JP2013502445A - 抗vegfモノクローナル抗体およびその抗体を含む薬学的組成物 - Google Patents
抗vegfモノクローナル抗体およびその抗体を含む薬学的組成物 Download PDFInfo
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Abstract
Description
本発明は、遺伝子操作された抗体の技術分野に関し、特に血管内皮増殖因子(VEGF)と特異的に結合する遺伝子操作された抗体、ならびにその抗体を含む薬学的組成物およびキットに関する。
血管内皮増殖因子(VEGF)は、インビボで血管形成を誘導することが可能である、血管内皮細胞に特異的なヘパリン結合増殖因子である。ヒトVEGFタンパク質は、1989年に米国人科学者によって成功裏に精製および同定され、彼はまた、その遺伝子をクローニングし、その遺伝子配列を決定した。
本発明のさらなる説明の前に、本発明は、記載された特定の実施形態によって限定されないことを理解することが必要である。換言すれば、特定の形式に違いがあってもよい。本発明の範囲は添付の特許請求の範囲に従うので、本明細書中の用語は、本発明を限定するのではなく、特定の実施形態を説明することのみを意図したものであることがさらに注意されるべきである。
本発明の目的は、VEGFとのより高い親和性を有するモノクローナル抗体を提供することである。本発明に従うVEGFモノクローナル抗体は、配列番号1、配列番号2および配列番号3のアミノ酸配列を含む重鎖の可変ドメイン、ならびに/または配列番号4、配列番号5および配列番号6のアミノ酸配列を含む軽鎖の可変ドメインを有する。
保存番号CGMCC NO.3233を有する細胞系統は、2009年8月20日にDatun Road,Chaoyang District,Beijingの所在地で保存されており、その分類名はチャイニーズハムスター卵巣細胞である。
実施例1:ヒトVEGF165ウサギモノクローナル抗体およびその遺伝子クローンを発現するハイブリッド腫瘍細胞の調製
ウサギモノクローナルクローン抗体はハイブリドーマ技術を用いて調製される。関連する実験計画についは、米国特許第7,429,487号、特に、実施例1〜4を参照のこと。
ヒト化技術については、米国特許第7,462,697号、特に、その好ましい実施形態の詳細な説明を参照のこと。
VEGF抗体はVEGFと結合して、受容体KDRとのその結合を遮断し、VEGFシグナルチャネルを阻害する。様々な組換え抗体(HZD−V1、HZD−V2、HZD−V5、HZD−V6)およびアバスチン(90μg/ml−45ng/ml)の1:3での段階希釈後、IgG Fc−hVEGF(1μg/ml)と混合し、混合した抗体−VEGF複合体をIgG Fc−VEGFR2を広げたプレートのウェルに加え、そしてマウス抗ヒトVEGF抗体を加えた後、ヤギ抗マウスIgG抗体−APを用いる発色を通して検出する。結果は、発現された組換え抗体が、VEGFのKDRとの結合の競合阻害においてアバスチンと同様の活性を有することを示す。測定結果は、HZD−V1、HZD−V2、HZD−V5、およびHZD−V6クローンによって発現されるすべての抗体がVEGFのKDRとの結合を遮断できることを示す(図1を参照のこと)。
HEK 293−6E細胞のHZD−V6クローンによって一過性に発現されたEPI0030抗体を精製した後に、特定の分析項目を用いて関連する定性分析を以下のように実施する:
A:純度
SDS−PAGE(還元および非還元)およびSEC−HPLCを使用して、図2および図3に示される結果を用いて純度を分析し、EPI0030抗体の純度は98%より高く、重合体含量は5%より低く、主ピーク(保持時間10.572分)面積は全体の面積の95%より大きく(左から右にピーク1、2、および3を示す)、そしてピーク1および2は重合体であることを示す。
IgG Fc−hVEGFを使用してプレートに広げ、1% BSAを使用してシールし、8段階の1:3段階希釈を通してEPI0030抗体およびアバスチンを希釈し(1μg/ml〜0.46ng/ml)、これをIgG Fc−hVEGFを広げたウェルに加え、−AP検出のためにロバ抗ヒトIgG抗体を加える。結果はEPI0030抗体およびアバスチンが同様の結合活性を有することを示す。
実験の2週間前に、液体窒素タンクから、凍結したヒト結腸癌HCT−116細胞およびヒト非小細胞肺癌NCI−H460細胞の1つの系統(約1×107細胞)を取り、これらを素早く37℃ウォーターバスに配置して融解させる。次いで、あらかじめ37℃に加熱したMcCoyの5A培地およびDMEM培地を有する75CM2細胞培地に細胞を接種し、それぞれ、10%ウシ胎仔血清(GIBCOより購入)を加え、細胞が80%融合比率まで増殖したときに1:5で継代培養し、そして連続して3回継代培養する。全細胞量が接種によって必要とされる数に達したとき、膵臓酵素で細胞を消化しおよび遠心分離し、PBSを使用して細胞を洗浄して血清を除去し、そして最後に、無血清で抗生物質を含まないMcCoyの5A培地およびDMEM培地を使用して、処理されたヒト結腸癌HCT−116細胞およびヒト非小細胞肺癌NCI−H460細胞の細胞密度を5×107/mlにそれぞれ調整し、細胞懸濁液を氷上に配置し、6−9週齢のヌードマウスの腹部に接種し、各マウスに0.1ml、すなわち、5×106細胞/マウスで接種する。