JP2019214586A - Pd−1に結合する抗原結合蛋白質 - Google Patents
Pd−1に結合する抗原結合蛋白質 Download PDFInfo
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Abstract
Description
該完全ヒト抗体は、配列番号1、配列番号3、配列番号5、配列番号7、配列番号9、配列番号11、配列番号13、配列番号15、配列番号17、配列番号19、配列番号21、配列番号23、配列番号25、配列番号27、配列番号29、配列番号31、配列番号33、配列番号35、配列番号37、配列番号38、配列番号39、配列番号40、配列番号41、配列番号42、配列番号43、配列番号44およびその組み合わせからなる群から選択されるアミノ酸配列と少なくとも95%同一である重鎖可変領域配列を有し、
配列番号2、配列番号4、配列番号6、配列番号8、配列番号10、配列番号12、配列番号14、配列番号16、配列番号18、配列番号20、配列番号22、配列番号24、配列番号26、配列番号28、配列番号30、配列番号32、配列番号34、配列番号36およびその組み合わせからなる群から選択されるアミノ酸配列と少なくとも95%同一である軽鎖可変領域配列を有し;
該Fab完全ヒト抗体断片は、配列番号1、配列番号3、配列番号5、配列番号7、配列番号9、配列番号11、配列番号13、配列番号15、配列番号17、配列番号19、配列番号21、配列番号23、配列番号25、配列番号27、配列番号29、配列番号31、配列番号33、配列番号35、配列番号37、配列番号38、配列番号39、配列番号40、配列番号41、配列番号42、配列番号43、配列番号44およびその組み合わせからなる群から選択されるアミノ酸配列と少なくとも95%同一である重鎖可変領域配列を有し、
配列番号2、配列番号4、配列番号6、配列番号8、配列番号10、配列番号12、配列番号14、配列番号16、配列番号18、配列番号20、配列番号22、配列番号24、配列番号26、配列番号28、配列番号30、配列番号32、配列番号34、配列番号36およびその組み合わせからなる群から選択されるアミノ酸配列と少なくとも95%同一である軽鎖可変領域配列を有し;
該一本鎖ヒト抗体は、配列番号1、配列番号3、配列番号5、配列番号7、配列番号9、配列番号11、配列番号13、配列番号15、配列番号17、配列番号19、配列番号21、配列番号23、配列番号25、配列番号27、配列番号29、配列番号31、配列番号33、配列番号35、配列番号37、配列番号38、配列番号39、配列番号40、配列番号41、配列番号42、配列番号43、配列番号44およびその組み合わせからなる群から選択されるアミノ酸配列と少なくとも95%同一である重鎖可変領域配列を有し、配列番号2、配列番号4、配列番号6、配列番号8、配列番号10、配列番号12、配列番号14、配列番号16、配列番号18、配列番号20、配列番号22、配列番号24、配列番号26、配列番号28、配列番号30、配列番号32、配列番号34、配列番号36およびその組み合わせからなる群から選択されるアミノ酸配列と少なくとも95%同一である軽鎖可変領域配列を有する。
配列番号1、配列番号3、配列番号5、配列番号7、配列番号9、配列番号11、配列番号13、配列番号15、配列番号17、配列番号19、配列番号21、配列番号23、配列番号25、配列番号27、配列番号29、配列番号31、配列番号33、配列番号35、配列番号37、配列番号38、配列番号39、配列番号40、配列番号41、配列番号42、配列番号43、配列番号44およびその組み合わせからなる群から選択されるアミノ酸配列と少なくとも95%同一である重鎖可変領域配列を有し、配列番号2、配列番号4、配列番号6、配列番号8、配列番号10、配列番号12、配列番号14、配列番号16、配列番号18、配列番号20、配列番号22、配列番号24、配列番号26、配列番号28、配列番号30、配列番号32、配列番号34、配列番号36およびその組み合わせからなる群から選択されるアミノ酸配列と少なくとも95%同一である軽鎖可変領域配列を有する、一本鎖ヒト抗体を提供する。好ましくは、該完全ヒト一本鎖抗体は、重鎖可変領域と軽鎖可変領域の両方を有し、配列番号1/配列番号2、配列番号3/配列番号4、配列番号5/配列番号6、配列番号7/配列番号8、配列番号9/配列番号10、配列番号11/配列番号12、配列番号13/配列番号14、配列番号15/配列番号16、配列番号17/配列番号18、配列番号19/配列番号20、配列番号21/配列番号22、配列番号23/配列番号24、配列番号25/配列番号26、配列番号27/配列番号28、配列番号29/配列番号30、配列番号31/配列番号32、配列番号33/配列番号34、配列番号35/配列番号36、配列番号37/配列番号24、配列番号38/配列番号24、配列番号39/配列番号24、配列番号40/配列番号24、配列番号41/配列番号24、配列番号42/配列番号24、配列番号43/配列番号24、配列番号44/配列番号24およびその組み合わせからなる群から選択される重鎖/軽鎖可変領域配列を有する。
