JP6857138B2 - Axlタンパク質に結合する抗体 - Google Patents
Axlタンパク質に結合する抗体 Download PDFInfo
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- JP6857138B2 JP6857138B2 JP2017558673A JP2017558673A JP6857138B2 JP 6857138 B2 JP6857138 B2 JP 6857138B2 JP 2017558673 A JP2017558673 A JP 2017558673A JP 2017558673 A JP2017558673 A JP 2017558673A JP 6857138 B2 JP6857138 B2 JP 6857138B2
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Description
本出願は、2015年5月18日出願の米国仮特許出願第62/163264号明細書の優先権を主張し、この出願の内容は、参照によってその全体が組み込まれる。
本出願は、電子フォーマットの配列表と共に提出されている。配列表は、32.4キロバイトのサイズである、2016年5月18日に作成された511582009840SEQLIST.TXTという表題のファイルとして提供される。配列表の電子フォーマットの情報は、参照によってその全体が組み込まれる。
該当せず。
I.)定義
II.)AXL抗体
III.)AXLを発現する癌の診断
IV.)AXLを発現する癌の処置
V.)抗体ベース治療のための、標的としてのAXL
VI.)AXL ADCカクテル
VII.)併用療法
VIII.)キット/製造品
別段の定めがない限り、本明細書中で用いられる全ての技術用語、表記、および他の科学用語または専門用語は、本発明が属する技術分野の当業者によって一般的に理解される意味を有することが意図される。場合によっては、一般的に理解される意味を有する用語が、本明細書中で、明瞭化のために、かつ/または容易な参照のために定義されており、本明細書におけるそのような定義の包含は、必ずしも、当該技術分野において一般に理解されるものに対する実質的な差異を表すと解釈されるべきでない。本明細書中で記載または参照される技術および手順の多くは、当業者によって、従来の方法論、例えば、Sambrook et al., Molecular Cloning:A Laboratory Manual 2nd. edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.に記載される、広く利用されている分子クローニング方法論を用いて、よく理解され、かつ一般的に使用される。必要に応じて、市販のキットおよび試薬の使用を含む手順は、特記しない限り、一般に、製造者が定義したプロトコルおよび/またはパラメータに従って実施される。
本発明の別の態様は、AXL関連タンパク質に結合する抗体を提供する(図1参照)。一実施形態において、AXL関連タンパク質に結合する抗体は、配列番号2のアミノ酸配列を含むAXLタンパク質に特異的に結合する抗体である。配列番号2のアミノ酸配列を含むAXLタンパク質に特異的に結合する抗体として、他のAXL関連タンパク質に結合し得る抗体が挙げられる。例えば、配列番号2のアミノ酸配列を含むAXLタンパク質に結合する抗体は、AXL変異体等のAXL関連タンパク質、およびその相同体または類似体に結合し得る。
本発明のAXL MAbは、対象における癌の存在の検出方法にまたは対象における癌の診断方法に用いられ得る。検出方法または診断方法における癌の例として、肉腫、膵臓癌、黒色腫、卵巣癌、および肺癌が挙げられる。また、本発明のAXL MAbは、癌患者等の対象から得られるサンプルにおけるAXL発現の検出方法に用いられ得る。癌細胞におけるAXL発現は、EGFR阻害剤(例えばエルロチニブ)による処置を経験した癌患者におけるEGFR阻害剤に対する耐性に関係があることが知られている。したがって、AXLキナーゼ阻害剤とEGFR阻害剤の組合せは、EGFR阻害剤抵抗性の低下および癌増殖の抑制に用いられ得る。本発明のAXL MAbは、AXL発現が陽性であるため、AXLキナーゼ阻害剤および/またはEGFR阻害剤による処置に曝される癌患者を同定する方法に用いられ得る。一実施形態において、癌は、肉腫、膵臓癌、黒色腫、卵巣癌、および肺癌からなる群から選択される。一実施形態において、患者は、EGFR阻害剤による処置を経験しており、癌は、EGFR阻害剤に対して耐性である。
