JP7479281B2 - 抗ox40抗体及びその用途 - Google Patents
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Description
ここで、選択されたVH CDRs 1、2及び3アミノ酸配列、並びに選択されたVL CDRs 1、2及び3アミノ酸配列は、以下のいずれの1つである、OX40(TNF受容体スーパーファミリーメンバー4)に結合できる抗体又はその抗原結合フラグメントを提供する。
(1)選択されたVH CDRs 1、2、3アミノ酸配列は、それぞれSEQ ID NOs: 1、2、3に示され、且つ、選択されたVL CDRs 1、2、3アミノ酸配列は、それぞれSEQ ID NOs: 4、5、6に示されること、
(2)選択されたVH CDRs 1、2、3アミノ酸配列は、それぞれSEQ ID NOs: 7、8、9に示され、且つ、選択されたVL CDRs 1、2、3アミノ酸配列は、それぞれSEQ ID NOs: 10、11、12に示されること、
(3)選択されたVH CDRs 1、2、3アミノ酸配列は、それぞれSEQ ID NOs: 13、14、15に示され、且つ、選択されたVL CDRs 1、2、3アミノ酸配列は、それぞれSEQ ID NOs: 16、17、18に示されること、
(4)選択されたVH CDRs 1、2、3アミノ酸配列は、それぞれSEQ ID NOs: 19、20、21に示され、且つ、選択されたVL CDRs 1、2、3アミノ酸配列は、それぞれSEQ ID NOs: 22、23、24に示されること。
(1)重鎖可変領域(VH)を含む免疫グロブリン重鎖又はそのフラグメントにおいて、前記重鎖可変領域(VH)は、それぞれSEQ ID NOs: 1、2及び3に示されるアミノ酸配列を含む相補性決定領域(CDRs)1、2及び3を含み、且つ前記VHはSEQ ID NO: 56、57、58又は80に示されるアミノ酸配列を含む軽鎖可変領域(VL)とペアリングする場合に、OX40に結合する免疫グロブリン重鎖又はそのフラグメント;
(2)VLを含む免疫グロブリン軽鎖又はそのフラグメントにおいて、前記VLは、それぞれSEQ ID NOs: 4、5及び6に示されるアミノ酸配列を含むCDRs 1、2及び3を含み、且つ前記VLは、SEQ ID NO: 53、54、55又は79に示されるアミノ酸配列を含むVHとペアリングする場合に、OX40に結合する免疫グロブリン軽鎖又はそのフラグメント;
(3)重鎖可変領域(VH)を含む免疫グロブリン重鎖又はそのフラグメントにおいて、前記重鎖可変領域(VH)は、それぞれSEQ ID NOs: 7、8及び9に示されるアミノ酸配列を含むCDRs 1、2及び3を含み、且つ前記VHは、SEQ ID NO: 62、63、64、65又は82に示されるアミノ酸配列を含む軽鎖可変領域(VL)とペアリングする場合に、OX40に結合する免疫グロブリン重鎖又はそのフラグメント;又は
(4)VLを含む免疫グロブリン軽鎖又はそのフラグメントにおいて、前記VLは、それぞれSEQ ID NOs: 10、11及び12に示されるアミノ酸配列を含むCDRs 1、2及び3を含み、且つ前記VLは、SEQ ID NO: 59、60、61又は81に示されるアミノ酸配列を含むVHとペアリングする場合に、OX40に結合する免疫グロブリン軽鎖又はそのフラグメント;
(5)重鎖可変領域(VH)を含む免疫グロブリン重鎖又はそのフラグメントにおいて、前記重鎖可変領域(VH)は、それぞれSEQ ID NOs: 13、14及び15に示されるアミノ酸配列を含むCDRs 1、2及び3を含み、且つ前記VHは、SEQ ID NOs: 69、70、71、72又は84に示されるアミノ酸配列を含む軽鎖可変領域(VL)とペアリングする場合に、OX40に結合する免疫グロブリン重鎖又はそのフラグメント;
(6)VLを含む免疫グロブリン軽鎖又はそのフラグメントにおいて、前記VLは、それぞれSEQ ID NOs: 16、17及び18に示されるアミノ酸配列を含むCDRs 1、2及び3を含み、且つ前記VLは、SEQ ID NOs: 66、67、68又は83に示されるアミノ酸配列を含むVHとペアリングする場合に、OX40に結合する免疫グロブリン軽鎖又はそのフラグメント;
