JP2022174167A - Ror1癌の治療および転移の阻害に使用するための抗体およびワクチン - Google Patents
Ror1癌の治療および転移の阻害に使用するための抗体およびワクチン Download PDFInfo
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Abstract
Description
本出願は、米国特許法119条(e)のもと、2012年8月24日に出願された米国特許出願第61/693,230号、2012年10月2日に出願された米国特許出願第61/709,055号、および2012年10月4日に出願された米国特許出願第61/709,803号に対する優先権の利益を主張するものであり、これらの内容全体は、参照により本明細書に組み込まれる。
添付の配列表の資料は、参考によりその全体が本明細書に組み込まれる。「ST-UCSD3820-1WO_ST25.txt」という名前の添付ファイルは、2013年3月14日に作成され、33Kbである。ファイルは、Windows OSを使用したコンピュータ上でMicrosoft Wordを使用してアクセスできる。
本発明は、国立衛生研究所よって授与されたP01-CA081534およびR37-CA049870、およびカリフォルニア再生医療学会のDR1-01430の下で政府の支援により行われた。アメリカ政府は、本発明において一定の権利を有する。
本発明は、概ね、受容体チロシンキナーゼ様オーファン受容体1抗体およびワクチン、ならびに転移を阻害するための方法に関する。
癌は、冠動脈疾患に続く人間の2番目に主要な死亡原因である。世界中で、何百万人もの人々が毎年癌で死亡している。米国だけでも、優に毎年50万人以上が癌で死亡しており、およそ毎年140万件の新しい症例が診断されている。心臓病による死亡が大幅に減少している一方で、一般的に癌に起因する死亡が増加している。受容体チロシンキナーゼ(RTK)は、細胞の分化、増殖、遊走、脈管形成、および生存において重要な役割を果たす。受容体チロシンキナーゼ様オーファン受容体1(ROR1)は、RORサブファミリーに属し、免疫グロブリン(Ig)様、フリッツルド、およびクリングルドメインを含有する細胞外ドメインを有する、進化的に保存されたI型膜タンパク質である。ROR1欠損マウスは、骨格および泌尿生殖器系内の種々の表現型の欠陥、ならびに生後の成長の遅れを示す。ROR1は、胚形成、および種々の異なる癌によって発現されるが、正常な分娩後組織によっては発現されず、腫瘍胚性表面抗原と見なすことができる。機能データは、ROR1が、悪性細胞の生存を促進するために、非カノニカルWNTシグナル伝達において機能し得ることを示唆している。さらに最近の研究は、非カノニカルWNTシグナル伝達が、乳癌転移の基底様および他のサブタイプにおいて主要な役割を果たすことを示している。ROR1ヒト乳癌の発現はまた、AKT-CREB経路の活性化および増大した腫瘍細胞の成長に関連している。
[本発明1001]
抗体99961と同じ結合特異性を有する単離された抗ROR1抗体。
[本発明1002]
hROR-1のアミノ酸130~160に結合する、本発明1001の抗体。
[本発明1003]
ROR1アミノ酸138がhROR-1への結合のためにグルタミン酸であることを必要とする、本発明1002の抗体。
[本発明1004]
配列番号1、配列番号5、配列番号9、配列番号13、および配列番号17からなる群から選択される重鎖可変領域、および配列番号3、配列番号7、配列番号11、配列番号15、および配列番号19からなる群から選択される軽鎖可変領域を備える、本発明1001の抗体。
[本発明1005]
結合親和性を有する前記抗体が、約500pM~約6nMの間である、本発明1001の抗体。
[本発明1006]
前記結合親和性が約800pMである、本発明1005の抗体。
[本発明1007]
99961、99961.1、99961.2、99961.3、および99961.4からなる群から選択される、本発明1001~1006のいずれかの抗体。
[本発明1008]
転移を阻害する、本発明1001~1007のいずれかの抗体。
[本発明1009]
ヒト、ヒト化、またはキメラ抗体である、本発明1001~1008のいずれかの抗体。
[本発明1010]
本発明1001~1009のいずれかの抗体をコードする単離された核酸。
[本発明1011]
ROR-1発現細胞に対するワクチンであって、抗体D10のROR-1結合領域に対して少なくとも95%の配列同一性を有するアミノ酸配列を有する、単離されたまたは合成的に産生されたペプチドの薬学的に許容される組成物を含む、ワクチン。
[本発明1012]
抗体D10の前記ROR-1結合領域のアミノ酸配列が、
である、本発明1011のワクチン。
[本発明1013]
抗体D10の前記ROR-1結合領域のアミノ酸配列が、
である、本発明1011のワクチン。
[本発明1014]
ROR-1発現細胞が癌細胞である、本発明1012のワクチン。
[本発明1015]
癌細胞が、B細胞白血病、リンパ腫、CLL、AML、B-ALL、T-ALL、卵巣癌、結腸癌、肺癌、皮膚癌、膵臓癌、精巣癌、膀胱癌、子宮癌、前立腺癌、および副腎癌からなる群から選択される、本発明1011のワクチン。
[本発明1016]
免疫原性アジュバントをさらに含む、本発明1012または1013のワクチン。
[本発明1017]
前記アジュバントは、結合ペプチドに複合体化された免疫原性担体ペプチドである、本発明1016のワクチン。
[本発明1018]
前記結合ペプチドのアミノ酸配列が、
であり、かつ前記免疫原性担体ペプチドが、キーホールリンペットヘモシアニン(KLH)、ウシ血清アルブミン、またはオボアルブミンである、本発明1017のワクチン。
[本発明1019]
前記結合ペプチドのアミノ酸配列が、
であり、かつ前記免疫原性担体ペプチドが、キーホールリンペットヘモシアニン(KLH)である、本発明1017のワクチン。
[本発明1020]
に対して少なくとも95%の配列同一性を有するアミノ酸配列を有する、ROR1結合ペプチド。
[本発明1021]
哺乳類由来である、本発明1020の結合ペプチド。
[本発明1022]
本発明1020の結合ペプチドをコードする、単離された核酸。
[本発明1023]
に対して少なくとも95%の配列同一性を有するアミノ酸配列を有する、ROR1結合ペプチド。
[本発明1024]
哺乳類のペプチドである、本発明1023の結合ペプチド。
[本発明1025]
本発明1023の結合ペプチドをコードする単離された核酸。
[本発明1026]
ROR-1発現癌の転移を抑制する方法であって、モノクローナル抗体99961の結合特異性を有する抗体、抗体D10のROR-1結合領域に対して少なくとも95%の配列同一性を有するアミノ酸配列を有するペプチドから構成されるワクチン、
に対して少なくとも95%の配列同一性を有するアミノ酸配列を有するROR-1結合ペプチド、または
に対して少なくとも95%の配列同一性を有するアミノ酸配列を有するROR-1結合ペプチドを投与することによって、腫瘍細胞の上皮間葉転換を妨害することを含む、方法。
[本発明1027]
前記ROR-1発現癌が、B細胞白血病、リンパ腫、CLL、AML、B-ALL、T-ALL、卵巣癌、結腸癌、肺癌、皮膚癌、膵臓癌、精巣癌、膀胱癌、子宮癌、前立腺癌、および副腎癌からなる群から選択される、本発明1026の方法。
[本発明1028]
対象において癌を治療または予防するための方法であって、モノクローナル抗体99961の結合特異性を有する抗体、抗体D10のROR-1結合領域に対して少なくとも95%の配列同一性を有するアミノ酸配列を有するペプチドから構成されるワクチン、
に対して少なくとも95%の配列同一性を有するアミノ酸配列を有するROR-1結合ペプチド、または
に対して少なくとも95%の配列同一性を有するアミノ酸配列を有するROR-1結合ペプチドを前記対象に投与することを含む、方法。
[本発明1028]
癌が、B細胞白血病、リンパ腫、CLL、AML、B-ALL、T-ALL、卵巣癌、結腸癌、肺癌、皮膚癌、膵臓癌、精巣癌、膀胱癌、子宮癌、前立腺癌、および副腎癌からなる群から選択される、本発明1027の方法。
本発明は、抗ROR1抗体またはこれらの抗原結合断片、ROR1抗体免疫複合体、ROR1ペプチドワクチン、またはROR1結合ペプチドを使用して、転移を阻害する組成物および方法の発展性のある発見に関する。
本出願人は、多数の癌細胞株およびサンプル中に完全長ROR1の発現を以前発見したが、非白血病患者または正常な成人ドナーの血液もしくは脾臓リンパ球を含めた他の組織では発見せず、かつ全長ヒトROR1に対するマウス抗血清をも生成した。Fukuda et al.,Blood:ASH Annual Meeting Abstracts 2004 104,Abstract 772(2004)(参照によりその全体が本明細書に組み込まれる)。ポリペプチドおよびROR1のためのコード配列は他にも報告されており、また、この参照により本明細書に組み込まれる(例えば、受託番号NP_005003.1およびNM_005012.1を参照されたい)。CLL細胞などのWnt5aタンパク質を発現する癌細胞は、ROR1と結合するのみならず、結果として付与された生存優位性を持っている。本発明は、したがって、癌を治療または予防するために、癌細胞におけるROR-1発現の特異性を利用する手段を提供する。
ある特定の実施形態は、ヒトROR1タンパク質に対して向けられる免疫ペプチドを含む。本明細書で記載される免疫グロブリンペプチドまたは抗体は、ROR1タンパク質に結合することが示される。ROR1結合活性は、特異的であり、ROR1に対する観察された抗体の結合は、非特異的な試薬により実質的に阻止されない。これらのROR1特異的な抗体を使用して、ROR1細胞と正常な細胞との間で区別することができる。ROR1特異的な抗体はまた、ROR-1癌の治療後の応答を判定し、転移を阻害するために、ROR1癌に対する免疫療法において使用することができる。このような免疫ペプチドは、当該技術分野で既知の種々の手段で産生され得る。
ポリクローナル抗体は、ウマ、ウシ、種々の家禽、ウサギ、マウス、またはラットなどの種々の温血動物から当業者によって容易に生成され得る。簡潔に述べると、ROR1抗原は、フロイント完全または不完全アジュバントなどのアジュバントで、腹腔内注射、筋肉内注射、眼内注射、または皮下注射を介して動物を免疫化するために利用される。数回の追加免疫の後、血清のサンプルが収集され、ROR1に対する反応性について試験される。特に好ましいポリクローナル抗血清は、これらのアッセイの1つに、背景よりも少なくとも3倍大きいシグナルを与えるであろう。動物の力価は、ROR1に対するその反応性に関して安定状態に達すると、より大量の抗血清が、動物を毎週採血するかまたは放血させるかのいずれかによって容易に取得され得る。
