JP2022516071A - 抗ctla-4結合タンパク質およびその使用方法 - Google Patents
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Abstract
Description
本出願は、その全内容が参照により本明細書に組み込まれる、2018年12月27日に出願した米国仮特許出願第62/785,659号の優先権および利益を主張する。
本出願は、EFS-Web経由で提出した11998の配列に関する配列表を含み、この配列表は、その全体が参照により本明細書に組み込まれる。2019年12月20日に作成した前記ASCIIコピーは、GGN-010WO_SL.txtという名であり、サイズは1,927,908バイトである。
CTLA-4に対する結合特異性を有する抗原結合タンパク質(ABP)、ならびに医薬組成物、診断組成物、およびキットを含めた、そのようなABPを含む組成物が、本明細書で提供される。CTLA-4 ABPを作製する方法、ならびにCTLA-4 ABPを、例えば治療目的、診断目的および研究目的で、使用する方法も、提供される。
細胞傷害性Tリンパ球関連タンパク質4およびCD152(表面抗原分類152)としても公知である、CTLA-4は、T細胞炎症活性を抑制する細胞表面受容体である。CTLA-4は、調節性T細胞(Treg)により構成的に発現され、刺激されたT細胞において上方調節される。樹状細胞(DC)などの抗原提示細胞(APC)にも発現されるCD80およびCD86は、CTLA-4の主要リガンドである。CTLA-4とそのリガンドとの相互作用は、T細胞炎症活性を抑制することによる免疫応答の下方調節および自己寛容の促進に極めて重要である。この活性は、免疫系ががん細胞を死滅させるのを防止するばかりでなく、自己免疫疾患も防止する。
CTLA-4に対する結合特異性を有する新規ABP、およびそのようなABPを使用する方法が、本明細書で提供される。CTLA-4は、ヒトCTLA-4(配列番号7001)またはヒトCTLA-4の断片である。
6.図面の簡単な説明
7.1.定義
本明細書中で別段の定義がない限り、本開示に関連して使用される科学および専門用語は、当業者により一般に理解されている意味を有するものとする。さらに、文脈上他の意味に解すべき場合を除き、単数形の用語は、複数形のものを含むものとし、複数形の用語は、単数形のものを含むものとする。一般に、本明細書に記載の細胞および組織培養、分子生物学、免疫学、微生物学、遺伝学ならびにタンパク質および核酸化学およびハイブリダイゼーションに関連して使用される命名法、ならびに本明細書に記載の細胞および組織培養、分子生物学、免疫学、微生物学、遺伝学ならびにタンパク質および核酸化学およびハイブリダイゼーションの技術は、当技術分野において周知の、一般に使用されているものである。本開示の方法および技術は、別段の指示がない限り、一般に、当技術分野において周知の従来の方法に従って、ならびに本明細書の至る所で言及され、論じられる様々な一般およびより特異的な参考文献に記載されているように、行われる。例えば、Sambrook et al. Molecular Cloning: A Laboratory Manual, 2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)およびAusubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates (1992)、およびHarlow and Lane Antibodies: A Laboratory Manual Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1990)を参照されたく、これらの参考文献は、参照により本明細書に組み込まれる。酵素反応および精製技術は、当技術分野において一般に遂行されているように、または本明細書に記載されるように、製造業者の仕様に従って行われる。本明細書に記載の分析化学、合成有機化学、医化学および薬化学に関連して使用される用語法、ならびに本明細書に記載の分析化学、合成有機化学、医化学および薬化学の実験手順および技術は、当技術分野において周知の、一般に使用されているものである。化学合成、化学分析、薬学的調製、製剤および送達、ならびに患者の処置には、標準的な技術を使用することができる。
7.2.他の解釈規定
7.3.核酸
7.4.発現ベクター
7.5.抗体
