JP2019505545A - 癌マーカーおよび治療標的としてのグリピカン2 - Google Patents
癌マーカーおよび治療標的としてのグリピカン2 Download PDFInfo
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Abstract
Description
本発明は、米国立衛生研究所により付与された助成金番号Genetics T32 T32GM008638およびACC T32 32CA009615による政府支援を得てなされた。米国政府は本発明において一定の権利を有する。
本願は、2015年11月9日に出願された米国仮出願第62/253,000号および2016年6月16日に出願された同第62/350,976号の優先権恩典を主張する。各出願の全内容は参照により組み入れられる。
1.分野
本開示は、概して、医学、腫瘍学および免疫療法の分野に関する。さらに詳細には、本開示は、グリピカン2(GPC2)陽性癌の検出および処置において使用するための免疫試薬の開発に関する。
高リスク神経芽細胞腫をもつ小児は強化集学的化学放射線療法(intensive multimodal chemoradiotherapy)を受けても予後不良である。ジシアロガングリオシドGD2を標的とするモノクローナル抗体は神経芽細胞腫におけるアウトカムを改善するが、この療法は、かなり大きな「腫瘍に向かわず、標的に向かう(on target-off tumor)」毒性と関連している。従って、正常小児組織と比較して腫瘍発現が特有のものであること、好ましくは、新規の細胞表面分子が腫瘍維持に必要とされることを含む、現代の免疫療法剤の厳格な判断基準に適合する新規の細胞表面分子の特定には大きな課題が依然としてある。
従って、本開示によれば、対象におけるグリピカン2陽性癌細胞を、グリピカン2に選択的に結合する抗体または抗体派生物と接触させる工程を含む、癌を処置する方法が提供される。グリピカン2陽性癌細胞は固形腫瘍癌細胞でもよい。固形腫瘍癌細胞は、肺癌細胞、脳癌細胞、頭頸部癌細胞、乳癌細胞、皮膚癌細胞、肝臓癌細胞、膵臓癌細胞、胃癌細胞、結腸癌細胞、腎臓癌細胞、直腸癌細胞、子宮癌細胞、子宮頸癌細胞、卵巣癌細胞、精巣癌細胞、皮膚癌細胞、または食道癌細胞でもよい。グリピカン2陽性癌細胞は胚性癌細胞でもよい。固形腫瘍癌細胞は肉腫細胞、神経芽細胞腫細胞、ラブドイド癌細胞、髄芽細胞腫細胞、または神経芽細胞腫細胞でもよい。癌細胞は小児癌細胞でもよい。
本発明者らは、グリピカン2(GPC2)は、高リスク神経芽細胞腫と、ことによると他の小児癌における細胞表面免疫療法標的の候補と推定癌遺伝子であることを確かめた。さらに包括的には、ここで示したデータから、ゲノム検証および機能検証と一体化したゲノムワイドトランスクリプトーム分析は、魅力的な免疫療法標的になり得る異なって発現する細胞表面癌遺伝子を特定できることが分かる。本開示のこれらの局面および他の局面は下記でさらに詳細に説明される。
グリピカン2(GPC2)はセレブログリカン(cerebroglycan)とも知られ、ヒトではGPC2遺伝子によってコードされるタンパク質である。セレブログリカンは、発達中の神経系において見出される、グリコホスファチジルイノシトールが連結している内在性膜ヘパラン硫酸プロテオグリカンである。セレブログリカンは細胞接着に関与し、軸索の成長および誘導を調節すると考えられている。セレブログリカンはラミニン-1に対して特に高い親和性を有する。ヒトグリピカン2 mRNA配列およびタンパク質配列のアクセッション番号は、それぞれ、参照により本明細書に組み入れられるNM_152742およびNP_689955である。
A.一般的な方法
グリピカン2に対する抗体は、当技術分野において周知のように標準的な方法によって作製することができる(例えば、Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988; 米国特許第4,196,265号を参照されたい)。モノクローナル抗体(MAb)を作製する方法は、一般的に、ポリクローナル抗体を調製する方針と同じ方針に沿って始まる。これらの両方法の第1の工程は、適切な宿主を免疫化する工程、または以前の自然感染により免疫のある対象を特定する工程である。当技術分野において周知のように、ある特定の免疫化用組成物は免疫原性の点で異なる場合がある。従って、ペプチドまたはポリペプチド免疫原を担体にカップリングすることによって成し遂げられるように宿主免疫系を追加免疫することが必要な場合が多い。例示的な、かつ好ましい担体は、キーホールリンペットヘモシアニン(KLH)およびウシ血清アルブミン(BSA)である。オボアルブミン、マウス血清アルブミン、またはウサギ血清アルブミンなどの他のアルブミンも担体として使用することができる。ポリペプチドを担体タンパク質に結合するための手段は当技術分野において周知であり、グルタルアルデヒド、m-マレイミドベンコイル(maleimidobencoyl)-N-ヒドロキシスクシンイミドエステル、カルボジイミドおよびbis-ビアゾ化(biazotized)ベンジジンを含む。これも当技術分野において周知なように、特定の免疫原組成物の免疫原性は、アジュバントとして知られる免疫応答の非特異的刺激物質を用いることによって増強することができる。例示的な、かつ好ましいアジュバントには、完全フロイントアジュバント(不活化した結核菌(Mycobacterium tuberculosis)を含有する、免疫応答の非特異的刺激物質)、不完全フロイントアジュバント、および水酸化アルミニウムアジュバントが含まれる。
