JP4494977B2 - Gd2に結合するマウス14.18抗体のヒト化抗体(h14.18)およびそのil−2融合タンパク質 - Google Patents
Gd2に結合するマウス14.18抗体のヒト化抗体(h14.18)およびそのil−2融合タンパク質 Download PDFInfo
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Description
ここ何年かの間に、抗体をベースにした治療の開発に著しい進歩がある。例えば、試験者は、様々な癌特異的マーカーだけではなく、それらのマーカーに特異的に結合する様々な抗体も同定した。抗体は、選択的に癌細胞を殺す目的で、マーカーを発現する癌細胞に、ある特定の分子、例えば毒素または免疫刺激性部分、例えばサイトカインを送達するのに用いることができる。
概括すれば、本発明は、ヒトにおける免疫原性が減弱されているが、m14.18が有するヒトGD2に対する結合親和力をなお保持している改変型m14.18抗体を提供するものである。
図1Aは、本発明による免疫グロブリン軽鎖可変領域のアミノ酸配列を示す。
本発明は、ヒトでの免疫原性が減弱されているが、依然としてヒトGD2に特異的に結合することができる改変型m14.18抗体を提供する。免疫原性の減弱は、免疫グロブリン可変ドメインにおける、1つまたは複数のアミノ酸配列の改変によって提供される。この抗体は、特にサイトカインまたは他の免疫変調因子に融合された場合に、GD2陽性腫瘍を治療するのに有用である。
本発明は、ヒト細胞表面スフィンゴ糖脂質GD2に、好ましくは特異的に、結合する抗体であって、m14.18抗体に由来する改変領域を有する抗体を主題とする。VHまたはVLアミノ酸配列(あるいはこれら両方)は、ヒトに投与された際の免疫原性を減弱させるために、改変またはヒト化されている。本発明によれば、例えば、deimmunization法を用いることで、m14.18抗体をヒト化することができる。この方法では、MHCクラスII分子に対するペプチドエピトープの結合を減弱させる変異を導入することよって、潜在的なT細胞エピトープの除去または減弱を行う(例えば国際公開第WO98/52976号および第WO00/34317号を参照)。別法では、非ヒトT細胞エピトープに変異を導入し、それらがヒト抗体内に存在するヒト自己エピトープに相当するようにする(例えば米国特許第5712120号を参照)。本発明は、少なくとも1つのヒト化されたFR配列を含み、それによって、ヒトに投与された際の免疫原性が減弱されているVL領域およびVH領域を有するGD2抗体を提供する。
上述のように、hu14.18は、m14.18抗体に由来するヒト化された可変部であって、ヒトGD2抗原に対する特異的結合性を保持する可変部を含む。本発明のある実施形態では、hu14.18抗体のVL領域は、次のポリペプチドを含む。
本発明の抗体可変領域は、任意選択でFc部分に融合される。本明細書において、Fc部分は、免疫グロブリン、好ましくはヒト免疫グロブリンの重鎖定常領域に由来するドメインを包含するものであり、これには上記定常領域のフラグメント、類似体、変種、変異体、または誘導体も含まれる。免疫グロブリン重鎖の定常領域は、CH1、ヒンジ、CH2、CH3、および、重鎖のクラスによってはCH4ドメインを含めた、重鎖C末端領域の少なくとも一部に相同性を有する天然存在のポリペプチド、または合成によって生成されたポリペプチドと定義される。「ヒンジ」領域は、CH1ドメインをFc部分のCH2−CH3領域に連結する。全哺乳動物の免疫グロブリン重鎖定常領域は、アミノ酸配列における広範な相同性を示す。これら免疫グロブリン領域のDNA塩基配列は当技術分野で周知である(例えば、Gilliesら(1989年)、J.Immunol.Meth.第125巻、191頁参照)。
本発明の抗体可変領域は、任意選択で、非免疫グロブリン部分に直接的に、または、リンカーペプチド(例えば、(Gly4−Ser)3(配列番号3))を介して間接的に連結または融合させることができる。開示された融合タンパク質の免疫原性は、米国特許出願公開第2003-0166877-A1号に記載されるように、融合接合部または接合部エピトープの、T細胞受容体と相互作用する能力を損なうことによって減弱させることができる。2つのヒトタンパク質、例えば、ヒトFcおよびヒトIL−2の間の融合においてさえ、融合接合部または接合部エピトープ周囲の領域は、通常はヒト体内に存在しないペプチド配列、したがって、免疫原性であり得るペプチド配列を含有する。例えば、接合部エピトープの免疫原性は、融合接合部近傍に1つまたは複数のグリコシル化部位を導入することによって、または、米国特許出願公開第2003-0166877-A1号に記載にされるように、接合部にまたがるT細胞エピトープ候補を同定し、接合部近傍のアミノ酸を改変してT細胞エピトープ候補の、T細胞受容体と相互作用する能力を低減させることによって、減弱させることができる。
