JP2023510075A - ヒト化抗ca ix抗体、およびその使用方法 - Google Patents
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Abstract
Description
本発明は、ヒト炭酸脱水酵素IXに特異的に結合することができるヒト化抗体に関する。より具体的には、本発明は、CA IXのプロテオグリカン領域に対する抗体に関する。前記抗体は、マウス由来の相補性決定領域、ならびに、ヒト化重鎖領域およびヒト化軽鎖領域を含む。
CA IXは、Zavada、Pastorekova、Pastorek(US5387676)によって同定された癌関連炭酸脱水酵素である。当該CA IXは、M75モノクローナル抗体(Pastorekova et al,Virology,187:620e626,1992にて最初に説明された)を使用して同定される。当該抗体は、cDNAおよびCA IXをコードする遺伝子のクローニング、腫瘍および正常組織におけるCA IX発現の評価、CA IX調節の研究、ならびに、癌の進行および治療抵抗性とCA IXとの関係の研究において使用された。これら全ての研究により、CA IXは発癌前の腫瘍マーカー/新生物の腫瘍マーカーとして診断および/または予後判定に使用することができ、かつ標的として治療に使用することができるという、最初のUS5387676でなされた仮定が立証された。これら全ての研究により、M75モノクローナル抗体は、種々の免疫学的検出方法および免疫標的アプローチに有用であり、価値あるCA IXに特異的な試薬であることが示された。
本発明は、ヒトCA IXのプロテオグリカン領域を特異的に認識するヒト化抗体を提供する。これらは、特異的かつ効果的な結合活性、ならびに癌細胞の浸潤および貪食能力の阻害において驚くべき活性を示す。さらに、それらは、安全であり、望ましくない副作用を引き起こさない。
a)下記の配列と同一であるCDR配列、または、下記の配列と1または2個のアミノ酸が異なるCDR配列を含む重鎖可変領域配列:
GFTFNTNAMH(配列番号1)、および、
RIRSKSNNYTTYYADSVKD(配列番号2)、および、
VCGSWFAY(配列番号3);
および、
b)下記の配列と同一であるCDR配列、または、下記の配列と1個または2個のアミノ酸が異なるCDR配列を含む軽鎖可変領域配列:
KSSQSLLNSSNQKNYLA(配列番号4)、および、
FTSTRQS(配列番号5)、および、
QQHYSIPLT(配列番号6)。
-下記の配列を含む、または、有する重鎖可変領域:
X32VQLVESGGGX33VQPGX34SLX35LSCAASGFTFNTNAMHWVRQAX36GX37GLEWVX38 RIRSKSNNYTTYYADSVKDRFTISRDX39SKX40TX41YLQX42NSLX43X44EDTAVYYCVCGSWFAYWGQGTX45VTVSS(配列番号7)
ここで、
X32=E、または、Q
X33=L、または、V
X34=G、または、R
X35=K、または、R
X36=S、または、P
X37=K、または、R
X38=A、または、G
X39=D、または、N
X40=N、または、S
X41=A、または、L
X42=M、または、V
X43=K、または、R
X44=T、または、A
X45=L、または、T;および、
-下記の配列を含む、または、有する軽鎖可変領域:
DX46X47MTQSPDSLAVSLGERX48TINCKSSQSLLNSSNQKNYLAWX49QQKPGQX50PX51X52X53IYFTSTRQSGVPDRFX54GSGSGTDFTLTIX55SLQAEDVAVYX56CQQHYSIPLTFGQGTX57X58EIK(配列番号8)
X46=V、または、I
X47=V、または、Q
X48=V、または、A
X49=Y、または、F
X50=S、または、P
X51=K、または、N
X52=L、または、V
X53=L、または、V
X54=S、または、T
X55=S、または、N
X56=Y、または、F
X57=K、または、Q
X58=L、または、V。
a)下記からなる群より選択される配列を含む、または、有する、重鎖可変領域アミノ酸配列:
EVQLVESGGGLVQPGGSLKLSCAASGFTFNTNAMHWVRQASGKGLEWVGRIRSKSNNYTTYYADSVKDRFTISRDDSKNTAYLQMNSLKTEDTAVYYCVCGSWFAYWGQGTLVTVSS(配列番号9)、
EVQLVESGGGLVQPGGSLKLSCAASGFTFNTNAMHWVRQASGKGLEWVGRIRSKSNNYTTYYADSVKDRFTISRDDSKSTAYLQMNSLKTEDTAVYYCVCGSWFAYWGQGTLVTVSS(配列番号10)、
QVQLVESGGGVVQPGGSLRLSCAASGFTFNTNAMHWVRQAPGRGLEWVARIRSKSNNYTTYYADSVKDRFTISRDNSKNTLYLQVNSLRAEDTAVYYCVCGSWFAYWGQGTLVTVSS(配列番号11)、
EVQLVESGGGVVQPGRSLRLSCAASGFTFNTNAMHWVRQAPGKGLEWVARIRSKSNNYTTYYADSVKDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVCGSWFAYWGQGTLVTVSS(配列番号12)、
EVQLVESGGGLVQPGGSLKLSCAASGFTFNTNAMHWVRQASGKGLEWVGRIRSKSNNYTTYYADSVKDRFTISRDDSKNTAYLQMNSLKTEDTAVYYCVCGSWFAYWGQGTTVTVSS(配列番号13);および、
b)下記からなる群より選択される配列を含む、または、有する軽鎖可変領域アミノ酸配列
DVVMTQSPDSLAVSLGERVTINCKSSQSLLNSSNQKNYLAWYQQKPGQSPKLLIYFTSTRQSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHYSIPLTFGQGTKLEIK(配列番号14)、
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSSNQKNYLAWFQQKPGQPPNLVIYFTSTRQSGVPDRFSGSGSGTDFTLTINSLQAEDVAVYFCQQHYSIPLTFGQGTQVEIK(配列番号15)、
DIQMTQSPDSLAVSLGERATINCKSSQSLLNSSNQKNYLAWYQQKPGQPPKLLIYFTSTRQSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYFCQQHYSIPLTFGQGTKVEIK(配列番号16)、
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSSNQKNYLAWFQQKPGQPPKVLIYFTSTRQSGVPDRFTGSGSGTDFTLTISSLQAEDVAVYYCQQHYSIPLTFGQGTKLEIK(配列番号17)、および、
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSSNQKNYLAWYQQKPGQPPKLLIYFTSTRQSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHYSIPLTFGQGTKLEIK(配列番号18)。
i)ヒト化抗体の複数の同一、または、異なる用量;
ii)ヒト化抗体の複数の漸増用量;または、
iii)1週間に1回、2週間に1回、3週間に1回、4週間に1回、または、5週間に1回投与するヒト化抗体の用量。
図1:肺転移形成に対するマウスIV/18モノクローナル抗体の効果。(A)全放射効率は、対照群またはIV/18mAb処置群のいずれかのマウス肺のHT1080-RFP癌細胞の量を反映する。(B)対照マウスおよびIV/18mAb処置マウスの、蛍光の肺転移の代表的なex vivo画像。
<略語>
本発明の詳細な説明および実施例の全体にわたって、下記の略語が使用される:
3D 三次元
ADCC 抗体依存性細胞障害
ADCP 抗体依存性細胞貪食
ccRCC 明細胞腎細胞癌
CA IX 炭酸脱水酵素IX
CDC 補体依存性細胞障害
CDR 相補性決定領域
CRA サイトカイン放出アッセイ
DOX ドキソルビシン
ELISA 酵素結合免疫吸着アッセイ
