JP2022022373A - 抗ctla-4抗体およびそれらの使用方法 - Google Patents
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Abstract
Description
本出願は、2016年12月7日出願の米国特許仮出願第62/431,272号の利益を主張し、これは、その全体が参照により本明細書に組み込まれる。
(a)CDRH1が、SYSMN(配列番号10)のアミノ酸配列を含み、
(b)CDRH2が、SISSSSSYIYYAXSVKG(配列番号18)のアミノ酸配列を含み、式中、Xが、EまたはDであり、
(c)CDRH3が、VGLXGPFDI(配列番号19)のアミノ酸配列を含み、式中、Xが、FまたはMであり、
(d)CDRL1が、RASQSVSRYLG(配列番号15)のアミノ酸配列を含み、
(e)CDRL2が、GASTRAT(配列番号16)のアミノ酸配列を含み、
(f)CDRL3が、QQYGSSPWT(配列番号17)のアミノ酸配列を含み、
抗体のCDRH1、CDRH2、およびCDRH3配列がそれぞれ、配列番号10、11、および13ではない、単離された抗体を提供する。
(a)CDRH1が、SYSMN(配列番号10)のアミノ酸配列を含み、
(b)CDRH2が、SISSSSSYIYYAXSVKG(配列番号18)のアミノ酸配列を含み、式中、Xが、EまたはDであり、
(c)CDRH3が、VGLXGPFDI(配列番号19)のアミノ酸配列を含み、式中、Xが、FまたはMであり、
(d)CDRL1が、RASQSVSRYLG(配列番号15)のアミノ酸配列を含み、
(e)CDRL2が、GASTRAT(配列番号16)のアミノ酸配列を含み、
(f)CDRL3が、QQYGSSPWT(配列番号17)のアミノ酸配列を含み、
抗体のCDRH1、CDRH2、およびCDRH3配列がそれぞれ、配列番号10、11、および13ではない、単離された抗体を提供する。
本明細書で使用される場合、「約」および「およそ」という用語は、数値または数値範囲を修飾するために使用される場合、その値または範囲を5%~10%上回り(例えば、最大5%~10%上回り)、かつ5%~10%下回る(例えば、最大5%~10%下回る)偏差が、列挙される値または範囲の意図される意味に留まることを示す。
一態様では、本開示は、CTLA-4(例えば、ヒトCTLA-4)に特異的に結合し、CTLA-4機能をアンタゴナイズする、抗体を提供する。例示的な抗体のアミノ酸配列を、本明細書の表1~4に示す。
(a)CDRH1は、SYSMN(配列番号10)のアミノ酸配列を含み、かつ/または
(b)CDRH2は、SISSSSSYIYYAXSVKG(配列番号18)のアミノ酸配列を含み、式中、Xが、EもしくはDであり、かつ/または
(c)CDRH3は、VGLXGPFDI(配列番号19)のアミノ酸配列を含み、式中、Xが、FもしくはMであり、かつ/または
(d)CDRL1は、RASQSVSRYLG(配列番号15)のアミノ酸配列を含み、かつ/または
(e)CDRL2は、GASTRAT(配列番号16)のアミノ酸配列を含み、かつ/または
(f)CDRL3は、QQYGSSPWT(配列番号17)のアミノ酸配列を含み、
を含み、抗体のCDRH1、CDRH2、およびCDRH3配列はそれぞれ、配列番号10、11、および13ではない。
生理学的に許容される担体、賦形剤、または安定剤中で所望の純度を有する本明細書に記載の抗CTLA-4抗体を含む組成物が本明細書に提供される(Remington’s Pharmaceutical Sciences(1990)Mack Publishing Co.,Easton,PA)。許容される担体、賦形剤、または安定剤は、用いられる投薬量および濃度で受容者に対して非毒性であり、これらには、リン酸、クエン酸、および他の有機酸などの緩衝液;アスコルビン酸およびメチオニンを含む抗酸化剤;保存剤(塩化オクタデシルジメチルベンジルアンモニウム;塩化ヘキサメトニウム;塩化ベンザルコニウム、塩化ベンゼトニウム;フェノール、ブチル、もしくはベンジルアルコール;メチルもしくはプロピルパラベンなどのアルキルパラベン;カテコール;レゾルシノール;シクロヘキサノール;3-ペンタノール;およびm-クレゾールなど);低分子量(約10未満の残基)ポリペプチド;血清アルブミン、ゼラチン、もしくは免疫グロブリンなどのタンパク質;ポリビニルピロリドンなどの親水性ポリマー;グリシン、グルタミン、アスパラギン、ヒスチジン、アルギニン、もしくはリジンなどのアミノ酸;グルコース、マンノース、もしくはデキストリンを含む単糖類、二糖類、および他の炭水化物;EDTAなどのキレート剤;スクロース、マンニトール、トレハロース、もしくはソルビトールなどの糖類;ナトリウムなどの塩形成対イオン;金属錯体(例えば、Zn-タンパク質錯体);ならびに/またはTWEEN(商標)、PLURONICS(商標)、もしくはポリエチレングリコール(PEG)などの非イオン界面活性剤が含まれる。
