JP2022521706A - 抗bag2抗体および癌を治療する方法 - Google Patents
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Abstract
Description
1.発明の分野
本開示は、BAG2ポリペプチドまたはそのフラグメントに特異的に結合する抗体またはその抗原結合フラグメントに関する。本出願はまた、本発明の組成物を用いた抗癌治療薬に関する。
コシャペロンBcl-2関連アタノジーン(BAG)タンパク質ファミリーは、細胞内タンパク質フォールディング、ストレス応答、神経細胞分化、アポトーシス、および細胞増殖を含む種々の生理学的プロセスを媒介し、様々な協調的タンパク質に機能的に結合する。抗アポトーシス活性を有するBAGドメインファミリーのメンバーの1種であるBAG2は、シャペロン関連ユビキチンリガーゼであるHsc70相互作用タンパク質のC-末端(CHIP)の負の調節因子である。CHIP活性の阻害を通したタンパク質調節におけるBAG2の主な役割は、PINK1およびCFTRなどのシャペロンに関係するタンパク質の安定化を通して神経変性疾患および常染色体劣性遺伝疾患に関連する。BAG2の発現がプロテアソーム阻害剤に誘導されたアポトーシスを増加させ、甲状腺癌細胞がプロテアソーム阻害剤MG132に暴露されるとBAG2ノックダウンがアポトーシスを部分的に阻害する、というように、BAG2がアポトーシス促進活性を有することが報告されている。BAGタンパク質は、BAG2-Hsp70複合体の形成とは別に、種々の結合パートナーと機能的に相互作用し、ストレスシグナル伝達、細胞分裂、アポトーシスおよび細胞分化などの様々な細胞プロセスを調節する。様々な変異体K-Rasに誘導された腫瘍において、BAG2の過剰発現が強力な腫瘍遺伝子であるSTK33タンパク質の安定化を促進し、これにより腫瘍の発達を促進することも、報告されている。加えて、BAG2タンパク質の発現および場所が、乳癌の進行または転移の間に癌細胞の組織病理学的および分子遺伝子学的病態に応じて変動し得ることが、示唆されている。BAG2タンパク質が、腫瘍形成の間に、タンパク質分解酵素であるカテプシンBとの相互作用により細胞から分泌されることが見出されており、かつBAG2タンパク質の損失が、乳癌の動物モデルにおいて癌形成および肺への転移を完全に阻害することが、確認されている。結果として、BAG2タンパク質阻害剤の開発は、癌患者の処置および生存に寄与するであろう。
本発明のこれらおよび他の目的は、本発明の以下の記載、それに付属の参照図面および添付の特許請求の範囲からより完全に理解されよう。
定義
本出願において、「1つの(a)」および「1つの(an)」は、単数および複数の両方の物体を指すために用いられる。
製造、貯蔵の間および生体内で、治療抗体は、多くの経路を介する分解のリスクがある。とりわけ、タンパク質で最も頻繁に発生する分解反応は、AsnおよびAsp残基の化学分解である。これらの反応は、最終的な薬物物質および薬物製品の適当な貯蔵および配合条件により抑制され得るが、発酵、下流の加工の間、および生体内での分解は多くの場合、充分に制御され得ない。AsnおよびAsp残基が抗原認識に関与する場合、それらの化学的改変は、重度の能力損失をもたらす可能性がある。複数の例で、これらの分解事象が、長期mAb機能を妨害することが報告された。生体内では、タンパク質分解事象は、タンパク質の経年変化と、アポトーシスを惹起することによる癌と、または他の生物学的機能に及ぼす重度の影響、例えばヒト水晶体ベータA3クリスタリンの安定性減少、異常なMAPKシグナル伝達、Aベータ生成過程の潜在的ベータセクレターゼ有効性および特異性の改変、またはバクテリア細胞に対するリゾチーム溶解活性の増加、と関連して記載される。分解を受け易い薬物候補の同定は、理想的には薬物開発工程の早期に実施され、それに応じて製造および配合工程を調整するか、または問題となる候補を再度操作して、そのようなホットスポットを除去する。
抗体をヒト化する工程は、周知であり、したがって従来の技術を用いて、ヒト化抗体を作製してよい。1つの例証されたプロトコルが、以下の通りであってよい:
QVQLVQSGAEVKKPGASVKVSCKASGYSFTDYTFYWVRQAPGQRLEWIGYIDPYNAGNTYNRKFKGRVTITVDKSASTAYMELSSLRSEDTAVYYCARGYYRYGGGGDFDYWGQGTLVTVSS(SEQ ID NO:75)