該完全ヒト抗体は、配列番号1、配列番号3、配列番号5、配列番号7、配列番号9、配列番号11、配列番号13、配列番号15、配列番号17、配列番号19、配列番号21、配列番号23、配列番号25、配列番号27、配列番号29、配列番号31、配列番号33、配列番号35、配列番号37、配列番号38、配列番号39、配列番号40、配列番号41、配列番号42、配列番号43、配列番号44およびその組み合わせからなる群から選択されるアミノ酸配列と少なくとも95%同一である重鎖可変領域を有し、配列番号2、配列番号4、配列番号6、配列番号8、配列番号10、配列番号12、配列番号14、配列番号16、配列番号18、配列番号20、配列番号22、配列番号24、配列番号26、配列番号28、配列番号30、配列番号32、配列番号34、配列番号36およびその組み合わせからなる群から選択されるアミノ酸配列と少なくとも95%同一である軽鎖可変領域配列を有し;
該Fab完全ヒト抗体断片は、配列番号1、配列番号3、配列番号5、配列番号7、配列番号9、配列番号11、配列番号13、配列番号15、配列番号17、配列番号19、配列番号21、配列番号23、配列番号25、配列番号27、配列番号29、配列番号31、配列番号33、配列番号35、配列番号37、配列番号38、配列番号39、配列番号40、配列番号41、配列番号42、配列番号43、配列番号44およびその組み合わせからなる群から選択されるアミノ酸配列と少なくとも95%同一である重鎖可変領域配列を有し、配列番号2、配列番号4、配列番号6、配列番号8、配列番号10、配列番号12、配列番号14、配列番号16、配列番号18、配列番号20、配列番号22、配列番号24、配列番号26、配列番号28、配列番号30、配列番号32、配列番号34、配列番号36およびその組み合わせからなる群から選択されるアミノ酸配列と少なくとも95%同一である軽鎖可変領域配列を有し;
該一本鎖ヒト抗体は、配列番号1、配列番号3、配列番号5、配列番号7、配列番号9、配列番号11、配列番号13、配列番号15、配列番号17、配列番号19、配列番号21、配列番号23、配列番号25、配列番号27、配列番号29、配列番号31、配列番号33、配列番号35、配列番号37、配列番号38、配列番号39、配列番号40、配列番号41、配列番号42、配列番号43、配列番号44、およびその組み合わせからなる群から選択されるアミノ酸配列と少なくとも95%同一である重鎖可変領域配列を有し、配列番号2、配列番号4、配列番号6、配列番号8、配列番号10、配列番号12、配列番号14、配列番号16、配列番号18、配列番号20、配列番号22、配列番号24、配列番号26、配列番号28、配列番号30、配列番号32、配列番号34、配列番号36およびその組み合わせからなる群から選択されるアミノ酸配列と少なくとも95%同一である軽鎖可変領域配列を有する。
特定の態様において、本発明の結合ポリペプチドは、さらに、翻訳後修飾を含んでいてもよい。翻訳後の蛋白質修飾の例としては、リン酸化、アセチル化、メチル化、ADP-リボース化、ユビキチン化、グリコシル化、カルボニル化、SUMO化、ビオチン化またはポリペプチド側鎖もしくは疎水性基の付加が挙げられる。結果として、修飾された可溶ポリペプチドには、非アミノ酸エレメント、例えば脂質、多糖もしくは単糖、およびリン酸が含まれていてよい。グリコシル化の好ましい形態は、該ポリペプチドに1つ以上のシアル酸部分を結合させる、シアル酸付加である。シアル酸部分は、該蛋白質の溶解度および血清半減期を改善する一方で、免疫原性を低下させる。Raju et al. Biochemistry. 2001 31; 40(30):8868-76を参照のこと。該非アミノ酸エレメントのポリペプチドの官能性に対する影響は、そのPD−L1またはPD−1の機能に対する拮抗作用、例えば血管新生または腫瘍成長に対する阻害効果について試験してよい。
式: X--O(CH2CH2O)n-1CH2CH2OH (1)