制限された組織において正常に発現されるが、表Iに列挙されるような癌においても発現されるタンパク質としてのAXLの同定は、そのような癌の処置へのいくつかの治療的アプローチおよび診断的アプローチを開く。
AXLは、抗体ベースの治療戦略にとって魅力的な標的である。細胞外分子および細胞内分子の双方を標的とするいくつかの抗体戦略が、当該技術分野において知られている(例えば、補体およびADCC媒介死、ならびにイントラボディの使用を参照)。AXLは、正常細胞に対して、対応する様々な系列の癌細胞によって発現されるので、免疫反応性組成物の、非標的臓器および非標的組織への結合によって、毒性、非特異的作用、および/または非標的作用が引き起こされることのない、優れた感受性を示す全身投与AXL免疫反応性組成物が調製される。AXLのドメインと特異的に反応する抗体は、好ましくは抗体薬物結合体(すなわちADC)として、AXL発現癌を全身的に処置するのに有用であり、結合体は、造影剤、毒素、または治療剤と共にある。
本発明の治療方法は、単一のAXL ADC、および異なるMAb(すなわち、AXL MAb、または別のタンパク質に結合するMAb)の組合せまたはカクテルの投与を意図する。そのようなMAbカクテルは、異なるエピトープを標的とするMAbを含有し、異なるエフェクタ機構を利用し、または直接細胞毒性MAbを、免疫エフェクタ機能に依存するMAbと組み合わせるので、ある種の利点を有し得る。そのようなMAbは組み合わされて、相乗的な治療効果を示し得る。また、AXL MAbは、様々な化学療法剤および生物剤、アンドロゲン遮断薬、免疫調節剤(例えば、IL−2、GM−CSF)、外科手術、または放射線が挙げられるが、これらに限定されない、他の治療法と同時に施され得る。好ましい実施形態において、AXL MAbは、結合形態で投与される。
一実施形態において、ヒト腫瘍が挙げられる腫瘍が、化学療法剤もしくは放射線またはそれらの組合せと併せて、AXL ADCで処置される場合、相乗効果がある。換言すれば、AXL ADCによる腫瘍増殖の阻害は、化学療法剤もしくは放射線、またはそれらの組合せと組み合わされた場合、予想されるよりも増強される。相乗効果は、例えば、AXL ADCのみの処置、またはAXL ADCおよび化学療法剤または放射線による処置の相加効果から予想されるよりも、併用処置による腫瘍増殖の阻害が大きいことによって、示され得る。好ましくは、相乗効果は、AXL ADCによる処置から、またはAXL ADCと化学療法剤もしくは放射線の付加的な組合せを用いた処置から寛解が予想されない場合での癌の寛解によって、示される。
本明細書中に記載される実験室、予後、予防、診断、および治療の用途に用いるためのキットが、本発明の範囲内である。そのようなキットは、バイアル、チューブ等の1つまたは複数の容器を受け入れるように区画されているキャリア、パッケージ、または容器を、本明細書中に記載される使用等の使用についての説明書を含むラベルまたは挿入物と共に含んでよく、各容器は、当該方法において用いられることになる別個の要素の1つを含む。例えば、容器は、検出可能に標識されている、または検出可能に標識され得る抗体を含んでよい。キットは、薬物単位を含む容器を含んでよい。
AXL抗原