DVVMTQSPLSLPVTLGQPASISCRSSQSLVHSNGNTYLHWFQQRPGQSPRLLIHKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQNTHIPPTFGGGTKVEIK(SEQ ID NO:76)
QVQLVQSGAEVKKPGASVKVSCKASGYSFTDYTFYWVRQAPGQRLEWIGYIDPYNAGNTYNRKFKGKVTITVDKSASTAYMELNSLRSEDTAVYYCARGYYRYGGGGDFDYWGQGTLVTVSS(SEQ ID NO:77)
DVVMTQSPLSLPVTLGQPASISCRSSQSLVHSNGNTYLHWFQQRPGQSPRLLIHKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQNTHIPPTFGGGTKVEIK(SEQ ID NO:78)
QVQLVQSGAEVKKPGASVKVSCKASGHAFTNYMIEWVRQAPGQGLEWMGVINPGSGGTYNSEKVKGRVTLTADRSISTAYMELSRLRSDDTAVYYCRIYGNYKGYFDHWGQGTLVTVSS(SEQ ID NO:79)
DIQMTQSPSSLSASVGDRVTITCKASQDMNSYLSWFQQKPGKAPKSLIYRSNRLVDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQNDEFPFTFGQGTKLEIK(SEQ ID NO:80)
QVQLVQSGSELKKPGASVKVSCKASGYSFTKYGMNWVKQAPGQGLEWMGWINTNTGEATYGEEVKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARLGLRYLDYWGQGTLVTVSS(SEQ ID NO:81)
DIQMTQSPSSLSASVGDRVTITCRASKSVSTSDYSYMHWYQQKPGKAPKLLIYLASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHNRELPPTFGQGTKLEIK(SEQ ID NO:82)
QVQLVQSGSELKKPGASVKVSCKASGYSFTKYGMNWVRQAPGQGLEWMGWINTNTGEATYGEEVKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARLGLRYLDYWGQGTLVTVSS(SEQ ID NO:83)
DIQMTQSPSSLSASVGDRVTITCRASKSVSTSDYSYMHWYQQKPGKAPKLLIYLASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHNRELPPTFGQGTKLEIK(SEQ ID NO:84)
QVQLVQSGSELKKPGASVKVSCKASGYSFTKYGMNWVKQAPGQGLEWMGWINTNTGEATYGEEVKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARLGLRYLDYWGQGTLVTVSS(SEQ ID NO:85)
DIQMTQSPSSLSASVGDRVTITCRASKSVSTSDYSYMHWYQQKPGKAPKLLIYLASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHNRELPPTFGQGTKLEIK(SEQ ID NO:86)
癌の成長またはより転移性の状態への移行を阻害するそれらの抗体を、抗癌治療薬としての使用のために選択し、癌の処置または予防のために患者に投与してよい。選択された抗体は、例えばヒトキメラ抗体または完全なヒト抗体を遺伝子操作または作製することにより、さらに最適化されてよい。このアプローチの有効性を実証するために、
第一の薬剤は、別の薬剤と併せて投与される。「~と併せて」は、同じ個体への抗BAG2抗体またはそのフラグメントの投与に加えた、本明細書に記載された免疫調整物質の投与などの、別の処置モダリティーに加えた1つの処置モダリティーの投与を指す。そのため、「~と併せて」は、個体への他の処置モダリティーの送達前、送達の間、または送達後の1つの処置モダリティーの投与を指す。そのような組み合わせは、単一処置レジメンまたはレジメの一部と見なされる。