FCS 胎仔血清
FR フレームワーク領域
HER-2 ヒト上皮増殖因子受容体2
HIF-1 低酸素誘導因子1
HRE 低酸素応答因子
HVR 超可変領域
IFNγ インターフェロンγ
IL インターロイキン
IMGT 免疫遺伝学情報システム
INN 国際一般名
kDa キロダルトン
KD 解離定数
mAb モノクローナル抗体
M モーラー
MCT モノカルボン酸輸送体
MHC 主要組織適合遺伝子複合体
NFAT 活性化T細胞の核因子
PBMC 末梢血単核球
PBS リン酸緩衝生理食塩水
PCR ポリメラーゼ連鎖反応
PD-1 プログラム細胞死タンパク質1
PD-L1 プログラム細胞死リガンド1
PG プロテオグリカン様領域
PKA プロテインキナーゼA
PPA プロテオームプロファイラアレイ
RFP 赤色蛍光タンパク質
SEB ブドウ球菌エンテロトキシンB
TNBC トリプルネガティブ乳癌
TNFα 腫瘍壊死因子α
VH 免疫グロブリン重鎖可変領域
VL 免疫グロブリン軽鎖可変領域
VEGF 血管内皮細胞増殖因子
VHL フォンヒッペルリンドウ病
WHO 世界保健機関
<細胞株>
8-MG-BA ヒト膠芽腫癌細胞(Cellosaurus CVCL_1052)
BT-20 ヒト乳癌細胞(ATCC HTB-19)
C-33a ヒト子宮頸癌細胞(ATCC HTB-31)
HT1080 ヒト線維肉腫癌細胞(ATCC CCL-121)
<定義>
本発明をより容易に理解することができるように、特定の技術用語および科学用語を下記に具体的に定義する。本明細書の他の箇所で特に定義されない限り、本明細書で使用される全ての技術用語および科学用語は、本発明が属する技術分野の当業者によって一般に理解される意味を有する。
本発明の医薬組成物は、抗体のためのキャリア、望ましくは薬学的に許容可能なキャリアを含む。薬学的に許容可能なキャリアは、任意の適切な薬学的に許容可能なキャリアであり得る。本明細書で使用される用語「薬学的に許容可能なキャリア」は、ヒトまたは家畜の患者への投与に適した、1つまたは複数の適合性の固体充填剤または液体充填材、希釈剤、他の賦形剤、またはカプセル化物質を意味する(例えば、生理的に許容されるキャリア、または薬理的に許容されるキャリア)。用語「キャリア」は、適用を容易にするために活性成分が組み合わされた、天然または合成の有機成分または無機成分を意味する。所望の薬学的効力を実質的に損なわないような方法で、組成物中に1つまたは複数の薬学的に許容可能なキャリアが存在する場合、薬学的に許容可能なキャリアは、1つまたは複数の活性成分(例えば、ハイブリッド分子)と、互いに同時混合することができる。「薬学的に許容可能な」材料は、一般的には望ましくない生理的な反応(例えば、悪心、めまい、発疹、または胃の不調)を有意に生じることなく、患者に投与することができる。例えば、薬学的に許容可能なキャリアを含む組成物は、治療を目的としてヒト患者に投与する場合、免疫原性でないことが望ましい。
本発明は、少なくとも1つのヒト化抗体を含む、診断用組成物を提供する。当該ヒト化抗体は、前述のようにヒトCA IXを特異的に認識する。
本明細書に提供されるいずれの抗CA IX抗体をも、治療方法にて使用され得る。
実施された実験および得られた結果を含む下記の実施例は、例示の目的のためにのみ提供されるものであって、本発明を限定するものとして解釈されるべきではない。
本実施例は、CA IXのプロテオグリカン領域に対するヒト化抗体変異体CA9hu-2の構築および特徴付けを実証する。
マウスVH領域は、下記の配列を含んでいた。マウスVH領域は、マウスシグナルペプチド配列を含まない:
EVQLVETGGGLVQPKGSLKLSCAASGFTFNTNAMHWVRQAPGKGLEWVARIRSKSNNYTTYYADSVKDRFTISRDDSQSMLYLQMNNLKTEDTAMYYCVCGSWFAYWGQGTLVTVSA(配列番号19)
CDR残基(下線)は、IMGT numbering systemまたはKabat numbering systemを使用して同定した。
GFTFNTNAMH
CDR2 VH IV/18(配列番号2)
RIRSKSNNYTTYYADSVKD
CDR3 VH IV/18(配列番号3)