モノクローナル抗体(mAb)技術を使用して、ROR1に対するmAbsを取得することができる。簡潔に述べると、ハイブリドーマが、ヒトROR1抗原で免疫化されたマウスからの脾臓細胞を使用して産生される。各免疫化されたマウスの脾臓細胞は、例えば、ポリエチレングリコール融合法(Galfre,G.and Milstein,C.,Methods Enzymol.,73:3-46(1981))を用いて、マウス骨髄腫Sp2/0細胞と融合される。ハイブリドーマの成長、HAT培地での選択、抗原に対するクローンのクローニングおよびスクリーニングは、標準的な手法を用いて実行される(Galfre,G.and Milstein,C.,Methods Enzymol.,73:3-46(1981))。
マウス抗体のヒト化形態は、組換えDNA技術(例えば、Queen et al.,Proc.Natl.Acad.Sci.USA 86:10029-10033,1989、および国際特許第WO90/07861号(各々が、参照により組み込まれる)を参照)によって、非ヒト抗体のCDR領域をヒト定常領域に連結することによって生成することができる。ヒト抗体は、ファージディスプレイ法を使用して取得できる(例えば、Dower et al.、国際特許第WO91/17271号、McCafferty et al.、国際特許第WO92/01047号を参照)。これらの方法で、メンバーがそれらの外表面上に異なる抗体を提示する、ファージのライブラリが産生される。抗体は、通常、FvまたはFab断片として提示される。所望の特異性を有する抗体を提示するファージは、親和性濃縮度によって選択され得る。
特定の用途のためにmAbの機能的断片を産生し使用することが所望であり得る。典型的なIgG分子の周知の基本構造は、2個の同一の軽ポリペプチド鎖(約220個のアミノ酸含有)および2個の同一の重ポリペプチド鎖(約440個のアミノ酸含有)からなる、約150,000~200,000ダルトンの対称四量体のY字型分子である。重鎖は、少なくとも1個のジスルフィド結合により互いに連結されている。各軽鎖は、ジスルフィド結合によって隣接する重鎖に連結されている。抗原結合部位またはドメインは、Y字型の抗体分子の各腕に位置し、ジスルフィド結合された軽鎖および重鎖の各対のアミノ末端領域の間に形成される。軽鎖および重鎖のこれらのアミノ末端領域は、最初の約110個のアミノ末端のアミノ酸からなり、軽鎖および重鎖の可変領域として知られている。
本明細書に記載される抗体を組換えて産生するために、軽鎖および重鎖可変領域をコードする核酸が、任意選択により、定常領域に連結され、発現ベクターに挿入される。軽鎖および重鎖は、同じまたは異なる発現ベクター内でクローニングすることができる。例えば、配列番号1~5の重鎖および軽鎖を、本発明に従って使用することができる。米国特許第6,287,569号(Kippsら)の教示は、その全体が参照により本明細書に組み込まれ、本明細書において提供される方法は、本発明のワクチンを作るために当業者によって容易に適合され得る。抗体鎖をコードするDNAセグメントは、抗体鎖の発現を確実にする発現ベクター(複数可)における制御配列に操作可能に連結される。このような制御配列は、シグナル配列、プロモータ、エンハンサ、および転写終結配列を含み得る。
本発明のROR1抗体またはこれらの抗原結合断片、変異体、もしくは誘導体は、「多重特異性」(例えば、二重特異性、三重特異性、またはそれ以上の多重特異性)であり得、これは、1個以上の異なる抗原(例えば、タンパク質)上に同時に存在する2個以上の異なるエピトープを認識し、それに結合することを意味する。したがって、ROR1抗体が「単一特異性」であるか、または「多重特異性」(例えば、「二重特異性」)であるかは、結合ポリペプチドが反応する異なるエピトープの数を指す。多重特異性抗体は、本明細書に記載の標的ポリペプチドの異なるエピトープに対して特異的であり得るか、または標的ポリペプチド、ならびに異種ポリペプチドまたは固体支持物質などの異種エピトープに対して特異的であり得る。
加えて、本発明は、単離または合成的に産生されたROR1結合ペプチドの薬学的に許容される組成物からなる、対象における治療のためのワクチン、癌の予防、または転移の阻害を提供する。本発明はまた、D10のROR-1結合領域に対して少なくとも95%の配列同一性を有するROR1結合ペプチドを提供する。さらなる態様において、本発明は、D10の結合領域に対して少なくとも95%、96%、97%、98%、99%、または100%配列同一性を有するROR1結合ペプチドを提供する。一態様において、D10の結合領域は、VATNGKEVVSSTGVLFVKFGPCである。追加の態様において、D10の結合領域は、EVVSSTGVLFVKFGPCである。一態様において、D10結合領域は、少なくとも22個のアミノ酸である。さらなる態様において、D10結合領域は、少なくとも10、11、12、13、14、15、16、17、18、19、20、21、または22個のアミノ酸である。
一実施形態において、本発明は、配列番号25および配列番号26からなる群から選択されるアミノ酸配列を含むROR1結合ペプチドを提供する。一態様において、ペプチドは、VATNGKEVVSSTGVLFVKFGPCに対して少なくとも95%の配列同一性を有するアミノ酸配列を有する。別の態様において、ペプチドは、EVVSSTGVLFVKFGPCに対して少なくとも95%の配列同一性を有するアミノ酸ペプチド配列を有する。別の態様において、結合ペプチドは哺乳類のものである。追加の態様において、結合ペプチドは、キメラおよび/またはヒト、マウス、ラット、ブタ、ウシ、霊長類、ネコ、イヌ、ウサギ、ヤギ、ニワトリまたはクマの起源である。
一実施形態において、本発明は、ROR-1発現癌の転移を抑制する方法を提供し、該方法は、モノクローナル抗体99961の結合特異性を有する抗体、抗体D10のROR-1結合領域に対して少なくとも95%の配列同一性を有するアミノ酸配列を有するペプチドから構成されるワクチン、VATNGKEVVSSTGVLFVKFGPCに対して少なくとも95%の配列同一性を有するアミノ酸配列を有するROR-1結合ペプチド、またはEVVSSTGVLFVKFGPCに対して少なくとも95%の配列同一性を有するアミノ酸配列を有するROR-1結合ペプチドを投与することによって腫瘍細胞の上皮間葉転換を妨害することを含む。一態様において、ROR-1発現癌は、B細胞白血病、リンパ腫、CLL、AML、B-ALL、T-ALL、卵巣癌、結腸癌、肺癌、皮膚癌、膵臓癌、精巣癌、膀胱癌、子宮癌、前立腺癌、または副腎癌である。
本明細書で使用されるとき、「治療する」または「治療」という用語は、治療的処置および予防法または予防措置の両方を指し、その目的は、癌の進行または拡大などの所望でない生理学的変化または障害を予防するまたは遅らせる(軽減する)ことである。有益なまたは所望の臨床結果としては、検出可能または検出不可能に関わらず、症状の緩和、疾患の程度の軽減、安定化した(すなわち、悪化しない)疾患の状態、疾患の進行の遅延または減速、疾患状態の改善または緩和、および寛解(部分的または全体的に関わらず)が挙げられるが、これらに限定されない。「治療」はまた、治療を受けない場合に予想される生存と比較して、延長された生存を意味し得る。治療を必要とする者としては、状態または障害を既に有する者、ならびに状態もしくは障害を有する傾向がある者、または予防されるべき状態または障害を有する者が挙げられる。
一定の治療的実施形態において、選択された抗体は典型的には、単独で、または1つ以上の組み合わせ治療剤と組み合わせて、もしくはそれと複合体化されて投与され得る抗ROR1抗体であるだろう。本明細書に記載の抗体が、治療剤として単独で投与される場合、それらは、種々の機構によって対象において有益な効果を発揮し得る。一定の実施形態において、hROR-1を特異的に結合するモノクローナル抗体は、1つ以上のhROR-1の活性を阻止するために、または1つ以上の形態のhROR-1の別の生体分子との相互作用を阻止するもしくは阻害するために、精製され、hROR-1の1つ以上の形態を中和するように患者に投与される。
元の部位から身体の遠隔領域への新生物細胞の広がりは癌関連死の90%の原因である。転移プロセスは、遠隔臓器への原発性腫瘍細胞の物理的な移動およびその後のコロニー化を含む。いくつかの悪い予後遺伝子シグネチャは、いくつかの原発性腫瘍内の細胞が、転移しやすいことを示唆している。しかしながら、転移の分子および細胞決定因子の理解は限られており、腫瘍細胞がこのイベントを体験するプロセスは、不明な点が多い。最近の注目は、現在、腫瘍の進行、運動性の獲得、浸潤性、転移、および自己複製特徴に顕著な要因と見なされる、上皮間葉転換(EMT)と呼ばれる細胞生物学的プログラムに集まっている。
582人の患者の組み合わされたコホートにおける患者から単離された乳癌細胞についてのGEOデータベースにおける、トランスクリプトームデータを調査した。これらの症例のおよそ3分の2(582人中426人)は、外科手術時点で所属リンパ節において検出可能な癌を有せず、補助療法を施与されなかった。残りの症例は、所属リンパ節において検出可能な疾患を有し、補助ホルモン療法および/または化学療法を受けた。582症例の中で、46%が再発し(n=270)、22.1ヶ月の無転移生存時間中央値を有した。我々は、患者を、彼らのROR1の相対的な癌細胞発現に基づいて3つの群に分離した。上位3分の1レベルのROR1 mRNA発現(ROR1H)を有する腫瘍を有する患者は、ROR1の下位3分の1レベル(ROR1L)または中間レベル(ROR1M)の発現を有した腫瘍を有する患者よりも、有意により短い無転移生存を有した(p<0.0001、図1A)。臓器部位別の無転移生存を検査した。ROR1H腫瘍を有する患者は、ROR1LまたはROR1M乳癌を有する患者よりも、肺(p=0.002、図45A)、骨(p=0.004、図45B)、または脳(p=0.04、図45C)へのより高い転移率を有することが見出された。ROR1H癌は、ROR1LまたはROR1Mである癌よりも、エストロゲン/プロゲステロン受容体またはHER2等の、予後良好の兆候を有する腫瘍の有意により低い割合を有した。