免疫調整剤または免疫療法薬は大まかに、4種のカテゴリー:チェックポイント阻害剤、サイトカイン、アゴニスト、およびアジュバント、に分別できる。チェックポイント阻害剤は、免疫応答をシャットダウンし腫瘍自体を防護するために腫瘍が頻繁に操作する免疫チェックポイント、即ち免疫系の「ブレーキ」を遮断することにより作用する。その結果、チェックポイント阻害剤は、癌に対する新しい免疫応答を引き出し、ならびに既存の応答を増強して癌細胞の排除を促進できる。2020年現在で、チェックポイント阻害剤は、おそらくこれまで開発された中で最も周知され、最も広く成功した免疫調整物質であろう。
抗BAG2抗体は、抗癌特性を有する他の薬剤または処置の補助として、またはそれと共に用いられてよい。抗BAG2抗体および他の薬剤(複数可)は、補助的に用いられる場合、単一の併用薬物配合剤として一緒に配合されてよく、または単一の協調的投与レジメンで、もしくは異なる投与レジメンで、別個に配合および投与されてよい。抗BAG2抗体へ補助的に、または抗体と共に投与される薬剤は典型的には、抗BAG2抗体への補足的活性を有し、そのため抗体または他の薬剤は、互いに有害に影響しない。
分泌されたBAG2タンパク質のレベル上昇を有すると診断された患者はその後、BAG2に特異的に結合する治療薬で処置される。それゆえ、BAG2の分泌レベル上昇と診断された患者は、BAG2を阻害する治療薬での処置から利益を享受するであろう。したがって、癌処置と、癌の処置または予防のための治療薬の有効量の投与との適切性を評定することは、1)癌を有することが疑われる患者、または癌を発症するリスクがある患者、または転移癌を発症するリスクがある患者から試料を得るステップと;2)分泌されたBAG2の量を測定するステップであって、測定されたレベルが、対照試料中で測定されたものを有意に上回る、ステップと;3)患者が癌を有すること、またはより攻撃的な癌もしくは転移癌を発症していることを決定するステップと;4)BAG2の発現を抑制する治療薬の有効量を患者に投与するステップ、からなる。
ポリペプチドまたは抗体治療薬は、短い循環半減期およびタンパク質分解および低溶解度の影響を被る可能性がある。本発明のバイオ医薬の薬物動態および薬力学特性を改善するために、アミノ酸配列の操作などの方法を行って、免疫原性を低下または上昇させ、タンパク質分解切断を減少させてよく、免疫グロブリンおよびアルブミンなどの血清蛋白質へのペプチドの融合またはコンジュゲーションを行ってよく;防護および徐放のための本発明のペプチドおよび抗体などのバイオ医薬のための薬物送達ビヒクルへの組み込みもまた行ってよく;天然または合成ポリマーへのコンジュゲーティングもまた企図される。詳細には、合成ポリマーコンジュゲーションのために、ペグ化、またはアシル化、例えばN-アシル化、S-アシル化なども、企図される。
また提供されるのは、本明細書に記載された本発明の核酸分子を含む発現ベクターであり、ここで核酸分子は、発現制御配列に動作可能に連結される。また提供されるのは、ポリペプチドの発現に適した宿主細胞に導入された本発明の発現ベクターを含むポリペプチドの生成のための宿主-ベクター系である。適切な宿主細胞は、E.コリなどのバクテリア細胞、ピキア・パストリスなどの酵母細胞、スポドプテラ・フルギペルダなどの昆虫細胞、またはCOS、HEKもしくはCHO細胞などの哺乳動物細胞であってよい。
遺伝子療法は、発現されたまたは発現可能な核酸の対象への投与により実施される治療を指す。本発明のこの実施形態において、核酸は、治療効果を媒介するそれらのコード化タンパク質を生成する。
治療化合物の配合剤は、当該技術分野で一般に知られており、簡便にはRemington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Co., Easton, Pa., USAで参照され得る。例えば、約0.05ng~約20mg/キログラム体重/日が、投与されてよい。投与レジメンは、最適な治療応答を提供するように調整されてよい。例えば複数の分割用量が、連日投与されてよく、または用量は、治療状況の急迫性により示される通り、比例して低減されてよい。活性化合物は、経口、静脈内(水溶性なら)、筋肉内、皮下、鼻内、眼内、皮内もしくは坐剤経路による、または埋め込み(例えば、腹腔内経路により徐放性分子を用いて、またはインビトロで感作されてレシピエントに養子移入された細胞、例えば単球もしくは樹状細胞を用いることにより)によるなどの、簡便な手法で投与されてよい。投与経路に応じて、ペプチドは、上記成分を不活性化し得る酵素、酸および他の自然条件の作用から防護するために材料でコートされることが必要とされてよい。