で表され、式中で、nは20〜2300であり、XはHまたは末端修飾、例えばC1-4アルキルである。態様の一において、本発明のPEGは、一方の末端がヒドロキシまたはメトキシである、すなわち、XがHまたはCH3である(「メトキシPEG」)。PEGは、さらに、結合反応に必要な化学基を含んでいてよく; それは、該分子の化学合成により生じたものか、または;分子の距離が最適になるためのスペーサーである。さらに、該PEGは、互いに結合している1つ以上のPEG側鎖からなっていてよい。2つ以上のPEG鎖を有するPEGは、多アーム(multiarmed)または分枝PEGと呼ばれる。分枝PEGは、例えば、ポリエチレンオキシドを種々のポリオール、例えば、グリセロール、ペンタエリトリトール(pentaerythriol)およびソルビトールに添加することにより作製し得る。例えば、4分枝PEGは、ペンタエリトリトール(pentaerythriol)とエチレンオキシドから作製し得る。分枝PEGは、例えば欧州特許出願公開第0 473 084号および米国特許第5,932,462号明細書に記載されている。PEGの形態の一つには、リジンの第一級アミノ基を介して結合した2PEG側鎖 (PEG2) が挙げられる(Monfardini et al., Bioconjugate Chem. 6 (1995) 62-69)。
式:--CO--(CH2)x--(OCH2CH2)m--OR
のポリ(エチレングリコール)基の1つに、該ポリ(エチレングリコール) 基の--CO (すなわちカルボニル)が、結合ポリペプチドのアミノ基の1つとアミド結合を形成するように、共有結合しており;Rは低級アルキルであり; xは2または3であり; mは約450〜約950であり; nおよびmは、結合体から結合性のポリペプチドを引いた分子量が約10〜40kDaになるように選択される。態様の一において、結合ポリペプチドのリジンの6-アミノ基は、利用可能な (遊離の) アミノ基である。
P--NHCO--(CH2)x--(OCH2CH2)m--OR (II)
によって表されてよく、式中、Pは本明細書に記載の結合ポリペプチドの基であり(すなわち式(II)に示すカルボニルとアミド結合を形成するアミノ基を含まない);Rは低級アルキルであり; xは2または3であり; mは約450〜約950であり、結合体から結合ポリペプチドを引いた分子量が約10〜約40kDaになるように選択される。本明細書において、「m」の特定の範囲は、配向について意味を持つ。「m」の範囲は、いずれの場合においても、PEG基の分子量によって厳密に決定される。
本発明は、PD−1の生物活性の阻害に応答する症状の処置または前症状の予防方法を特徴づける。好ましい例は、炎症または細胞の過剰増殖により特徴づけられる症状である。投与技術および用量は、具体的なポリペプチドの種類および処置する具体的な症状によって変わるが、これは当業者によって容易に決定し得るものである。一般的に、規制当局は、治療剤として用いる蛋白質製剤は、発熱物質が許容できる程度に低いレベルになるように製剤することを要求している。したがって、一般的に治療剤は、本質的に発熱性物質を含まないか、または適当な規制当局(例えばFDA)により決定された許容されるレベル以下の発熱性物質しか含まないという点において、他の製剤と異なる。
本明細書に記載の抗PD−1抗体と治療用ワクチンの組み合わせ治療製品または製剤は、相乗的な腫瘍治療上の利点をもたらす。例えば、本発明は、本明細書に記載の抗PD−1抗体と、米国特許第8,222,214号に記載されている、アジュバントとしてGM-CSFを組み合わせた、HER2/neuから単離されたE75由来の9merの合成ペプチドである「Neuvax」との組み合わせ剤を提供し、該文献の記載内容は、引用により本明細書に包含される。さらに、本発明は、本明細書に記載の抗PD−1抗体と、がん胎児抗原と組み合わせたカナリアポックスウイルスであるALVAC-CEAワクチンとの組み合わせ剤を提供する。
本明細書に記載のPD−1結合蛋白質およびその関連する変異体は、多数の治療および診断への適用に有用である。これらには、PD−1への結合の競合または遮断によるPD−1の生物活性の阻害ならびに、細胞、特にPD−1発現細胞への細胞毒性またはイメージング剤の送達が含まれる。これらの分子のサイズが小さく、構造が安定していることは、薬物の製造、急速なクリアランスが望ましい特定の適用における、体内からの急速なクリアランスまたは、かかる特徴を有する分子を用いた、適当なまたは改善した新規の送達系への製剤について特に有用であり得る。
本発明は、疾患、障害、症状または疾病(「症状」)を処置、予防、治療、軽減または改善(「処置」)するための、対象の処置方法を提供する。処置する症状には、PD−1の不適当な発現または活性に特徴づけられる症状が含まれる。かかる症状には、発現または活性のレベルが高すぎるものがあり、処置にはPD−1拮抗剤を投与することが含まれる。該障害または症状はがんと関連するものである。特に、それらのがんには、肺がん、卵巣がんおよび結腸がんおよび種々の骨髄腫が含まれるが、これらに限定されるものではない。