別の態様では、本開示は、本明細書に記載の抗CTLA-4抗体を使用して対象を治療する方法を提供する。本明細書に記載の抗CTLA-4抗体を使用して、CTLA-4機能の阻害から利益を得るであろう対象における任意の疾患または障害を治療することができる。本明細書に記載の抗CTLA-4抗体は、腫瘍に対する免疫系耐性を阻害するのに特に有用であり、したがって、がんを有する対象のための免疫療法として使用することができる。例えば、特定の実施形態では、本開示は、対象における抗原に応答したT細胞活性化を増加させる方法であって、対象に有効量の本明細書に記載の抗CTLA-4抗体またはその薬学的組成物を投与することを含む、方法を提供する。特定の実施形態では、本開示は、対象におけるがんを治療する方法であって、対象に有効量の本明細書に記載の抗体または薬学的組成物を投与することを含む、方法を提供する。
別の態様では、CTLA-4(例えば、ヒトCTLA-4)抗原に特異的に結合する本明細書に記載の抗体またはその断片(例えば、軽鎖可変領域および/または重鎖可変領域)をコードするヌクレオチド配列を含むポリヌクレオチド、ならびにベクター、例えば、宿主細胞(例えば、E.coliおよび哺乳動物細胞)内での組み換え発現のためのそのようなポリヌクレオチドを含むベクターが本明細書に提供される。本明細書に提供される抗体のいずれかをコードするヌクレオチド配列を含むポリヌクレオチド、ならびにそのようなポリヌクレオチド配列を含むベクター、例えば、宿主細胞、例えば、哺乳動物細胞内でのそれらの効率的な発現のための発現ベクターが本明細書に提供される。
6.6 キット
この実施例は、ヒトCTLA-4に結合するマウス抗体の特徴付けを説明する。具体的には、この実施例は、ヒトCTLA-4に特異的に結合し、CTLA-4の機能を阻害する抗体の特徴付けを説明する。これらの抗体の可変領域の配列情報を、表4に提供する。全ての抗体を、IgG1抗体として発現させ、以下に記載のアッセイにおいて分析した。
ヒトCTLA-4を構成的に発現するように操作したJurkat細胞(Promega)を使用して、抗CTLA-4抗体の結合を分析した。簡潔には、96ウェルプレート中、2μg/mlの抗体を使用して、5×105個の細胞/ウェルで4℃で30分間細胞を染色した。細胞を2回洗浄し、抗ヒトIgG二次抗体(Thermo Scientific、カタログ番号31529)とともに4℃で20分間インキュベートした。細胞を洗浄し、PBS中に調製した50μlの2%のパラホルムアルデヒド(Alfa Aesar、カタログ番号43368)中に懸濁させた。データをBD FACS Canto IIで収集した。
ブドウ球菌エンテロトキシンA(SEA)刺激後に、初代ヒトPBMCに対する抗CTLA-4抗体AGEN1884.H3(IgG1)の機能的活性を評価した。簡潔には、凍結保存したPBMCを、10μg/mlの抗CTLA-4抗体またはアイソタイプ対照抗体(IgG1)の不在下または存在下で100ng/mlのSEA超抗原(Toxin Technologies、カタログ番号at101red)で、37℃および5%のCO2で5日間刺激した。培養上清中のIL-2濃度をAlphaLISA(Perkin Elmer、カタログ番号AL221F)によって分析した。