6個の基底細胞型乳癌細胞株および8個の管腔細胞型乳癌細胞株を含む、14個の明確に異なる乳癌上皮細胞株のROR1の発現を検査した。ROR1の発現のレベルは、基底細胞型乳癌細胞株において、概してROR1を発現しなかった管腔細胞型乳癌細胞株におけるROR1の発現のレベルと比べて、有意により高かった。その上、ROR1の相対的発現レベルは、三種陰性ERNegPRNegHER2/NeuNeg等の、攻撃的腫瘍表現型、ならびにインビトロでの高レベルの遊走能および浸潤能と相関していた。
細胞培養
乳癌細胞株MDA-MB-231、HS-578T、BT549、MDA-MB-415、MDA-MB-435s、MDA-MB-436、MDA-MB-157、MDA-MB-134、MCF7、BT-474、MDA-MB-453、SKBR3、MDA-MB-330、およびBT-483を、American Type Culture Collection(ATCC)から得、以前に記載されたように維持した(Neve et al.Cancer Cell,10:515(2006))。
ROR1のノックダウンを、以前に記載されたように(Zhang,S.Et al.,Cancer Cell,16:67(2009))、配列5′-TCC GGA TTG GAA TTC CCA TG-3′(shRNA1)、および5′-CTT TAC TAG GAG ACG CCA ATA-3′(shRNA2)を標的とすることによって達成した。非特異的なshRNA対照を、配列5′-AGC GGA CTA AGT CCA TTG C-3′を標的とすることによって作り出した。Virapower(商標)レンチウイルス発現システム(Invitrogen)を使用して、製造業者の指示に従ってshRNAを発現させた。ROR1-shRNA1およびCTRL-shRNA1構築物はまた、赤色蛍光タンパク質(RFP)もコードした。ROR1-shRNA1およびCTRL-shRNA1構築物に対するオリゴヌクレオチドを合成し(Integrated DNA Technologies)、RFP-pLKO.1ベクターに挿入した。ROR1-shRNA2およびCTRL-shRNA2構築物は、Open Biosystems(イリノイ州、ロックフォード)から購入した。乳癌細胞株の感染のためのウイルス粒子を、293-FTパッケージング細胞株のトランスフェクションによって得、トランスフェクション後48および72時間時点で細胞上清から収集した。上清を濾過し、43,000×gで遠心分離してウイルス粒子を濃縮し、それを使用して、コンフルエントに達していない培養物を、5μg/mlのポリブレンの存在下で一晩感染させた。
癌細胞を、成長因子を含まない0.2%ウシ胎仔血清(FBS)を補充したダルベッコ変法イーグル培地中で一晩馴化した。翌日、細胞をトリプシン処理し、成長因子を含まない0.2%FBS DMEM培地中に再懸濁させた。腫瘍細胞を、遊走アッセイについて1ウェル当たり25,000細胞の密度でトランスウェルインサート(3μM細孔サイズ、BD Falcon)中に、または1ウェル当たり50,000細胞の密度でマトリゲルコーティング、成長因子低減、浸潤チャンバ(8μM細孔サイズ、BD Biosciences)中に播種した。遊走アッセイについては6時間後、または浸潤アッセイについては22時間後に、ウェルをリン酸緩衝生理食塩水(PBS)で洗浄し、4%パラホルムアルデヒドで固定した。各インサートの頂端側上の細胞を、削り落とすことによって除去した。膜の基底側に遊走した細胞を染色し、ニコン倒立顕微鏡で可視化した。
総RNAを、RNeasyキット(Qiagen)を用いて精製し、2μgの各試料を使用して、高性能cDNA Reverser転写キット(ABI)を用いてcDNAを生成した。各cDNAを、ABI 7500 FastリアルタイムPCRシステム(Applied Biosystem)を使用して3系列で分析した。タンパク質発現レベルを、プロテアーゼ阻害剤(Roche)を含有する溶解緩衝液(20mM HEPES(pH 7.9)、25%グリセロール、0.5N NaCl、1mM EDTA、1%NP-40、0.5mMジチオトレイトール、および0.1%デオキシコール酸塩)中の細胞溶解物(40~60μg)で、抗ROR1(Cell Signaling)および抗β-アクチン抗体(Cell Signaling)を使用して、免疫ブロット分析によって評価した。
乳癌細胞をフローサイトメトリーによって染色またはプール選別した。細胞を洗浄し、PBS溶液中の2%ウシ血清アルブミン(BSA)(Sigma)中に再懸濁させ、ROR1発現に対して、製造業者のプロトコルに従ってAlex488複合体化抗体(クローン4A5またはクローンD10)またはAlex488複合体化IgG2bもしくはIgG2aアイソタイプ対照を使用して染色した。フローサイトメトリーデータを、FACSCalibur血球計算器(BD Biosciences)を使用して収集し、FlowJoソフトウェアを使用して分析した。
マウス肺を4%パラホルムアルデヒドで固定し、病理組織検査のためにOCTでパラフィン包埋または凍結させた。組織切片(5μm thick)を調製し、ヘマトキシリン&エオジン(H&E)、またはp-AKT(Ser473、D9E、Cell Signaling)、p-Creb(Ser133、87G3、Cell Signaling)、CK-19(RCK108、Dako)、もしくはビメンチン(D21H3、Cell Signaling)一次抗体で染色した。画像を、Delta Vision顕微鏡を使用して収集し、SPOTソフトウェアで処理した。
メスRag-/-γ-/-マウスに、親MDA-MB-231 ROR1-shRNA1細胞(群1)、および親MDA-MB-231に対する対照shRNA細胞(群2)のプールを注射した。細胞を、100μLのPBS中、側面尾静脈を通じて静脈内注射したか(群1~2について5×105、群3~4について2×105)、または100μLのPBS中、心内注射によって投与した(群5~6について1×105)。非侵襲的な生物発光撮像をIVIS 200撮像システムによって毎週行った。事前に死亡しなかったかまたは病気であるように見えなかった全てのマウスを、注射の3~4週間後に安楽死させ、それらの肺を摘出し、10%ホルマリン中に固定した。
Pubmed GEOデータベース(GEO2603、GSE5327、GSE2034、およびGSE12276)からの582人の患者のマイクロアレイデータセットを編集した。これらのデータセットを、log2によって変換し、各マイクロアレイを全てのプローブの中央値の中心に合わせた。各患者について、無転移生存を、外科手術と転移の診断との間の時間間隔として定義した。ヒト組織におけるROR1 mRNA発現の相対レベルを、公開された遺伝子発現データセットのOncomine癌マイクロアレイデータベース分析(www.oncomine.org)によって決定した。データをlog2変換し、このうち中央値をゼロに設定し、標準偏差を1に設定した。
ROR1-shRNAまたはCTRL-shRNAがトランスフェクトされたMDA-MB-231細胞を、6~8週齢のRag-/-γ-/-マウスに、静脈内(5×105細胞)または心内(1×105細胞)注射を介して投与して、静脈血中または動脈血中のいずれかに注射された細胞の転移可能性の差異について評価した。CTRL-shRNAがトランスフェクトされた細胞を側面尾静脈中に受けた全ての動物は、肺転移に起因して注射の32日以内に死亡した。同等の数のROR1-shRNAがトランスフェクトされた細胞を尾静脈に注射された動物は、有意により長く生存した(図4A)。CTRL-shRNAがトランスフェクトされた細胞を注射された動物は、ROR1をサイレンシングされた細胞を注射されたマウスよりも、肺においてそれぞれ21日目または28日目に19倍または60倍高い生物発光を有した(図4B)。我々はまた、別の実験において種々の時点で動物を屠殺して、転移性疾患について肺を検査した。発生期の転移巣は、CTRL-shRNAがトランスフェクトされた細胞の注射の3日後に容易に検出された一方で、ROR1がサイレンシングされた細胞を注射された動物の肺において検出することができた転移巣は、より後の時点でさえも、たとえあったとしてもほんのわずかであった(図4C~E)。その上、CTRL-shRNAがトランスフェクトされた細胞を注射されたマウスから摘出された肺は、ROR1がサイレンシングされた細胞を注射されたマウスの肺よりも、有意により高いエクスビボ生物発光および重量中央値(それぞれ21および28日目に3倍および6倍)を有した(図4F~G、データは図示されず)。CTRL-shRNAがトランスフェクトされた細胞を注射された動物において発達した転移巣はまた、我々がROR1がサイレンシングされた細胞を注射されたマウスにおいて検出したほんのわずかな転移巣(それはより高いレベルのCK-19およびより低いレベルのビメンチンを代わりに発現した)よりも、より高いレベルのホスホ-AKTおよびホスホ-CREBを発現し、より高い割合の増殖性細胞を有した(図47)。
ROR1の細胞外ドメインに特異的なモノクローナル抗体(mAb)を生成し、D10と指定されるものは、37℃で表面ROR1の急速な下方調節を誘導することができた(図5A)。D10によるMDA-MB-231の処理は、共焦点顕微鏡を介して評価したとき、ROR1内在化を引き起こした(図5B)。これは、ROR1の明確に異なる非交差遮断(non-cross-blocking)エピトープに特異的な異なるmAbを使用して、フローサイトメトリーを介して評価したとき、表面ROR1の有意な低減をもたらした(図5C)。D10によるMDA-MB-231の処理はまた、共免疫沈降研究においてROR1に結合した(図5E)、細胞質ビメンチンの発現も低減した(図5D)。D10による処理はまた、インビトロでMDA-MB-231の遊走および浸潤能を有意に阻害した(図5FおよびG)。D10はまた、他のROR1+癌細胞株(例えば、HS-578TおよびBT549(図9))の遊走/浸潤能を阻害することもできた。