VCGSWFAY。
AGP01286(配列番号20)
EVQLVESGGGLVQPGGSLKLSCAASGFTFSGSAMHWVRQASGKGLEWVGRIRSKANSYATAYAASVKGRFTISRDDSKNTAYLQMNSLKTEDTAVYYCTRLVGAIPFDYWGQGTLVTVSS
AEX29087(配列番号21)
EVQLVESGGGLVQPGGSLKLSCAASGFNFSGPAIHWVRQASGKGLEWVGRIRSKAKNFATAYAASVKGRFTISRDDSKSTAYLQMNSLKTEDTAVYYCTTTSSSINDYWGQGTLVTVSS
ACS95862(配列番号22)
QVQLVESGGGVVQPGGSLRLSCAASGFAFSSYGMHWVRQAPGRGLEWVAFIRSDGSNTYYSDSVKGRFTISRDNSKNTLYLQVNSLRAEDTAVYYCAFGGDYYFGYWGQGTLVTVSS
BAC01516(配列番号23)
EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGRTGDYWGQGTLVTVSS
IGHV3-73(配列番号24)
EVQLVESGGGLVQPGGSLKLSCAASGFTFSGSAMHWVRQASGKGLEWVGRIRSKANSYATAYAASVKGRFTISRDDSKNTAYLQMNSLKTEDTAVYYCTRYYGMDVWGQGTTVTVSS。
HC1 CA9hu-2(配列番号9)
EVQLVESGGGLVQPGGSLKLSCAASGFTFNTNAMHWVRQASGKGLEWVGRIRSKSNNYTTYYADSVKDRFTISRDDSKNTAYLQMNSLKTEDTAVYYCVCGSWFAYWGQGTLVTVSS
HC2 CA9hu-2(配列番号10)
EVQLVESGGGLVQPGGSLKLSCAASGFTFNTNAMHWVRQASGKGLEWVGRIRSKSNNYTTYYADSVKDRFTISRDDSKSTAYLQMNSLKTEDTAVYYCVCGSWFAYWGQGTLVTVSS
HC3 CA9hu-2(配列番号11)
QVQLVESGGGVVQPGGSLRLSCAASGFTFNTNAMHWVRQAPGRGLEWVARIRSKSNNYTTYYADSVKDRFTISRDNSKNTLYLQVNSLRAEDTAVYYCVCGSWFAYWGQGTLVTVSS
HC4 CA9hu-2(配列番号12)
EVQLVESGGGVVQPGRSLRLSCAASGFTFNTNAMHWVRQAPGKGLEWVARIRSKSNNYTTYYADSVKDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVCGSWFAYWGQGTLVTVSS
HC5 CA9hu-2(配列番号13)
EVQLVESGGGLVQPGGSLKLSCAASGFTFNTNAMHWVRQASGKGLEWVGRIRSKSNNYTTYYADSVKDRFTISRDDSKNTAYLQMNSLKTEDTAVYYCVCGSWFAYWGQGTTVTVSS。
マウスVL領域は、下記の配列を含んでいた。マウスVL領域は、マウスシグナルペプチド配列を含まない:
DIVMTQSPSSLAMSLGQKVTMSCKSSQSLLNSSNQKNYLAWFQQKPGQSPKLLVYFTSTRQSGVPDRFIGSGSGTDFTLTISSVQAEDLADYFCQQHYSIPLTFGAGTKLELK(配列番号25)
CDR残基(下線)は、IMGT numbering systemまたはKabat numbering systemを使用して同定した。
KSSQSLLNSSNQKNYLA
CDR2 VL IV/18(配列番号5)
FTSTRQS
CDR3 VL IV/18(配列番号6)
QQHYSIPLT。
AAW69164(配列番号26)
DVVMTQSPDSLAVSLGERVTINCKSSQSVLNTSNNKNYLVWYQQKPGQSPKLLIYLASTREFGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYHSSPHTFGQGTKLEIK
CAI99839(配列番号27)