次に、IL-2-ルシフェラーゼレポーターアッセイを使用して、抗CTLA-4抗体AGEN1884.H3(IgG1)の機能的活性を更に分析した。簡潔には、CD3およびCD28を内在的に発現するヒトT細胞株(Jurkat)を操作して、IL-2プロモーターによって駆動されて細胞表面CTLA-4およびルシフェラーゼレポーター遺伝子を構成的に発現するようにした。Jurkatレポーター細胞株を、CD80およびCD86を内在的に発現する抗原提示細胞株(Raji)とともに共培養し、専売T細胞活性化剤(Promega)を発現するように操作した。T細胞受容体(TCR)トリガー(シグナル1)は、T細胞活性化剤によって達成され、共刺激シグナル伝達(シグナル2)は、Raji細胞上で発現されるCD80およびCD86によってトランスで提供された。Jurkat T細胞株内のTCRシグナル伝達は、IL-2発現を引き起こし、T細胞活性化の代替マーカーであるルシフェラーゼ産生をもたらした。これら2つの細胞株の共培養は、(Jurkat細胞上に発現される)阻害性共受容体CTLA-4と、T細胞活性化を阻害する(Raji細胞上に発現される)その天然リガンドCD80およびCD86との関与をもたらし、これは、ルシフェラーゼ発現の欠如を実証した。この阻害は、増加する濃度の抗CTLA-4遮断抗体の添加時に軽減された。Bio-Glo(商標)試薬を使用して、ルシフェラーゼ発現を定量化し、結果として生じるデータを使用して、アイソタイプ対照抗体(IgG1))と比較した反応倍率値(AGEN1884.H3(IgG1)での増加倍率)を決定した。
抗CTLA-4抗体がCTLA-4に共関与し、活性化Fcガンマ受容体を介してシグナル伝達する能力を、Fcガンマ受容体IIIA(FcγRIIIA)(Promega)を発現するレポーター細胞株を使用して評価した。簡潔には、Jurkat細胞を操作して、細胞表面上にヒトCTLA-4を構成的に発現するようにした。これらの標的細胞を、ホタルルシフェラーゼの発現を駆動するNFAT応答配列(RE)の上流でFcγRIIIA(V158バリアント)を発現するように操作したエフェクター細胞株(Jurkat)とともに共培養した。漸増用量のAGEN1884.H3(IgG1)またはアイソタイプ対照抗体(IgG1)を共培養物に添加し、37℃で一晩インキュベートした。標的細胞株(Fab領域によるCTLA-4への結合)およびエフェクター細胞株(Fc領域によるFcγRIIIAへの結合)によるAGEN1884.H3の同時関与は、NFAT REレポーター遺伝子活性化およびルシフェラーゼ発現を引き起こす。翌日、Bio-Glo試薬(Promega)を共培養物に添加し、EnVison Multimodeプレートリーダー(Perkin Elmer)によって蛍光を測定し、相対光単位(RLU)を記録して、反応倍率値(アイソタイプ対照抗体(IgG1)と比較したAGEN1884.H3(IgG1)での増加倍率)を計算した。
この実施例は、抗CTLA-4抗体の機能的活性に対するFc/Fc受容体相互作用の影響を分析する。AGEN1884.H3を、IgG1 Fc領域がEU番号付けシステムに従って番号付けされたS239D/I332E、S239D/A330L/I332E、またはL235V/F243L/R292P/Y300L/P396L変異を含む抗体として発現させ、以下に記載の機能的アッセイにおいて試験した。抗体AGEN1884.H3(IgG1 S239D/I332E)は、配列番号24のアミノ酸配列を含む重鎖と、配列番号27のアミノ酸配列を含む軽鎖とを含む。抗体AGEN1884.H3(IgG1 S239D/A330L/I332E)は、配列番号25のアミノ酸配列を含む重鎖と、配列番号27のアミノ酸配列を含む軽鎖とを含む。抗体AGEN1884.H3(IgG1 L235V/F243L/R292P/Y300L/P396L)は、配列番号26のアミノ酸配列を含む重鎖と、配列番号27のアミノ酸配列を含む軽鎖とを含む。比較のために、AGEN1884を、野生型IgG1抗体、EU番号付けシステムに従って番号付けされたS239D/I332EもしくはS239D/A330L/I332E変異を含むIgG1抗体、または脱フコシル化IgG1抗体としても発現させ、いくつかの機能的アッセイにおいて試験した。
抗CTLA-4抗体AGEN1884.H3(IgG1 S239D/I332E)、AGEN1884.H3(IgG1 S239D/A330L/I332E)、およびAGEN1884.H3(IgG1 L235V/F243L/R292P/Y300L/P396L)の、CTLA-4発現細胞への結合を、上記と同様に特徴付けた。簡潔には、ヒトCTLA-4を構成的に発現するように操作したJurkat細胞(Promega)をまず、5μg/mlの抗CTLA-4抗体またはアイソタイプ対照抗体で染色し、その後抗ヒトIgG二次抗体(Thermo Scientific、カタログ番号31529)で染色した。BD FACS Canto IIを使用して、細胞を分析した。