本明細書に記載の特定の方法には、PD−1結合性の抗原結合蛋白質を対象に投与し、それにより、PD−1誘発性の、特定の症状において機能する生物応答を低下させることが含まれる。特定の態様において、本発明の方法は、内在性のPD−1をPD−1結合性の抗原結合蛋白質と、例えば対象への投与または生体外手法により接触させることを含む。
本発明は、PD−1阻害性抗原結合蛋白質と1種以上の他の処置を用いて対象を処置する方法を提供する。かかる組み合わせ療法により、例えば、腫瘍中の複数の部位または分子標的を攻撃することにより、相乗効果または相加効果が達成される。用い得る組み合わせ療法の種類としては、単一の疾患関連性経路、標的細胞の複数の経路および標的組織内の複数の細胞型における複数の結節(nodes)を阻害または活性化すること(何れか適切な方)が挙げられる。
抗PD−1抗体の、免疫応答性調節能を、混合リンパ球反応(MLR)を用いて評価した。このアッセイによって、抗PD−1抗体(RG1H10)の、細胞活性化ならびに、IL−2およびインターフェロンγ両方の産生に対する影響を測定した。MLRは、1人のドナー由来の精製ヒトCD4+細胞105個を、他のドナーから調製した単球由来の樹状細胞104個とともに培養することにより行った。樹状細胞を調製するために、精製した単球を、GM-CSF (1,000 U/ml)およびIL-4 (500 U/ml)とともに7日間培養した。とくにことわらない限り、抗PD−1抗体または対照抗体を、同種MLR培養物に10μg/mlになるように添加した。市販のELISAキット(Biolegend)を用いてIL−2およびIFNγをそれぞれ測定するために、2日目または3日目、および5日目に上清を回収できるように、プレートを並行して準備した。5日目の残りの細胞を、細胞活性化の指標として、CD25発現について評価した。
本実施例は、細胞結合EC50測定および細胞結合特異性についての試験管内データを示す。より具体的には、本実施例は、抗PD−1抗体(図4に示す)の、特異的な細胞結合および50%結合飽和(EC50)に到達する濃度についての結合特性を示す。本実施例では、抗PD−1抗体を、市販されている治療用抗PD−1抗体であるBMS 5C4と比較する。手順は以下の通りである: CHO-PD−1細胞およびCHO-PD−L1細胞を、CHO-K1細胞にPD−1 cDNA ORFクローン(Origene RG210364)およびPD−L1 cDNA ORFクローン(Origene RG213071)をそれぞれ安定的に形質導入することにより得た。ネオマイシンで2週間選択した後、クローンを蛍光標示式細胞分取器 (FACS) により単離し、さらに増殖させた。卵巣がんからES-2細胞株を確立し(ATCC CRL-1978)、これは、検出できるレベルのPD−1を発現しない。細胞結合アッセイのために、50,000個のCHO−PD−1細胞、CHO−PD−L1細胞およびES-2細胞を100μl FACSバッファー(PBS + 2% FBS)中で、96ウェル、v字底プレートに加えた。12ポイントの、各抗PD−1抗体の希釈曲線(x3)を、FACSバッファー中で50μg/ml (3.33x10-7 M)から出発して作成した。細胞のスピンダウン、FACSバッファーを用いた2回の洗浄後の、抗体溶液25μlでの再懸濁を3つ組みで行った。0.5時間インキュベーションした後、細胞をFACSバッファーで1回洗浄し、PE結合型のヤギ抗ヒトIgG (γ鎖特異的) 二次抗体 (Southern Biotech カタログ番号2040-09) 50μlで再懸濁した。細胞をさらに0.5時間インキュベーションした後、FACSバッファーで1回洗浄した。細胞をFACSバッファー25μl中で再懸濁した後、FL2-Hチャンネルの蛍光強度中央値(MFI: median fluorescence intensity)を、Intellicyt HTFCフローサイトメーターを用いて決定した。データは、非線形回帰適合を用いて、Graph Pad Prismで解析およびプロットを行った。
本実施例は、組換えPD−1の組換えPD−L1に対する結合の、抗PD−1抗体による阻害の解析を示す(図5)。端的には、ELISAプレートをPD−L1-Hisでコートし、PBS中のカゼインでブロッキングした後、抗PD−1抗体(scFv)および組換えヒトPD−1蛋白質の混合物を添加して、プレインキュベーションを行った。PD−1蛋白質のPD−L1蛋白質への残存する結合を測定した。