DIVMTQSPDSLAVSLGERATINCKSSQSVLYNSNNKNYLAWFQQKPGQPPNLVIYWASTRESGVPDRFSGSGSGTDFTLTINSLQAEDVAVYFCLQYYSTPLTFGQGTQVEIK
AMK70392(配列番号28)
DIQMTQSPDSLAVSLGERATINCKASQSVLYSSKNKNYLAWYQQKPGQPPKLLIYRASTRDSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYFCQQYYSTPQTFGQGTKVEIK
ALV87854(配列番号29)
DIVMTQSPDSLAVSLGERATINCKSSQSVLYRSKNKNYLAWFQQKPGQPPKVLIYSTSTRASGVPDRFTGSGSGTDFTLTISSLQAEDVAVYYCLQYYITPYTFGQGTKLEIK
IGKV4-1(配列番号30)
DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPYTFGQGTKLEIK。
LC1 CA9hu-2(配列番号14)
DVVMTQSPDSLAVSLGERVTINCKSSQSLLNSSNQKNYLAWYQQKPGQSPKLLIYFTSTRQSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHYSIPLTFGQGTKLEIK
LC2 CA9hu-2(配列番号15)
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSSNQKNYLAWFQQKPGQPPNLVIYFTSTRQSGVPDRFSGSGSGTDFTLTINSLQAEDVAVYFCQQHYSIPLTFGQGTQVEIK
LC3 CA9hu-2(配列番号16)
DIQMTQSPDSLAVSLGERATINCKSSQSLLNSSNQKNYLAWYQQKPGQPPKLLIYFTSTRQSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYFCQQHYSIPLTFGQGTKVEIK
LC4 CA9hu-2(配列番号17)
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSSNQKNYLAWFQQKPGQPPKVLIYFTSTRQSGVPDRFTGSGSGTDFTLTISSLQAEDVAVYYCQQHYSIPLTFGQGTKLEIK
LC5 CA9hu-2(配列番号18)
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSSNQKNYLAWYQQKPGQPPKLLIYFTSTRQSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHYSIPLTFGQGTKLEIK。
ヒト化変異体は、ヒト化抗体の世界保健機関(WHO)の定義に従って、ヒト化されたか否かを決定するために試験された:ヒト化鎖の可変領域は、他の種よりもヒトに近いV領域アミノ酸配列を有する。これは、全体として分析される(IMGT(登録商標)DomainGapAlign toolを使用して評価される)(例えば、Ehrenmann et al,Nucleic Acids Res 38,D301-307,2010を参照のこと)。
主要組織適合遺伝子複合体(MHC) Class II分子の溝にペプチド配列が提示されると、CD4+T細胞の活性化および免疫原性応答が起こる。この応答を減少させるために、治療タンパク質は、MHC Class II分子への結合の親和性を減少させることによって、T細胞を活性化し得る「T細胞エピトープ」の取り込みを回避するように設計され得る。
Fvグリコシル化
N結合グリコシル化モチーフは、NXS/Tである。ここで、Xはプロリンを除く任意のアミノ酸である。このモチーフNYTは、マウスCDR2 VH変異体中に存在し、CDRがマウスCDR2 VH変異体全体に移植された際に、全てのヒト化変異体に運ばれた。