7.6.抗原結合タンパク質
7.7.モノクローナル抗体
7.8.抗体を生成する方法
7.9.配列
7.10.1.薬学的有効成分の含量
7.10.2.一般的な製剤化
7.10.3.注射に適合される医薬組成物
7.11.単位剤形
7.12.使用方法
7.12.1.CTLA-4阻害剤または活性化剤に応答する疾患を処置する方法
以下は、本開示を実行するための特定の実施形態の例である。実施例は、例示目的のみのために提供され、本開示の範囲をいかなるようにも限定することを意図しない。使用される数値(例えば、量、温度など)に関して正確性を確保するための努力がなされているが、幾分かの実験誤差およびばらつきは、当然のことながら許容されるべきである。
(実施例1)
8.1.実施例1:抗原結合タンパク質の生成
(実施例2)
8.2.実施例2:酵母ディスプレイによるCTLA-4バインダーの単離
(実施例3)
8.3.実施例3:抗原結合タンパク質の生物学的特徴
(実施例4)
8.4.実施例4:腫瘍成長へのCTLA-4 ABPの影響
平均阻害%=(平均(C)-平均(T)/平均(C)×100%
T - 本発明の群の値
C - 対照群の値
実施例5:全身的抗腫瘍免疫へのCTLA4 ABPの影響
8.5.実施例6:CTLA-4 ABPの増加した投与量の影響
平均阻害%=(平均(C)-平均(T)/平均(C)×100%
T - 本発明の群の値
C - 対照群の値
(実施例7)
8.6.実施例7:第2の腫瘍モデルへのCTLA-4 ABPの影響
平均阻害%=(平均(C)-平均(T)/平均(C)×100%
T - 本発明の群の値
C - 対照群の値
平均%Δ阻害=((平均(C)-平均(C0))-(平均(T)-平均(T0)))/(平均(C)-平均(C0))×100%
T - 本発明の群の値
T0 - 本発明の群の初期値
C - 対照群の値
C0 - 対照群の初期値
(実施例9)
8.8.実施例9:免疫に関連する有害事象
(実施例10)
8.9.実施例10:末梢フローサイトメトリー
(実施例11)
8.10.実施例11:低用量のCTLA-4研究による処置
10.均等物
Claims (23)
- ヒト細胞傷害性Tリンパ球関連タンパク質4(CTLA-4)に特異的に結合する単離された抗原結合タンパク質(ABP)であって、
(a)配列番号3001~3028から選択される配列を有するCDR3-L、および配列番号6001~6028から選択される配列を有するCDR3-H;または
(b)配列番号9984~10479から選択される配列を有するCDR3-L、および配列番号11472~11967から選択される配列を有するCDR3-H;または
(c)ATCC受託番号PTA-125512の下で寄託されたライブラリー内のクローンのいずれか1つのCD3-Lの配列を有するCDR3-L、およびATCC受託番号PTA-125512の下で寄託されたライブラリー内のクローンのいずれか1つのCD3-Lの配列を有するCDR3-L
を含む、単離された抗原結合タンパク質(ABP)。 - 前記CDR3-Lおよび前記CDR3-Hが、同族対である、請求項1に記載のABP。
- (a)配列番号1001~1028から選択される配列を有するCDR1-L;および配列番号2001~2028から選択される配列を有するCDR2-L;および配列番号4001~4028から選択される配列を有するCDR1-H;および配列番号5001~5028から選択される配列を有するCDR2-H;または
(b)配列番号8992~9487から選択される配列を有するCDR1-L;および配列番号9488~9983から選択される配列を有するCDR2-L;および配列番号10480~10975から選択される配列を有するCDR1-H;および配列番号10976~11471から選択される配列を有するCDR2-H;または
(c)ATCC受託番号PTA-125512の下で寄託されたライブラリー内のクローンのいずれか1つのCDR1-Lから選択される配列を有するCDR1-L;およびATCC受託番号PTA-125512の下で寄託されたライブラリー内のクローンのいずれか1つのCDR2-Lから選択される配列を有するCDR2-L;およびATCC受託番号PTA-125512の下で寄託されたライブラリー内のクローンのいずれか1つのCDR1-Hから選択される配列を有するCDR1-H;およびATCC受託番号PTA-125512の下で寄託されたライブラリー内のクローンのいずれか1つのCDR2-Hから選択される配列を有するCDR2-H