本実施例は、BIAcore方法論を用いた、該抗体ヒンジ領域の228番目のセリン残基をプロリンに変える安定化変異(S228P)を有する、免疫グロブリンγ1(IgG1)および免疫グロブリンγ4(IgG4)としての、特定の抗PD−1抗体RG1H10の親和性測定値の比較を提供する。端的には、CM5チップを抗ヒトFc抗体でコートし、該抗PD1 mAbを捕捉した後、系列希釈した組換えヒトPD1 (His-タグ)蛋白質を解析に用いた。
本実施例は、細胞結合EC50の測定値についての試験管内データを示す。より具体的には、本実施例は、細胞結合および50%結合飽和(EC50)に達する濃度についての、IgG1またはIgG4(S228P)としての、抗PD−1抗体の結合特性を示す。手順は以下の通りである。末梢血単核細胞(PBMC)を24ウェルプレートに添加し、抗CD3 (3 ng/ml)で刺激した。3日間細胞を培養した後、回収し、100μl FACSバッファー(PBS + 2% FBS)中で、96ウェルv字底プレートのウェルに添加した。12ポイントの、各抗PD−1抗体の希釈曲線(x3)を、FACSバッファー中で、10μg/ml (0.6 x10-7 M)から出発して作成した。細胞のスピンダウン、FACSバッファーでの2回洗浄後の、抗体溶液25μl中への再懸濁を3つ組みで行った。0.5時間インキュベーションした後、細胞をFACSバッファーで1回洗浄し、PE結合型ヤギ抗ヒトIgG (γ鎖特異的)二次抗体(Southern Biotech カタログ番号2040-09) 50μlで再懸濁した。細胞をさらに0.5時間インキュベーションした後、FACSバッファーで1回洗浄した。細胞をFACSバッファー25μlで再懸濁し、Intellicyt HTFCフローサイトメーターを用いてFL2-HチャンネルのMFIを決定した。データは、非線形回帰適合を用いて、Graph Pad Prismで解析およびプロットを行った。
本実施例は、RG1H10の、組換えPD−1には特異的に結合するが、他の関連蛋白質には結合しない性質についての解析を示す (図6)。端的には、適当な組換え蛋白質、すなわちヒトPD−1、カニクイザルPD−1、ヒトCTLA-4、ヒトCD28およびヒトICOSでコートしたELISAプレートをPBS中のカゼインでブロッキングした後、抗PD−1抗体(RG1H10)とともにインキュべーションした。RG1H10の結合を測定した。
混合リンパ球反応(MLR) を用いて、RGH10の2つのアイソタイプ、すなわちIgG1およびIgG4(S228P)の、免疫応答性調節能を測定した。このアッセイによって、抗PD−1抗体の、細胞活性化ならびに、IL−2およびインターフェロンγ産生に対する影響を測定した。該MLRは、1人のドナー由来の、精製ヒトCD4+細胞 105個を、他のドナーから調製した単球由来の樹状細胞104個とともに培養することにより行った。樹状細胞を調製するために、精製した単球を、GM-CSF (1,000U/ml)およびIL−4 (500U/ml) とともに7日間培養した。とくにことわらない限り、抗PD−1抗体または対照抗体を、同種MLR培養物に10μg/ml添加した。市販のELISAキット(Biolegend)を用いてIL−2およびIFNγをそれぞれ測定するために、2日目または3日目、および5日目に上清を回収できるように、プレートを並行して準備した。5日目の残りの細胞を、細胞活性化の指標として、CD25発現について評価した。
親和性成熟プロセスにより、重鎖配列をさらに最適化した。具体的には、抗体RG1H10 (重鎖配列番号23) の親和性成熟により、軽鎖配列番号24とともに、末尾の配列表に記載する12のさらなる重鎖配列 (配列番号37〜49) を得た。
本実施例は、図5に示す抗体を用いた、PD−1ブロッキングELISAアッセイを示す。ELISAプレートをPD−L1-Hisでコートし、PBS中のカゼインでブロッキングした後、scFvおよびPD1/Fcのプレインキュベーションした混合物 (12.5μL 10μg/ml PD1/Fc+ 12.5μl ファージスープ)を添加した。インキュベーションを1時間行い、PBSで3回洗浄した。カゼイン中に 1:200で希釈した抗ヒトFc-HRPを添加した。30分間インキュベーションし、PBSで3回洗浄した。基質としてTMBを用い、2M H2SO4を用いて反応を停止した。O.D. 450nmの値を測定した。GA2およびH7を除く、試験した全ての抗体が、PD−1受容体を遮断した。
本実施例は、図5に示す抗体を用いたPD−1ブロッキングアッセイを示す。ELISAプレートを、PD−L1-Hisでコートし、PBS中のカゼインでブロッキングした後、scFvおよびPD1/Fcのプレインキュベーションした混合物(12.5μL 0.7μg/ml PD1/Fc+ 12.5 μlファージスープ)を添加した。1時間インキュベーションし、PBSで3回洗浄した。カゼイン中に1:500で希釈した抗ヒトFc-HRPを添加した。30分間インキュベーションし、PBSで3回洗浄した。基質としてTMB を用い、2M H2SO4を用いて反応を停止した。O.D. 450nmの値を測定した。