AXL(それ以外ではTyro7、UFO、およびARK(ならびにGenBank登録番号:NM_021913)として知られている)は、ヒトtrk、eph、eck、およびrosタンパク質、ならびにインスリン様増殖因子1受容体とのアミノ酸類似度が高い受容体チロシンキナーゼをコードするタンパク質である。この遺伝子によってコードされるタンパク質は、Rse/Tyro3受容体およびMER受容体を含む膜貫通型受容体チロシンキナーゼ(TRK)ファミリに属する。このファミリは、免疫グロブリン様フィブロネクチンIII様ドメインの特有の細胞外組成物によって特徴付けられる。これらの構造的所見は、Axlファミリメンバが、細胞接着および細胞内シグナル伝達の双方に関与している可能性があることを示唆している。Sainaghi,et al,J.Cell.Phys.204:36−44(2005)参照。また、O’Bryan,et al,J.Bio.Chem.,Vol.270 no.2,pp.551−557(1995)参照。また、Axlは、複数の癌、例えば肺癌、乳癌、卵巣癌、甲状腺癌、胃癌、腎臓癌、結腸癌、および骨髄性白血病において発現されることが指摘されてきた。更なる参考文献について、Shieh,et al,Neoplasia,vol 7,No.12 pp 1058−1064(Dec.2005);Berclaz,et al.Annals of Oncology,vol.12 pp.819−824(2001);Sun,et al.Oncology 2004;66:450−457(2004);Ito,et al,Thyroid,vol.9:No.6,pp.563−567(1999);Wu,et al,Anticancer Res.,vol.22,pp.1071−1078(2002);Chung,et al.DNA and Cell Bio.,Vol.22:No.8,pp.533−540(2003);Craven,et al,Int.J.Cancer,vol.60 pp.791−797(1995)。AXL cDNAは、4,743bpの長さであり、894個のアミノ酸ORFをコードする(図1参照)。AXL抗原の例示的な実施形態について、図1参照。
AXLモノクローナル抗体(MAb)の作出
一実施形態において、AXLに対する診断用モノクローナル抗体(「mAb」)は、AXLに特異的なエピトープと反応する抗体を含み、これは、患者の生検から調製した、凍結し、またはパラフィン包埋し、ホルマリン固定した組織切片中の細胞上に発現されたAXLに結合するであろう。そのようなMAbの作出用の免疫原として、AXLタンパク質配列をコードまたは含有するように設計された免疫原が挙げられる。免疫原として、ペプチド、組換えタンパク質、AXLを内在的に発現する細胞、またはAXLを発現するように操作された細胞(293T−AXL等)が挙げられる。
AXL ADCを用いた、ヒト癌腫の処置および診断についてのヒト臨床試験
AXLに特異的に結合するAXL ADCを、本発明に従って用いて、特定の腫瘍、好ましくは表1に列挙する腫瘍の処置に用いる。これらの徴候のそれぞれに関して、2つの臨床的アプローチを首尾よく遂行する。
投薬レジメンを調節して、最適な所望の反応を実現することができる。例えば、単回のボーラス投与をしてもよいし、いくつかの分割用量を経時的に投与してもよいし、治療状況の示される緊急性に比例させて用量を増減させてもよい。投与を容易にし、かつ投薬量を均一にするために、非経口組成物を投薬単位形態で処方することが特に有利である。本明細書中で用いる投薬単位形態とは、処置することになる哺乳動物対象のための単位投薬量として適した、物理的に別個の単位を指す;各単位は、必要とされる医薬キャリアと協働して所望の治療効果をもたらすように算出した所定量の活性化合物を含有する。本発明の投与単位形態についての仕様は、(a)抗体および/またはADCの特有の特徴、ならびに達成されることになる特定の治療効果または予防効果、ならびに(b)調剤技術において固有の制限、例えば処置用の活性化合物の、個体における感受性によって決定され、かつこれらに直接依存する。
CDPを、補助療法または単剤療法と併せたAXL ADCの処置に従わせて開発する。治験は、最初に、安全性を実証し、その後、反復用量の有効性を確認する。治験は、標準的な化学療法を、標準的な治療法プラスAXL ADCと比較する非盲検である。認識されるように、患者の登録に関連して利用することができる非限定的な一基準が、生検によって判断した当該患者の腫瘍におけるAXL発現レベルである。
IHCによる、癌患者標本におけるAXLタンパク質の検出