を含む、請求項1に記載のABP。 - CDR1-L、CDR2-L、CDR3-L、CDR1-H、CDR2-HおよびCDR3-Hを含み、
前記CDR1-Lが、配列番号1001からなり、前記CDR2-Lが、配列番号2001からなり、前記CDR3-Lが、配列番号3001からなり、前記CDR1-Hが、配列番号4001からなり、前記CDR2-Hが、配列番号5001からなり、前記CDR3-Hが、配列番号6001からなるか;または
前記CDR1-Lが、配列番号1002からなり、CDR2-Lが、配列番号2002からなり、前記CDR3-Lが、配列番号3002からなり、前記CDR1-Hが、配列番号4002からなり、前記CDR2-Hが、配列番号5002からなり、前記CDR3-Hが、配列番号6002からなるか;または
前記CDR1-Lが、配列番号1003からなり、前記CDR2-Lが、配列番号2003からなり、前記CDR3-Lが、配列番号3003からなり、前記CDR1-Hが、配列番号4003からなり、前記CDR2-Hが、配列番号5003からなり、前記CDR3-Hが、配列番号6003からなるか;または
前記CDR1-Lが、配列番号1004からなり、前記CDR2-Lが、配列番号2004からなり、前記CDR3-Lが、配列番号3004からなり、前記CDR1-Hが、配列番号4004からなり、前記CDR2-Hが、配列番号5004からなり、前記CDR3-Hが、配列番号6004からなるか;または
前記CDR1-Lが、配列番号1005からなり、前記CDR2-Lが、配列番号2005からなり、前記CDR3-Lが、配列番号3005からなり、前記CDR1-Hが、配列番号4005からなり、前記CDR2-Hが、配列番号5005からなり、前記CDR3-Hが、配列番号6005からなるか;または
前記CDR1-Lが、配列番号1006からなり、前記CDR2-Lが、配列番号2006からなり、前記CDR3-Lが、配列番号3006からなり、前記CDR1-Hが、配列番号4006からなり、前記CDR2-Hが、配列番号5006からなり、前記CDR3-Hが、配列番号6006からなるか;または
前記CDR1-Lが、配列番号1007からなり、前記CDR2-Lが、配列番号2007からなり、前記CDR3-Lが、配列番号3007からなり、前記CDR1-Hが、配列番号4007からなり、前記CDR2-Hが、配列番号5007からなり、前記CDR3-Hが、配列番号6007からなるか;または
前記CDR1-Lが、配列番号1008からなり、前記CDR2-Lが、配列番号2008からなり、前記CDR3-Lが、配列番号3008からなり、前記CDR1-Hが、配列番号4008からなり、前記CDR2-Hが、配列番号5008からなり、前記CDR3-Hが、配列番号6008からなるか;または
前記CDR1-Lが、配列番号1009からなり、前記CDR2-Lが、配列番号2009からなり、前記CDR3-Lが、配列番号3009からなり、前記CDR1-Hが、配列番号4009からなり、前記CDR2-Hが、配列番号5009からなり、前記CDR3-Hが、配列番号6009からなるか;または
前記CDR1-Lが、配列番号1010からなり、前記CDR2-Lが、配列番号2010からなり、前記CDR3-Lが、配列番号3010からなり、前記CDR1-Hが、配列番号4010からなり、前記CDR2-Hが、配列番号5010からなり、前記CDR3-Hが、配列番号6010からなるか;または
前記CDR1-Lが、配列番号1011からなり、前記CDR2-Lが、配列番号2011からなり、前記CDR3-Lが、配列番号3011からなり、前記CDR1-Hが、配列番号4011からなり、前記CDR2-Hが、配列番号5011からなり、前記CDR3-Hが、配列番号6011からなるか;または
前記CDR1-Lが、配列番号1012からなり、前記CDR2-Lが、配列番号2012からなり、前記CDR3-Lが、配列番号3012からなり、前記CDR1-Hが、配列番号4012からなり、前記CDR2-Hが、配列番号5012からなり、前記CDR3-Hが、配列番号6012からなるか;または
前記CDR1-Lが、配列番号1013からなり、前記CDR2-Lが、配列番号2013からなり、前記CDR3-Lが、配列番号3013からなり、前記CDR1-Hが、配列番号4013からなり、前記CDR2-Hが、配列番号5013からなり、前記CDR3-Hが、配列番号6013からなるか;または