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本開示に従う抗体は、第1の場合では、結合特異性によって、この場合ではグリピカン2に対する結合特異性によって定義される場合がある。一態様において、抗体は免疫グロブリンG(IgG)抗体アイソタイプである。IgGはヒトにおける血清免疫グロブリンの約75%に相当し、循環中に見出される最も豊富な抗体アイソタイプである。IgG分子は血漿B細胞によって合成および分泌される。ヒトには、血清中での存在量の順で名付けられた4種類のIgGサブクラス(IgG1、2、3、および4)がある(IgG1が最も豊富である)。これらは、Fc受容体に対して高親和性から親和性なしまで及ぶ。
様々な態様では、発現の改善、交差反応性の改善、オフターゲット結合の低下、または1つもしくは複数の天然エフェクター機能、例えば、補体活性化もしくは免疫細胞(例えば、T細胞)動員の抑止などの様々な理由で、特定された抗体の配列を操作することが選ばれる場合がある。特に、IgM抗体がIgG抗体に変換される場合がある。以下は、抗体を操作するための関連する技法の大まかな議論である。
本開示に従う核酸は、抗体、任意で、他のタンパク質配列と連結した抗体をコードする。本願において用いられる「グリピカン2抗体をコードする核酸」という用語は、全ての細胞核酸が無い状態で単離されている核酸分子を指す。ある特定の態様では、本開示は、本明細書において示された任意の配列によってコードされる抗体に関する。
「プロモーター」とは、転写の開始および速度が制御される核酸配列の一領域である制御配列である。「プロモーター」は、調節タンパク質および調節分子、例えば、RNAポリメラーゼおよび他の転写因子が結合することができる遺伝因子を含有してもよい。「機能的に配置された」、「機能的に連結された」、「制御下にある」、および「転写制御下にある」という句は、プロモーターが、核酸配列の転写開始および/または発現を制御するために、核酸配列に対して正しい機能的な位置および/または方向にあることを意味する。プロモーターは「エンハンサー」と共に用いられてもよく、「エンハンサー」と共に用いられなくてもよい。「エンハンサー」とは、核酸配列の転写活性化に関与するシス作用調節配列を指す。
本開示のある特定の態様では、多重遺伝子のメッセージまたはポリシストロニックなメッセージを作り出すために、配列内リボソーム進入部位(IRES)エレメントの使用が用いられる。IRESエレメントは5'メチル化Cap依存性翻訳のリボソームスキャニングモデルを迂回し、内部部位で翻訳を開始することができる(Pelletier and Sonenberg, 1988)。ピコルナウイルス科の2つのメンバー(ポリオおよび脳心筋炎)に由来するIRESエレメントが述べられおり(Pelletier and Sonenberg, 1988)、哺乳動物メッセージに由来するIRESも述べられている(Macejak and Sarnow, 1991)。IRESエレメントは異種オープンリーディングフレームと連結することができる。それぞれIRESによって分けられた複数のオープンリーディングフレームを一緒に転写して、ポリシストロニックなメッセージを作り出すことができる。IRESエレメントによって、それぞれのオープンリーディングフレームは効率的な翻訳のためにリボソームに接近することができる。1種類のプロモーター/エンハンサーを用いて1本のメッセージを転写するように、複数の遺伝子を効率的に発現させることができる(それぞれ参照により本明細書に組み入れられる、米国特許第5,925,565号および同第5,935,819号を参照されたい)。
ベクターはマルチクローニングサイト(MCS)を含んでもよい。マルチクローニングサイトは、複数の制限酵素部位を含有する核酸領域であり、どの制限酵素部位も、ベクターを消化するために標準的な組換え技術と共に使用することができる。参照により本明細書に組み入れられる、Carbonelli et al., 1999、Levenson et al., 1998、およびCocea, 1997を参照されたい。「制限酵素消化」とは、核酸分子の特定の位置でしか機能しない酵素による核酸分子の触媒切断を指す。これらの制限酵素の多くは市販されている。このような酵素の使用は当業者に広く理解されている。外因性配列がベクターに連結できるように、MCS内で切断する制限酵素を用いてベクターは直線化または断片化されることが多い。「連結」とは、2つの核酸断片間でホスホジエステル結合を形成するプロセスを指し、2つの核酸断片は互いに連続してもよく、連続してなくてもよい。制限酵素および連結反応を伴う技法は組換え技術の当業者に周知である。
転写されたほとんどの真核生物RNA分子は、一次転写物からイントロンを取り除くRNAスプライシングを受ける。タンパク質発現のために転写物が正しく処理されるためには、ゲノム真核生物配列を含むベクターにはドナースプライシング部位および/またはアクセプタースプライシング部位が必要とされることがある(参照により本明細書に組み入れられる、Chandler et al., 1997を参照されたい)。
本開示のベクターまたは構築物は、一般的に、少なくとも1つの終結シグナルを含む。「終結シグナル」または「ターミネーター」は、RNAポリメラーゼによるRNA転写物の特異的な終結に関与するDNA配列で構成される。従って、ある特定の態様では、RNA転写物の生成を終了させる終結シグナルが意図される。望ましいメッセージレベルを実現するために、ターミネーターがインビボで必要な場合がある。