この実施例では、Fcバリアント抗CTLA-4抗体AGEN1884.H3(IgG1-S239D/A330E/I332E)が、ヒトCTLA-4とそのリガンド(CD80およびCD86)との間の結合を遮断する能力を試験した。
この実施例では、上記のSEA刺激アッセイを使用して、抗CTLA-4抗体の機能的活性に対するFc領域の影響を分析した。簡潔には、ヒトPBMCを、異なるFc領域を有する抗CTLA-4抗体またはアイソタイプ対照抗体の不在下または存在下で100ng/mlのSEAペプチド(Toxin Technologies、カタログ番号at101red)とともにインビトロで培養した。5日後、AlphaLISA(Perkin Elmer、カタログ番号AL221F)を使用して、T細胞活性化のマーカーである培養上清中のIL-2の濃度を測定した。
この実施例では、TCR関与後にTCRに動員され、リン酸化され下流のシグナル伝達事象を促進する、タンパク質チロシンキナーゼZAP70のリン酸化の程度を測定するアッセイを使用して、T細胞抗原提示細胞(APC)シナプスにおける抗CTLA-4抗体の機能的活性に対するFc領域の影響を分析した。
この実施例では、結腸癌のマウスモデル(CT26腫瘍担持マウス)を使用して、抗CTLA-4抗体の抗腫瘍および腫瘍内制御性T細胞(Treg)枯渇活性に対するFc領域の影響を分析した。
この実施例では、HPV+TC-1同系腫瘍マウスモデルにおいて、マウス抗CTLA-4抗体とHPV腫瘍ワクチンとの組み合わせの、腫瘍成長に対する効果を試験した。
この実施例では、増殖させ、活性化したT細胞集団を、遺伝子発現およびCpGメチル化について特徴付けた。簡潔には、天然CD4+CD25+FOXP3+制御性T細胞またはCD4+CD25+/-FOXP3-非制御性T細胞を健康なヒトドナーの末梢血から単離し、増殖させ、活性化した。その後、T細胞を、フローサイトメトリーによってFOXP3およびCTLA-4の発現について特徴付け、FOXP3およびCTLA4遺伝子座内のCpG領域でのDNA CpGメチル化を試験することによって系列安定性について評価した。当該技術分野において既知であるように、これらのCpG部位での低メチル化を使用して、エフェクター系列対制御性T細胞系列を正確に描写することができる(Waight et al.,2015,J.Immunol.194(3):878-882)。
この実施例では、カスパーゼ3/7活性化のハイコンテンツ顕微鏡観察を使用して、ADCC活性を定量化して、ヒトCTLA-4発現T細胞の抗体依存性細胞傷害性(ADCC)に対する抗CTLA-4抗体AGEN1884.H3(IgG1)またはそのFcバリアントの効果を評価した。
この実施例では、初代ヒトT細胞機能に対する、抗PD-1抗体と組み合わせた抗CTLA-4抗体の効果を試験した。
AGEN1884(AGEN1884-Fab)のFab断片と、ヒトCTLA-4の細胞外ドメインとの相互作用を、水素-重水素交換(HDX)質量分析によって研究した。CTLA-4細胞外ドメイン単独、またはリン酸緩衝食塩水溶液(pH7.4)中でのAGEN1884-Fabとの組み合わせを、10倍の体積の重水標識緩衝液で希釈し、室温で異なる時間(0、60、300、1800、および7200秒間)にわたってインキュベートした。1体積の4Mの塩酸グアニジン、0.85MのTCEP(トリス(2-カルボキシエチル)ホスフィン)緩衝液を添加することによって重水素と水素との交換を停止させ、最終pHは2.5であった。その後、試料を、オンカラムペプシン/プロテアーゼXIII型消化およびLC-MS分析に供した。質量スペクトルを、MSのみモードにおいて記録した。重水素組み込みの計算のために、所与のペプチドの質量スペクトルを、抽出したイオンクロマトグラムピークにわたって組み合わせ、加重平均m/zを計算した。天然ペプチド(0分)の質量から加重平均した質量への質量増加は、重水素組み込みのレベルに対応する。全てのペプチドの交換時間にわたる重水素蓄積曲線を、更なる分析のためにプロットし、HDExaminerソフトウェアで比較した。
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Claims (101)
- ヒトCTLA-4に特異的に結合する単離された抗体であって、前記抗体が、相補性決定領域CDRH1、CDRH2、およびCDRH3を含む重鎖可変領域、ならびに相補性決定領域CDRL1、CDRL2、およびCDRL3を含む軽鎖可変領域を含み、
