JP6795603B2 - EGFRvIII(Epidermal Growth Factor Receptor Variant III)に対する抗体およびその用途 - Google Patents
EGFRvIII(Epidermal Growth Factor Receptor Variant III)に対する抗体およびその用途 Download PDFInfo
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Description
以下、本発明を実施例を挙げて詳述する。これらの実施例は単に本発明をより具体的に説明するためのものであり、本発明の範囲がこれらの実施例に制限されないことは当業者において通常の知識を有する者にとって自明である。
一般に、ファージディスプレイ法により抗体を選別するためには、標的抗原タンパク質を免疫チューブ(Immunotube)に吸着させた後、組換えタンパク質に対して優れた結合能を有する抗体のみをバイオパニング法を用いて選別する。但し、組換えタンパク質は立体配座変化(conformational change)現象が起こらないため、立体配座変化現象が起こる細胞の表面に発現されたタンパク質を用いて抗体を選別すれば、抗原の配座変化を認知する抗体を開発することができる。そこで、本発明では、EGFRvIIIを有する膠芽細胞腫患者由来細胞を用いた細胞パニング法により、EGFRvIIIを特異的に認知する抗体を選別した。
抗体選別に関連して、合成scFvファージライブラリを用いて、EGFRvIII特異的なscFv抗体断片をファージディスプレイスクリーニングにより同定した。ファージディスプレイスクリーニング過程は、図2のとおりである。
scFv抗体断片単独の結合力および機能を確認するために、タンパク質発現菌株(TOP10F´)を用いてB4A3抗体断片を発現した。B4A3 scFvタンパク質は、Ni‐NTA beadを用いたHis‐tag精製過程を経て準備した。
三星ソウル病院難治性癌事業団(Samsung medical center、Institute for Refractory Cancer Research)の脳組織バンク(Brain Avatar Tissue Bank)から、膠芽細胞腫(Glioblastoma Multiforme)患者由来細胞(NT352T1、626、780)の分譲を受けて実験を行った。NT352T1の場合、EGFRおよびEGFRvIIIのない細胞であって、EGFRvIIIのみを発現する細胞を作製するために、EGFRvIII過発現ベクターを導入してvIII352T1細胞を作製し、後続実験で引き続き使用した。EGFRおよびEGFRvIIIの発現パターンを確認するために、それぞれの患者由来細胞を溶解させた後、30μgのタンパク質溶解物を用いてウエスタンブロットを行い、その結果を図8に示した。1次抗体としてEGFR Rabbit mAb(#4267, Cell Signaling Technology, Inc.)、2次抗体としてはAnti‐rabbit IgG、HRP‐linked Antibody(#7074, Cell Signaling Technology, Inc.)を使用した。患者細胞のEGFR、EGFRvIIIの発現パターンの確認結果を表4に示した。
EGFRを発現する正常細胞と、EGFRvIIIを発現するvIII352T1細胞を用いて、B4A3 EGFRvIII抗体の特異性を検証した。FACS実験に使用されたB4A3抗体は、B4A3 human IgG1の形態に変換して使用した。EGFRのみを発現する正常細胞であるEpidermal cell[Primary Epidermal Keratinocytes;Normal、Human、Adult(ATCC PCS‐200‐011TM)]は、ATCC社から購買して使用した。FACS実験は、上述の方法と同様の方法により行われ、1次抗体としてはセツキシマブ、B4A3 IgGを使用し、2次抗体としてはAlexa Fluor 488 Goat Anti‐Human IgG(H+L)Antibody(Life Technologies)を使用した。上記の結果に基づき、B4A3抗体(IgG1)は、EGFRvIIIのみを発現するvIII352T1に特異的に結合する(図11)とともに、正常細胞では、対照抗体であるセツキシマブに比べて最小化された結合様相を示した(図10)。正常細胞での最小化された結合能に基づき、B4A3抗体は正常細胞で最小化された毒性を示すはずであると考えられる。