発現、特に、真核生物での発現において、典型的には、転写物の適切なポリアデニル化をもたらすためにポリアデニル化シグナルが含まれる。ポリアデニル化シグナルがどういったものであるかは本開示の実施の成功に重要だと考えられていない、および/またはこのような任意の配列を使用することができる。好ましい態様には、便利な、および/または様々な標的細胞において良好に機能することが知られているSV40ポリアデニル化シグナルおよび/またはウシ成長ホルモンポリアデニル化シグナルが含まれる。ポリアデニル化は転写物の安定性を高めてもよく、細胞質への輸送を容易にしてもよい。
宿主細胞内でベクターを増殖させるために、ベクターは1つまたは複数の複製起点部位(「ori」と呼ばれることが多い)を含有してもよい。複製起点は、複製が開始する特定の核酸配列である。または、宿主細胞が酵母であれば、自己複製配列(ARS)を使用することができる。
本開示のある特定の態様では、本開示の核酸構築物を含有する細胞は、発現ベクター内にマーカーを含めることによってインビトロまたはインビボで同定することができる。このようなマーカーは特定可能な変化を細胞に付与し、それにより、発現ベクターを含有する細胞を容易に特定できるようになる。一般的に、選択マーカーは、選択を可能にする特性を付与するものである。正の選択マーカーは、マーカーが存在すると細胞の選択が可能になるものであるのに対して、負の選択マーカーは、マーカーが存在すると細胞の選択が妨げられるものである。正の選択マーカーの一例は薬物耐性マーカーである。
ある特定のウイルスベクターは効率的に細胞に感染するか、または入り、宿主細胞ゲノムに組み込まれ、ウイルス遺伝子を安定して発現することができるので、多くの異なるウイルスベクターシステムが開発および適用された(Robbins et al., 1998)。エクスビボ遺伝子導入用およびインビボ遺伝子導入用のベクターとして使用するためのウイルスシステムが現在開発されている。例えば、癌、嚢胞性線維症、ゴーシェ病、腎臓病、および関節炎などの疾患を処置するために、アデノウイルス、単純ヘルペスウイルス、レトロウイルス、およびアデノ随伴ウイルスベクターが現在評価されている(Robbins and Ghivizzani, 1998; Imai et al., 1998; 米国特許第5,670,488号)。本開示において使用するために、他のウイルスベクター、例えば、ポックスウイルス;例えば、ワクシニアウイルス(Gnant et al., 1999; Gnant et al., 1999)、アルファウイルス; 例えば、シンドビスウイルス、セムリキ森林ウイルス(Lundstrom, 1999)、レオウイルス(Coffey et al., 1998)、およびインフルエンザAウイルス(Neumann et al., 1999)が考えられ、目的のシステムの必要な性質に応じて選択することができる。
本開示と共に使用するために、細胞小器官、細胞、組織、または生物を形質転換するための核酸送達に適した方法は、本明細書に記載のように、または当業者に公知なように核酸(例えば、DNA)を細胞小器官、細胞、組織、または生物に導入することができる実質的に任意の方法を含むと考えられる。このような方法には、例えば、マイクロインジェクション(参照により本明細書に組み入れられる、Harland and Weintraub, 1985; 米国特許第5,789,215号)を含む注射(米国特許第5,994,624号、同第5,981,274号、同第5,945,100号、同第5,780,448号、同第5,736,524号、同第5,702,932号、同第5,656,610号、同第5,589,466号、および同第5,580,859号。それぞれ参照により本明細書に組み入れられる); エレクトロポレーション(参照により本明細書に組み入れられる、米国特許第5,384,253号);リン酸カルシウム沈殿(Graham and Van Der Eb, 1973; Chen and Okayama, 1987; Rippe et al., 1990); DEAE-デキストランに続く、ポリエチレングリコールの使用(Gopal, 1985);ダイレクトソニックローディング(direct sonic loading)(Fechheimer et al., 1987); リポソームを介したトランスフェクション(Nicolau and Sene, 1982; Fraley et al., 1979; Nicolau et al., 1987; Wong et al., 1980; Kaneda et al., 1989; Kato et al., 1991); 微粒子銃(PCT出願番号WO94/09699および95/06128; 米国特許第5,610,042号;同第5,322,783号、同第5,563,055号、同第5,550,318号、同第5,538,877号、および同第5,538,880号。それぞれ参照により本明細書に組み入れられる);炭化ケイ素繊維を用いた攪拌(Kaeppler et al., 1990; 米国特許第5,302,523号および同第5,464,765号。それぞれ参照により本明細書に組み入れられる);またはPEGを介したプロトプラスト形質転換(Omirulleh et al., 1993; 米国特許第4,684,611号および同第4,952,500号。それぞれ参照により本明細書に組み入れられる);乾燥/阻害を介したDNA取り込み(Potrykus et al., 1985)によるDNAの直接送達が含まれるが、これに限定されない。これらの技法などの技法を適用することによって、細胞小器官、細胞、組織、または生物が安定して形質転換されてもよく、一過的に形質転換されてもよい。