(7)重鎖可変領域(VH)を含む免疫グロブリン重鎖又はそのフラグメントにおいて、前記重鎖可変領域(VH)は、それぞれSEQ ID NOs: 19、20及び21に示されるアミノ酸配列を含むCDRs 1、2及び3を含み、且つ前記VHは、SEQ ID NOs: 76、77、78又は86に示されるアミノ酸配列を含む軽鎖可変領域(VL)とペアリングする場合に、OX40に結合する免疫グロブリン重鎖又はそのフラグメント;
(8)VLを含む免疫グロブリン軽鎖又はそのフラグメントにおいて、前記VLは、それぞれSEQ ID NOs: 22、23及び24に示されるアミノ酸配列を含むCDRs 1、2及び3を含み、且つ前記VLは、SEQ ID NO: 73、74、75又は85に示されるアミノ酸配列を含むVHとペアリングする場合に、OX40に結合する免疫グロブリン軽鎖又はそのフラグメント;を含む核酸を提供する。
(1)選択されたVH配列は、SEQ ID NO: 53、54、55又は79であり、且つ選択されたVL配列は、SEQ ID NO: 56、57、58又は80であり;
(2)選択されたVH配列は、SEQ ID NO: 59、60、61又は81であり、且つ選択されたVL配列是SEQ ID NO: 62、63、64、65又は82であり;
(3)選択されたVH配列は、SEQ ID NO: 66、67、68又は83であり、且つ選択されたVL配列は、SEQ ID NO: 69、70、71、72又は84であり;
(4)選択されたVH配列は、SEQ ID NO: 73、74、75又は85であり、且つ選択されたVL配列は、SEQ ID NO: 76、77、78又は86である。
免疫系は、体内の正常な細胞と「外来」とみなされる細胞とを区別することができる。これにより、免疫系は、正常な細胞に影響を与えずに、外来細胞を攻撃できる。このメカニズムには、免疫チェックポイントと呼ばれるタンパク質が関与する場合がある。免疫チェックポイントは、免疫システムの内、シグナルを増幅したり(共刺激分子)、シグナルを抑制する分子である。
本開示は、抗OX40抗体及その抗原結合フラグメントを提供する。一般的に、抗体(免疫グロブリンとも呼ばれる)は、軽鎖及び重鎖の両方のポリペプチド鎖からなる。本開示に係る非限定的な抗体は、2本の重鎖及び2本の軽鎖を含む無傷の4本の免疫グロブリン鎖抗体である。抗体の重鎖は、IgM、IgG、IgE、IgA又はIgDを含む任意のアイソタイプ、或いはIgG1、IgG2、IgG2a、IgG2b、IgG3、IgG4、IgE1、IgE2などを含むサブアイソタイプであってもよい。軽鎖はκ軽鎖又はλ軽鎖であってもよい。抗体は、軽鎖の2つの同一コピー及び重鎖の2つの同一コピーを含んでもよい。それぞれ1つの可変ドメイン(又は可変領域、VH)及び複数の定常ドメイン(又は定常領域)を含む重鎖は、その定常領域内のジスルフィド結合を介して互いに結合し、抗体の「幹」を形成する。それぞれ1つの可変ドメイン(又は可変領域、VL)及び1つの定常ドメイン(又は定常領域)を含む軽鎖は、それぞれジスルフィド結合を介して1本の重鎖に結合する。各軽鎖の可変領域は、それが結合する重鎖の可変領域とペアリングしている。軽鎖と重鎖の両方の可変領域は、いずれもより保存的なフレームワーク領域(FR)の間にある3つの超可変領域を含む。
本開示は、OX40に特異的に結合する抗体及その抗原結合フラグメントを提供する。本明細書に記載の抗体及び抗原結合フラグメントは、OX40に結合でき、OX40シグナル伝達経路を促進できるため、免疫応答を増強させる。本開示は、例えば、マウス抗OX40抗体07-9H3(「9H3」)、07-9A4(「9A4」)、11-5C1(「5C1」)、17-5D10(「5D10」)、及びキメラ抗体、そのヒト化抗体(例えば、表3に示される抗体)を提供する。
本明細書に記載の抗体又はその抗原結合フラグメントは、OX40とOX40Lの結合を遮断することができる。