エピトープ研究を上述のROR1抗体D10に対して行った。ヒトおよびマウスROR1の広がりを含む一連のキメラタンパク質を生成して、インビトロでROR1を下方調節し、ビメンチンの発現の低減をもたらし、癌細胞遊走(転移を形成する癌の能力の良好な代用マーカー)を阻害し得るD10によって認識される、エピトープ(複数可)をマッピングした。関与するROR1の唯一の領域は、ROR1のアミノ末端上にあるIg様ドメインである。各構築物は、キメラIg様ドメインならびにヒトCRDおよびクリングルドメイン(マウス部分は明色であり、ヒト部分は暗色である)を含有する。Ig様ドメインのみがここでは示される(図6)。これらの構築物をフリースタイル(free-style)293細胞内で発現させた。培養培地を免疫ブロットに使用し、精製タンパク質をELISAに使用した。D10 mAb抗ROR1は、ヒトROR1を認識したが、マウスROR1を認識しなかったため、これらの構築物うちのどちらが結合可能または不可能であったかを見出すことは、D10によって認識されるエピトープをマッピングする一助となり得た。結果は、抗体D10が、CRDドメインと隣接するIg様ドメインのC末端でROR1に結合することを示す(図7)。図8は、ROR1抗体4A5に対するエピトープのマッピングを示す。示されるように、4A5エピトープは、D10エピトープとは異なる。
ヒト臍帯血再構成免疫不全マウスにおいてCLL細胞に対する99961の特異的活性を実証するために、アッセイを実施した。ヒト免疫系を発生するようにヒト臍帯血(CB)細胞で再構成されたRag-/-γ-/-マウスに、新鮮なまたは凍結したCLL PBMCを腹腔内注射した。翌日、マウスに1mg/kgの99961またはD10または対照mIgGを静脈内で与えた。7日後、腹腔からのCLL PBMC細胞を採取し、フローサイトメトリーによって分析した(図13A)。データは、99961が、90%超のCLL細胞を排除し、正常なヒトB細胞またはT細胞発生には何の影響も及ぼさないことを示す(図13B、C)。
上で考察されるように、D10が、ROR1のCRDドメインに隣接するIg様ドメインのカルボキシ末端で結合することが示された。抗体4A5は、Ig様ドメイン内で異なるエピトープに結合し、生物活性を欠いている。mAbのエピトープは、ヒトとマウスのROR1との間の異なるアミノ酸のキメラROR1-細胞外および部位突然変異によって確認された。D10、4A5、および他のROR1抗体が結合するROR1の細胞外ドメインに対応するペプチド、すなわちA19、R22、およびK19を構築した。A19ペプチドは、4A5 mAbによって認識されるエピトープに対応し、R22ペプチドは、D10 mAb、99961 mAb(すなわち、VATNGKEVVSSTGVLFVKFGPC)、およびヒト化99961 mAbsによって認識されるエピトープに対応し、K19ペプチドは、ROR1特異的な他のmAbによって認識されるクリングルドメイン内の領域に対応する(図18)。3つのペプチドは各々、フロイント完全アジュバント(CFA)またはフロイント不完全アジュバント(IFA)のアジュバントにおいて、免疫化のためのキーホールリンペットヘモシアニン(KLH)とC末端で複合体化された。システイン(C)は、C末端に付加され、MBSとのKLHの複合体化のために使用された(図20)。複合体化反応は、図19に示されている。複合体化されたペプチドが、D10および99961に結合することが示される(図21)。C57BL/6およびトランスジェニックマウスは、複合体化されたペプチドで免疫化された。抗体力価は、免疫化後4週目に収集した。R22-KLHワクチンは、C57BL/6マウスまたはROR1-Tgマウスのいずれかにおいて、抗ROR1抗血清の最も高い力価を誘導した(図28)。この実験を、D10エピトープの16個のアミノ酸ペプチド、R16により再び行い、このペプチドもまた、ヒトのROR1タンパク質と反応する抗体を誘導したが、力価は一般的に、R22-KLHによって誘導されたものよりも低かった(データは示されない)。
R22-KLHを使用して、図33に示されるスキーマに従ってC57BL/6マウスを免疫化した。KLHまたはR22-KLHペプチドの第1の注射は、CFAにおいてであった。第2の注射およびその後の注射は、IFAにおいてであった。これらの動物は、紫色の矢印でマークされた日に採血された。第1の注射の日から44日後に、C57BL/6マウスは、ヒトROR1トランスジェニックマウスに由来するヒトROR1発現CLL細胞で喚起され、これはまた、T細胞白血病1(TCL1遺伝子)についてトランスジェニックであった。両方の導入遺伝子は、B細胞特異的プロモータ/エンハンサ(E-Cμ)の制御下にある。この白血病はヒトCLLに類似し、ヒト表面ROR1を発現する。
トランスジェニックマウスは、図38に示されるように、R22-KLHまたはKLHのいずれかを注射された。マウスは、B細胞特異的プロモータ/エンハンサ(E-Cμ)下でヒトROR1にトランスジェニックである。KLHまたはR22-KLHペプチドの第1の注射は、CFAにおいてであった。第2の注射およびその後の注射は、IFAにおいてであった。これらの動物は、紫色の矢印でマークされた日に採血された。第1の注射の日から44日後に、C57BL/6マウスは、ヒトROR1-Tgマウスに由来するヒトROR1発現CLL細胞で喚起され、これはまた、T細胞白血病1(TCL1遺伝子)についてトランスジェニックであった。両方の導入遺伝子は、B細胞特異的なプロモータ/エンハンサ(E-Cμ)の制御下にある。それゆえに、これらのROR1-Tgマウスは、ヒトROR1を発現するB細胞を有する。結果は、R22-KLHペプチドが、ROR1を発現するマウスにおける抗ROR1保護的免疫を誘導できることを実証し、それゆえに、自己寛容を破壊する
BALB/cマウスは、図22に示されているように、KLHまたはR22-KLHで免疫化された。このため、KLHまたはKLHと複合体化されたペプチドは各々、アジュバント(CFAまたはIFA)と乳剤を形成した。CFAは、第1の免疫化のために使用され、IFAは、その後のブーストのために使用された。採血およびペプチド注射の日が示されている。
トランスジェニックマウスは、図24に示されるように、KLHまたはR22-KLHのいずれかで免疫化された。ペプチドと複合体化されたKLHは、アジュバントと混合された(CFAまたはIFA)。CFAは、第1の免疫化のために使用され、IFAは、続くブーストのために使用された。ELISAの結果は、抗ROR1抗体の濃度は、R22-KLHで免疫化されたROR1トランスジェニックマウスに経時的に誘導されたことを示した。FACS分析は、細胞の表面上でのROR1への、R22-KLHで免疫化されたROR1トランスジェニックマウスからの抗血清の結合を確認した。
SEQUENCE LISTING
<110> THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
<120> ANTIBODIES AND VACCINES FOR USE IN TREATING ROR1 CANCERS AND
INHIBITING METASTASIS
<150> US 61/709,803
<151> 2012-10-04
<150> US 61/709,055
<151> 2012-10-02
<150> US 61/693,230
<151> 2012-08-24
<160> 46
<170> PatentIn version 3.5
<210> 1
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 1
Glu Ile Gln Leu Gln Gln Ser Gly Pro Val Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr Ala Tyr
20 25 30
Asn Ile His Trp Val Arg Gln Ser His Gly Lys Arg Leu Glu Trp Ile
35 40 45
Gly Ser Phe Asp Pro Tyr Asp Gly Gly Ser Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr
65 70 75 80
Met His Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Trp Tyr Tyr Phe Asp Tyr Trp Gly His Gly Thr Thr Leu
100 105 110
Thr Val Ser Ser
115
<210> 2
<211> 348
<212> DNA
<213> Mus musculus
<400> 2
gagatccagc tgcagcagtc tggacctgtc ctggtgaagc ctggggcttc agtgaaggtt 60
tcttgcaagg cttctggtta tgcattcact gcctacaaca tacactgggt gagacagagc 120
catggaaagc gccttgagtg gattggatct tttgatcctt acgatggtgg tagtagttac 180
aaccagaagt tcaaggacaa agccacattg actgtagaca aatcttccac cacagcctac 240
atgcatctca acagcctgac atctgaggac tctgcagtct attactgtgc aagggggtgg 300
tactactttg actactgggg ccacgggacc actctcacag tctcctca 348
<210> 3
<211> 108
<212> PRT
<213> Mus musculus
<400> 3
Asp Val Gln Ile Thr Gln Ser Pro Ser Tyr Leu Ala Ala Ser Pro Gly
1 5 10 15
Glu Thr Ile Thr Ile Asn Cys Arg Ala Ser Lys Ser Ile Ser Lys Tyr
20 25 30
Leu Ala Trp Tyr Gln Glu Lys Pro Gly Lys Thr Asn Lys Leu Leu Ile
35 40 45
Tyr Ser Gly Ser Thr Leu Gln Ser Gly Ile Pro Ser Arg Phe Arg Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Met Tyr Tyr Cys Gln Gln His Asp Glu Ser Pro Tyr
85 90 95
Thr Phe Gly Glu Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 4
<211> 324
<212> DNA
<213> Mus musculus
<400> 4
gacgtccaga taacccagtc tccatcttat cttgctgcat ctcctggaga aaccattact 60