アミノ酸モチーフSNG、ENN、LNG、および、LNNは、アスパラギンのアスパラギン酸への脱アミド化を起こしやすい傾向にあり得る(例えば、Chelius et al,Anal Chem 77(18):6004-11,2005を参照のこと)。他のモチーフ内のアスパラギンは、脱アミド化の傾向がない。これら4つのモチーフは、IV/18mAbのVHまたはVLのマウスまたはヒト化変異体中には存在しない。
本実施例は、炭酸脱水酵素IXに対する25個のCA9hu-2ヒト化変異体の望ましい結合特性を実証する。
細胞障害効果を媒介するヒト化抗体変異体の能力を評価するために、ADCCレポーターバイオアッセイシステム(Promega、Madison WI、USA)を適用した。ADCCレポーターバイオアッセイシステムは、ADCC作用メカニズムにおける治療用抗体薬剤による経路活性化に関する生物学的活性を定量するための生物発光レポーターアレイを示す(例えば、Chung et al,Monoclonal Antibodies 4:326-40,2012を参照のこと)。当該ADCCレポーターバイオアッセイシステムは、エフェクター細胞として、FcγRIIIa受容体、V158高親和性変異体、およびホタルルシフェラーゼの発現を駆動するNFAT(活性化T細胞の核因子)応答因子を安定に発現する、操作されたJurkat細胞を使用する。従って、ADCC作用メカニズムは、NFAT活性化の結果として、ルシフェラーゼ産生を介して定量される。
CDCに関与するヒト化抗体変異体の能力を評価するために、細胞力価青色生存率アッセイキット(Promega)を適用した。当該細胞力価青色生存率アッセイは、指示薬色素レザズリンを介して生存細胞の数を推定するための、従って、細胞の生存率の指標としての細胞の代謝能力の測定のための、均質蛍光測定法を提供する。生存細胞において、レザズリンは、蛍光シグナルを生成する高度に蛍光性のレゾルフィンに還元される。当該レゾルフィンは、測定可能であり得る(530Ex/590Em)。従って、細胞力価青色試薬由来の蛍光シグナルは、生存細胞の数に比例する。
本実施例は、三次元培養においてADCC活性を媒介するヒト化抗体変異体の望ましい特性を実証する。
本実施例は、抗体依存性細胞貪食(ADCP)について、ヒト化抗体の望ましい関与を実証する。
本実施例は、ヒト化抗体が癌細胞の浸潤を阻害するという驚くべき特性を実証する。
本実施例は、ヒト化抗体変異体が細胞生存率に影響を及ぼさないという望ましい特性を実証する。
本実施例は、in vitroサイトカイン放出アッセイにて、選択されたヒト化抗体変異体の望ましい特性を実証する。
本実施例は、分離状態の間の多細胞凝集を阻害するヒト化抗体変異体の驚くべき特性を実証する。
本実施例は、サイトカインパターンならびに抗腫瘍免疫の回避に関与するタンパク質の発現に影響を及ぼす、ヒト化抗体の予想外の特性を実証する。
Claims (16)
- GFTFNTNAMH(配列番号1)、および、RIRSKSNNYTTYYADSVKD(配列番号2)、および、VCGSWFAY(配列番号3)の配列と同一であるCDR配列、または、当該配列と1個または2個のアミノ酸が異なるCDR配列を含む重鎖可変領域配列;および、
KSSQSLLNSSNQKNYLA(配列番号4)、および、FTSTRQS(配列番号5)、および、QQHYSIPLT(配列番号6)の配列と同一であるCDR配列、または、当該配列と1個または2個のアミノ酸が異なるCDR配列を含む軽鎖可変領域配列を含む、ヒトCA IXのプロテオグリカン領域を特異的に認識するヒト化抗体。 - 前記ヒト化抗体は、下記からなる群より選択される少なくとも1つの可変領域を含む、請求項1に記載のヒト化抗体:
-下記の配列を含む、または、有する重鎖可変領域:
X32VQLVESGGGX33VQPGX34SLX35LSCAASGFTFNTNAMHWVRQAX36GX37GLEWVX38 RIRSKSNNYTTYYADSVKDRFTISRDX39SKX40TX41YLQX42NSLX43X44EDTAVYYCVCGSWFAYWGQGTX45VTVSS(配列番号7)
ここで、
X32=E、または、Q
X33=L、または、V
X34=G、または、R
X35=K、または、R
X36=S、または、P
X37=K、または、R
X38=A、または、G
X39=D、または、N
X40=N、または、S
X41=A、または、L