(a)CDRH1が、SYSMN(配列番号10)のアミノ酸配列を含み、
(b)CDRH2が、SISSSSSYIYYAXSVKG(配列番号18)のアミノ酸配列を含み、式中、Xが、EまたはDであり、
(c)CDRH3が、VGLXGPFDI(配列番号19)のアミノ酸配列を含み、式中、Xが、FまたはMであり、
(d)CDRL1が、RASQSVSRYLG(配列番号15)のアミノ酸配列を含み、
(e)CDRL2が、GASTRAT(配列番号16)のアミノ酸配列を含み、
(f)CDRL3が、QQYGSSPWT(配列番号17)のアミノ酸配列を含み、
前記抗体の前記CDRH1、CDRH2、およびCDRH3配列がそれぞれ、配列番号10、11、および13ではない、単離された抗体。 - CDRH2が、配列番号12のアミノ酸配列を含む、請求項1に記載の単離された抗体。
- CDRH3が、配列番号14のアミノ酸配列を含む、請求項1または2に記載の単離された抗体。
- ヒトCTLA-4に特異的に結合する単離された抗体であって、前記抗体が、相補性決定領域CDRH1、CDRH2、およびCDRH3を含む重鎖可変領域、ならびに相補性決定領域CDRL1、CDRL2、およびCDRL3を含む軽鎖可変領域を含み、CDRH1、CDRH2、CDRH3、CDRL1、CDRL2、およびCDRL3がそれぞれ、配列番号10、12、14、15、16、および17に示されるアミノ酸配列を含む、単離された抗体。
- 前記抗体が、配列番号20のアミノ酸配列を含む重鎖可変領域を含む、請求項1に記載の単離された抗体。
- 前記抗体が、配列番号2および4~8からなる群から選択されるアミノ酸配列と少なくとも75%、80%、85%、90%、95%、99%、または100%同一であるアミノ酸配列を含む重鎖可変領域を含む、請求項1に記載の単離された抗体。
- 前記重鎖可変領域が、配列番号2および4~8からなる群から選択されるアミノ酸配列を含む、請求項6に記載の単離された抗体。
- 前記重鎖可変領域が、配列番号8のアミノ酸配列を含む、請求項7に記載の単離された抗体。
- 前記抗体が、配列番号9のアミノ酸配列と少なくとも75%、80%、85%、90%、95%、99%、または100%同一であるアミノ酸配列を含む軽鎖可変領域を含む、請求項1~8のいずれか1項に記載の単離された抗体。
- 前記抗体が、配列番号9のアミノ酸配列を含む軽鎖可変領域を含む、請求項9に記載の単離された抗体。
- ヒトCTLA-4に特異的に結合する単離された抗体であって、配列番号2~8からなる群から選択されるアミノ酸配列を含む重鎖可変領域を含む、単離された抗体。
- 前記重鎖可変領域が、配列番号8のアミノ酸配列を含む、請求項11に記載の単離された抗体。
- 前記抗体が、配列番号23~26からなる群から選択されるアミノ酸配列を含む重鎖を含む、請求項12に記載の単離された抗体。
- ヒトCTLA-4に特異的に結合する単離された抗体であって、前記抗体が、重鎖可変領域および軽鎖可変領域を含み、前記重鎖可変領域および前記軽鎖可変領域がそれぞれ、配列番号2および9、3および9、4および9、5および9、6および9、7および9、または8および9に示されるアミノ酸配列を含む、単離された抗体。
- 前記重鎖可変領域および前記軽鎖可変領域がそれぞれ、配列番号8および9に示されるアミノ酸配列を含む、請求項14に記載の単離された抗体。
- ヒトCTLA-4に特異的に結合する単離された抗体であって、前記抗体が、ヒトIGHV3-21生殖系列配列由来のアミノ酸配列を有する重鎖可変領域を含み、前記重鎖可変領域が、配列番号14に示されるアミノ酸配列を含む、単離された抗体。
- 前記抗体が、ヒトIGKV3-20生殖系列配列由来のアミノ酸配列を有する軽鎖可変領域を含む、請求項16に記載の単離された抗体。
- ヒトCTLA-4に特異的に結合する単離された抗体であって、配列番号23のアミノ酸配列を含む重鎖、および配列番号27のアミノ酸配列を含む軽鎖を含む、単離された抗体。
- ヒトCTLA-4に特異的に結合する単離された抗体であって、配列番号24のアミノ酸配列を含む重鎖、および配列番号27のアミノ酸配列を含む軽鎖を含む、単離された抗体。
- ヒトCTLA-4に特異的に結合する単離された抗体であって、配列番号25のアミノ酸配列を含む重鎖、および配列番号27のアミノ酸配列を含む軽鎖を含む、単離された抗体。