上記で議論した組成物の少なくとも一部または全てを含む非常に多くの発現システムが存在する。本開示と共に使用して核酸配列、またはそのコグネイトポリペプチド、タンパク質、およびペプチドを生成するために、原核生物および/または真核生物に基づくシステムを使用することができる。多くのこのようなシステムが商業的にかつ広く入手することができる。
ある特定の態様では、本開示の抗体は精製されてもよい。本明細書で使用する「精製された」という用語は、他の成分から単離可能な組成物を指すことが意図され、この場合、タンパク質は、天然に入手可能な状態と比べて任意の程度まで精製される。従って、精製されたタンパク質はまた、天然に生じ得る環境を含まないタンパク質も指す。「実質的に精製された」という用語が用いられる場合、この表示は、タンパク質またはペプチドが組成物の主要成分を形成している、例えば、組成物中にあるタンパク質の約50%、約60%、約70%、約80%、約90%、約95%、またはそれより多くを構成する組成物を指す。
単鎖可変断片(scFv)は、免疫グロブリンの重鎖および軽鎖の可変領域が短い(通常、セリン、グリシン)リンカーと一緒に連結されて融合したものである。このキメラ分子はシングルドメイン抗体とも知られ、定常領域が除去され、リンカーペプチドが導入されていても、元々の免疫グロブリンの特異性を保持している。この改変があっても、通常、特異性は変化しないままである。これらの分子は、ファージディスプレイを容易にするために歴史を通して作り出された。ファージディスプレイは、1本のペプチドとして抗原結合ドメインを発現させることが極めて便利である。または、ハイブリドーマに由来するサブクローニングされた重鎖および軽鎖から直接、scFvを作り出すことができる。シングルドメインまたは単鎖可変断片には、完全な抗体分子に見出される定常Fc領域が無く、従って、抗体を精製するために用いられる共通の結合部位(例えば、プロテインA/G)が無い(単鎖抗体はFc領域を含む)。これらの断片は、多くの場合、プロテインLを用いて精製/固定化することができる。なぜなら、プロテインLはκ軽鎖の可変領域と相互作用するからである。
1.CAR
人工T細胞受容体(キメラT細胞受容体、キメラ免疫受容体、キメラ抗原受容体(CAR)とも知られる)は、任意の特異性を免疫エフェクター細胞に移植する操作された受容体である。典型的に、これらの受容体は、モノクローナル抗体の特異性をT細胞に移植するのに用いられ、これらの受容体のコード配列の導入はレトロウイルスベクターによって促進される。このように、養子細胞移入のために多数の癌特異的T細胞を作製することができる。このアプローチの第I相臨床研究は効力を示している。
シグナルペプチドは新生タンパク質を小胞体に向ける。受容体がグリコシル化され、細胞膜に固定されるのであれば、これは必要不可欠である。通常、どんな真核生物シグナルペプチド配列もうまく働く。一般的に、最もアミノ末端側の成分に天然で取り付けられているシグナルペプチドが用いられる(例えば、軽鎖-リンカー-重鎖の方向をもつscFvでは、軽鎖の天然シグナルが用いられる)。
膜貫通ドメインは、膜を貫通する疎水性αヘリックスである。一般的に、エンドドメインの最も膜に近い成分に由来する膜貫通ドメインが用いられる。興味深いことに、CD3ζ膜貫通ドメインを用いると、人工TCRが、天然CD3ζ膜貫通荷電アスパラギン酸残基の存在に依存する因子である天然TCRに組み込まれる可能性がある。異なる膜貫通ドメインが異なる受容体安定性をもたらす。CD28膜貫通ドメインを用いると、活発に発現する安定した受容体が生じる。
これは、受容体の「役目を果たす先端部分(business-end)」である。抗原が認識された後に、受容体はクラスター化し、シグナルが細胞に伝達される。最も一般的に用いられるエンドドメイン成分は、3つのITAMを含むCD3ζである。これは、抗原結合後に活性化シグナルをT細胞に伝達する。CD3ζは、十分に能力がある活性化シグナルを供給しない場合があり、さらなる補助刺激シグナル伝達が必要とされる。例えば、増殖/生存シグナルを伝達するためにCD3ζと共にキメラCD28およびOX40が用いられてもよく、3つ全てが一緒に用いられてもよい。
抗体薬物結合体すなわちADCは、癌のある人を処置するための標的療法として設計された新しいクラスの非常に強力な生物製剤薬物である。ADCは、安定した化学リンカーを介して不安定結合によって、生物学的に活性な細胞毒性(抗癌性)ペイロードまたは薬物に連結された抗体(mAb全体または抗体断片、例えば、単鎖可変断片、またはscFv)で構成される複合分子である。抗体薬物結合体は生物結合体および免疫結合体の例である。
二重特異性T細胞エンゲージャー(Bi-specific T-cell engager)(BiTE)は、抗癌薬物として使用するために研究されている人工二重特異性モノクローナル抗体の一種である。それらは宿主の免疫系を、具体的にはT細胞の細胞毒性活性を癌細胞に向ける。BiTEはMicromet AGの登録商標である。
A.癌
