JP4734319B2 - ヒト抗上皮成長因子受容体抗体 - Google Patents
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Description
本発明は、上皮成長因子受容体(EGFR)特異的なモノクローナル抗体に関する。これらの抗体は新生物性疾患、とりわけ過剰増殖障害の治療に用いることができる。
正常な細胞は成長因子受容体チロシンキナーゼ(RTK)のそれぞれのリガンドによるそれらRTKの高度に制御された活性化によって増殖するが、癌細胞もまた成長因子受容体の活性化によって増殖する。しかし、癌細胞の場合は正常な増殖の慎重な制御を失う。この制御の喪失は、成長因子および/または受容体の過剰発現や、成長因子により調節される生化学的経路の自己活性化などの無数の要因により引き起こされる可能性がある。腫瘍形成に関与するRTKの幾つかの例は、上皮成長因子受容体(EGFR)、血小板由来成長因子受容体(PDGFR)、インスリン様成長因子受容体(IGFR)、神経成長因子受容体(NGFR)、および線維芽細胞成長因子(FGF)受容体である。これらの成長因子がそれらの細胞表面の受容体と結合すると受容体の活性化を誘発し、それが情報伝達経路を起動、修飾し、細胞の増殖および分化を引き起こす。
本発明は、EGFR、好ましくはEGFRの細胞外領域に対して特異的な、配列番号2、配列番号4、配列番号6、配列番号10、配列番号12、および配列番号14からなる群から選択される1個から6個の相補性決定領域(CDR)をどこかに含むモノクローナル抗体またはその断片を提供する。好ましくは、これら抗体はヒトのものである。より好ましくは本発明の抗体またはその断片は、配列番号2、配列番号4、および配列番号6を含む。あるいは、好ましくは本発明の抗体またはその断片は、配列番号10、配列番号12、および配列番号14を含む。より好ましくは本発明の抗体またはその断片は、配列番号8の重鎖可変領域および/または配列番号16の軽鎖可変領域を含む。本発明のこのような抗体またはその断片は、EGFRを中和する能力およびEGFRのリガンドがその受容体と結合するのを妨げる能力を含めた様々な特性を有する。
本発明は、EGFRに対して特異的なモノクローナル抗体とその断片、およびこれら抗体をコードする単離または精製ポリヌクレオチド配列を提供する。本発明の抗体は、好ましくはヒトのものであり、充実性および非充実性腫瘍を含めた新生物性疾患の治療、および過剰増殖性障害の治療に用いることができる。
最終的にはそのヒンジ領域が抗体のFabおよびFc部分を分離し、その結果これらFab互いに対するまたFcに対するFabの易動性を与え、またそれら2個の重鎖の共有結合による連結のための多重ジスルフィド結合を囲い込む。
(1)疎水性のメチオニン(M)、アラニン(A)、バリン(V)、ロイシン(L)、イソロイシン(I)、
(2)親水性のシステイン(C)、セリン(S)、スレオニン(T)、アスパラギン(N)、グルタミン(Q)、
(3)酸性のアスパラギン酸(D)、グルタミン酸(E)、
(4)塩基性のヒスチジン(H)、リシン(K)、アルギニン(R)、
(5)芳香族のフェニルアラニン(F)、チロシン(Y)、およびトリプトファン(W)、
(6)鎖の配向に影響を及ぼす残基のGly、Pro、
が挙げられるが、これらには限定されない。
手短に言えば、これらのヒト抗体は、EGFR陽性腫瘍から単離した可溶性ヒトEGFRに対するバイオパンニングによって、Dyax, Cambridge, MAから得られるヒトのナイーブFabバクテリオファージライブラリーから単離された。ヒトの抗体産生細胞(末梢Bリンパ球)の重鎖および軽鎖可変領域を含有するこのナイーブFabバクテリオファージライブラリーは、V遺伝子特異的フォワードおよびリバーズプライマーを用いて一次PCR反応で増幅し、これらの個々のVHおよびVL遺伝子を別々のベクター中にクローン化することによって、未感作の免疫していないヒトと、胃の癌腫を有する患者由来の腫瘍のない脾臓細胞とから構築された(国際公開第WO00/70023号)。
11F8 Fabをコードする遺伝子を含有するプラスミドを用いて非サプレッサーE. coli宿主HB2151を形質転換した。HB2151中でのFab断片の発現は、1 mMイソプロピル−1−チオ−β−D−ガラクトピラノシド(IPTG, Sigma)を含有する2YTA培地中で30℃で細胞を培養することによって誘発した。細胞の周辺抽出液は、20%(w/v)スクロース、200 mM NaCl、1 mM EDTA、および1 mM PMSFを含有する25 mMトリス(pH 7.5)中にこの細胞ペレットを再懸濁し、続いて1時間静かに振とうしながら4℃でインキュベートすることによって調製した。遠心分離後、可溶性Fabタンパク質を、製造業者の実験計画案(Amersham Pharmacia Biotech)に従ってタンパク質Gカラムを用いるアフィニティークロマトグラフィーにより上澄みから精製した。