免疫組織化学によるAXLタンパク質の発現を、肉腫、膵臓癌、黒色腫、卵巣癌、および肺癌のサンプル由来の腫瘍標本において試験した。簡潔には、ホルマリン固定したパラフィンワックス包埋組織を4ミクロン切片に切って、ガラススライド上に載せた。切片を脱ワックスして、再水和させて、BOND−MAX自動化IHC染色系(Leica Biosystems,Buffalo Grove,IL)内で、Novocastra Bond Epitope Retrieval Solution 2(Leica Biosystems,Buffalo Grove,IL)と 100℃にて30分間処理してから、室温にて12分間放置した。次いで、切片を、V77−2a37.1と表したモノクローナルマウス抗AXL抗体またはアイソタイプコントロールとインキュベートした。その後、切片を、Novocastra Bond Polymer Refine Detection Systemで処理した。これは、ポストプライマリウサギ抗マウスIgG試薬中でのインキュベーションに続く、ポリマー抗ウサギポリHRP−IgG試薬(Leica Biosystems,Buffalo Grove,IL)とのインキュベーションからなる。次いで、切片を3%過酸化水素溶液で処理して、内因性ペルオキシダーゼ活性を不活化した。DAB精製キット(Leica Biosystems,Buffalo Grove,IL)を用いて、クロモゲン基質の可視化を進め、ヘマトキシリンを用いて核を染色し、そしてAperio ePathology Scanscope撮像系(Leica Biosystems,Vista,CA)上でスライドをスキャンして分析した。AXL特異的V77−2a37.1抗体を用いて、患者標本において、ブラウン染色によって示される特異的染色を検出した。(図5A、図5C、図5E、図5G、および図5I参照)。対照的に、アイソタイプコントロール抗体は、腫瘍標本を染色しなかった。(図5B、図5D、図5F、図5H、および図5J参照)。
V77−2a37.1 MAbのエピトープマッピング
2つの抗体のエピトープが重なっており、または互いに近接しているならば、当該エピトープ同士の近接によって決定される程度に、抗体は互いを阻止すると予想されることが、当該技術分野において知られている。一抗体を標識して、モル過剰の非標識抗体でチャレンジしてから、固定化した標的タンパク質と反応させる抗体競合実験は、2つの抗体が互いに近接して位置するエピトープに結合するかを判定する容易な方法である。
細胞ブロックサンプルを用いたAXL検出用の免疫組織化学試薬としてのC89E7 MAbおよびAF154 MAbの評価
この実験では、ヒト肺癌細胞株NCI−H292およびHCC827(American Type Culture Collectionから購入)、ならびにNCI−H727(European Collection of Cell Cultureから購入)の3つの細胞ブロックサンプルを、10%ウシ胎児血清(Sigma−Aldrich,St.Louis,MO)を補充したRPMI1640培地(Thermo Fisher Scientific,Waltham,MA)中で培養して、遠心分離して洗浄した後に、細胞を10%リン酸塩緩衝ホルマリン中で一晩固定した。次いで、細胞ペレットを、O.C.T.コンパウンド(サクラファインテックジャパン株式会社)と混合して、細胞ブロックを得、これをその後、パラフィン包埋した。
抗AXL V77−2a37.1MAb、M77−297b81.1.1MAb、およびC89E7MAbを用いた、選択されたAXL RNA(+)(−)FFPEサンプルにおける比較免疫組織化学
抗AXL抗体V77−2a37.1、M77−297b81.1.1(ATCC名称PT A−122092)、およびAXL(C89E7)による非特異的IHC染色を、***(図7A〜図7D)、肝細胞(図7E〜図7H)、および結腸(図7I〜図7L)の癌腫サンプル由来のAXL陰性腫瘍標本(qPCRによって測定した)において、評価した。
Claims (18)