癌は、組織に由来する細胞のクローン集団が増殖した結果生じる。発癌と呼ばれる癌の発症は多くのやり方でモデル化し、特徴付けることができる。癌発症と炎症との間には関連性があることが長く認められている。炎症応答は微生物感染に対する宿主防御に関与し、組織の修復および再生の原動力ともなる。かなり多くの証拠から、炎症と癌発症リスクとの間に関係があることが、すなわち、慢性炎症が異形成の原因となり得ることが指摘されている。
本開示は、抗グリピカン2抗体を含む薬学的組成物を提供する。特定の態様において、「薬学的に許容される」という用語は、連邦政府もしくは州政府の規制当局によって認可されているか、または米国薬局方、もしくは動物において使用するための、さらに詳細には、ヒトにおいて使用するための、一般に認められている他の薬局方に列挙されていることを意味する。「担体」という用語は、治療剤と共に投与される希釈剤、賦形剤、またはビヒクルを指す。このような薬学的担体は、石油、動物、野菜、または合成に由来するもの、例えば、ピーナッツ油、ダイズ油、鉱油、ゴマ油などを含む、滅菌した液体、例えば、水および油でもよい。他の適切な薬学的賦形剤には、デンプン、グルコース、ラクトース、スクロース、食塩水、デキストロース、ゼラチン、麦芽、米、小麦粉、チョーク、シリカゲル、ステアリン酸ナトリウム、モノステアリン酸グリセロール、タルク、塩化ナトリウム、脱脂粉乳、グリセロール、プロピレングリコール、水、エタノールなどが含まれる。
本開示の文脈において、本明細書に記載の抗グリピカン2抗体は、化学療法介入もしくは放射線療法介入または他の処置と一緒に同様に使用できることも意図される。特に、抗グリピカン2抗体を、グリピカン2機能の異なる局面を標的とする他の療法と組み合わせることも有効だと分かる場合がある。
「化学療法」という用語は、癌を処置するための薬物の使用を指す。「化学療法剤」は、癌の処置において投与される化合物または組成物を暗示するために用いられる。これらの薬剤または薬物は、細胞内での活性機序、例えば、細胞周期に影響を及ぼすかどうか、またはどの段階で細胞周期に影響を及ぼすのかによって分類される。または、DNAを直接架橋する能力、DNAの中に挿入される能力、または核酸合成に影響を及ぼすことによって染色体異常および有糸分裂異常を誘導する能力に基づいて薬剤が特徴付けられることがある。ほとんどの化学療法剤は、以下のカテゴリー:アルキル化剤、代謝拮抗物質、抗腫瘍性抗生物質、有糸分裂阻害剤、およびニトロソ尿素に分類される。
放射線療法は放射線治療とも呼ばれ、電離放射線を用いた癌および他の疾患の処置である。電離放射線は、細胞を損傷または破壊するエネルギーを、細胞の遺伝物質を傷つけることで処置されている領域に蓄積し、そのために、これらの細胞は増殖し続けることができなくなる。放射線は癌細胞および正常細胞をどちらも傷つけるが、後者はひとりでに修復し、正しく機能することができる。
癌処置の文脈において、免疫療法は、一般的に、癌細胞を標的化および破壊するために免疫エフェクター細胞および免疫エフェクター分子の使用に頼る。このような例はトラスツズマブ(ハーセプチン(商標))である。免疫エフェクターは、例えば、腫瘍細胞の表面にある、何らかのマーカーに特異的な抗体でもよい。抗体が単独で療法のエフェクターとして働いてもよく、実際に細胞死滅に影響を及ぼす他の細胞を動員してもよい。抗体はまた薬物または毒素(化学療法剤、放射性核種、リシンA鎖、コレラ毒素、百日咳毒素など)に結合され、単に標的化薬剤として働いてもよい。または、エフェクターは、腫瘍細胞標的と直接的または間接的に相互作用する表面分子を運ぶリンパ球でもよい。様々なエフェクター細胞には細胞傷害性T細胞およびNK細胞が含まれる。治療モダリティーの組み合わせ、すなわち、直接的な細胞毒性活性と、ErbB2の阻害または低減を用いると、ErbB2過剰発現癌の処置において治療利益が得られるだろう。
癌がある人のうち約60%が何らかのタイプの外科手術を受ける。外科手術には、予防手術、診断または病期決定のための手術、根治手術、および緩和手術が含まれる。根治手術は、本開示の処置、化学療法、放射線療法、ホルモン療法、遺伝子療法、免疫療法、および/または代替療法などの他の療法と共に用いられ得る癌処置である。
抗体は少なくとも1種類の薬剤に連結されて抗体結合体を形成してもよい。診断剤または治療剤として抗体分子の効力を高めるために、少なくとも1つの望ましい分子または部分を連結または共有結合または複合体化することは従来のやり方である。このような分子または部分は少なくとも1つのエフェクターまたはレポーター分子でもよいが、これに限定されない。エフェクター分子は、望ましい活性、例えば、抗癌/一般細胞毒性を有する分子を含む。このような分子の非限定的な例を上記で示した。このような分子は、任意で、このような分子が標的部位で、または標的部位の近くで放出されるように設計された切断可能なリンカーを介して取り付けられる。
なおさらなる態様において、グリピカン2を結合する、精製する、除去する、定量する、そうでなければおおまかに検出するための免疫検出方法がある。一部の免疫検出方法には、いくつか述べると、酵素結合免疫測定法(ELISA)、ラジオイムノアッセイ(RIA)、免疫放射線測定法、フルオロイムノアッセイ(fluoroimmunoassay)、化学発光アッセイ、生物発光アッセイ、およびウエスタンブロットが含まれる。特に、グリピカン2抗体を検出および定量するための競合アッセイも提供される。様々な有用な免疫検出方法の工程は、例えば、Doolittle and Ben-Zeev(1999)、Gulbis and Galand(1993)、De Jager et al(1993)、および Nakamura et al(1987)などの科学文献に記載されている。一般的に、前記の免疫結合方法は、試料を得る工程と、本明細書において議論される態様に従って試料を第1の抗体と、場合によっては免疫複合体を形成するのに有効な条件下で接触させる工程を含む。