- ヒトCTLA-4に特異的に結合する単離された抗体であって、配列番号26のアミノ酸配列を含む重鎖、および配列番号27のアミノ酸配列を含む軽鎖を含む、単離された抗体。
- 前記抗体が、ヒトIgG1、IgG2、IgG3、IgG4、IgA1、およびIgA2からなる群から選択される重鎖定常領域を含む、請求項1~12または14~17のいずれか1項に記載の単離された抗体。
- 前記抗体が、IgG1重鎖定常領域を含む、請求項1~12または14~17のいずれか1項に記載の単離された抗体。
- 前記抗体が、配列番号28のアミノ酸配列を含む重鎖定常領域を含む、請求項23に記載の単離された抗体。
- 前記IgG1重鎖定常領域のアミノ酸配列が、EU番号付けシステムに従って番号付けされたS239D/I332E変異を含む、請求項23に記載の単離された抗体。
- 前記抗体が、配列番号29のアミノ酸配列を含む重鎖定常領域を含む、請求項25に記載の単離された抗体。
- 前記IgG1重鎖定常領域のアミノ酸配列が、EU番号付けシステムに従って番号付けされたS239D/A330L/I332E変異を含む、請求項23に記載の単離された抗体。
- 前記抗体が、配列番号30のアミノ酸配列を含む重鎖定常領域を含む、請求項27に記載の単離された抗体。
- 前記IgG1重鎖定常領域のアミノ酸配列が、EU番号付けシステムに従って番号付けされたL235V/F243L/R292P/Y300L/P396L変異を含む、請求項23に記載の単離された抗体。
- 前記抗体が、配列番号31のアミノ酸配列を含む重鎖定常領域を含む、請求項29に記載の単離された抗体。
- 前記IgG1重鎖定常領域が、脱フコシル化IgG1である、請求項23に記載の単離された抗体。
- 前記抗体が、野生型ヒトIgG重鎖定常領域のバリアントであるヒトIgG重鎖定常領域を含み、前記バリアントヒトIgG重鎖定常領域が、前記野生型ヒトIgG重鎖定常領域がFcγRIIIAに結合するよりも高い親和性をもってFcγRIIIAに結合する、請求項1~12または14~17のいずれか1項に記載の単離された抗体。
- 前記バリアントヒトIgG重鎖定常領域が、バリアントヒトIgG1重鎖定常領域である、請求項32に記載の単離された抗体。
- 前記抗体が、ヒトIgκおよびIgλからなる群から選択される軽鎖定常領域を含む、請求項1~17または22~33のいずれか1項に記載の単離された抗体。
- 前記抗体が、Igκ軽鎖定常領域を含む、請求項34に記載の単離された抗体。
- 前記抗体が、配列番号32のアミノ酸配列を含む軽鎖定常領域を含む、請求項35に記載の単離された抗体。
- 前記抗体が、配列番号8のアミノ酸配列を含む重鎖可変領域および配列番号9のアミノ酸配列を含む軽鎖可変領域を含む抗体と同じヒトCTLA-4のエピトープに結合する、請求項1~36のいずれか1項に記載の単離された抗体。
- 前記抗体が、配列番号34~39からなる群から選択されるアミノ酸配列からなるヒトCTLA-4の領域内に位置するエピトープに結合する、請求項1~37のいずれか1項に記載の単離された抗体。
- 前記抗体が、ヒト抗体である、請求項1~38のいずれか1項に記載の単離された抗体。
- 前記抗体が、二重特異性抗体である、請求項1~39のいずれか1項に記載の単離された抗体。
- 前記抗体が、ヒトCTLA-4に対してアンタゴニスト性である、請求項1~40のいずれか1項に記載の単離された抗体。
- 前記抗体が、ヒトCTLA-4の活性を非活性化、低減、または阻害する、請求項1~41のいずれか1項に記載の単離された抗体。
- 前記抗体が、ヒトCTLA-4のヒトCD80またはヒトCD86への結合を阻害する、請求項42に記載の単離された抗体。
- 前記抗体が、ブドウ球菌エンテロトキシンA(SEA)で刺激した末梢血単核球(PBMC)によるIL-2産生を誘導する、請求項42に記載の単離された抗体。
- 細胞傷害性剤、細胞分裂阻害剤、毒素、放射性核種、または検出可能な標識に共役されている、請求項1~44のいずれか1項に記載の単離された抗体。
- 前記抗体の前記重鎖可変領域および/または前記軽鎖可変領域のN末端アミノ酸残基が、ピログルタミン酸に変換されている、請求項1~45のいずれか1項に記載の単離された抗体。
- 請求項1~46のいずれか1項に記載の抗体と、薬学的に許容される担体または賦形剤と、を含む、薬学的組成物。
- 請求項1~45のいずれか1項に記載の抗体の重鎖および/または軽鎖をコードする、単離されたポリヌクレオチド。