本実施例は、図10に示すヒトおよびマウス抗PD−1抗体間の交叉反応の有無を示す。1μg/ml ヒトPD−L1/HisまたはマウスPD1/His (対照: PBS) を、Ni-NTAプレート上に50μlロードし、1時間インキュベーションし、PBSで3回洗浄した、カゼインで希釈したIgGを添加し、30分間インキュベーションした。PBSで3回洗浄した。カゼイン中に1:300で希釈したヤギ抗ヒトFc-HRPを添加した。30分間インキュベーションし、PBSで3回洗浄した。基質としてTMBを用い、2M H2SO4を用いて反応を停止した。O.D. 450nmを測定した。
本実施例は、抗体である5C4およびRG1H10のエピトープの比較を示す。IgG5C4を、AR2Gセンサー上にコートした。PBSでベースラインを測定した。PD1/Hisをセンサー上で捕捉した。その後、該センサーをPBSおよびRG1H10を含むウェル中に浸した。
本実施例は、本明細書に記載の抗PD−1抗体の親和性の比較を示す。抗ヒトFc抗体を約1000 RUで、CM5センサーチップ上に固定した。抗体(約10μg/ml)を、流速10μl/分で60秒間捕捉した。PD1/Hisをランニングバッファー(HBS-EP)中に連続的に希釈した。測定は全て、流速30μL/分で行った。60秒間、3M MgCl2を用いて表面を再生した。1:1 (Langmuir) 結合モデルをデータに当てはめた。
本実施例は、RG1H10抗体の、3つの抗PD−1競合抗体に対する標的(PD−1)特異性を示す試験である。抗ヒトIgG4重鎖または抗ヒトλ軽鎖検出反応薬のいずれかを用いた試験管内ELISAアッセイを用いて、RG1H10が組換えヒトおよびカニクイザルPD−1には特異的に結合するが、マウスPD−1には結合しないことを確認することができる。ヒトおよびカニクイザルのPD−1に対するRG1H10の結合についてのEC50値は、それぞれ0.391nMおよび0.840nMであり、試験した3つの参照抗体、競合抗体1 (ヒトEC50 0.419 nM、カニクイザルEC50 1.02 nM)、競合抗体2 (ヒトEC50 0.495nM、カニクイザルEC50 0.773 nM)および競合抗体3 (ヒトEC50 0.390 nM、カニクイザルEC50 1.295nM)と基本的に同等であった。さらに、RG1H10は、他の構造的に関連のあるファミリーメンバー、例えばヒトCTLA4、ヒトCD28およびヒトICOSには結合しない。これらの結果は、RG1H10がPD−1に対する特有の標的特異性を有することを示すものである。
本実施例は、Biacore親和性特徴付けおよび細胞ベースの結合試験を用いた、3つの抗PD−1競合抗体に対するRG1H10抗体の、標的(PD−1)親和性を示す試験である。Biacore親和性測定のために、抗PD−1抗体を、プロテイン-Aを固定したCM5センサーチップ上に捕捉した後、単量体の組換えヒトPD−1をチップ上に流した。この条件下において、RG1H10は、競合抗体1(7.0 nM)、競合抗体2(3 nM)および競合抗体3 (42 nM)に対して、3.2 nMの親和性(KD)を示した。これらの試験は、RG1H10が、競合分子1および2と同等の標的親和性を示し、競合分子3の約10倍の高さの親和性を有することを示す。
項1. PD−1エピトープに、少なくとも10-6Mの結合親和性で結合するIgGクラスの完全ヒト抗体であって、配列番号1、配列番号3、配列番号5、配列番号7、配列番号9、配列番号11、配列番号13、配列番号15、配列番号17、配列番号19、配列番号21、配列番号23、配列番号25、配列番号27、配列番号29、配列番号31、配列番号33、配列番号35、配列番号37、配列番号38、配列番号39、配列番号40、配列番号41、配列番号42、配列番号43、配列番号44およびその組み合わせからなる群から選択されるアミノ酸配列と少なくとも95%同一である重鎖可変領域配列を有し、
配列番号2、配列番号4、配列番号6、配列番号8、配列番号10、配列番号12、配列番号14、配列番号16、配列番号18、配列番号20、配列番号22、配列番号24、配列番号26、配列番号28、配列番号30、配列番号32、配列番号34、配列番号36およびその組み合わせからなる群から選択されるアミノ酸配列と少なくとも95%同一である軽鎖可変領域配列を有する、完全ヒト抗体。