ヒトOX40の単離フラグメントは、ポリクローナル及びモノクローナル抗体の作製のための標準的技術を使用して抗体を生成する免疫原として用いられる。ポリクローナルは、抗原性ペプチド又はタンパク質の複数回の注射(例えば、皮下又は腹腔内注射)により動物内で発生されることができる。幾つかの実施態様において、抗原性ペプチド又はタンパク質は、少なくとも1つのアジュバントとともに注射される。幾つかの実施態様において、抗原性ペプチド又はタンパク質は、予防接種を受ける種において免疫原性である試薬と複合化されることができる。動物に抗原性ペプチド又はタンパク質を1回超え(例えば、2回、3回又は4回)注射することができる。
本開示は、本明細書に開示される単離されたポリヌクレオチド(例えば、本明細書に開示されるポリペプチドをコードするポリヌクレオチド)を含む組換えベクター(例えば、発現ベクター)において、組換えベクターが導入される宿主細胞(即ち、宿主細胞はポリヌクレオチド及び/又はポリヌクレオチド含有ベクターを含む)、及び組換え技術による組換え抗体ポリペプチド又はそのフラグメントの生産を提供する。
本開示の抗体又はその抗原結合フラグメントは、多くの治療目的に用いられる。一つの側面では、本開示は、対象の癌を治療するための方法、対象の腫瘍体積の経時的増大の速率を低減させる方法、転移のリスクを低下させる方法、又は対象の一般以外の転移が発症するリスクを低下させる方法を提供する。幾つかの実施態様において、治療は、癌の進行を停止、退縮、遅延、または阻害することができる。幾つかの実施態様において、治療は、対象の癌の1種又は複数種の症状の数、重症度及び/又は持続期間の減少をもたらすことができる。
本明細書には、さらに、本明細書に記載の抗体又は抗原結合フラグメントの少なくとも1種(例えば、1種、2種、3種又は4種)を含む医薬組成物を提供する。本明細書に記載の抗体又は抗原結合フラグメントのいずれかの2種又はそれ以上(例えば、2種、3種又は4種)は、任意に組み合わせて医薬組成物に存在することができる。医薬組成物は、当技術分野で知られている任意の方法で製剤化することができる。
ヒトOX40(hOX40;SEQ ID NO: 49)に対するマウス抗体を産生するために、6~8週齢の雌性BALB/cマウスをヒトOX40で予防接種した。抗hOX40抗体は、以下に記載の方法により収集された(図1及び図2を参照)。
6~8週齢の雌性BALB/cマウスを100μg/mlの濃度で20μg/マウスでHisタグ付きヒトヒトOX40タンパク質で予防接種した。Hisタグ付きヒトOX40タンパク質をアジュバントで乳化し、マウスの背中の4つの位置に注射した。1回目の皮下(s.c.)注射では、希釈された抗原を同体積の完全フロイントアジュバント(CFA)で乳化した。次の皮下注射では、タンパク質を同体積の不完全フロイントアジュバント(IFA)で乳化した。3回目の注射又は追加予防接種の3日後、血液(血清)を収集し、ELISAを使用して抗体価を分析した。
脾臓組織を粉砕した。まず、CD3εマイクロビーズ及び抗マウスIgMマイクロビーズにより脾臓細胞を選択し、次に、SP2/0細胞と融合させた。その後、細胞をヒポキサンチン-アミノプテリン-チミジン(HAT)培地を含む96ウェルプレートにプレーティングした。
標準的プロトコルに従って、蛍光活性化セルソーティング(Fluorescence-Activated Cell Sorting、FACS)を使用し、96ウェルプレートでのハイブリドーマ上清の1次スクリーニングを行った。スクリーニングの前に、チャイニーズハムスター卵巣(Chinese hamster ovary、CHO)細胞を96ウェルプレート(ウェルあたり2×104細胞)に加えた。上清50μlを使用した。実験で使用された抗体は、
ClonePix2を使用してサブクローン化を施した。簡単的には、1次スクリーニング中に同定された陽性ウェルを半固体培地に移し、IgG陽性クローンを同定してテストした。FITC抗マウスIgG Fc抗体を使用した。
1×106個の陽性ハイブリドーマ細胞をB-NDG(登録商標)マウス(Beijing Biocytogen、北京、中国)に腹腔内注射した。マウスの腹腔内でハイブリドーマ細胞を増殖させることによりモノクローナル抗体を産生した。ハイブリドーマ細胞は、マウスの腹部に増殖し腹水を産生した。腹水は、高濃度の抗体を含み、それを採取して後で使用するために用意した。