X42=M、または、V
X43=K、または、R
X44=T、または、A
X45=L、または、T;および、
-下記の配列を含む、または、有する軽鎖可変領域:
DX46X47MTQSPDSLAVSLGERX48TINCKSSQSLLNSSNQKNYLAWX49QQKPGQX50PX51X52X53IYFTSTRQSGVPDRFX54GSGSGTDFTLTIX55SLQAEDVAVYX56CQQHYSIPLTFGQGTX57X58EIK(配列番号8)
X46=V、または、I
X47=V、または、Q
X48=V、または、A
X49=Y、または、F
X50=S、または、P
X51=K、または、N
X52=L、または、V
X53=L、または、V
X54=S、または、T
X55=S、または、N
X56=Y、または、F
X57=K、または、Q
X58=L、または、V。 - 前記ヒト化抗体は、下記からなる群より選択される少なくとも1つの可変領域を含む、請求項2に記載のヒト化抗体:
a)下記からなる群より選択される配列を含む、または、有する重鎖可変領域アミノ酸配列
EVQLVESGGGLVQPGGSLKLSCAASGFTFNTNAMHWVRQASGKGLEWVGRIRSKSNNYTTYYADSVKDRFTISRDDSKNTAYLQMNSLKTEDTAVYYCVCGSWFAYWGQGTLVTVSS(配列番号9)、
EVQLVESGGGLVQPGGSLKLSCAASGFTFNTNAMHWVRQASGKGLEWVGRIRSKSNNYTTYYADSVKDRFTISRDDSKSTAYLQMNSLKTEDTAVYYCVCGSWFAYWGQGTLVTVSS(配列番号10)、
QVQLVESGGGVVQPGGSLRLSCAASGFTFNTNAMHWVRQAPGRGLEWVARIRSKSNNYTTYYADSVKDRFTISRDNSKNTLYLQVNSLRAEDTAVYYCVCGSWFAYWGQGTLVTVSS(配列番号11)、
EVQLVESGGGVVQPGRSLRLSCAASGFTFNTNAMHWVRQAPGKGLEWVARIRSKSNNYTTYYADSVKDRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVCGSWFAYWGQGTLVTVSS(配列番号12)、および、
EVQLVESGGGLVQPGGSLKLSCAASGFTFNTNAMHWVRQASGKGLEWVGRIRSKSNNYTTYYADSVKDRFTISRDDSKNTAYLQMNSLKTEDTAVYYCVCGSWFAYWGQGTTVTVSS(配列番号13);および、
b)下記からなる群より選択される配列を含む、または、有する軽鎖可変領域アミノ酸配列
DVVMTQSPDSLAVSLGERVTINCKSSQSLLNSSNQKNYLAWYQQKPGQSPKLLIYFTSTRQSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHYSIPLTFGQGTKLEIK(配列番号14)、
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSSNQKNYLAWFQQKPGQPPNLVIYFTSTRQSGVPDRFSGSGSGTDFTLTINSLQAEDVAVYFCQQHYSIPLTFGQGTQVEIK(配列番号15)、
DIQMTQSPDSLAVSLGERATINCKSSQSLLNSSNQKNYLAWYQQKPGQPPKLLIYFTSTRQSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYFCQQHYSIPLTFGQGTKVEIK(配列番号16)、
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSSNQKNYLAWFQQKPGQPPKVLIYFTSTRQSGVPDRFTGSGSGTDFTLTISSLQAEDVAVYYCQQHYSIPLTFGQGTKLEIK(配列番号17)、および、