attaattgca gggcaagtaa gagcattagc aaatatttag cctggtatca agagaaacct 120
gggaaaacta ataagctcct tatctactct ggatccactt tgcaatctgg aattccatca 180
agattcaggg gcagtggatc tggtacagat ttcactctca ccatcagtag cctggagcct 240
gaagattttg caatgtatta ctgtcaacag catgatgaat ccccgtacac gttcggagag 300
gggaccaagc tggaaataaa acgg 324
<210> 5
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 5
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ala Phe Thr Ala Tyr
20 25 30
Asn Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ser Phe Asp Pro Tyr Asp Gly Gly Ser Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val
65 70 75 80
Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Gly Trp Tyr Tyr Phe Asp Tyr Trp Gly His Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 6
<211> 348
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 6
caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60
acctgcactg tctctggtta tgcattcact gcctacaaca tacactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggttct tttgatcctt acgatggtgg tagtagttac 180
aaccagaagt tcaaggacag actcaccatc tccaaggaca cctccaaaaa ccaggtggtc 240
cttacaatga ccaacatgga ccctgtggac acagccacgt attactgtgc aagagggtgg 300
tactactttg actactgggg ccacggaacc ctggtcaccg tctcctca 348
<210> 7
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 7
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ala Ser Lys Ser Ile Ser Lys Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Ser Gly Ser Thr Leu Gln Ser Gly Ile Pro Pro Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Asn Ile Glu Ser
65 70 75 80
Glu Asp Ala Ala Tyr Tyr Phe Cys Gln Gln His Asp Glu Ser Pro Tyr
85 90 95
Thr Phe Gly Glu Gly Thr Lys Val Glu Ile Lys
100 105
<210> 8
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 8
gatattgtga tgacccagac tccactctcc ctgcccgtca cccctggaga gccggcctcc 60
atctcctgca gggcaagtaa gagcattagc aaatatttag cctggtacca gcagaaacct 120
ggccaggctc ccaggctcct catctattct ggatccactt tgcaatctgg gatcccacct 180
cgattcagtg gcagcgggta tggaacagat tttaccctca caattaataa catagaatct 240
gaggatgctg catattactt ctgtcaacag catgatgaat ccccgtacac gttcggcgag 300
gggaccaagg tggaaatcaa a 321
<210> 9
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 9
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ala Phe Thr Ala Tyr
20 25 30
Asn Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ser Phe Asp Pro Tyr Asp Gly Gly Ser Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val
65 70 75 80
Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Gly Trp Tyr Tyr Phe Asp Tyr Trp Gly His Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 10
<211> 348
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 10
caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60
acctgcactg tctctggtta tgcattcact gcctacaaca tacactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggttct tttgatcctt acgatggtgg tagtagttac 180
aaccagaagt tcaaggacag actcaccatc tccaaggaca cctccaaaaa ccaggtggtc 240
cttacaatga ccaacatgga ccctgtggac acagccacgt attactgtgc aagagggtgg 300
tactactttg actactgggg ccacggaacc ctggtcaccg tctcctca 348
<210> 11
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 11
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ala Ser Lys Ser Ile Ser Lys Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Gly Ser Thr Leu Gln Ser Gly Ile Pro Pro Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Asn Ile Glu Ser
65 70 75 80
Glu Asp Ala Ala Tyr Tyr Phe Cys Gln Gln His Asp Glu Ser Pro Tyr
85 90 95
Thr Phe Gly Glu Gly Thr Lys Val Glu Ile Lys
100 105
<210> 12
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 12
gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60
atctcctgca gggcaagtaa gagcattagc aaatatttag cctggtatca gcagaaacca 120
gggaaagctc ctaagctcct gatctattct ggatccactt tgcaatctgg gatcccacct 180
cgattcagtg gcagcgggta tggaacagat tttaccctca caattaataa catagaatct 240
gaggatgctg catattactt ctgtcaacag catgatgaat ccccgtacac gttcggcgag 300
gggaccaagg tggaaatcaa a 321
<210> 13
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 13
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ala Phe Thr Ala Tyr
20 25 30
Asn Ile His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ser Phe Asp Pro Tyr Asp Gly Gly Ser Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val
65 70 75 80
Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Gly Trp Tyr Tyr Phe Asp Tyr Trp Gly His Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 14
<211> 348
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 14
caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60
acctgcactg tctctggtta tgcattcact gcctacaaca tacactggat ccgccagccc 120
ccagggaagg ggctggagtg gattggttct tttgatcctt acgatggtgg tagtagttac 180