腹水中の抗体は、GE AKTAタンパク質液体クロマトグラフィー(GE Healthcare、 Chicago、 Illinois、 United States)を使用して精製した。07-9H3(「9H3」)、07-9A4(「9A4」)、11-5C1(「5C1」)、17-5D10(「5D10」)、08-6A11(「6A11」)及び14-7F11(「7F11」)は、上記の方法で産生されたマウス抗体に存在した。
ヒト化の出発点は、マウス抗体(例えば、9H3、9A4、5C1及び5D10)である。これらのマウス抗体の重鎖可変領域及び軽鎖可変領域のアミノ酸配列を決定した。
ブロッキングアッセイを行って、抗hOX40抗体がhOX40とhOX40Lの間の結合を遮断できるかどうかを調べた。
抗hOX40抗体は、マウス腹水から収集され、クロマトグラフィーにより精製された。ヒトOX40で一過性にトランスフェクトされたCHO細胞25μlをプレートの各ウェルに加えた。精製された抗体を、最終濃度が50、5、0.5、0.05、0.005 μg/mlになるまで滴下された。滴下された抗体は、各ウェルにウェルあたり25 μl4℃で添加し、30分間インキュベートした。
CHO細胞にアカゲザルOX40(rmOX40、SEQ ID NO: 51)、マウスOX40(mOX40、SEQ ID NO: 50)及びキメラ(マウス及びヒト)OX40(chiOX40、SEQ ID NO: 52)をトランスフェクトした。
抗体とhOX40の結合を測定した。抗体の親和性は、タンパク質Aが固定化されたセンサーチップを搭載した表面プラズモン共鳴(Biacore T200バイオセンサー、 Biacore、 INC、 Piscataway N.J.)により決定された。
サーモフルオアッセイ分析は、Protein Thermal Shift(商標)色素キット(Thermo Fisher Scientific)及びQuantStudio(商標) 5リアルタイムPCRシステム(Thermo Fisher Scientific)を使用して行われた。そのアッセイは、タンパク質が展開するときに露出した疎水性パッチに結合する蛍光色素を使用して、熱安定性を測定した。
in vivoで抗hOX40抗体をテストし、これらの抗体の人体への作用を予測するために、OX40ヒト化マウスモデルを作成した。OX40ヒト化マウスモデルは、マウスOX40タンパク質の細胞外領域の一部がヒトOX40細胞外領域置換されたキメラOX40タンパク質(SEQ ID NO: 52)を発現するように設計された。マウスOX40(SEQ ID NO: 50)の31~195番目のアミノ酸残基は、ヒトOX40(SEQ ID NO: 49)の35~197番目のアミノ酸残基に置き換えられた。ヒト化マウスモデル(B-hOX40ヒト化マウス)は、ヒトとマウスOX40を発現する通常のマウスの臨床結果の差を大幅に減らすことにより、臨床設定で新しい治療法をテストするための新しいツールを提供できる。OX40ヒト化マウスモデルに関する詳細は、PCT/CN2017/099575に参照され、その全体が援引により本明細書に組み込まれた。
B-hOX40ヒト化マウス(OX40ヒト化マウス)には、マウス抗-hOX40抗体07-9H3、07-9A4、11-5C1、17-5D10、08-6A11及び14-7F11を投与した。マウスの体重は、治療期間全体にわたってモニタリングされた。異なる群のマウスの体重は、すべて増加した(図7及び図8)。対照群と抗hOX40治療群の間で体重に有意差は観察されなかった。結果は、抗hOX40抗体は忍容性が高く、マウスに対して毒性がないことを示した。
B-hOX40ヒト化マウス(ヒト化OX40マウス)に、腹腔内投与によりマウス抗hOX40抗体9H3、キメラ抗hOX40抗体 9H3-mHvKv-IgG1、9H3-mHvKv-IgG2、9H3-mHvKv-IgG4及び9H3-mHvKv-IgG1-N297Aを投与した。注射量は、3mg/kgでマウスの体重に基づいて計算された。毎週の1日目及び4日目に抗体を投与した(合計5回の注射)。
OX40ヒト化マウスでヒト化抗hOX40抗体をテストし、in vivoでの腫瘍増殖に対するその作用を実証した。
併用療法の有効性を評価するために、マウスには抗hOX40抗体を幾つかの他の治療剤とともに投与した。