副尺付きカリパスを使用して、2日ごとにヌードマウスの腫瘍直径を測定し、すべてのマウスの腫瘍が100mm3−300mm3に成長したときに、腫瘍体積SD<1/3のものを選択し、それらを、群あたり6匹の5つの群にランダムに分ける。ヒト結腸癌HCT−116モデル群は、モデル対照群、(1群)、5mg/kg アバスチン(1群)、および5mg/kg EPI−0030(1群)であり、そして生理食塩水を使用してアバスチンおよびEPI−0030を0.5mg/mlに希釈する。ヒト非小細胞肺癌NCI−H460モデル群は、モデル対照群(1群)、5mg/kg アバスチン(1群)、および1.5mg/kg、5mg/kg EPI−0030(2群)であり、そして生理食塩水を使用してアバスチンおよびEPI−0030を0.5mg/mlおよび0.15mg/mlに希釈する。薬物投与群については、0.2ml アバスチンおよびEPI−0030は、それぞれ、各週の1日、3日、および5日に1回、腹腔内注射を通して投与され、0.2ml生理食塩水は同時にかつ同じやり方を介してモデル対照群に投与され、投与は3週間継続された(21日間、全体で9回)。
Claims (12)
- モノクローナル抗体であって、その重鎖の可変ドメインが配列番号l、配列番号2、および配列番号3のアミノ酸配列を含み、および/またはその軽鎖の可変ドメインが配列番号4、配列番号5、および配列番号6のアミノ酸配列を含むことを特徴とする、モノクローナル抗体。
- 請求項1に記載のモノクローナル抗体であって、前記モノクローナル抗体は、単鎖抗体、二本鎖抗体、キメラ抗体、ヒト化抗体、ならびに上記の抗体の誘導体、機能的等価物および相同物を含み、抗体セグメント、および抗原結合ドメインを含む任意のポリペプチドをさらに含んでもよいことを特徴とする、モノクローナル抗体。
- 請求項1または2に記載のモノクローナル抗体であって、その重鎖可変ドメインのアミノ酸配列が配列番号7によって示され、またはその重鎖可変ドメインが配列番号7によって示されるアミノ酸配列の1個もしくは数個のアミノ酸の置換、欠失、もしくは付加によって誘導され、配列番号7と少なくとも95%同一性を有し、そして前記モノクローナル抗体がVEGFと特異的に結合する活性を有することを特徴とする、モノクローナル抗体。
- 請求項1または2に記載のモノクローナル抗体であって、その軽鎖可変ドメインのアミノ酸配列が配列番号8によって示され、またはその軽鎖可変ドメインが配列番号8によって示されるアミノ酸配列の1個もしくは数個のアミノ酸の置換、欠失、もしくは付加によって誘導され、配列番号8と少なくとも95%同一性を有し、そして前記モノクローナル抗体がVEGFと特異的に結合する活性を有することを特徴とする、モノクローナル抗体。
- 請求項1または2に記載のモノクローナル抗体であって、その重鎖アミノ酸配列が配列番号9によって示され、またはその重鎖が配列番号9によって示されるアミノ酸配列の1個もしくは数個のアミノ酸の置換、欠失、もしくは付加によって誘導され、配列番号9と少なくとも95%同一性を有し、そして前記モノクローナル抗体がVEGFと特異的に結合する活性を有することを特徴とする、モノクローナル抗体。
- 請求項1または2に記載のモノクローナル抗体であって、その軽鎖のアミノ酸配列が配列番号10によって示され、またはその軽鎖が配列番号10によって示されるアミノ酸配列の1個もしくは数個のアミノ酸の置換、欠失、もしくは付加によって誘導され、配列番号10と少なくとも95%同一性を有し、そして前記モノクローナル抗体がVEGFと特異的に結合する活性を有することを特徴とする、モノクローナル抗体。
- 保存番号CGMCC No.3233を有する細胞系統によって産生されることを特徴とする、請求項1〜6のいずれかに記載のモノクローナル抗体。
- 保存番号CGMCC No.3233を有するCGMCCに保存されていることを特徴とする細胞系統。
- VEGF関連疾患を治療するための薬物を調製する際の請求項1〜7のいずれかに記載のモノクローナル抗体の使用。
- 前記VEGF関連疾患が腫瘍、AMD、神経変性疾患、肥満、および糖尿病を含むことを特徴とする、請求項9に記載のモノクローナル抗体の使用。
- 請求項1〜7のいずれかに記載の有効量のモノクローナル抗体および薬学的に受容可能なキャリアを含むことを特徴とする薬学的組成物。
- 請求項1〜7のいずれかに記載の上記のモノクローナル抗体を含む、試薬、キット、またはチップ。
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EP2471814A4 (en) | 2013-04-03 |
ES2657226T3 (es) | 2018-03-02 |
CN102448987A (zh) | 2012-05-09 |
JP5738294B2 (ja) | 2015-06-24 |
US20120231011A1 (en) | 2012-09-13 |
US8986692B2 (en) | 2015-03-24 |
CN102448987B (zh) | 2014-06-04 |
CN102002104A (zh) | 2011-04-06 |
WO2011023130A1 (zh) | 2011-03-03 |
EP2471814A1 (en) | 2012-07-04 |
EP2471814B1 (en) | 2018-01-03 |
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