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSSNQKNYLAWYQQKPGQPPKLLIYFTSTRQSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHYSIPLTFGQGTKLEIK(配列番号18)。 - 前記ヒト化抗体は、配列番号11および配列番号12からなる群より選択される配列を含む、または、有する重鎖可変領域アミノ酸配列;および、配列番号14、配列番号15および配列番号18からなる群より選択される配列を含む、または、有する軽鎖可変領域アミノ酸配列、を含む、請求項3に記載のヒト化抗体。
- 前記ヒト化抗体は、配列番号12の配列を含む、または、有する重鎖可変領域アミノ酸配列と、配列番号18の配列を含む、または、有する軽鎖可変領域アミノ酸配列とを含む、請求項4に記載のヒト化抗体。
- 前記ヒト化抗体は、重鎖のアロタイプG1m17、1のヒトIgG定常領域、および、軽鎖のアロタイプKm3のヒトκ定常領域を有する、請求項1~5のいずれか1項に記載のヒト化抗体。
- 請求項1~6のいずれか1項に記載のヒト化抗体の治療有効量、および、薬学的に許容可能なキャリア、希釈剤または賦形剤を含み、
前記ヒト化抗体は、ヒトCA IXを特異的に認識するものである、医薬組成物。 - 細胞増殖性疾病または細胞増殖性障害から選択される疾病または障害の治療に使用するための、前記ヒト化抗体、または、前記医薬組成物であって、
前記疾病または障害は、好ましくは、扁平上皮癌、骨髄腫、小細胞肺癌、非小細胞肺癌、神経膠腫、ホジキンリンパ腫、非ホジキンリンパ腫、急性骨髄性白血病、多発性骨髄腫、消化器(管)癌、腎臓癌、卵巣癌、肝臓癌、リンパ芽球性白血病、リンパ球性白血病、大腸癌、子宮内膜癌、腎臓癌、前立腺癌、甲状腺癌、黒色腫、軟骨肉腫、神経芽腫、膵臓癌、多形性膠芽腫、子宮頸癌、脳腫瘍、胃癌、膀胱癌、ヘパトーマ、乳癌、結腸癌、中皮腫、および、頭頚部癌からなる群より選択される癌である、請求項1~6のいずれか1項に記載のヒト化抗体、または、請求項7に記載の医薬組成物。 - CA IXを発現する乳癌、中皮腫、または多形性膠芽腫の治療における、請求項8に記載の使用のためのヒト化抗体または医薬組成物。
- 請求項1~6のいずれか1項に記載のヒト化抗体の治療有効量の組み合わせを含み、
前記ヒト化抗体は、ヒトCA IXを特異的に認識するものであり、
前記ヒト化抗体の1つが、第2のヒト化抗体の投与前または投与後に投与される、細胞増殖性疾病または細胞増殖性障害の治療に使用するための、医薬組成物。 - CA IXに対する前記ヒト化抗体の日用量または週用量は、0.001mg/kg体重~15mg/kg体重の範囲である、請求項8~10のいずれか1項に記載の使用のためのヒト化抗体または医薬組成物。
- 下記i)~iii)の用量レジメンが含まれる、請求項8~11のいずれか1項に記載の使用のためのヒト化抗体または医薬組成物:
i)前記ヒト化抗体の複数の同一、または、異なる用量;
ii)前記ヒト化抗体の複数の漸増用量;または、
iii)1週間に1回、2週間に1回、3週間に1回、4週間に1回、または、5週間に1回投与する前記ヒト化抗体の用量。 - 用量レジメンは、1~10の投与サイクルを含み、
前記投与サイクルはそれぞれ、ヒト化抗体を使用した、1~4週間毎の2~5投入/用量を含み、
前記投与サイクルは、それぞれ2つのサイクルの間に1~8週間の中断が続く、請求項8~12のいずれか1項に記載の使用のためのヒト化抗体または医薬組成物。 - 請求項1~6のいずれか1項に記載のヒト化抗体の少なくとも1つ、および、少なくとも1つのキャリア、希釈剤、または、賦形剤を含む、診断用組成物。
- それを必要とする対象の癌を診断するための方法であって、
前記方法は、請求項14に記載の前記診断用組成物を、前記対象に由来する、または、前記対象から得られた生物学的サンプルと接触させる工程を含み、
ここで、規定の閾値を超える複合体の形成は、前記対象内の癌を示す、方法。 - 請求項1~6のいずれか1項に記載の前記ヒト化抗体は、常磁性、放射性、または、蛍光性である部分に対して、連結、結合、または、共役され、
前記部分は、イメージング時に検出可能なものである、請求項15に記載の対象の癌を診断するための方法。
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