ヒト抗EGFR Fabを遺伝子工学的に完全ヒトIgG1に作り変えた。選択されたFab候補C11F8は、ヒトEGFR(ErbB)との高い親和性結合およびそのリガンド遮断活性に関してヒトのナイーブFabファージディスプレイライブラリーから特定された。そのC11F8 Fab軽鎖の可変領域(配列番号15)および重鎖遺伝子(配列番号7)をコードするDNA配列はPCR増幅によって得られ、Lonza Biologics, Inc.から入手したグルタミンシンターゼ発現系を用いてヒトIgG1不変ドメインを含有する発現ベクター中にクローン化した。
安定なトランスフェクションのために単一プラスミドベクターを、軽鎖含有p12.1Lベクター中にCMVプロモーター含有重鎖発現カセットのNot I−Sal I断片をクローン化することによって生成させた。得られたプラスミドベクターpGS−11F8の制限地図を作成した(図1C参照)。その制限消化分析結果を図2に示した。
これら抗体をIMC−11F8とIMC−C225の結合特性を比較する固相ELISAでスクリーニングした。96ウェルマイクロタイタプレートを、4℃の炭酸緩衝液に溶かした1μg/mLの膜で一晩覆った。それらプレートを、10%の新生ウシ血清を補ったリン酸緩衝塩類溶液(PBS)により37℃で1時間遮断した。様々な量のIMC−11F8またはIMC−C225をそれらプレートに加え、室温でさらに60分間インキュベートし、次いでPBSで洗浄した。マウス抗ヒトFc抗体−ワサビダイコンペルオキシダーゼ(HRP)複合体を加え、室温でさらに60分間インキュベートし、次いでPBSで徹底的に洗浄した。次いでこのプレートをHRP基質と共に30秒〜2分間インキュベートし、反応を0.1M H2SO4で停止させた。これらプレートをELISAリーダを用いてOD450nmで読み取った。
IMC−11F8とIMC−C225 IgG抗体、およびそれらそれぞれのFab断片の結合速度動態を、BIAコアセンサー(Pharmacia Biosensor)を用いて測定した。EGFR−AP融合タンパク質をセンサーチップ上に固定化し、可溶性のIMC−11F8およびIMC−C225抗体を1.5 nMから100 nMの範囲にわたる濃度で注入した。センサーグラムが各濃度で得られ、これを速度定数konおよびkoffを求めるためのプログラムであるBIA Evaluation 2.0により分析した。親和性定数Kdを速度定数の比koff/konから計算した。
EGFRとの抗体の結合を125I-EGF競合検定により評価した。24ウェルCOSTAR(Fisher Scientific, U.S.A.)で1ウェル当たりHT29細胞2×104個を、1.5 mM L‐グルタミン、10%CS、および抗生物質を補った37℃のMcCoyの5a培地中に播種した。次いでこの細胞の単層を、様々な量の125Iで標識したEGFと混合した様々な濃度の標識していないEGF、11F8、またはIMC−C225と共に室温で1時間インキュベートした。これら細胞を冷PBS で洗浄し、細胞に随伴する放射能をガンマカウンタで測定した。
手短に言えばキナーゼ受容体活性化検定(KIRA検定)、すなわちリン酸化検定を、BxPC3またはA431細胞を用いて行った。細胞を、まず重炭酸ナトリウム1.5 g/Lおよびグルコース4.5 g/L を含有するように調整した4 mM L‐グルタミンおよび10%CSを補ったDME中で37℃で集密度90%まで成長させた。実験に先立って細胞を、0.5%CSを補ったDME中で24時間絶食させた。EGFが誘発するEGFRの活性化に及ぼす抗体、IMC−11F8、IMC−C225、およびIMC−1C11の効果を評価するために、様々な濃度の抗体を30分間、室温で事前に結合させ、続いて8 ng/mLのEGFでさらに15分間刺激した。刺激後、これら細胞の単層を1 mMオルトバナジン酸ナトリウムを含有する冷PBSで洗浄した。