イムノアッセイは最も簡単な意味では結合アッセイである。ある特定の好ましいイムノアッセイは、当技術分野において公知の様々なタイプの酵素結合免疫測定法(ELISA)およびラジオイムノアッセイ(RIA)である。組織切片を用いた免疫組織化学的検出も特に有用である。しかしながら、検出は、このような技法に限定されず、ウェスタンブロッティング、ドットブロッディング、FACS分析なども用いられてもよいことが容易に理解される。
ウエスタンブロット(または、タンパク質イムノブロット)は、組織ホモジネートまたは抽出物のある特定の試料中にある特定のタンパク質を検出するのに用いられる分析技法である。ウエスタンブロットでは、ポリペプチドの長さによって(変性条件)、またはタンパク質の3D構造によって(天然/非変性条件)、天然タンパク質または変性タンパク質を分離するためにゲル電気泳動を使用する。次いで、タンパク質は膜(典型的にはニトロセルロースまたはPVDF)に転写され、膜の中で、標的タンパク質に特異的な抗体を用いてプローブ(検出)される。
抗体はまた、免疫組織化学(IHC)による研究のために調製された、新鮮凍結した組織ブロックおよび/またはホルマリン固定し、パラフィン包埋した組織ブロックと一緒に用いられる場合がある。これらの粒子標本から組織ブロックを調製する方法は様々な予後因子の以前のIHC研究において首尾良く用いられており、当業者に周知である(Brown et al., 1990; Abbondanzo et al., 1990; Allred et al., 1990)。
なおさらなる態様では、前記の免疫検出方法と共に使用するための免疫検出キットがある。従って、免疫検出キットは、適切な容器手段の中に、グリピカン2抗原に結合する第1の抗体と、任意で、免疫検出試薬を含む。
以下の実施例は、好ましい態様を証明するために含まれる。以下の実施例に開示される技法は、本発明者らが発見した技法が態様の実施において十分に機能することを示し、従って、本発明を実施するための好ましい態様を構成すると考えられると当業者に理解されるはずである。しかしながら、本開示を考慮すれば、本開示の精神および範囲から逸脱することなく、開示された特定の態様において多くの変更を加えることができ、それでもなお、類似または同様の結果を得ることができると当業者に理解される。
トランスクリプトームに基づいた初期の発見の取り組みから、649個の有意に異なって発現する遺伝子が同定され(各組織について腫瘍対正常のlog倍率変化>1;補正p<0.05)、このうち86個(13%)の遺伝子が潜在的な細胞表面分子だと推定された。本発明者らの分析パイプラインによって、本発明者らは、検証のために、ロバストな差次的RNA発現(腫瘍対正常組織のlog倍率変化=2.1〜8.2;p<3x10-10)と、高レベルの絶対RNA発現(中央値FPKM=57; 腫瘍の85%がFPKM>25)と、有意に高いGPC2発現(p<0.0001)と関連する一貫性のあるDNAコピー数増加(原発性神経芽細胞腫の31%;N=177)が示された、細胞外グリコシルホスファチジルイノシトール(GPI)に固定化されたシグナル伝達コレセプター、グリピカン-2(GPC2)に優先順位を付けた。イムノブロット分析によって、遍在性のGPC2タンパク質発現(N=8高リスク神経芽細胞腫および23の細胞株)が確認され、膜抽出、IF、およびIHCによって、神経芽細胞腫細胞株において高密度の原形質膜関連GPC2タンパク質発現が確認された。小児正常組織(N=37)のパラレルアレイ(parallel array)と比較した原発性神経芽細胞腫腫瘍(N=83)のIHC分析によって、GPC2タンパク質発現は膜に関連し、かつ腫瘍特異的であり、正常組織発現は非常に制限されていることがさらに確認された。12の神経芽細胞腫細胞株のパネルにおいて、レンチウイルスを介したRNAiによって誘導したGPC2枯渇によって、一過的なCellTiter-GloおよびCaspase-Gloアッセイの両方において、ならびに細胞増殖の長期リアルタイムモニタリング(RT-CES)を用いて、有意なアポトーシスおよび増殖阻害が認められた(対照に対して、増殖が20〜87%減少し、カスパーゼ3/7レベルが1.5〜18.4倍増加した)。GPC2過剰発現によって細胞増殖が有意に増加した(対照に対して2.7倍の増殖増加、p<0.0001)。最後に、GPC2はまた、他の胚性癌、特に髄芽細胞腫においても有意に異なって過剰発現することが見出された。
Claims (66)
- 対象におけるグリピカン2陽性癌細胞を、グリピカン2に選択的に結合する抗体または抗体派生物と接触させる工程を含む、癌を処置する方法。
- グリピカン2陽性癌細胞が固形腫瘍癌細胞である、請求項1記載の方法。
- 固形腫瘍細胞が、肺癌細胞、脳癌細胞、頭頸部癌細胞、乳癌細胞、皮膚癌細胞、肝臓癌細胞、膵臓癌細胞、胃癌細胞、結腸癌細胞、腎臓癌細胞、直腸癌細胞、子宮癌細胞、子宮頸癌細胞、卵巣癌細胞、精巣癌細胞、皮膚癌細胞、または食道癌細胞である、請求項2記載の方法。
- グリピカン2陽性癌細胞が胚性癌細胞である、請求項1記載の方法。
