1224)、マウスIgG2b抗ヒトB7−H2(R&D Systems,MAB165)、マウスIgG1抗ヒトB7−H3(R&D Systems,MAB1027)、マウスIgG1抗ヒトCD28(R&D Systems,MAB342)、マウスIgG2a抗ヒトCTLA−4(Abcam,ab33320)、マウスIgG2b抗ヒトPD1(R&D Systems,MAB1086)、およびラットIgG2a抗マウスB7−H1(R&D Systems,MAB1019)を使用して、NUNCプレートにコーティングする抗原を示す対照実験を実施した。3%の乾燥粉乳を含有するPBS中5μg/mLで一次抗体を2時間インキュベートした。3%の乾燥粉乳を含有するPBSに1:5000に希釈された二次抗体の抗マウスIgGペルオキシダーゼ共役体(Sigma,A2554)、または抗ラットIgGペルオキシダーゼ共役体(Sigma,A5795)を1時間室温でインキュベートし、続いてTMB(Sigma,T0440)を添加することにより、検出を実施した。8つの抗原全てをMaxisorp NUNCプレート上で検出することができた。非特異的結合を5μg/mLのIgG1アイソタイプ対照でコーティングしたウェルを使用して決定した。ヒトB7−H1に対するのと比較した、抗原への特異的結合の割合(%)で、交差反応性を計算した。
BIAcore T100装置(BIAcore,Uppsala,Sweden)を使用して、表面プラズモン共鳴により単量体ヒトおよびカニクイザルのB7−H1に対するIgG1−TM形式の抗B7−H1抗体の結合親和性および動態パラメータを決定した。簡潔に、実験は、泳動緩衝液としてHBS−EP緩衝液(10mMのHEPES、150mMのNaCl、3mMのEDTA、0.05%v/v界面活性剤P20)を使用して、25℃で実施した。製造者の指示(BIAapplications Handbook,BIAcore)に従い、プロテインGを介してCM5センサチップ(BIAcore)の表面上にIgGを親和捕捉し、これは、約500応答単位(RU)の密度を達成するようにCM5表面上にアミン結合された。組み換え単量体のヒトもしくはカニクイザルのB7−H1 FlagHis10細胞外ドメイン(ECD)を分析物として使用した。泳動緩衝液中のB7−H1 ECDの希釈物(200−3.12nM)を60秒間、100μl/分の一定流量で注入した。全ての測定値は、対照(活性−不活化)流れ細胞により得られたセンサーグラムを引くことによりベースライン補正され、またブランク(ゼロ分析物濃度)注入と二重参照された。T−100 BIAevaluationソフトウェアパッケージを使用してデータを分析し、ローカルRmaxおよび0に設定されたバルク屈折率を用いた、簡単な1:1ラングミュア結合モデルに適合させた。少なくとも2つの独立した実験からデータを計算した。物質移動効果は、親和捕捉されたIgGのレベルを250RU以下に保つことにより制限された。全ての検査された抗体より得られたセンサーグラムは、単一指数関数的1:1結合モデル上に容易に適合され、一貫して0.3以下のカイ二乗値で良好に適合し得る。
エピトープマッピングを、抗B7−H1抗体への結合に関与するヒトB7−H1残基を特定するために実施した。マウスPD1と複合するヒトB7H1の細胞外ドメインの構造は、以前に文献(Lin,D et al.,2008,Proc.Natl.Acad.Sci.USA,Vol.105,p3011−3016)に記載され、14のB7−H1残基がPD1への結合に関与していることが明らかにされている(表23)。
ヒトB7−H1タンパク質の細胞外ドメインをコードする遺伝子(Uniprot受入番号Q9NZQ7、アミノ酸[19−238])を、DNA2.0 Inc.により外部で合成し、B7H1_FOR(5’−AATAATGGCCCAGCCGGCCATGGCCTTTACCGTGACGGTACCG−3’)およびB7H1_REV(5’−AATAATGCGGCCGCCCTTTCGTTTGGGGGATGC−3’)のプライマーを使用して、PCRによって増幅し、それぞれ、5’端および3’端のSfi IおよびNot I制限部位に導入した。次いで、Sfi IおよびNot I制限部位を使用して、PCR産物をpCANTAB6ベクターに一方向にクローン化した(McCafferty J.et al.,1994,Appl.Biochem.Biotechnol.,Vol.47,p157−173)。大腸菌株TG1を連結により形質転換し、個別のコロニーを配列決定によりスクリーニングし、B7−H1_pCANTA6と命名されるB7−H1形質転換体を特定した。
B7−H1変異体は、完全無作為化NNSプライマー(表24)およびDNAテンプレートとしてのプラスミドB7−H1_pCANTA6を使用して、PD1接触面の14の残基の全てで、飽和変異誘発によって生成された。変異誘発は、製造者の指示に従い、Stratagene’s QuickChange多重部位特異的変異誘発キット(カタログ#200513)を用いて実施した。大腸菌株TG1を形質転換するために変異反応を使用し、個別のコロニーを配列決定によりスクリーニングし、B7−H1変異形を特定した。280(20のアミノ酸×14の位置)の可能性のある変異形のうちの合計252の変異形を特定し、3つの96ウェル培養プレートに選別した。