細胞を溶菌緩衝液(20 mMトリスHCl(pH 7.4)、1%トリトンX-100、137 mM NaCl、10%グリセロール、10 mM EDTA、2 mMオルトバナジン酸ナトリウム、100 mM NaF、100 mMピロリン酸ナトリウム、5 mM PEFABLOC(登録商標)SC(Boehringer Mannheim Biochemicals, Indianapolis, IN)、アプロチニン100μg、およびロイペプチン100μg/mL)中で溶解し、14,000 x gで10分間遠心分離した。透明になった細胞ライゼートを、ポリクローナル抗EGFR抗体の膜で覆った96ウェルプレートの各プレートに加えた。プレートを洗浄して非特異的に結合したタンパク質を除去し、EGFRリン酸化のレベルを抗ホスホチロシン抗体の添加によって判定した。徹底的に洗浄した状態で、結合した抗ホスホチロシン抗体の量をELISAリーダを用いてOD450nmで測定した。
MTT細胞増殖検定は、代謝活性細胞による黄色テトラゾリウムMTT(臭化3−(4, 5−ジメチルチアゾリル−2)−2, 5−フェニルテトラゾリウム)の細胞内紫色ホルマザン生成物への還元の結果として色を計量的に測定する。この生成物は、可溶化し、分光光度的手段により定量することができる。手短に言えば、DiFi細胞をDMEM−10%CS中で一晩培養した。抗体、IMC−11F8、IMC−C225、またはIMC−1C11を3部分からなるウェルに加え、5%CO2で37℃においてさらに72時間インキュベートした。細胞成長を測定するために各ウェルにテトラゾリウム染料のアリコート20μLを加え、細胞を37℃で3時間インキュベートした。顕微鏡で紫色の沈殿がはっきり認識できたとき、細胞を界面活性剤試薬100μLの添加により溶解した。増殖の定量値としてこのホルマザン生成物の吸光度をOD570nmにおいて測定した。
細胞死を判定する一方法は、抗体依存性細胞障害検定すなわちADCCによるものであり、一般には放射性同位元素を使用する。51Crで標識した標的細胞を抗体と混合し、死滅の度合いを51Crの放出により判定する。手短に言えばDiFi細胞約3×106個を培養液0.5μL中に懸濁し、0.5 mCiのNa51CrO4を加えた。この混合物を時折振とうしながら37℃で1時間インキュベートした。次いでこの細胞を冷培養液で3回洗浄した。次いでこの標識した細胞を様々な濃度の抗EGFR抗体(IMC−11F8またはIMC−C225)を含有する培養液100μL中に懸濁し、4℃で30分間インキュベートした。次いでこの細胞を遠心分離によって培養液で3回洗浄した。ウサギの補体を加え、その処理細胞を37℃で1時間さらにインキュベートした。次いで冷培地50μLを加え遠心分離した。次いで上澄みを取り出し、その上澄み中に細胞によって放出された放射能をガンマカウンタによって測定した。放射能の最大放出はその標的細胞に1%トリトンXを加えることによって得られた。細胞障害パーセントは、実験に基づく放出cpmからバックグラウンドcpmを引いたものに100%を掛け、次にそれを最大放出cpmからバックグラウンドcpmを引いたもので割る方法で計算した。
IMC−11F8が異種移植モデルにおいて腫瘍細胞の成長を遮断するかどうかを判定するためにin vivoでの抗腫瘍調査を計画した。無胸腺マウス(nu/nu、Charles River Lab, Wilmington, MA)の脾腹に1〜2百万個のA431またはBxPC-3細胞を皮下注射した。抗EGFR抗体(IMC−11F8およびIMC−C225)または対照抗体を1用量当たり1 mgまたは0.3 mgのいずれかで週3回腹膜内に投与した。腫瘍の大きさを少なくとも週3回カリパスで測定し、腫瘍体積を計算した(例えばBaselga等の論文J. Natl. Cancer Inst. (1993) 85:1327〜1333参照)。
約200〜300 mm3のヒト結腸直腸腫瘍異種移植片GEO、DLD-1、またはHT-29を持ったヌードマウスを、週2回、1回の注射当たり0.3 mgまたは1.0 mgのIMC−11F8を単独、またはイリノテカン(CPT−11)の週1回、100 mg/kgの用量と併用して腹膜内注射により処理した。腫瘍の大きさを週2回測定した。
IMC−11F8の薬物動態をカニクイザルで検討し、IMC−C225の薬物動態と比較した。20.5 mg/kgの125I標識IMC−11F8およびIMC−C225の単回投与による薬物動態の検討の場合、サルに別個に静脈内注射し、血液を日中に引き抜いてその動物の血漿中に保持されている抗体量を求めた。表6は、カニクイザルにおけるIMC−11F8およびIMC−C225の薬物動態比較を提供する。
Claims (12)