B4A3抗体が標的細胞のEGFRvIII/EGFRに特異的に結合して標的細胞内へ内在化できる細胞内在化可能性およびAntibody‐Drug Conjugatesとしての適用可能性を検証するために、B4A3抗体へのサポリン(Saporin)の結合により細胞毒性実験を行った。B4A3抗体への毒性物質であるサポリンの結合は、ZAP抗体内在化キット(ZAP antibody internalization kit:Advanced Targeting Systems,Inc.)を用いて行った。ZAP抗体内在化キットで提供する毒性物質サポリンは、抗‐ヒトIgG‐IgGに結合された形態であって、ヒトIgGであるB4A3抗体に二次抗体の形態で結合される。サポリンは単独で細胞内に入ることができず、標的抗原であるEGFRvIIIにB4A3ヒトIgG/サポリン接合抗‐ヒトIgG‐IgGの複合体が結合して細胞内在化される。サポリンは、細胞内に放出され、リボソームを非活性化させる形態で細胞毒性を誘導する。サポリン接合抗‐ヒトIgG‐IgGは、患者由来細胞などを含む一般的な細胞の表面に結合されないため、それ自体では細胞毒性が発生しない。実験は、キットの製造社から提供されるプロトコルに従って進行された。詳細に、96ウェルの細胞培養プレートに、EGFRvIIIの発現がないNT352T1患者細胞と、EGFRvIIIが発現されたvIII352T1患者細胞を、90μl体積で5000個/ウェル分注した。翌日、B4A3ヒトIgG/サポリン接合抗‐ヒトIgG‐IgG結合体は細胞培養培地に10μl処理し、B4A3抗体は、最高濃度10nMから1/10ずつ希釈して8つの濃度で、実験を3回繰り返して進行した。抗体特異的な細胞毒性であるかを確認するために、サポリン単独処理群およびサポリン接合抗‐ヒトIgG‐IgG処理群を対照群として追加して実験を進行し、複合体およびサポリンなどを処理した後、72時間後に細胞成長を分析した。分析は、EZ‐Cytox kit(WST based Cell Viability/Cytotoxicity Assay Kit)を用いて行い、発色試薬処理した後、2時間、37℃でCO2培養器で培養した。その後、450nmでOD値を分析した。その結果、標的抗原であるEGFRvIIIを発現しないNT352T1では、細胞毒性が発生しないことが確認され、vIII352T1患者細胞では、サポリン単独処理群およびサポリン接合抗‐ヒトIgG処理群では細胞毒性が発生しなかったが、B4A3 IgG/サポリン接合抗‐ヒトIgG‐IgG処理群では細胞毒性が確認された(図12)。このようなことから、B4A3抗体のADC(Antibody‐Drug Conjugates)としての適用可能性が確認された。
B4A3抗体のEGFRおよびEGFRvIIIに対する親和度を定量するために、SPR(Surface Plasmon Resonance)に基づくBiacore T200(GE Healthcare Life Sciences)を用いた。抗体の親和度の決定に使用した抗原であるEGFRvIII組換えタンパク質は自製し、www.uniprot.orgからEGFR(Entry:P00533)配列に基づく文献を参考して、EGFRの細胞外ドメイン(Extracellular domain)のアミノ酸配列において30番から297番までのアミノ酸を除去した後、29番と298番が接する部位の間にグリシンアミノ酸を添加し、c‐末端にFcタグ(IgG1 CH2、CH3ドメインのPro110‐Lys330)を添加したベクター(配列番号20、図14)を作り、動物細胞(Expi293, Gibco)を用いて生産/精製して使用した。EGFR組換えタンパク質としては、Recombinant Human EGFR/ErbB1 Fc Chimera Protein(R&D systems, 344-ER)を使用した。
B4A3抗体のEGFRおよびEGFRvIIIに対するIn‐vivo効能を確認するために、GBM患者由来細胞のうちNS07‐464Tを使用した。NS07‐464Tは、EGFRが過発現/増幅するとともに、EGFRvIII突然変異を有しているGBM患者由来細胞である。三星ソウル病院難治性癌事業団で分析した遺伝子データに基づき、EGFRvIII突然変異細胞としてNS07‐464Tを選別し、三星ソウル病院難治性癌事業団のバイオバンクから分譲を受け、RT‐PCRおよびウエスタンブロット法によりEGFRvIIIの発現を確認した(図2)。NS07‐464T患者細胞を用いて皮下異種移植モデル(subcutaneous xenograft model)を作製し、約265mm3の大きさの腫瘍が形成された時にヒトIgG(Sigma、I4506)、セツキシマブ(Merck)、B4A3抗体を、それぞれ週2回、10mg/kgで総4回投与した。群当たりのマウスは、ヒトIgG、セツキシマブの群はそれぞれ5匹、B4A3処理群は4匹であった。抗体を投与し始めた時点から13日が経過した時に、ヒトIgGを処理した群は1426.5mm3の腫瘍が形成された。セツキシマブは13日目に1228.5mm3の大きさの腫瘍が形成され、対照群に対する腫瘍形成抑制能が14%と確認された。B4A3抗体は、投与13日目に699.5mm3の腫瘍が形成され、対照群に対する腫瘍形成抑制能が51%と確認された。このようなことから、B4A3の、EGFRvIII突然変異を有する患者由来細胞での卓越な坑癌効能が検証された。