遺伝子IIIタンパク質と融合したB7−H1細胞外ドメインがファージ表面で提示され得ることを確認した後、B7−H1変異体の抗B7−H1抗体2.14H9OPT、2.7A4OPT、または参照抗体#1への結合をファージELISAにより評価した。慎重に採取されたTG1培養物を成長させ、M13K07ヘルパーファージで重感染させ、それらの表面でB7−H1変異体を示すファージ粒子を産生した。ファージ上清をPBS+3%の脱脂乳で遮断し、一晩、PBS中の1μg/mLの2.14H9OPT、2.7A4OPT、または参照抗体#1で予めコーティングし、PBS+3%の脱脂乳で遮断されたNUNC MaxiSorbプレートでインキュベートした。ビオチン化抗M13二次抗体(Progen)を用いてインキュベートした後、ユーロピウム(Perkin Elmer)と結合したストレプトアビジンを使用して、結合ファージを検出した。
ヒトB7−H1野生型および変異体の細胞外ドメインを細菌に発現させ、以前に記載されているように親和性クロマトグラフィーにより精製した(Bannister D.et al.,2006,Biotechnology and bioengineering,94,931−937)。
PD−1とのB7−H1相互作用が、抗原特異的T細胞応答を阻害することが示されている。抗B7−H1抗体のこの阻害に対する作用を評価するために、準最適抗原想起アッセイを実施した。
B7−H1は、可能性のある阻害シグナル伝達特性を有することが示されている。そのような阻害シグナル伝達を促進するかもしれない作動薬として機能する抗B7−H1抗体の可能性は、抗原想起応答を阻害するそれらの能力を検証することにより検査された。
易感染性NOD/SCID(非肥満糖尿病/重症複合免疫不全)マウスを使用した異種移植マウスモデルで抗ヒトB7−H1抗体の生体内活性を調査した。健康なドナーの抹消血単核細胞から単離し、アロ反応性エフェクターT細胞用に培養して富化したヒトB7−H1ならびにヒトCD4+およびCD8+T細胞を発現するヒト癌細胞系をマウスの皮下(SC)に移植した。ヒト膵癌細胞系HPACまたはヒトメラノーマ細胞系A375を接種されたマウスに抗ヒトB7−H1抗体を腹腔内(IP)投与した。2000mm3の腫瘍体積または肉眼的な腫瘍壊死までの腫瘍成長において、抗体の作用を観察した。
各群において、結果を算術平均として報告する。抗癌作用は、腫瘍成長阻害(TGI)%として表され、以下の方法により計算された:
TGI%=[1−(治療群の平均腫瘍V)÷(対照群の平均腫瘍V)]×100
試験1において、抗B7−H1抗体2.14H9 IgG2aおよび2.7A4OPTは、アイソタイプ対照群と比較して、30日目で、それぞれ、最大61%および50%まで、大幅にHPAC(膵臓)癌細胞の成長を阻害した(図8および表26)。
特許、特許出願、論文、教科書等を含む本明細書に引用される全ての参考文献、ならびにそこに引用される参考文献は、それらが既に引用されていない限り、ここで参照によりそれらの全体が本明細書に組み込まれる。2009年11月24日に出願された米国仮特許出願第61/264,061号、その中の図、および配列は、参照によりその全体が本明細書に組み込まれる。
前述の明細書は、当業者が本発明を実践するのに十分であると考えられる。前述の説明および実施例は、本発明のある好ましい実施形態を詳述し、発明者により企図される最適な方法を記載する。しかしながら、たとえ上述が詳細に本文で使用されているとしも、本発明は、多くの手法で実践することができ、本発明は、付属の請求項およびあらゆるその等価物により解釈されるべきであることを理解する。
NCIMB 41598
NCIMB 41599
Claims (26)
- B7−H1に特異的に結合する単離された抗体またはその抗原結合断片であって、該抗体は、
アミノ酸配列Thr Tyr Ser Met Asnを有するVH CDR1、および
アミノ酸配列Ser Ile Ser Ser Ser Gly Asp Tyr Ile Tyr Tyr Ala Asp Ser Val Lys Glyを有するVH CDR2、および
アミノ酸配列Asp Leu Val Thr Ser Met Val Ala Phe Asp Tyrを有するVH CDR3、および
アミノ酸配列Ser Gly Asp Ala Leu Pro Gln Lys Tyr Val Pheを有するVL CDR1、および
アミノ酸配列Glu Asp Ser Lys Arg Pro Serを有するVL CDR2、および