aaccagaagt tcaaggacag actcaccatc tccaaggaca cctccaaaaa ccaggtggtc 240
cttacaatga ccaacatgga ccctgtggac acagccacgt attactgtgc aagagggtgg 300
tactactttg actactgggg ccacggaacc ctggtcaccg tctcctca 348
<210> 15
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 15
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ala Ser Lys Ser Ile Ser Lys Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Ser Gly Ser Thr Leu Gln Ser Gly Ile Pro Pro Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Asn Ile Glu Ser
65 70 75 80
Glu Asp Ala Ala Tyr Tyr Phe Cys Gln Gln His Asp Glu Ser Pro Tyr
85 90 95
Thr Phe Gly Glu Gly Thr Lys Val Glu Ile Lys
100 105
<210> 16
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 16
gatattgtga tgacccagac tccactctcc ctgcccgtca cccctggaga gccggcctcc 60
atctcctgca gggcaagtaa gagcattagc aaatatttag cctggtacca gcagaaacct 120
ggccaggctc ccaggctcct catctattct ggatccactt tgcaatctgg gatcccacct 180
cgattcagtg gcagcgggta tggaacagat tttaccctca caattaataa catagaatct 240
gaggatgctg catattactt ctgtcaacag catgatgaat ccccgtacac gttcggcgag 300
gggaccaagg tggaaatcaa a 321
<210> 17
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 17
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ala Phe Thr Ala Tyr
20 25 30
Asn Ile His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ser Phe Asp Pro Tyr Asp Gly Gly Ser Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val
65 70 75 80
Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Gly Trp Tyr Tyr Phe Asp Tyr Trp Gly His Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 18
<211> 348
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 18
caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60
acctgcactg tctctggtta tgcattcact gcctacaaca tacactggat ccgccagccc 120
ccagggaagg ggctggagtg gattggttct tttgatcctt acgatggtgg tagtagttac 180
aaccagaagt tcaaggacag actcaccatc tccaaggaca cctccaaaaa ccaggtggtc 240
cttacaatga ccaacatgga ccctgtggac acagccacgt attactgtgc aagagggtgg 300
tactactttg actactgggg ccacggaacc ctggtcaccg tctcctca 348
<210> 19
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 19
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ala Ser Lys Ser Ile Ser Lys Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Gly Ser Thr Leu Gln Ser Gly Ile Pro Pro Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Asn Ile Glu Ser
65 70 75 80
Glu Asp Ala Ala Tyr Tyr Phe Cys Gln Gln His Asp Glu Ser Pro Tyr
85 90 95
Thr Phe Gly Glu Gly Thr Lys Val Glu Ile Lys
100 105
<210> 20
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 20
gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60
atctcctgca gggcaagtaa gagcattagc aaatatttag cctggtatca gcagaaacca 120
gggaaagctc ctaagctcct gatctattct ggatccactt tgcaatctgg gatcccacct 180
cgattcagtg gcagcgggta tggaacagat tttaccctca caattaataa catagaatct 240
gaggatgctg catattactt ctgtcaacag catgatgaat ccccgtacac gttcggcgag 300
gggaccaagg tggaaatcaa a 321
<210> 21
<211> 252
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 21
Asp Ile Val Met Thr Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro
1 5 10 15
Gly Glu Pro Ala Ser Ile Ser Cys Arg Ala Ser Lys Ser Ile Ser Lys
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Ser Gly Ser Thr Leu Gln Ser Gly Ile Pro Pro Arg Phe Ser
50 55 60
Gly Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Asn Ile Glu
65 70 75 80
Ser Glu Asp Ala Ala Tyr Tyr Phe Cys Gln Gln His Asp Glu Ser Pro
85 90 95
Tyr Thr Phe Gly Glu Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly
100 105 110
Ser Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser
115 120 125
Thr Lys Gly Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly
130 135 140
Pro Gly Leu Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val
145 150 155 160
Ser Gly Tyr Ala Phe Thr Ala Tyr Asn Ile His Trp Val Arg Gln Ala
165 170 175
Pro Gly Gln Gly Leu Glu Trp Met Gly Ser Phe Asp Pro Tyr Asp Gly
180 185 190
Gly Ser Ser Tyr Asn Gln Lys Phe Lys Asp Arg Leu Thr Ile Ser Lys
195 200 205
Asp Thr Ser Lys Asn Gln Val Val Leu Thr Met Thr Asn Met Asp Pro
210 215 220
Val Asp Thr Ala Thr Tyr Tyr Cys Ala Arg Gly Trp Tyr Tyr Phe Asp
225 230 235 240
Tyr Trp Gly His Gly Thr Leu Val Thr Val Ser Ser
245 250
<210> 22
<211> 753
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 22
gatattgtga tgacccagac tccactctcc ctgcccgtca cccctggaga gccggcctcc 60
atctcctgca gggcaagtaa gagcattagc aaatatttag cctggtacca gcagaaacct 120
ggccaggctc ccaggctcct catctattct ggatccactt tgcaatctgg gatcccacct 180
cgattcagtg gcagcgggta tggaacagat tttaccctca caattaataa catagaatct 240
gaggatgctg catattactt ctgtcaacag catgatgaat ccccgtacac gttcggcgag 300
gggaccaagg tggaaatcaa aggtggtggt ggtagcggct ccacctctgg atccggcaag 360
cccggatctg gcgagggatc caccaagggc ggaggaggag gaagtcaggt gcagctgcag 420