様々な送達システム、例えばリポソーム中のカプセル化、マイクロ粒子、マイクロカプセル、化合物を発現することが可能な組換え細胞、受容体介在性エンドサイトーシス、レトロウイルスまたは他のベクターの一部としての核酸の構築など、が公知であり、本発明の化合物を投与するために用いられ得る。導入の方法としては、皮内、筋肉内、腹腔内、静脈内、皮下、鼻内、眼内、硬膜外、および経口経路が挙げられるが、これらに限定されない。化合物または組成物は、任意の簡便な経路により、例えば輸液またはボーラス注射により、上皮または皮膚粘膜ライニング(mucocutaneous lining)(例えば、口腔粘膜、直腸および腸管粘膜ほか)を通した吸収により投与されてよく、および他の生物活性剤と一緒に投与されてよい。投与は、全身または局所であり得る。加えて、本発明の医薬化合物または組成物を、脳室内および髄腔内注射を含む、任意の適切な経路により中枢神経系に導入することが望ましく、脳室内注射は、例えばOmmayaリザーバーなどのリザーバーに取り付けられた、脳室内カテーテルにより容易にされ得る。肺投与もまた、例えば吸入器またはネブライザーの使用、およびエアロゾル化剤の配合により、用いられ得る。
実施例1:抗BAG2抗体の選択、シーケンシングおよび抗原-抗体反応
1.BAG2を標的とするモノクローナル抗体の選択およびそのアミノ酸配列の解析
本発明者らは、BAG2を標的とする抗体を選択し、それらのアミノ酸配列を解析し、抗体のそれぞれの相補性決定領域(CDR)を決定した。
図1は、10種のマウスハイブリドーマ細胞から生成された抗BAG2抗体の免疫ブロッティングの結果を示す。具体的には、ヒト乳癌細胞であるMDA-MB-231細胞を、10%FBS、100U/mlペニシリンおよび100μg/mlストレプトマイシンを含有するDMEM(Welgene)培地中にて、37℃の温度で培養した。細胞を、ウェルから剥離し、PBSで洗浄し、1% Brij97、5mM EDTA、0.02M HEPES pH7.3、0.15M NaCl、1mM PMSF、0.5mM NaF、10μg/rni アプロチニン、0.2mMオルトバナジン酸ナトリウムを含有する溶解緩衝溶液に溶解した。氷上での15分のインキュベーション後に、核を、遠心分離により細胞から除去し、上清を、採取した。20%グリセロール、4.6%SOS、0.125M Tris pH6.8、0.1%ブロモフェノールブルーからなる2X試料緩衝液を、適当な量の上清に添加した。10μgのタンパク質試料を、mini-Protean IIシステム(Bio-Rad、カリフォルニア州ハーキュリーズ所在)を用いることによる、標準条件下の12%ゲル上でのSOS-PAGE解析に供した。免疫ブロッティングのために、タンパク質を、Millipore PVDF膜の上に移した。TBS中の0.1%Tween 20および5%ウシ血清アルブミン(BSA)からなるブロッキング溶液を、1時間反応させた。次に一次抗体は、ハイブリドーマ細胞培養物から抽出された抗BAG2抗体の1/2000希釈液であり、二次抗体として用いられるヤギ抗マウスHRPコンジュゲート(Dako)を、1/5000に希釈した。フィルム感光を、EGL試薬(Amersham Pharmacia Biotech)を基質として用い暗所で実施した。感光されたバンドを、標準の分子マーカと比較して、BAG2のサイズに対応するバンドを同定した。
抗BAG2の10種のハイブリドーマ細胞株を、製造業者(GE Healthcare Biosciences AB)の使用説明に従いSepharoseタンパク質A/Gカラムでのアフィニティークロマトグラフィーにより各培養上清から精製した。対照Mu-IgG2a(ATCC、CCL-167(商標))を、アイソタイプ対照抗体として用い、American Type Culture Collectionから得た。インビトロおよびインビボ試験で用いられた抗BAG2マウス抗体およびアイソタイプ対照抗体を、Nanotoolによりエンドトキシン不含条件(<0.01EU/ug)で生成した。