- 相補性決定領域:CDRH1に配列番号2、CDRH2に配列番号4、CDRH3に配列番号6、CDRL1に配列番号10、CDRL2に配列番号12、およびCDRL3に配列番号14を含む、単離されたヒト抗EGFR抗体または抗体断片。
- 配列番号8の重鎖可変領域および配列番号16の軽鎖可変領域を含む、単離されたヒト抗EGFR抗体または抗体断片。
- EGFRがEGFリガンドと結合するのを阻害する、請求項1または2に記載の抗体または抗体断片。
- EGFRを中和する、請求項1または2に記載の抗体または抗体断片。
- 単鎖抗体、Fab、単鎖Fv、ダイアボディー、トリアボディー、Fc、二価断片F(ab’) 2 、および単一ドメイン抗体からなる群から選択される、請求項1または2に記載の抗体または抗体断片。
- 請求項1または2に記載の前記抗体または抗体断片の複合体。
- 哺乳動物において腫瘍成長を阻害するための医薬としての使用のための抗体であって、治療上有効量の請求項1から5のいずれか1項に記載の抗体。
- 哺乳動物において腫瘍成長を阻害するための医薬としての使用のための抗体であって、前記腫瘍が、結腸直腸の腫瘍、頭部および頸部の腫瘍、膵臓の腫瘍、肺の腫瘍、乳房の腫瘍、腎臓細胞の癌腫、および神経膠芽腫からなる群から選択される、請求項7に記載の抗体。
- 医薬としての使用のための抗体であって、前記抗体または抗体断片が抗悪性腫瘍薬と併用して投与される、請求項7に記載の抗体。
- 前記抗悪性腫瘍薬が化学療法薬である、請求項9に記載の抗体。
- 前記抗悪性腫瘍薬がイリノテカン(CPT-11)である、請求項9に記載の抗体。
- 前記抗悪性腫瘍薬が放射線である、請求項9に記載の抗体。
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US9822148B2 (en) | 2012-06-25 | 2017-11-21 | Hoya Corporation | EGFR-binding peptide |
Also Published As
Publication number | Publication date |
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CN103007279B (zh) | 2017-01-11 |
CA2560305A1 (en) | 2005-09-29 |
HUS1600030I1 (hu) | 2016-07-28 |
CY1113037T1 (el) | 2016-04-13 |
MXPA06010715A (es) | 2007-05-23 |
EP2332990A1 (en) | 2011-06-15 |
JP2008500815A (ja) | 2008-01-17 |
CA2560305C (en) | 2016-07-05 |
CY2016016I2 (el) | 2016-12-14 |
RU2402569C2 (ru) | 2010-10-27 |
DK1735348T3 (da) | 2012-07-16 |
EP1735348B1 (en) | 2012-06-20 |
US20070264253A1 (en) | 2007-11-15 |
CN103007279A (zh) | 2013-04-03 |
PL1735348T3 (pl) | 2012-11-30 |
PT1735348E (pt) | 2012-07-24 |
LTC1735348I2 (lt) | 2017-11-10 |
AU2005224267A1 (en) | 2005-09-29 |
NL300819I2 (ja) | 2016-07-21 |
AU2005224267B2 (en) | 2011-07-21 |
US7598350B2 (en) | 2009-10-06 |
HUS000495I2 (hu) | 2021-03-29 |
WO2005090407A1 (en) | 2005-09-29 |
LU93093I2 (fr) | 2016-08-01 |
WO2005090407A8 (en) | 2005-12-01 |
ES2387809T3 (es) | 2012-10-02 |
EP1735348A1 (en) | 2006-12-27 |
CY2016016I1 (el) | 2016-12-14 |
RU2006137060A (ru) | 2008-04-27 |
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