gagtcgggcc caggactggt gaagccttca cagaccctgt ccctcacctg cactgtctct 480
ggttatgcat tcactgccta caacatacac tgggtgcgac aggcccctgg acaagggctt 540
gagtggatgg gttcttttga tccttacgat ggtggtagta gttacaacca gaagttcaag 600
gacagactca ccatctccaa ggacacctcc aaaaaccagg tggtccttac aatgaccaac 660
atggaccctg tggacacagc cacgtattac tgtgcaagag ggtggtacta ctttgactac 720
tggggccacg gaaccctggt caccgtctcc tca 753
<210> 23
<211> 251
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 23
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ala Ser Lys Ser Ile Ser Lys Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Gly Ser Thr Leu Gln Ser Gly Ile Pro Pro Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Asn Ile Glu Ser
65 70 75 80
Glu Asp Ala Ala Tyr Tyr Phe Cys Gln Gln His Asp Glu Ser Pro Tyr
85 90 95
Thr Phe Gly Glu Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr
115 120 125
Lys Gly Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Pro
130 135 140
Gly Leu Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser
145 150 155 160
Gly Tyr Ala Phe Thr Ala Tyr Asn Ile His Trp Val Arg Gln Ala Pro
165 170 175
Gly Gln Gly Leu Glu Trp Met Gly Ser Phe Asp Pro Tyr Asp Gly Gly
180 185 190
Ser Ser Tyr Asn Gln Lys Phe Lys Asp Arg Leu Thr Ile Ser Lys Asp
195 200 205
Thr Ser Lys Asn Gln Val Val Leu Thr Met Thr Asn Thr Asp Pro Val
210 215 220
Asp Thr Ala Thr Tyr Tyr Cys Ala Arg Gly Trp Tyr Tyr Phe Asp Tyr
225 230 235 240
Trp Gly His Gly Thr Leu Val Thr Val Ser Ser
245 250
<210> 24
<211> 753
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 24
gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60
atctcctgca gggcaagtaa gagcattagc aaatatttag cctggtatca gcagaaacca 120
gggaaagctc ctaagctcct gatctattct ggatccactt tgcaatctgg gatcccacct 180
cgattcagtg gcagcgggta tggaacagat tttaccctca caattaataa catagaatct 240
gaggatgctg catattactt ctgtcaacag catgatgaat ccccgtacac gttcggcgag 300
gggaccaagg tggaaatcaa aggtggtggt ggtagcggct ccacctctgg atccggcaag 360
cccggatctg gcgagggatc caccaagggc ggaggaggag gaagtcaggt gcagctgcag 420
gagtcgggcc caggactggt gaagccttca cagaccctgt ccctcacctg cactgtctct 480
ggttatgcat tcactgccta caacatacac tgggtgcgac aggcccctgg acaagggctt 540
gagtggatgg gttcttttga tccttacgat ggtggtagta gttacaacca gaagttcaag 600
gacagactca ccatctccaa ggacacctcc aaaaaccagg tggtccttac aatgaccaac 660
atggaccctg tggacacagc cacgtattac tgtgcaagag ggtggtacta ctttgactac 720
tggggccacg gaaccctggt caccgtctcc tca 753
<210> 25
<211> 22
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 25
Val Ala Thr Asn Gly Lys Glu Val Val Ser Ser Thr Gly Val Leu Phe
1 5 10 15
Val Lys Phe Gly Pro Cys
20
<210> 26
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 26
Glu Val Val Ser Ser Thr Gly Val Leu Phe Val Lys Phe Gly Pro Cys
1 5 10 15
<210> 27
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 27
Gly Tyr Ala Phe Thr Ala Tyr Asn
1 5
<210> 28
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 28
Phe Asp Pro Tyr Asp Gly Gly Ser
1 5
<210> 29
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 29
Gly Trp Tyr Tyr Phe Asp Tyr
1 5
<210> 30
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 30
Lys Ser Ile Ser Lys Tyr
1 5
<210> 31
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 31
Ser Gly Ser
1
<210> 32
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 32
Gln Gln His Asp Glu Ser Pro Tyr
1 5
<210> 33
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 33
Ser Gly Tyr Ala Phe Thr Ala Tyr Asn Ile His Trp Val Arg Gln
1 5 10 15
<210> 34
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 34
Gly Ser Phe Asp Pro Tyr Asp Gly Gly Ser Ser Tyr Asn Gln Lys Phe
1 5 10 15
Lys Asp
<210> 35
<211> 23
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 35
Tyr Tyr Cys Ala Arg Gly Trp Tyr Tyr Phe Asp Tyr Trp Gly His Gly
1 5 10 15
Thr Leu Val Thr Val Ser Ser
20
<210> 36
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 36
Cys Arg Ala Ser Lys Ser Ile Ser Lys Tyr Leu Ala Trp Tyr
1 5 10
<210> 37
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 37
Leu Leu Ile Tyr Ser Gly Ser Thr Leu Gln Ser Gly
1 5 10
<210> 38
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic construct
<400> 38
Cys Gln Gln His Asp Glu Ser Pro Tyr Thr Phe Gly Glu Gly Thr Lys
1 5 10 15
Val Glu Ile Lys
20
<210> 39
<211> 117
<212> PRT
<213> Mus musculus
<400> 39
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ala Gly Gly Phe Thr Asn Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Leu Leu
65 70 75 80
Lys Met Thr Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Arg Gly Ser Ser Tyr Ser Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 40
<211> 351
<212> DNA
<213> Mus musculus
<400> 40
caggtgcagc tgaaggagtc aggacctggc ctggtggcgc cctcacagac tctgtccatc 60