腫瘍分泌BAG2タンパク質は、腫瘍微小環境において、抗免疫性(適応または自然免疫)のためにリンパ、骨髄、および間質細胞に結合し得る。本発明者らは、BAG2中和が、リンパ、骨髄、または間質に媒介された免疫抑制を標的とし、一方で免疫チェックポイント阻害薬が、アネルギー化された抗腫瘍T細胞の機能および骨髄細胞の抗炎症性を回復させると仮定した。
結果は、以下を示す。
結果は、以下を示す。
結果は、以下を示す。
背景
高頻度マイクロサテライト不安定性(MSI)の大腸癌(CRC)は、ミスマッチ修復性(MMR)の欠損、ならびにPD-L1、LAG-3およびIDOのレベル増加を有し、抗プログラム細胞死(PD)療法に対し明確に応答する。臨床現場において腫瘍の大部分を構成する低頻度MSIまたはマイクロサテライト安定性(MSS)CRCは、PD-1阻害によるいずれの利益も認めなかった。MSS CRCは、MSI CRCに比較してより高い割合のKRAS発癌性変異を有する。抗BAG2抗体と抗PD-1剤の併用療法を、C57BL/6(MC38;KRASwt、MSI)およびBALB/c(CT26;KRASmut、MSS)マウスの相乗性モデルにおいて試験した。
結果は、以下に示す。
結果は、以下を示す。
結果は、以下を示す。
寄託:韓国生命工学研究院(Korea Research Institute of Bioscience and Biotechnology)
アクセッション番号:KCTC13737BP
寄託日:2018年11月28日
寄託:韓国生命工学研究院
アクセッション番号:KCTC13738BP
寄託日:2018年11月28日
寄託:韓国生命工学研究院
アクセッション番号:KCTC13739BP
寄託日:2018年11月28日
寄託:韓国生命工学研究院
アクセッション番号:KCTC13740BP
寄託日:2018年11月28日
寄託:韓国生命工学研究院
アクセッション番号:KCTC13741BP
寄託日:2018年11月28日
寄託:韓国生命工学研究院
アクセッション番号:KCTC13742BP
寄託日:2018年11月28日
寄託:韓国生命工学研究院
アクセッション番号:KCTC13743BP
寄託日:2018年11月28日
寄託:韓国生命工学研究院
アクセッション番号:KCTC13744BP
寄託日:2018年11月28日
寄託:韓国生命工学研究院
アクセッション番号:KCTC13745BP
寄託日:2018年11月28日
寄託:韓国生命工学研究院
アクセッション番号:KCTC13746BP
寄託日:2018年11月28日
Claims (28)
- BAG2ポリペプチドまたはそのフラグメントに特異的に結合する抗体またはその抗原結合フラグメント。
- SEQ ID NO:33のアミノ酸配列からなる相補性決定領域(VH-CDR)1と、SEQ ID NO:39のアミノ酸配列からなるVH-CDR2と、SEQ ID NO:45のアミノ酸配列からなるVH-CDR3とを含む重鎖可変領域、およびSEQ ID NO:51のアミノ酸配列からなる相補性決定領域(VL-CDR)1と、SEQ ID NO:57のアミノ酸配列からなるVL-CDR2と、SEQ ID NO:63のアミノ酸配列からなるVL-CDR3とを含む軽鎖可変領域、
SEQ ID NO:34のアミノ酸配列からなるVH-CDR1と、SEQ ID NO:40のアミノ酸配列からなるVH-CDR2と、SEQ ID NO:46のアミノ酸配列からなるVH-CDR3とを含む重鎖可変領域、およびSEQ ID NO:52のアミノ酸配列からなるVL-CDR1と、SEQ ID NO:58のアミノ酸配列からなるVL-CDR2と、SEQ ID NO:64のアミノ酸配列からなるVL-CDR3とを含む軽鎖可変領域、
SEQ ID NO:35のアミノ酸配列からなるVH-CDR1と、SEQ ID NO:41のアミノ酸配列からなるVH-CDR2と、SEQ ID NO:47のアミノ酸配列からなるVH-CDR3とを含む重鎖可変領域、およびSEQ ID NO:53のアミノ酸配列からなるVL-CDR1と、SEQ ID NO:59のアミノ酸配列からなるVL-CDR2と、SEQ ID NO:65のアミノ酸配列からなるVL-CDR3とを含む軽鎖可変領域、