アミノ酸配列Tyr Ser Thr Asp Arg Ser Gly Asn His Arg Valを有するVL CDR3を含む、前記抗体またはその抗原結合断片。 - アイソタイプ対照抗体と比較して、異種移植モデルにおけるヒト癌細胞系の成長を阻害する、請求項1に記載の抗体またはその抗原結合断片。
- 前記抗体は、122位のAsp、125位のArg、または113位のArgの3つのアミノ酸残基のうちの少なくとも2つを含む、ヒトB7−H1の細胞外ドメイン上のエピトープに結合する、請求項1または2に記載の抗体またはその抗原結合断片。
- 前記抗体は、競合アッセイによって決定して、ヒトB7−H1上の54位にIle、117位にSer、および121位にAlaを含むエピトープへの結合を示さない、請求項3に記載の抗体またはその抗原結合断片。
- 前記抗体は、前記ヒトB7−H1上の前記113位のArgがAla、またはTyr、またはLeuに変異される場合、野生型B7−H1への結合と比較して、競合アッセイによって決定される、ヒトB7−H1に結合するその能力を失う、請求項3に記載の抗体またはその抗原結合断片。
- 前記抗体は、前記ヒトB7−H1上の前記125位のArgがAla、またはGln、またはSerに変異される場合、野生型B7−H1への結合と比較して、競合アッセイによって決定される、ヒトB7−H1に結合するその能力を失う、請求項3に記載の抗体またはその抗原結合断片。
- 前記抗体は、前記ヒトB7−H1上の123位のArgがAla、またはPhe、またはThrに変異される場合、野生型B7−H1への結合と比較して、競合アッセイによって決定される、ヒトB7−H1に結合するその能力を保持する、請求項3に記載の抗体またはその抗原結合断片。
- 前記抗体は、ヒトB7−H1上の19位のPhe、20位のThr、または122位のAspの3つのアミノ酸残基のうちの少なくとも2つに結合する、請求項1または2に記載の抗体またはその抗原結合断片。
- 前記抗体は、野生型B7−H1への結合と比較して、競合アッセイによって決定される、ヒトB7−H1上の54位にIle、115位にMet、117位にSer、および121位にAlaを含むエピトープへの結合を示さない、請求項8に記載の抗体またはその抗原結合断片。
- 前記抗体は、前記ヒトB7−H1上の前記19位のPheがAla、またはGly、またはSerに変異される場合、野生型B7−H1への結合と比較して、競合アッセイによって決定される、ヒトB7−H1に結合するその能力を失う、請求項8に記載の抗体またはその抗原結合断片。
- 前記抗体は、前記ヒトB7−H1上の前記20位のThrがAla、またはVal、またはAspに変異される場合、野生型B7−H1への結合と比較して、競合アッセイによって決定される、ヒトB7−H1に結合するその能力を失う、請求項8に記載の抗体またはその抗原結合断片。
- 前記抗体は、前記ヒトB7−H1上の前記122位のAspがAsnまたはGluに変異される場合、野生型B7−H1への結合と比較して、競合アッセイによって決定される、ヒトB7−H1に結合するその能力を失う、請求項8に記載の抗体またはその抗原結合断片。
- 前記抗体は、前記ヒトB7−H1上の123位のArgがAla、またはPhe、またはThrに変異される場合、野生型B7−H1への結合と比較して、競合アッセイによって決定される、ヒトB7−H1に結合するその能力を保持する、請求項8に記載の抗体またはその抗原結合断片。
- 前記抗体は、モノクローナル抗体である、請求項1または2に記載の抗体。
- 前記抗体は、完全ヒトモノクローナル抗体である、請求項14に記載の抗体。
- 前記抗体は、Fc変異体をさらに含み、Fc領域は、Kabatに記述されているEU指標により番号付けして、234F、235F、および331Sから成る群より選択される、少なくとも1つのアミノ酸を含む、請求項15に記載の抗体。
- 請求項16に記載の抗体をコードする核酸分子。
- 請求項17に記載の核酸分子を含むベクターを形質移入された宿主細胞。
- 請求項18に記載の、前記抗体を発現する前記宿主細胞を培養することを含む方法により産生される抗体。
- 請求項1または2に記載の抗体を含む組成物。
- 請求項1または2に記載の抗体と、薬学的に許容される担体とを含む医薬組成物。
- 配列番号62のアミノ酸配列に少なくとも90%の同一性を有する重鎖可変ドメイン及び配列番号67のアミノ酸配列に少なくとも90%の同一性を有する軽鎖可変ドメインを含む、請求項1または2に記載の抗体。
- 配列番号2のアミノ酸配列を有する重鎖可変ドメイン及び配列番号7のアミノ酸配列を有する軽鎖可変ドメインを含む、請求項22に記載の抗体。
- 配列番号62のアミノ酸配列を有する重鎖可変ドメイン及び配列番号67のアミノ酸配列を有する軽鎖可変ドメインを含む、請求項22に記載の抗体。
- 請求項22〜24のいずれか一項に記載の抗体を含む組成物。
- 請求項22〜24のいずれか一項に記載の抗体と薬学的に許容される担体とを含む医薬組成物。
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