- 請求項48に記載のポリヌクレオチドを含む、ベクター。
- 請求項48に記載のポリヌクレオチドまたは請求項49に記載のベクターを含む、組み換え宿主細胞。
- ヒトCTLA-4に特異的に結合する抗体を産生する方法であって、前記ポリヌクレオチドが発現され、前記抗体が産生されるように、請求項50に記載の宿主細胞を培養することを含む、方法。
- 対象における抗原に応答したT細胞活性化を増加させる方法であって、前記対象に有効量の請求項1~47のいずれか1項に記載の抗体または薬学的組成物を投与することを含む、方法。
- 対象におけるがんを治療する方法であって、前記対象に有効量の請求項1~47のいずれか1項に記載の抗体または薬学的組成物を投与することを含む、方法。
- 前記がんが、転移性または局所進行性腫瘍である、請求項53に記載の方法。
- 前記がんが、固形腫瘍である、請求項53または54に記載の方法。
- 前記がんが、転移性または局所進行性の切除不能な扁平上皮細胞癌、腺扁平上皮癌、または子宮頸部腺癌である、請求項53~55のいずれか1項に記載の方法。
- 前記がんに利用可能な標準的治療法が存在しない、請求項53~56のいずれか1項に記載の方法。
- 前記がんが、標準的治療法に対して難治性である、請求項53~56のいずれか1項に記載の方法。
- 前記がんが、標準的治療法後に再発している、請求項53~56のいずれか1項に記載の方法。
- 前記標準的治療法が、プラチナ含有化学療法を含む、請求項58または59に記載の方法。
- 前記標準的治療法が、プラチナ含有ダブレットを含む、請求項60に記載の方法。
- 前記がんが、HPV陽性である、請求項53~61のいずれか1項に記載の方法。
- 前記がんが、非小細胞肺癌(NSCLC)である、請求項53~55のいずれか1項に記載の方法。
- 前記がんが、転移性NSCLCである、請求項63に記載の方法。
- 前記NSCLCが、EGFRまたはALKゲノム腫瘍異常を有しない、請求項63または64に記載の方法。
- 前記NSCLCが、EGFR感作変異またはALK転座を有しない、請求項63~65のいずれか1項に記載の方法。
- 前記対象が、前記NSCLCに対する事前の全身化学療法治療を受けていない、請求項63~66のいずれか1項に記載の方法。
- 前記がんが、皮膚扁平上皮細胞癌(cSCC)である、請求項53~55のいずれか1項に記載の方法。
- 前記がんが、IV期cSCCである、請求項68に記載の方法。
- 前記cSCCが、米国がん合同委員会病期分類マニュアルの第8版に従って組織学的または細胞学的に診断されている、請求項69に記載の方法。
- 前記cSCCが、放射線療法で治癒可能ではない、請求項68~70のいずれか1項に記載の方法。
- PD-L1の検出可能な膜発現を呈する前記がんの試料中の腫瘍細胞のパーセンテージが、少なくとも1%、2%、3%、4%、5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、60%、70%、80%、または90%である、請求項53~71のいずれか1項に記載の方法。
- 前記抗体が、前記がんの診断後に第1のがん療法として投与される、請求項53~72のいずれか1項に記載の方法。
- 前記抗体が、
(a)前記がんを異なるがん療法で以前に治療したにも関わらず生じた腫瘍進行の診断、または
(b)異なるがん療法の毒性の診断
後に前記第1のがん療法として投与され、任意で、前記抗体が、前記対象に投与される第2のがん療法である、請求項53~73のいずれか1項に記載の方法。 - 前記抗体または薬学的組成物が、静脈内投与される、請求項52~75のいずれか1項に記載の方法。
- 前記抗体または薬学的組成物が、任意で2週間に1回の間隔で、0.01mg/kg、0.03mg/kg、0.1mg/kg、0.3mg/kg、1mg/kg、3mg/kg、6mg/kg、または10mg/kgで静脈内投与される、請求項75に記載の方法。
- 前記抗体または薬学的組成物が、任意で3週間に1回の間隔で、0.01mg/kg、0.03mg/kg、0.1mg/kg、0.3mg/kg、1mg/kg、3mg/kg、6mg/kg、または10mg/kgで静脈内投与される、請求項75に記載の方法。
- 前記抗体または薬学的組成物が、任意で4週間に1回の間隔で、0.01mg/kg、0.03mg/kg、0.1mg/kg、0.3mg/kg、1mg/kg、3mg/kg、6mg/kg、または10mg/kgで静脈内投与される、請求項75に記載の方法。