配列番号2、配列番号4、配列番号6、配列番号8、配列番号10、配列番号12、配列番号14、配列番号16、配列番号18、配列番号20、配列番号22、配列番号24、配列番号26、配列番号28、配列番号30、配列番号32、配列番号34、配列番号36およびその組み合わせからなる群から選択されるアミノ酸配列と少なくとも95%同一である軽鎖可変領域配列を有する、Fab完全ヒト抗体断片。
配列番号2、配列番号4、配列番号6、配列番号8、配列番号10、配列番号12、配列番号14、配列番号16、配列番号18、配列番号20、配列番号22、配列番号24、配列番号26、配列番号28、配列番号30、配列番号32、配列番号34、配列番号36およびその組み合わせからなる群から選択されるアミノ酸配列と少なくとも95%同一である軽鎖可変領域配列を有する、一本鎖ヒト抗体。
該抗PD−1ポリペプチドが、PD−1エピトープに少なくとも10-6Mの結合親和性で結合する、IgGクラスの完全ヒト抗体、重鎖由来の可変領域と軽鎖由来の可変領域を有するFab完全ヒト抗体断片、重鎖由来の可変領域と軽鎖由来の可変領域および重鎖と軽鎖の可変領域をつなぐペプチドリンカーを有する一本鎖ヒト抗体およびその組み合わせからなる群から選択され;ここで、
該完全ヒト抗体が、配列番号1、配列番号3、配列番号5、配列番号7、配列番号9、配列番号11、配列番号13、配列番号15、配列番号17、配列番号19、配列番号21、配列番号23、配列番号25、配列番号27、配列番号29、配列番号31、配列番号33、配列番号35、配列番号37、配列番号38、配列番号39、配列番号40、配列番号41、配列番号42、配列番号43、配列番号44およびその組み合わせからなる群から選択されるアミノ酸配列と少なくとも95%同一である重鎖可変領域配列を有し、
配列番号2、配列番号4、配列番号6、配列番号8、配列番号10、配列番号12、配列番号14、配列番号16、配列番号18、配列番号20、配列番号22、配列番号24、配列番号26、配列番号28、配列番号30、配列番号32、配列番号34、配列番号36およびその組み合わせからなる群から選択されるアミノ酸配列と少なくとも95%同一である軽鎖可変領域配列を有しており;
該Fab完全ヒト抗体断片が、配列番号1、配列番号3、配列番号5、配列番号7、配列番号9、配列番号11、配列番号13、配列番号15、配列番号17、配列番号19、配列番号21、配列番号23、配列番号25、配列番号27、配列番号29、配列番号31、配列番号33、配列番号35、配列番号37、配列番号38、配列番号39、配列番号40、配列番号41、配列番号42、配列番号43、配列番号44およびその組み合わせからなる群から選択されるアミノ酸配列と少なくとも95%同一である重鎖可変領域配列を有し、
配列番号2、配列番号4、配列番号6、配列番号8、配列番号10、配列番号12、配列番号14、配列番号16、配列番号18、配列番号20、配列番号22、配列番号24、配列番号26、配列番号28、配列番号30、配列番号32、配列番号34、配列番号36およびその組み合わせからなる群から選択されるアミノ酸配列と少なくとも95%同一である軽鎖可変領域配列を有しており;
該一本鎖ヒト抗体が、配列番号1、配列番号3、配列番号5、配列番号7、配列番号9、配列番号11、配列番号13、配列番号15、配列番号17、配列番号19、配列番号21、配列番号23、配列番号25、配列番号27、配列番号29、配列番号31、配列番号33、配列番号35、配列番号37、配列番号38、配列番号39、配列番号40、配列番号41、配列番号42、配列番号43、配列番号44およびその組み合わせからなる群から選択されるアミノ酸配列と少なくとも95%同一である重鎖可変領域配列を有し、
配列番号2、配列番号4、配列番号6、配列番号8、配列番号10、配列番号12、配列番号14、配列番号16、配列番号18、配列番号20、配列番号22、配列番号24、配列番号26、配列番号28、配列番号30、配列番号32、配列番号34、配列番号36およびその組み合わせからなる群から選択されるアミノ酸配列と少なくとも95%同一である軽鎖可変領域配列を有する、処置方法。
該完全ヒト抗体が、配列番号1/配列番号2、配列番号3/配列番号4、配列番号5/配列番号6、配列番号7/配列番号8、配列番号9/配列番号10、配列番号11/配列番号12、配列番号13/配列番号14、配列番号15/配列番号16、配列番号17/配列番号18、配列番号19/配列番号20、配列番号21/配列番号22、配列番号23/配列番号24、配列番号25/配列番号26、配列番号27/配列番号28、配列番号29/配列番号30、配列番号31/配列番号32、配列番号33/配列番号34、配列番号35/配列番号36、配列番号37/配列番号24、配列番号38/配列番号24、配列番号39/配列番号24、配列番号40/配列番号24、配列番号41/配列番号24、配列番号42/配列番号24、配列番号43/配列番号24、配列番号44/配列番号24およびその組み合わせからなる群から選択される重鎖/軽鎖可変領域配列を有する、処置方法。