- 癌細胞が、肉腫細胞、神経芽細胞腫細胞、ラブドイド癌細胞、髄芽細胞腫細胞または神経芽細胞腫細胞である、請求項1記載の方法。
- グリピカン2陽性癌細胞を第2の抗癌剤または処置と接触させる工程をさらに含む、請求項1〜5のいずれか一項記載の方法。
- 第2の抗癌剤または処置が、化学療法、放射線療法、免疫療法、ホルモン療法、または毒素療法より選択される、請求項6記載の方法。
- グリピカン2抗体が第2の薬剤または処置の前に与えられる、請求項6記載の方法。
- 第2の抗癌剤または処置が第1の薬剤と同時に与えられる、請求項6記載の方法。
- 第1の薬剤の前および/または後に第2の抗癌剤または処置が与えられる、請求項6記載の方法。
- グリピカン2陽性癌細胞が、転移癌細胞、多剤耐性癌細胞、または再発性癌細胞である、請求項1〜10のいずれか一項記載の方法。
- 抗体が単鎖抗体である、請求項1〜11のいずれか一項記載の方法。
- 抗体がシングルドメイン抗体である、請求項1〜11のいずれか一項記載の方法。
- 抗体がキメラ抗体である、請求項1〜11のいずれか一項記載の方法。
- 抗体派生物がFab断片である、請求項1〜11のいずれか一項記載の方法。
- 抗体が、グリピカン2および異なる癌細胞表面抗原に対して特異性を有する組換え抗体である、請求項11〜15のいずれか一項記載の方法。
- 抗体が、IgGなどのマウス抗体である、請求項1〜16のいずれか一項記載の方法。
- 抗体がヒト抗体である、請求項1〜16のいずれか一項記載の方法。
- 抗体がヒト化抗体である、請求項1〜15のいずれか一項記載の方法。
- ヒト化抗体がIgGである、請求項18〜19のいずれか一項記載の方法。
- 抗体が、抗体に連結された抗腫瘍薬物をさらに含む、請求項1〜20のいずれか一項記載の方法。
- 抗腫瘍薬物が感光性リンカーを介して抗体に連結されている、請求項21記載の方法。
- 抗腫瘍薬物が、酵素によって切断されるリンカーを介して抗体に連結されている、請求項21記載の方法。
- 抗腫瘍薬物が、毒素、放射性同位体、サイトカイン、または酵素である、請求項21記載の方法。
- 抗体が標識をさらに含む、請求項1〜24のいずれか一項記載の方法。
- 標識が、ペプチドタグ、酵素、磁気粒子、発色団、蛍光分子、化学発光分子、または色素である、請求項25記載の方法。
- 抗体がリポソームまたはナノ粒子に結合されている、請求項1〜26のいずれか一項記載の方法。
- 抗体が、例えば抗体依存性細胞毒性または補体を介した細胞毒性によって、細胞死を誘導する、請求項1〜27のいずれか一項記載の方法。
- 抗体派生物がキメラ抗原受容体または二重特異性抗体である、請求項1記載の方法。
- 抗体または抗体断片が、CDR配列SEQ ID NO:5〜10、15〜20、または25〜30によって特徴付けられる、請求項1記載の方法。
- (i)グリピカン2に選択的に結合する第1の単鎖抗体であって、
(a)IgG抗体であり、
(b)癌細胞増殖を阻害し、
(c)癌細胞死を誘導する
第1の単鎖抗体と、
(ii)T細胞またはB細胞に結合する第2の単鎖抗体と
を含む、融合タンパク質。 - 第1の抗体または抗体断片が、CDR配列SEQ ID NO:5〜10、15〜20、または25〜30によって特徴付けられる、請求項31記載の融合タンパク質。
- 第2の単鎖抗体が、例えばCD3を介して、T細胞に結合する、請求項31記載の融合タンパク質。
- 第2の単鎖抗体がB細胞に結合する、請求項31記載の融合タンパク質。
- 標識または治療部分をさらに含む、請求項31記載の融合タンパク質。
- (i)グリピカン2に選択的に結合する単鎖抗体可変領域を含むエクトドメインであって、該抗体が、
(a)IgG抗体であり、
(b)癌細胞増殖を阻害し、
(c)癌細胞死を誘導し、
該単鎖抗体可変領域のC末端に取り付けられた可動性ヒンジを有する、
エクトドメインと、
(ii)膜貫通ドメインと、
(iii)エンドドメインと
を含む、キメラ抗原受容体であって、該単鎖抗体可変領域がグリピカン2と結合した場合に該エンドドメインがシグナル伝達機能を含む、キメラ抗原受容体。 - 第1の単鎖抗体が、CDR配列SEQ ID NO:5〜10、15〜20、または25〜30によって特徴付けられる、請求項36記載の受容体。
- 膜貫通ドメインおよびエンドドメインが同じ分子に由来する、請求項36記載の受容体。
- エンドドメインがCD3ζドメインまたは高親和性FcεRIを含む、請求項36記載の受容体。
- 可動性ヒンジがCD8αまたはIgに由来する、請求項36記載の受容体。
- 請求項36〜40のいずれか一項記載のキメラ抗原受容体を発現する、細胞。
- エンドドメインがCD3ζドメインまたは高親和性FcεRIを含む、請求項41記載の細胞。
- 可動性ヒンジがCD8αまたはIgに由来する、請求項41記載の細胞。
- 請求項31記載の融合タンパク質を発現する、細胞。
- 第2の単鎖抗体が、CD3、T細胞、またはB細胞に結合する、請求項44記載の細胞。
- 抗体または抗体断片が、CDR配列SEQ ID NO:5〜10、15〜20、または25〜30によって特徴付けられる、モノクローナル抗体。
- 抗体または抗体断片が、それぞれSEQ ID NO:1および3、11および13、ならびに21および23である重鎖可変配列および軽鎖可変配列によってコードされる、請求項46記載のモノクローナル抗体。
- 抗体または抗体断片が、それぞれSEQ ID NO:1および3、11および13、ならびに21および23に対して少なくとも70%、80%、または90%の同一性を有する重鎖可変配列および軽鎖可変配列によってコードされる、請求項46記載のモノクローナル抗体。