- 前記抗体または薬学的組成物が、任意で6週間に1回の間隔で、0.01mg/kg、0.03mg/kg、0.1mg/kg、0.3mg/kg、1mg/kg、3mg/kg、6mg/kg、または10mg/kgで静脈内投与される、請求項75に記載の方法。
- 前記抗体または薬学的組成物が、任意で12週間に1回の間隔で、0.01mg/kg、0.03mg/kg、0.1mg/kg、0.3mg/kg、1mg/kg、3mg/kg、6mg/kg、または10mg/kgで静脈内投与される、請求項75に記載の方法。
- 前記抗体または薬学的組成物が、皮下投与される、請求項52~75のいずれか1項に記載の方法。
- 前記抗体または薬学的組成物が、腫瘍内投与される、請求項53~75のいずれか1項に記載の方法。
- 前記抗体または薬学的組成物が、任意で3週間に1回の間隔で、0.03mg/kg、0.1mg/kg、または0.3mg/kgで腫瘍内投与される、請求項82に記載の方法。
- 前記抗体または薬学的組成物が、腫瘍流入領域リンパ節に送達される、請求項52~75のいずれか1項に記載の方法。
- 前記抗体が、請求項25~33のいずれか1項に記載の抗体である、請求項81~84のいずれか1項に記載の方法。
- 前記抗体が、単独療法として投与される、請求項52~85のいずれか1項に記載の方法。
- 前記対象に追加の治療剤を投与することを更に含む、請求項52~85のいずれか1項に記載の方法。
- 前記追加の治療剤が、全身投与される、請求項87に記載の方法。
- 前記追加の治療剤が、抗PD-1抗体であり、任意で、前記抗PD-1抗体が、ペムブロリズマブまたはニボルマブである、請求項87または88に記載の方法。
- 前記追加の治療剤が、200mgで3週間に1回投与されるペムブロリズマブである、請求項89に記載の方法。
- 前記対象が、頭頸部扁平上皮細胞癌を有し、前記追加の治療剤が、抗EGFR抗体であり、任意で、前記抗EGFR抗体が、セツキシマブであり、
任意で、前記方法が、前記対象に化学療法剤を投与することを更に含み、任意で、前記化学療法剤が、全身投与され、任意で、前記化学療法剤が、ゲムシタビンである、請求項87または88に記載の方法。 - 前記対象が、HER2+乳癌を有し、前記追加の治療剤が、抗HER2抗体であり、任意で、前記抗HER2抗体が、トラスツズマブであり、
任意で、前記方法が、前記対象に化学療法剤を投与することを更に含み、任意で、前記化学療法剤が、全身投与され、任意で、前記化学療法剤が、ゲムシタビンである、請求項87または88に記載の方法。 - 前記追加の治療剤が、化学療法剤またはチェックポイント標的剤である、請求項87または88に記載の方法。
- 前記チェックポイント標的剤が、アンタゴニスト抗PD-1抗体、アンタゴニスト抗PD-L1抗体、アンタゴニスト抗PD-L2抗体、アンタゴニスト抗CTLA-4抗体、アンタゴニスト抗TIM-3抗体、アンタゴニスト抗LAG-3抗体、アンタゴニスト抗CEACAM1抗体、アゴニスト抗GITR抗体、アゴニスト抗OX40抗体、およびアゴニスト抗CD137抗体からなる群から選択される、請求項93に記載の方法。
- 前記追加の治療剤が、インドールアミン-2,3-ジオキシゲナーゼ(IDO)の阻害剤である、請求項87または88に記載の方法。
- 前記阻害剤が、エパカドスタット、F001287、インドキシモド、およびNLG919からなる群から選択される、請求項95に記載の方法。
- 前記追加の治療剤が、ワクチンである、請求項87または88に記載の方法。
- 前記ワクチンが、抗原ペプチドと複合体化した熱ショックタンパク質を含む熱ショックタンパク質ペプチド複合体(HSPPC)を含む、請求項97に記載の方法。
- 前記熱ショックタンパク質が、hsc70であり、腫瘍関連抗原ペプチドと複合体化される、請求項98に記載の方法。
- 前記熱ショックタンパク質が、gp96タンパク質であり、腫瘍関連抗原ペプチドと複合体化され、前記HSPPCが、対象から得られた腫瘍に由来する、請求項98に記載の方法。
- 対象における感染症を治療する方法であって、前記対象に有効量の請求項1~47のいずれか1項に記載の抗体または薬学的組成物を投与することを含む、方法。
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