前記CDR1-Lが、配列番号1014からなり、前記CDR2-Lが、配列番号2014からなり、前記CDR3-Lが、配列番号3014からなり、前記CDR1-Hが、配列番号4014からなり、前記CDR2-Hが、配列番号5014からなり、前記CDR3-Hが、配列番号6014からなるか;または
前記CDR1-Lが、配列番号1015からなり、前記CDR2-Lが、配列番号2015からなり、前記CDR3-Lが、配列番号3015からなり、前記CDR1-Hが、配列番号4015からなり、前記CDR2-Hが、配列番号5015からなり、前記CDR3-Hが、配列番号6015からなるか;または
前記CDR1-Lが、配列番号1016からなり、前記CDR2-Lが、配列番号2016からなり、前記CDR3-Lが、配列番号3016からなり、前記CDR1-Hが、配列番号4016からなり、前記CDR2-Hが、配列番号5016からなり、前記CDR3-Hが、配列番号6016からなるか;または
前記CDR1-Lが、配列番号1017からなり、前記CDR2-Lが、配列番号2017からなり、前記CDR3-Lが、配列番号3017からなり、前記CDR1-Hが、配列番号4017からなり、前記CDR2-Hが、配列番号5017からなり、前記CDR3-Hが、配列番号6017からなるか;または
前記CDR1-Lが、配列番号1018からなり、前記CDR2-Lが、配列番号2018からなり、前記CDR3-Lが、配列番号3018からなり、前記CDR1-Hが、配列番号4018からなり、前記CDR2-Hが、配列番号5018からなり、前記CDR3-Hが、配列番号6018からなるか;または
前記CDR1-Lが、配列番号1019からなり、前記CDR2-Lが、配列番号2019からなり、前記CDR3-Lが、配列番号3019からなり、前記CDR1-Hが、配列番号4019からなり、前記CDR2-Hが、配列番号5019からなり、前記CDR3-Hが、配列番号6019からなるか;または
前記CDR1-Lが、配列番号1020からなり、前記CDR2-Lが、配列番号2020からなり、前記CDR3-Lが、配列番号3020からなり、前記CDR1-Hが、配列番号4020からなり、前記CDR2-Hが、配列番号5020からなり、前記CDR3-Hが、配列番号6020からなるか;または
前記CDR1-Lが、配列番号1021からなり、前記CDR2-Lが、配列番号2021からなり、前記CDR3-Lが、配列番号3021からなり、前記CDR1-Hが、配列番号4021からなり、前記CDR2-Hが、配列番号5021からなり、前記CDR3-Hが、配列番号6021からなるか;または
前記CDR1-Lが、配列番号1022からなり、前記CDR2-Lが、配列番号2022からなり、前記CDR3-Lが、配列番号3022からなり、前記CDR1-Hが、配列番号4022からなり、前記CDR2-Hが、配列番号5022からなり、前記CDR3-Hが、配列番号6022からなるか;または
前記CDR1-Lが、配列番号1023からなり、前記CDR2-Lが、配列番号2023からなり、前記CDR3-Lが、配列番号3023からなり、前記CDR1-Hが、配列番号4023からなり、前記CDR2-Hが、配列番号5023からなり、前記CDR3-Hが、配列番号6023からなるか;または
前記CDR1-Lが、配列番号1024からなり、前記CDR2-Lが、配列番号2024からなり、前記CDR3-Lが、配列番号3024からなり、前記CDR1-Hが、配列番号4024からなり、前記CDR2-Hが、配列番号5024からなり、前記CDR3-Hが、配列番号6024からなるか;または
前記CDR1-Lが、配列番号1025からなり、前記CDR2-Lが、配列番号2025からなり、前記CDR3-Lが、配列番号3025からなり、前記CDR1-Hが、配列番号4025からなり、前記CDR2-Hが、配列番号5025からなり、前記CDR3-Hが、配列番号6025からなるか;または
前記CDR1-Lが、配列番号1026からなり、前記CDR2-Lが、配列番号2026からなり、前記CDR3-Lが、配列番号3026からなり、前記CDR1-Hが、配列番号4026からなり、前記CDR2-Hが、配列番号5026からなり、前記CDR3-Hが、配列番号6026からなるか;または
前記CDR1-Lが、配列番号1027からなり、前記CDR2-Lが、配列番号2027からなり、前記CDR3-Lが、配列番号3027からなり、前記CDR1-Hが、配列番号4027からなり、前記CDR2-Hが、配列番号5027からなり、前記CDR3-Hが、配列番号6027からなるか;または