- 抗体または抗体断片が、それぞれSEQ ID NO:1および3、11および13、ならびに21および23に対して少なくとも95%の同一性を有する重鎖可変配列および軽鎖可変配列によってコードされる、請求項46記載のモノクローナル抗体。
- 抗体または抗体断片が、それぞれSEQ ID NO:2および4、12および14、ならびに22および24を含む重鎖可変配列および軽鎖可変配列を含む、請求項46記載のモノクローナル抗体。
- 抗体または抗体断片が、それぞれSEQ ID NO:2および4、12および14、ならびに22および24に対して95%の同一性を有する軽鎖可変配列および重鎖可変配列を含む、請求項46記載のモノクローナル抗体。
- 抗体断片が、組換えScFv(単鎖断片可変)抗体、Fab断片、F(ab')2断片、またはFv断片である、請求項46〜51のいずれか一項記載のモノクローナル抗体。
- キメラ抗体または二重特異性抗体である、請求項46〜51のいずれか一項記載のモノクローナル抗体。
- IgGである、および/または標識に結合されている、および/または治療剤に結合されている、請求項46〜53のいずれか一項記載のモノクローナル抗体。
- 抗体または抗体断片が標識をさらに含む、請求項46〜54のいずれか一項記載のモノクローナル抗体。
- CDR配列SEQ ID NO:5〜10、15〜20、または25〜30によって特徴付けられる抗体または抗体断片をコードする、ハイブリドーマまたは操作された細胞。
- 抗体または抗体断片が、それぞれSEQ ID NO:1および3、11および13、ならびに21および23である軽鎖可変配列および重鎖可変配列によってコードされる、請求項56記載のハイブリドーマまたは操作された細胞。
- 抗体または抗体断片が、それぞれSEQ ID NO:1および3、11および13、ならびに21および23に対して少なくとも70%、80%、または90%の同一性を有する軽鎖可変配列および重鎖可変配列によってコードされる、請求項56記載のハイブリドーマまたは操作された細胞。
- 抗体または抗体断片が、それぞれSEQ ID NO:1および3、11および13、ならびに21および23に対して95%の同一性を有する軽鎖可変配列および重鎖可変配列によってコードされる、請求項56記載のハイブリドーマまたは操作された細胞。
- 抗体または抗体断片が、それぞれSEQ ID NO:2および4、12および14、ならびに22および24を含む軽鎖可変配列および重鎖可変配列を含む、請求項56記載のハイブリドーマまたは操作された細胞。
- 抗体または抗体断片が、それぞれSEQ ID NO:2および4、12および14、ならびに22および24に対して少なくとも70%、80%、または90%の同一性を有する軽鎖可変配列および重鎖可変配列によってコードされる、請求項56記載のハイブリドーマまたは操作された細胞。
- 抗体または抗体断片が、それぞれSEQ ID NO:2および4、12および14、ならびに22および24に対して95%の同一性を有する軽鎖可変配列および重鎖可変配列を含む、請求項56記載のハイブリドーマまたは操作された細胞。
- 抗体断片が、組換えScFv(単鎖断片可変)抗体、Fab断片、F(ab') 2断片、またはFv断片である、請求項56〜62のいずれか一項記載のハイブリドーマまたは操作された細胞。
- 抗体がキメラ抗体または二重特異性抗体である、請求項56〜63のいずれか一項記載のハイブリドーマまたは操作された細胞。
- 抗体がIgGである、請求項56〜63のいずれか一項記載のハイブリドーマまたは操作された細胞。
- 請求項46〜55のいずれか一項記載のモノクローナル抗体を含む、薬学的組成物。
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FI3373968T3 (fi) | 2024-07-17 |
AU2023278110A1 (en) | 2024-01-04 |
EP3373968A1 (en) | 2018-09-19 |
CA3004438A1 (en) | 2017-05-18 |
AU2016354440A1 (en) | 2018-05-24 |
AU2016354440B2 (en) | 2023-09-28 |
US20180318444A1 (en) | 2018-11-08 |
DK3373968T3 (da) | 2024-05-13 |
JP6987068B2 (ja) | 2021-12-22 |
JP2022033851A (ja) | 2022-03-02 |
US20240084034A1 (en) | 2024-03-14 |
US11814440B2 (en) | 2023-11-14 |
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WO2017083296A1 (en) | 2017-05-18 |
EP3373968B1 (en) | 2024-04-17 |
JP2023156470A (ja) | 2023-10-24 |
EP3373968A4 (en) | 2019-06-26 |
EP4382127A2 (en) | 2024-06-12 |
JP7335937B2 (ja) | 2023-08-30 |
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