(i)本発明は、癌細胞の表面に発現されたEGFRvIIIに結合した後、細胞内に内在化される抗‐EGFRvIII抗体およびその医薬用途を提供する。
(ii)本発明の抗体は、EGFRvIIIを発現する癌細胞の浸潤と転移を抑制する。
(iii)本発明の抗体は、癌の治療または診断に用いられることができ、EGFRvIIIは癌細胞の表面に過発現される分子であるため、本発明の抗体を用いると、正常細胞に与える影響を最小化しながら癌細胞のみを選択的にターゲットとすることができる。
一態様において、本発明は以下を提供する。
[項目1]
EGFRvIII(Epidermal Growth Factor Receptor Variant III)に結合する抗体またはその抗原結合断片であって、前記抗体またはその抗原結合断片は、配列番号1の配列を有するEGFRvIIIのエピトープに結合することを特徴とする抗体またはその抗原結合断片。
[項目2]
配列番号2の配列を有するCDR(complementarity determining region)H1、配列番号3の配列を有するCDRH2、及び配列番号4の配列を有するDRH3を含む重鎖可変領域と、
配列番号5の配列を有するCDRL1、配列番号6の配列を有するCDRL2、及び配列番号7の配列をCDRL3を含む軽鎖可変領域と、を含むことを特徴とする項目1に記載の抗体またはその抗原結合断片。
[項目3]
配列番号8〜15の配列で構成された群から選択された一つ以上の配列を有する骨格領域(FR)を含むことを特徴とする項目1に記載の抗体またはその抗原結合断片。
[項目4]
配列番号16の配列を有する重鎖可変領域を含むことを特徴とする項目1に記載の抗体またはその抗原結合断片。
[項目5]
配列番号17の配列を有する軽鎖可変領域を含むことを特徴とする項目1に記載の抗体またはその抗原結合断片。
[項目6]
項目1〜5のいずれかに記載の抗体またはその抗原結合断片をコードする核酸。
[項目7]
配列番号18または配列番号19の配列を有することを特徴とする項目6に記載の核酸。
[項目8]
項目6に記載の核酸を含む発現ベクター。
[項目9]
項目8に記載の発現ベクターで形質転換された細胞。
[項目10]
下記の段階を含む項目1〜5のいずれかに記載の抗体またはその抗原結合断片の製造方法:
(a)項目9に記載の細胞を培養する段階;および
(b)前記培養された細胞から抗体またはその抗原結合断片を回収する段階。
[項目11]
項目1〜5のいずれかに記載の抗体を有効性分として含む癌の予防または治療用組成物。
[項目12]
前記癌は、肺癌、大腸癌、胃癌、腎臓癌、前立腺癌、乳癌、膠芽細胞腫、および卵巣癌で構成された群から選択されることを特徴とする項目11に記載の組成物。
[項目13]
項目1〜5のいずれかに記載の抗体またはその抗原結合断片を含む癌診断用組成物。
[項目14]
項目13に記載の癌診断用組成物を含む癌診断用キット。
Claims (10)
- EGFRvIII(Epidermal Growth Factor Receptor Variant III)に結合する抗体またはその抗原結合断片であって、配列番号1の配列を有するEGFRvIIIのエピトープに結合し、
配列番号16の配列を含む重鎖可変領域と、
配列番号17の配列を含む軽鎖可変領域を含む、前記抗体またはその抗原結合断片。 - 請求項1に記載の抗体またはその抗原結合断片をコードする核酸。
- 配列番号18または配列番号19の配列を含むことを特徴とする請求項2に記載の核酸。
- 請求項2に記載の核酸を含む発現ベクター。
- 請求項4に記載の発現ベクターで形質転換された細胞。
- 下記の段階を含む請求項1に記載の抗体またはその抗原結合断片の製造方法:
(a)請求項5に記載の細胞を培養する段階;および
(b)前記培養された細胞から抗体またはその抗原結合断片を回収する段階。 - 請求項1に記載の抗体またはその抗原結合断片を有効性分として含む癌の予防または治療用組成物。
- 前記癌は、肺癌、大腸癌、胃癌、腎臓癌、前立腺癌、乳癌、膠芽細胞腫、および卵巣癌で構成された群から選択されることを特徴とする請求項7に記載の組成物。
- 請求項1に記載の抗体またはその抗原結合断片を含む癌診断用組成物。
- 請求項9に記載の癌診断用組成物を含む癌診断用キット。
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KR1020170020416A KR101887977B1 (ko) | 2016-02-15 | 2017-02-15 | EGFRvIII (Epidermal Growth Factor Receptor Variant III)에 대한 항체 및 이의 용도 |
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