SEQ ID NO:36のアミノ酸配列からなるVH-CDR1と、SEQ ID NO:42のアミノ酸配列からなるVH-CDR2と、SEQ ID NO:48のアミノ酸配列からなるVH-CDR3と、を含む重鎖可変領域、およびSEQ ID NO:54のアミノ酸配列からなるVL-CDR1と、SEQ ID NO:60のアミノ酸配列からなるVL-CDR2と、SEQ ID NO:66のアミノ酸配列からなるVL-CDR3と、を含む軽鎖可変領域、
SEQ ID NO:37のアミノ酸配列からなるVH-CDR1と、SEQ ID NO:43のアミノ酸配列からなるVH-CDR2と、SEQ ID NO:49のアミノ酸配列からなるVH-CDR3とを含む重鎖可変領域、およびSEQ ID NO:55のアミノ酸配列からなるVL-CDR1と、SEQ ID NO:61のアミノ酸配列からなるVL-CDR2と、SEQ ID NO:67のアミノ酸配列からなるVL-CDR3とを含む軽鎖可変領域、ならびに
SEQ ID NO:38のアミノ酸配列からなるVH-CDR1と、SEQ ID NO:44のアミノ酸配列からなるVH-CDR2と、SEQ ID NO:50のアミノ酸配列からなるVH-CDR3とを含む重鎖可変領域、およびSEQ ID NO:56のアミノ酸配列からなるVL-CDR1と、SEQ ID NO:62のアミノ酸配列からなるVL-CDR2と、SEQ ID NO:68のアミノ酸配列からなるVL-CDR3とを含む軽鎖可変領域、
を含む、請求項1に記載の抗体またはその抗原結合フラグメント。 - SEQ ID NO:21~26から選択される任意の1種のアミノ酸配列を含む重鎖可変領域と;
SEQ ID NO:27~32から選択される任意の1種のアミノ酸配列を含む軽鎖可変領域、
を含む、請求項1に記載の抗体またはその抗原結合フラグメント。 - SEQ ID NO:21の重鎖可変領域およびSEQ ID NO:27の軽鎖可変領域;SEQ ID NO:22の重鎖可変領域およびSEQ ID NO:28の軽鎖可変領域;SEQ ID NO:23の重鎖可変領域および
SEQ ID NO:29の軽鎖可変領域;SEQ ID NO:24の重鎖可変領域およびSEQ ID NO:30の軽鎖可変領域;SEQ ID NO:25の重鎖可変領域およびSEQ ID NO:31の軽鎖可変領域;もしくはSEQ ID NO:26の重鎖可変領域およびSEQ ID NO:32の軽鎖可変領域;またはそれらの組み合わせである、請求項1に記載の抗体またはその抗原結合フラグメント。 - モノクローナル抗体である、請求項1に記載の抗体またはその抗原結合フラグメント。
- 検出可能な標識または検出可能なシグナルを発することができる標識を付けられる、請求項1に記載の抗体またはその抗原結合フラグメント。
- 前記抗体が、ヒト化される、請求項1に記載の抗体またはその抗原結合フラグメント。
- ホットスポットが、前記抗体のCDRの外部および内部で操作される(engineered out in)、請求項1に記載の抗体またはその抗原結合フラグメント。
- 前記モノクローナル抗体が、一価、Fab、または一本鎖可変領域フラグメント抗体(scFv)である、請求項1に記載の抗体またはその抗原結合フラグメント。
- 前記モノクローナル抗体が、二価、二重特異性、または三重特異性である、請求項1に記載の抗体またはその抗原結合フラグメント。
- 前記モノクローナル抗体が、化学物質またはタンパク質に融合される、請求項1に記載の抗体またはその抗原結合フラグメント。
- 前記モノクローナル抗体が、毒素またはサイトカインに融合される、請求項11に記載の抗体またはその抗原結合フラグメント。
- アクセッション番号KCTC 13737BP、KCTC 13738BP、KCTC 13739BP、KCTC 13740BP、KCTC 13741BP、KCTC 13742BP、KCTC 13743BP、KCTC 13744BP、KCTC 13745BPおよびKCTC 13746BPで寄託されたハイブリドーマ細胞から選択されるハイブリドーマ細胞により生成される、請求項1に記載の抗体またはその抗原結合フラグメント。
- 複数の抗体またはその抗原結合フラグメントを含む、請求項1に記載の抗体またはその抗原結合フラグメント。
- 請求項1に記載の抗体またはその抗原結合フラグメントをコードするポリヌクレオチドを含むポリヌクレオチド。
- ベクターである、請求項15に記載のポリヌクレオチド。
- 検出可能な標識または検出可能なシグナルを発することができる標識が、前記ポリヌクレオチドとコンジュゲートされる、請求項16に記載のポリヌクレオチド。