前記CDR1-Lが、配列番号1028からなり、前記CDR2-Lが、配列番号2028からなり、前記CDR3-Lが、配列番号3028からなり、前記CDR1-Hが、配列番号4028からなり、前記CDR2-Hが、配列番号5028からなり、前記CDR3-Hが、配列番号6028からなる、請求項1に記載のABP。 - 配列番号1~28から選択される配列と少なくとも97%同一の配列を含む可変軽鎖(VL)、および配列番号101~128から選択される配列と少なくとも97%同一の配列を含む可変重鎖(VH);または
配列番号8000~8495から選択される配列と少なくとも97%同一の配列を含む可変軽鎖(VL)、および配列番号8496~8991から選択される配列と少なくとも97%同一の配列を含む可変重鎖(VH);または
ATCC受託番号PTA-125512の下で寄託されたライブラリー内のクローンのいずれか1つのVL配列と少なくとも97%同一の配列を含む可変軽鎖(VL)、およびATCC受託番号PTA-125512の下で寄託されたライブラリー内のクローンのいずれか1つのVH配列と少なくとも97%同一の配列を含む可変重鎖(VH)
を含む、請求項1に記載のABP。 - 前記VLおよび前記VHが、同族対である、請求項5に記載のABP。
- 配列番号1~28から選択される配列を含む可変軽鎖(VL)、および配列番号101~128から選択される配列を含む可変重鎖(VH);または
配列番号8000~8495から選択される配列を含む可変軽鎖(VL)、および配列番号8496~8991から選択される配列を含む可変重鎖(VH);または
ATCC受託番号PTA-125512の下で寄託されたライブラリー内のクローンのいずれか1つのVL配列を含む可変軽鎖(VL)、およびATCC受託番号PTA-125512の下で寄託されたライブラリー内のクローンのいずれか1つのVH配列を含む可変重鎖(VH)
を含む、請求項1に記載のABP。 - 前記VLおよび前記VHが、同族対である、請求項7に記載のABP。
- scFvまたは全長モノクローナル抗体を含む、請求項1から8のいずれかに記載のABP。
- 免疫グロブリン定常領域を含む、請求項1から8のいずれかに記載のABP。
- 表面プラズモン共鳴により測定して、500nM未満のKDでヒトCTLA-4に結合する、前記請求項のいずれかに記載のABP。
- 表面プラズモン共鳴により測定して、200nM未満のKDでヒトCTLA-4に結合する、請求項11に記載のABP。
- 表面プラズモン共鳴により測定して、25nM未満のKDでヒトCTLA-4に結合する、請求項12に記載のABP。
- 25nM未満のKDで細胞表面上のヒトCTLA-4と結合する、請求項1から13のいずれかに記載のABP。
- 請求項1から14のいずれかに記載のABPと賦形剤とを含む、医薬組成物。
- 疾患を処置する方法であって、
それを必要とする対象に、請求項1から14のいずれかに記載のABPまたは請求項15に記載の医薬組成物の有効量を投与するステップ
を含む、方法。 - 前記疾患が、がん、AIDS、アルツハイマー病およびウイルスまたは細菌感染症からなる群から選択される、請求項16に記載の方法。
- 前記対象に1つまたは複数の追加の治療剤を投与するステップをさらに含む、請求項16から17のいずれかに記載の方法。
- 前記追加の治療剤が、CTLA-4阻害剤、TIGIT阻害剤、化学療法剤、免疫刺激剤、放射線、サイトカイン、サイトカインをコードするポリヌクレオチド、およびこれらの組合せから選択される、請求項18に記載の方法。
- 請求項1から10のいずれかに記載のABPをコードする、単離されたポリヌクレオチド。
- 請求項20に記載の単離されたポリヌクレオチドを含むベクター。
- 請求項20に記載の単離されたポリヌクレオチドまたは請求項21に記載のベクターを含む宿主細胞。
- ヒトCTLA-4に特異的に結合する単離された抗原結合タンパク質(ABP)を産生する方法であって、
請求項22に記載の宿主細胞において前記ABPを発現させること、および前記ABPを単離すること
を含む方法。
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US20240067740A1 (en) * | 2020-12-31 | 2024-02-29 | Novarock Biotherapeutics, Ltd. | Antibodies to tnfr2 and uses thereof |
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