acttgcactg tctctgggtt ttcattaacc agttatggtg tacactgggt tcgccagcct 120
ccaggaaagg gtctggagtg gctgggagta atatgggctg gtggattcac aaattataat 180
tcggctctca agtccagact gagcatcagc aaagacaact ccaagagcca agttctctta 240
aaaatgacca gtctgcaaac tgatgacaca gccatgtact actgtgccag gagaggtagt 300
tcctattcta tggactattg gggtcaagga acctcagtca ccgtctcctc a 351
<210> 41
<211> 106
<212> PRT
<213> Mus musculus
<400> 41
Glu Ile Val Leu Ser Gln Ser Pro Ala Ile Thr Ala Ala Ser Leu Gly
1 5 10 15
Gln Lys Val Thr Ile Thr Cys Ser Ala Ser Ser Asn Val Ser Tyr Ile
20 25 30
His Trp Tyr Gln Gln Arg Ser Gly Thr Ser Pro Arg Pro Trp Ile Tyr
35 40 45
Glu Ile Ser Lys Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Ile Tyr Tyr Cys Gln Gln Trp Asn Tyr Pro Leu Ile Thr
85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu Ile Gln
100 105
<210> 42
<211> 318
<212> DNA
<213> Mus musculus
<400> 42
gaaattgtgc tctctcagtc tccagccatc acagctgcat ctctgggcca aaaggtcacc 60
atcacctgca gtgccagttc aaatgtaagt tacatccact ggtaccagca gaggtcaggc 120
acctccccca gaccatggat ttatgaaata tccaaactgg cttctggagt cccagttcgc 180
ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagcat ggaggctgaa 240
gatgctgcca tttattattg tcagcagtgg aattatcctc ttatcacgtt cggctcgggg 300
acaaagttgg aaatacaa 318
<210> 43
<211> 119
<212> PRT
<213> Mus musculus
<400> 43
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ile Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Arg Gly Gly Thr Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Val Arg Asn Ile Leu Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys Gly
85 90 95
Arg Tyr Asp Tyr Asp Gly Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser
115
<210> 44
<211> 357
<212> DNA
<213> Mus musculus
<400> 44
gaagtgaaac tggtggagtc tgggggaggc ttagtgaagc ctggagggtc cctgaaactc 60
tcctgtgcag cctctggatt cactttcagt agctatgcca tgtcttgggt tcgccagatt 120
ccagagaaga ggctggagtg ggtcgcatcc attagtcgtg gtggtaccac ctactatcca 180
gacagtgtga agggccgatt caccatctcc agagataatg tcaggaacat cctgtacctg 240
caaatgagca gtctgaggtc tgaggacacg gccatgtatt actgtggaag atatgattac 300
gacgggtact atgcaatgga ctactggggt caaggaacct cagtcaccgt ctcctca 357
<210> 45
<211> 107
<212> PRT
<213> Mus musculus
<400> 45
Asp Ile Lys Met Thr Gln Ser Pro Ser Ser Met Tyr Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Ile Thr Cys Lys Ala Ser Pro Asp Ile Asn Ser Tyr
20 25 30
Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Lys Thr Leu Ile
35 40 45
Tyr Arg Ala Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Gly Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Asn Ser Leu Glu Tyr
65 70 75 80
Glu Asp Met Gly Ile Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Met Lys
100 105
<210> 46
<211> 322
<212> DNA
<213> Mus musculus
<400> 46
gacatcaaga tgacccagtc tccatcttcc atgtatgcat ctctaggaga gagagtcact 60
atcacttgca aggcgagtcc ggacattaat agctatttaa gctggttcca gcagaaacca 120
gggaaatctc ctaagaccct gatctatcgt gcaaacagat tggttgatgg ggtcccatca 180
aggttcagtg gcggtggatc tgggcaagat tattctctca ccatcaacag cctggagtat 240
gaagatatgg gaatttatta ttgtctacag tatgatgaat ttccgtacac gttcggaggg 300
gggaccaagc tggaaatgaa ac 322
Claims (29)
- 抗体99961と同じ結合特異性を有する単離された抗ROR1抗体。
- hROR-1のアミノ酸130~160に結合する、請求項1に記載の抗体。
- ROR1アミノ酸138がhROR-1への結合のためにグルタミン酸であることを必要とする、請求項2に記載の抗体。
- 配列番号1、配列番号5、配列番号9、配列番号13、および配列番号17からなる群から選択される重鎖可変領域、および配列番号3、配列番号7、配列番号11、配列番号15、および配列番号19からなる群から選択される軽鎖可変領域を備える、請求項1に記載の抗体。
- 結合親和性を有する前記抗体が、約500pM~約6nMの間である、請求項1に記載の抗体。
- 前記結合親和性が約800pMである、請求項5に記載の抗体。
- 99961、99961.1、99961.2、99961.3、および99961.4からなる群から選択される、請求項1~6のいずれか一項に記載の抗体。
- 転移を阻害する、請求項1~7のいずれか一項に記載の抗体。
- ヒト、ヒト化、またはキメラ抗体である、請求項1~8のいずれか一項に記載の抗体。
- 請求項1~9のいずれか一項に記載の抗体をコードする単離された核酸。
- ROR-1発現細胞に対するワクチンであって、抗体D10のROR-1結合領域に対して少なくとも95%の配列同一性を有するアミノ酸配列を有する、単離されたまたは合成的に産生されたペプチドの薬学的に許容される組成物を含む、ワクチン。
- ROR-1発現細胞が癌細胞である、請求項12に記載のワクチン。
- 癌細胞が、B細胞白血病、リンパ腫、CLL、AML、B-ALL、T-ALL、卵巣癌、結腸癌、肺癌、皮膚癌、膵臓癌、精巣癌、膀胱癌、子宮癌、前立腺癌、および副腎癌からなる群から選択される、請求項11に記載のワクチン。
- 免疫原性アジュバントをさらに含む、請求項12または13に記載のワクチン。
- 前記アジュバントは、結合ペプチドに複合体化された免疫原性担体ペプチドである、請求項16に記載のワクチン。
- 哺乳類由来である、請求項20に記載の結合ペプチド。
- 請求項20に記載の結合ペプチドをコードする、単離された核酸。
- 哺乳類のペプチドである、請求項23に記載の結合ペプチド。
- 請求項23に記載の結合ペプチドをコードする単離された核酸。
- 前記ROR-1発現癌が、B細胞白血病、リンパ腫、CLL、AML、B-ALL、T-ALL、卵巣癌、結腸癌、肺癌、皮膚癌、膵臓癌、精巣癌、膀胱癌、子宮癌、前立腺癌、および副腎癌からなる群から選択される、請求項26に記載の方法。
- 癌が、B細胞白血病、リンパ腫、CLL、AML、B-ALL、T-ALL、卵巣癌、結腸癌、肺癌、皮膚癌、膵臓癌、精巣癌、膀胱癌、子宮癌、前立腺癌、および副腎癌からなる群から選択される、請求項27に記載の方法。
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US201261709803P | 2012-10-04 | 2012-10-04 | |
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JP2021001318A JP7138735B2 (ja) | 2012-08-24 | 2021-01-07 | Ror1癌の治療および転移の阻害に使用するための抗体およびワクチン |
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