- 請求項15に記載のポリヌクレオチドを含む宿主細胞。
- 請求項18に記載の宿主細胞を培養すること;および
前記得られた培養物から抗体またはその抗原結合フラグメントを分離すること、
を含む、抗体またはその抗原結合フラグメントを生成する方法。 - 前記抗体またはその抗原結合フラグメントを印付けることをさらに含む、請求項19に記載の方法。
- 個体における原発または転移癌である癌を処置するための方法であって、請求項1に記載の抗BAG2またはその抗原結合フラグメントをそれを必要とする前記個体に投与することを含む、方法。
- 既存の治療薬を共投与することまたは連続で投与することを含む、請求項21に記載の方法。
- 前記既存の治療が、癌免疫療法薬である、請求項22に記載の方法。
- 前記免疫療法薬が、免疫チェックポイント分子への阻害薬である、請求項23に記載の方法。
- 前記免疫チェックポイント分子が、PD-1、PD-L1、またはCTLA-4である、請求項24に記載の方法。
- 前記免疫療法薬が、顆粒球-マクロファージコロニー刺激因子(GM-CSF)、マクロファージコロニー刺激因子(M-CSF)、顆粒球コロニー刺激因子(G-CSF)、インターロイキン2(IL-2)、インターロイキン3(IL-3)、インターロイキン12(IL-12)、インターロイキン15(IL-15)、B7-1(CD80)、B7-2(CD86)、4-1BBリガンド、GITRL、OX-40L、抗CD3抗体、抗CD27抗体、抗CTLA4抗体、抗PD-1抗体、抗PD-L1抗体、抗GITR抗体、抗OX-40抗体、抗4-1BB抗体、抗LAG-3抗体、および抗TIM-3抗体からなる群から選択される、請求項23に記載の方法。
- 前記癌が、例えば、乳癌、大腸癌、頭頸部癌、結腸癌、皮膚癌、膵臓癌、肺癌、胃癌、前立腺癌、膀胱癌、尿道癌、肝臓癌、腎臓癌、淡明細胞肉腫、黒色腫、脳脊髄腫瘍、脳癌、胸腺、中皮腫、食道癌、胆管癌、精巣癌、胚細胞腫瘍、甲状腺癌、副甲状腺癌、子宮頸癌、子宮内膜癌、リンパ腫、骨髄異形成症候群(MOS)、骨髄線維症、急性白血病、慢性白血病、多発性骨髄腫、ホジキン病、内分泌癌、および肉腫から選択される、請求項21に記載の方法。
- 前記癌が、乳癌、肺癌、黒色腫、大腸癌、または膵臓癌である、請求項27に記載の方法。
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KR1020190016359A KR102241558B1 (ko) | 2019-02-12 | 2019-02-12 | Bag2 폴리펩티드 또는 이의 단편에 특이적으로 결합하는 항체 또는 그의 항원 결합 단편 |
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PCT/IB2020/051136 WO2020165794A1 (en) | 2019-02-12 | 2020-02-12 | Anti-bag2 antibody and methods of treating cancer |
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2020
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US20230194534A1 (en) | 2023-06-22 |
CN114761803A (zh) | 2022-07-15 |
AU2020222326A1 (en) | 2021-08-19 |
CA3129748A1 (en) | 2020-08-20 |
CN114269779A (zh) | 2022-04-01 |
EP3938788A4 (en) | 2023-01-04 |
US20230183324A1 (en) | 2023-06-15 |
EP3924382A4 (en) | 2023-01-04 |
WO2020165794A1 (en) | 2020-08-20 |
WO2020165797A1 (en) | 2020-08-20 |
EP3924382A1 (en) | 2021-12-22 |
BR112021015940A2 (pt) | 2021-10-05 |
MX2021009690A (es) | 2021-10-01 |
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