本発明の抗体可変領域は、診断用薬および/または治療薬に結合させることができる。これら薬剤を抗体に融合させて、融合タンパク質を生成することができる。別法として、これらの薬剤を抗体に化学的に結合させて、免疫複合体を生成することもできる。このような薬剤は、例えば、毒素、放射性標識、イメージング剤、免疫活性化部分、または同様のものであり得る。
I.hu14.18抗体構築体
本発明は、上記タイプのタンパク質それぞれを発現することができる核酸も主題とする。これらには、例えば、配列番号1に記載のアミノ酸配列;配列番号2に記載のアミノ酸配列;huVLFR1アミノ酸配列を含むhu14.18抗体VL領域;huVHFR1アミノ酸配列を含むhu14.18抗体VH領域;huVHFR3アミノ酸配列を含むhu14.18抗体VH領域;ならびに上記のヒト化されたFR配列を少なくとも1つを含むhu14.18抗体と、1つまたは複数の治療薬とを含む融合タンパク質をコードする核酸が含まれる。
本発明のタンパク質をコードする核酸は、それが発現される適切な受容細胞内に導入するために、1つまたは複数の発現ベクターに構築または挿入することができる。発現ベクターへの核酸の導入は、標準的な分子生物学技法で実行できる。好ましい発現ベクターには、コードされているタンパク質を細菌または哺乳類のいずれかの細胞内で、それから発現できるベクターが含まれる。
本発明の核酸は、癌と、特定の細胞型を免疫系の標的にすることが望ましい他の疾患とを治療するための遺伝子療法薬として用いることができる。例えば、ヒトまたは動物から細胞を取り出すことが可能であり、それらの細胞内に本発明の抗体をコードする1つまたは複数の核酸を形質移入することができる。細胞は、その後ヒトまたは動物に再導入される。形質移入される細胞は、正常細胞であることも、癌細胞であることもある。別法として、核酸は生体内原位置(in situ)で細胞内に導入することもできる。ヒトまたは動物は、その後、癌細胞に対して免疫応答を引き起こし、それによって、癌が治癒されるか、またはその重篤度が軽減され得る。本発明の抗体可変領域は、哺乳類細胞内で発現を促進する適切な調節エレメントに結合され、リン酸カルシウム、「遺伝子銃」、アデノウイルスベクター、カチオン性リポソーム、レトロウイルスベクター、または他のいかなる効率的形質移入法も含めた様々な技法のいずれによっても細胞内に形質移入することができる。
実施例1
hu14.18−IL2の精製および製剤
1つの試験では、hu14.18−IL2をNS/0細胞から発現させ、組織培養上清を収集し、Abx混合樹脂カラムクロマトグラフィー、組換え型プロテインAクロマトグラフィー、およびQセファロースカラムクロマトグラフィーを順序通りに用いてhu14.18−IL2タンパク質を精製し、続いてペリコン2接線流ダイアフィルトレーションで製剤緩衝液に緩衝液交換を行った。これらの精製ステップの詳細を以下に記載する。ウイルス不活性化ステップおよび排除ステップは、以下に記載するように、これらのステップの間に組み入れた。ウイルス不活性化ステップおよび排除ステップは、精製それ自体には必要なかったが、規定の要件を満たすために用いられた。
1.マンニトール 4%
2.塩酸アルギニンUSP/NF 100mM
3.クエン酸USP−FCC 5mM
4.ポリソルベート80 0.01%(w.v)
製剤緩衝液のpHを1M NaOHで7に調整した。
第I相臨床試験で観測されたhu14.18−IL−2融合タンパク質の抗腫瘍活性
hu14.18−IL−2の安全および有効性を評価するために、第I相臨床試験を行った。適格患者は、外科的および医学的に不治であると考えられメラノーマを有することが組織学的に確認されていた。これらの患者は測定可能または評価可能な転移性疾患を有してもよく、また、遠隔転移または領域再発疾患の外科切除後に疾患の証跡が無くてもよかった。複数(2つ以上)の局所または領域再発を伴う患者は、患者にリンパ節関与の以前の証跡があり、かつ各再発が少なくとも2カ月までの期間内に分離された場合にのみ含まれた。すべての患者は、適切な骨髄機能(総白血球(WBC)>3500/ml、または総顆粒球>2000/ml、血小板>100000/ml、およびヘモグロビン>10.0g/dlで定義する)、適切な肝機能[アスパラギン酸アミノトランスフェラーゼ(AST)<3x正常値、および総ビリルビン<2.0mg/dlで定義する]、および適切な腎臓機能(血清クレアチニン<2.0mg/dl、またはクレアチニンクリアランス>60ml/分間で定義する)を有する必要があった。すべての患者は、皮質脳波検査(ECOG)パフォーマンスステータスが0または1であり、少なくとも12週間の平均余命があった。試験前4週間以内に事前に化学療法、放射線治療、または他の免疫抑制療法を受けた患者は除外した。患者は、試験を開始する前に少なくとも4週間治療され、安定している場合には、以前に中枢神経系(CNS)転移があってもよかった。すべての患者からインフォームドコンセントを得た。