該完全ヒト抗体Fab断片が、重鎖可変領域と軽鎖可変領域の両方を有し、該抗体が、配列番号1/配列番号2、配列番号3/配列番号4、配列番号5/配列番号6、配列番号7/配列番号8、配列番号9/配列番号10、配列番号11/配列番号12、配列番号13/配列番号14、配列番号15/配列番号16、配列番号17/配列番号18、配列番号19/配列番号20、配列番号21/配列番号22、配列番号23/配列番号24、配列番号25/配列番号26、配列番号27/配列番号28、配列番号29/配列番号30、配列番号31/配列番号32、配列番号33/配列番号34、配列番号35/配列番号36、配列番号37/配列番号24、配列番号38/配列番号24、配列番号39/配列番号24、配列番号40/配列番号24、配列番号41/配列番号24、配列番号42/配列番号24、配列番号43/配列番号24、配列番号44/配列番号24およびその組み合わせからなる群から選択される重鎖/軽鎖可変領域配列を有する、処置方法。
該ヒト完全一本鎖抗体が重鎖可変領域および軽鎖可変領域の両方を有し、配列番号1/配列番号2、配列番号3/配列番号4、配列番号5/配列番号6、配列番号7/配列番号8、配列番号9/配列番号10、配列番号11/配列番号12、配列番号13/配列番号14、配列番号15/配列番号16、配列番号17/配列番号18、配列番号19/配列番号20、配列番号21/配列番号22、配列番号23/配列番号24、配列番号25/配列番号26、配列番号27/配列番号28、配列番号29/配列番号30、配列番号31/配列番号32、配列番号33/配列番号34、配列番号35/配列番号36、配列番号37/配列番号24、配列番号38/配列番号24、配列番号39/配列番号24、配列番号40/配列番号24、配列番号41/配列番号24、配列番号42/配列番号24、配列番号43/配列番号24、配列番号44/配列番号24およびその組み合わせからなる群から選択される重鎖/軽鎖可変領域配列を有する、処置方法。
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US9067998B1 (en) | 2014-07-15 | 2015-06-30 | Kymab Limited | Targeting PD-1 variants for treatment of cancer |
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WO2014194302A3 (en) | 2015-02-26 |
JP2016521692A (ja) | 2016-07-25 |
CN111423511B (zh) | 2024-02-23 |
CN111423511A (zh) | 2020-07-17 |
EP3004169A4 (en) | 2017-02-22 |
US20210130468A1 (en) | 2021-05-06 |
CA3175360A1 (en) | 2014-12-04 |
EP3004169B1 (en) | 2023-03-22 |
HK1221964A1 (zh) | 2017-06-16 |
CA2913977C (en) | 2022-11-29 |
US9676853B2 (en) | 2017-06-13 |
EP3004169A2 (en) | 2016-04-13 |
US10584168B2 (en) | 2020-03-10 |
CN105683217A (zh) | 2016-06-15 |
CN105683217B (zh) | 2019-12-10 |
JP2023099773A (ja) | 2023-07-13 |
JP6563906B2 (ja) | 2019-08-21 |
US20220242954A1 (en) | 2022-08-04 |
HK1238648A1 (zh) | 2018-05-04 |
JP2022027968A (ja) | 2022-02-14 |
US20140356363A1 (en) | 2014-12-04 |
US11242391B2 (en) | 2022-02-08 |
CA2913977A1 (en) | 2014-12-04 |
WO2014194302A2 (en) | 2014-12-04 |
US20170313776A1 (en) | 2017-11-02 |
JP6997743B2 (ja) | 2022-02-04 |
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