- 重鎖可変領域相補性決定領域1(CDR−H1)、CDR−H2、及びCDR−H3を含む重鎖可変領域と、軽鎖可変領域相補性決定領域1(CDR−L1)、CDR−H2、及びCDR−H3を含む軽鎖可変領域と、を含み、
前記CDR−H1、CDR−H2、及びCDR−H3は、配列番号8に示される重鎖可変領域配列中の各CDR−H1、CDR−H2、及びCDR−H3に対応するアミノ酸配列からなり、前記CDR−L1、CDR−H2、及びCDR−H3は、配列番号10に示される軽鎖可変領域配列中の各CDR−L1、CDR−L2、及びCDR−L3に対応するアミノ酸配列からなり、
前記各CDRは、「Kabat」、「Chothia」、又は「Contact」ナンバリングスキームにより決定される、癌組織中のAXLタンパク質の検出に適している、AXLタンパク質に結合する抗体又はその抗原結合フラグメント。 - 前記抗体又はその抗原結合フラグメントは、配列番号20に示されるアミノ酸配列からなるCDR−H1、配列番号22に示されるアミノ酸配列からなるCDR−H2、配列番号23に示されるアミノ酸配列からなるCDR−H3、配列番号11に示されるアミノ酸配列からなるCDR−L1、配列番号12に示されるアミノ酸配列からなるCDR−L2、および配列番号13に示されるアミノ酸配列からなるCDR−L3を含む、請求項1に記載の抗体又はその抗原結合フラグメント。
- 前記抗体又はその抗原結合フラグメントは、配列番号8に示されるアミノ酸配列からなる重鎖可変領域、及び配列番号10に示されるアミノ酸配列からなる軽鎖可変領域を含む、請求項1又は2に記載の抗体又はその抗原結合フラグメント。
- 前記抗体または前記抗原結合フラグメントは、配列番号8に示される重鎖可変領域アミノ酸配列と約99%の配列同一性を有するアミノ酸配列からなる重鎖可変領域、および配列番号10に示される軽鎖可変領域アミノ酸と約99%の配列同一性を有するアミノ酸配列からなる軽鎖可変領域を含み、約99%の配列同一性を占めるアミノ酸の相違は、どのCDR領域中にもあたらない、請求項1又は2に記載の抗体又はその抗原結合フラグメント。
- 前記抗体は、配列番号7に示されるアミノ酸配列からなる重鎖、及び配列番号9に示されるアミノ酸配列からなる軽鎖を含む、請求項1〜3のいずれか1項に記載の抗体。
- 前記フラグメントは、Fab、F(ab’)2、Fv、又はscFvである、請求項1〜4のいずれか1項に記載の抗原結合フラグメント。
- 前記抗体は完全ヒト抗体である、請求項1〜4のいずれか1項に記載の抗体。
- 前記抗体又は前記抗原結合フラグメントは、組換えにより生産される、請求項1〜7のいずれか1項に記載の抗体又はその抗原結合フラグメント。
- 前記抗体又は前記抗原結合フラグメントは、造影剤に結合されている、請求項1〜8のいずれか1項に記載の抗体又はその抗原結合フラグメント。
- 前記抗体または前記抗原結合フラグメントは、癌の処置及び管理のために患者をスクリーニングするコンパニオン診断(CDx)として用いられる、請求項1〜9のいずれか1項に記載の抗体又はその抗原結合フラグメント。
- 対象におけるAXLの発現を検出する方法であって、請求項1〜10のいずれか1項に記載の抗体又はその抗原結合フラグメントを、前記対象から得られた試料と接触させる工程を含む、方法。
- 前記対象は癌患者である、請求項11に記載の方法。
- 前記癌は、肉腫、膵臓癌、黒色腫、卵巣癌、及び肺癌からなる群から選択される、請求項12に記載の方法。
- AXLの発現が陽性である癌患者を同定する方法であって、請求項1〜10のいずれか1項に記載の抗体又はその抗原結合フラグメントを、前記対象から得られた試料と接触させる工程を含む、方法。
- 前記癌は、肉腫、膵臓癌、黒色腫、卵巣癌、及び肺癌からなる群から選択される、請求項14に記載の方法。
- 前記癌患者は、EGFR阻害剤による処置を経験している、請求項14又は15に記載の方法。
- 前記癌は、EGFR阻害剤に対して耐性である、請求項14〜16のいずれか1項に記載の方法。
- 請求項1〜10のいずれか1項に記載の抗体又はその抗原結合フラグメントを含む、AXLの発現を検出するためのキット。
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