hu14.18−IL−2で治療された患者に関して、免疫刺激の指標も検査した。末梢血リンパ球減少が2〜4日目に起こり、この後、5〜22日目には反跳性リンパ球増多症が起こった。これらの変化は両方とも用量依存性であった(それぞれ、p<0.01およびp<0.05)。5、8、15および22日目におけるリンパ球数は、コース1のベースラインより有意に大きかった。コース2のベースラインリンパ球数(コース1の29日目)は、コース1のベースラインリンパ球数より増加しており、これは第1コースの治療の効果が29日目でもまだ存在していることを示す。さらに、これら12人の患者の、コース2における5、8および15日目のリンパ球数は、コース1における5、8、および15日目の対応する値より大きかった。
Claims (5)
- 配列番号5の軽鎖および配列番号6の重鎖を含む、GD2に特異的に結合し免疫機能を刺激するhu14.18−IL2として示されるヒト化抗体−IL2融合タンパク質。
- 請求項1の融合タンパク質をコードする核酸配列を含む配列番号4のヌクレオチド配列を含むベクター。
- 請求項1の融合タンパク質と調剤用担体または賦形剤とを含む医薬組成物。
- GD2陽性であるがん患者における、病気の進行を安定化させるための薬剤の製造のための、請求項1に記載の融合タンパク質の使用。
- GD2陽性であるがん患者における、ADCCおよびNK−分解を増加するための薬剤の製造のための、請求項1に記載の融合タンパク質の使用。
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WO2004055056A1 (en) | 2004-07-01 |
US7169904B2 (en) | 2007-01-30 |
US20070059282A1 (en) | 2007-03-15 |
PL211180B1 (pl) | 2012-04-30 |
DE60333121D1 (de) | 2010-08-05 |
US7767405B2 (en) | 2010-08-03 |
MXPA05006384A (es) | 2005-08-29 |
DK1572748T3 (da) | 2010-08-23 |
US20100210831A1 (en) | 2010-08-19 |
RU2005119305A (ru) | 2006-01-20 |
CA2510180A1 (en) | 2004-07-01 |
AU2003298187B2 (en) | 2010-09-16 |
EP1572748B1 (en) | 2010-06-23 |
CN1726227A (zh) | 2006-01-25 |
EP1572748A1 (en) | 2005-09-14 |
US20040203100A1 (en) | 2004-10-14 |
CN100432105C (zh) | 2008-11-12 |
ZA200505681B (en) | 2006-04-26 |
BR0317376A (pt) | 2005-11-16 |
KR101086660B1 (ko) | 2011-11-24 |
AU2003298187A1 (en) | 2004-07-09 |
ES2346205T3 (es) | 2010-10-13 |
PL377337A1 (pl) | 2006-01-23 |
BRPI0317376B8 (pt) | 2021-05-25 |
ATE471946T1 (de) | 2010-07-15 |
CA2510180C (en) | 2012-09-11 |
RU2366664C2 (ru) | 2009-09-10 |
PT1572748E (pt) | 2010-09-28 |
BRPI0317376B1 (pt) | 2019-12-03 |
KR20050085775A (ko) | 2005-08-29 |
US8470991B2 (en) | 2013-06-25 |
JP2006521085A (ja) | 2006-09-21 |
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EXPY | Cancellation because of completion of term |