B-hOX40ヒト化マウスにMC-38癌腫瘍細胞を皮下注射した。マウスの腫瘍が150±50 mm3の体積に達したとき、腫瘍の体積に基づいてマウスを異なる群にランダムに分けた(各群あたり6匹のマウス)。次いで、腹腔内投与によりマウスに(G1)PS(対照)、(G2)キイトルーダ(0.3mg/kg)(Merck)、(G3)9H3(3mg/kg)、および(G4)キイトルーダ(0.3mg/kg)及び9H3(3mg/kg)を注射した。毎週の1日目及び4日目に抗体を投与し、3週周持続した(合計6回の注射)。
B-hOX40ヒト化マウスにEL4癌腫瘍細胞(化学的に誘導されたリンパ腫に由来するマウス腫瘍細胞株)を皮下注射した。マウスの腫瘍が150±50 mm3の体積に達したとき、腫瘍の体積に基づいてマウスを異なる群にランダムに分けた(各群あたり5匹のマウス)。次いで、腹腔内投与によりマウスに(G1)PS(対照)、(G2)9H3(3mg/kg)、(G3)キイトルーダ(3mg/kg)、および(G4)キイトルーダ(3mg/kg)及び9H3(3mg/kg)を注射した。毎週の1日目及び4日目に抗体を投与し、3週周持続した(合計6回の注射)。
併用療法の有効性を評価するために、マウスには抗hOX40抗体を抗PD1又は抗PDL1抗体とともに投与した。
併用療法の有効性を評価するために、マウスに抗hOX40抗体を抗LAG-3、抗TIGIT、抗BTLA、抗CTLA-4又は抗GITR抗体とともに投与した。
(G1)PS(対照);
(G2)9H3(1mg/kg);
(G3)mLAG-3(C9B7W)(マウス抗LAG-3抗体;BioXcell、カタログ番号:BE0174)(3mg/kg);
(G4)9H3(1mg/kg)及びmLAG-3(C9B7W)(3mg/kg);
(G5)mTIGIT(1G9)(マウス抗mTIGIT抗体;BioXcell、カタログ番号:BE0274)(3mg/kg);
(G6)9H3(1mg/kg)及びmTIGIT(1G9)(3mg/kg);
(G7)mBTLA(PJ196)(マウス抗mBTLA抗体;BioXcell、カタログ番号:BE0196)(10mg/kg);
(G8)9H3(1mg/kg)及びmBTLA(PJ196)(10mg/kg);
(G9)mCTLA-4(9D9)(マウス抗mCTLA-4抗体;BioXcell、カタログ番号:BE0164)(1mg/kg);
(G10)9H3(1mg/kg)及びmCTLA-4(9D9)(1mg/kg);
(G11)mGITR(DTA-1)(マウス抗mGITR抗体;BioXcell、カタログ番号:BE0063)(0.3mg/kg);
(G12)9H3(1mg/kg)及びmGITR(DTA-1)(0.3mg/kg)を注射した。
OX40ヒト化マウスにおいてヒト化9A4、5C1及び5D10抗体をテストし、in vivoでの腫瘍増殖に対するそれらの作用を実証した。
本発明に係る具体的な実施形態と組み合わせて本発明を説明したが、上記の説明は、特許請求の範囲によって定義される本発明の範囲を限定するのではなく例示することを意図していることを理解すべきである。他の側面、利点及び修正案も添付の特許請求の範囲内にある。
Claims (12)
- 相補性決定領域(CDRs)1、2及び3を含む重鎖可変領域(VH)と、
CDRs 1、2及び3を含む軽鎖可変領域(VL)と、を含むOX40(TNF受容体スーパーファミリーメンバー4)に結合する抗体又はその抗原結合フラグメントであって、
前記VH CDRs 1、2及び3のアミノ酸配列及び前記VL CDRs 1、2及び3アミノ酸配列は、
(1)前記VH CDRs 1、2、3アミノ酸配列は、それぞれSEQ ID NOs: 1、2、3に示され、且つ前記選択されたVL CDRs 1、2、3アミノ酸配列は、それぞれSEQ ID NOs: 4、5、6に示される、
(2)前記VH CDRs 1、2、3アミノ酸配列は、それぞれSEQ ID NOs: 7、8、9に示され、且つ前記VL CDRs 1、2、3アミノ酸配列は、それぞれSEQ ID NOs: 10、11、12に示される;
(3)前記VH CDRs 1、2、3アミノ酸配列は、それぞれSEQ ID NOs: 13、14、15に示され、且つ前記VL CDRs 1、2、3アミノ酸配列は、それぞれSEQ ID NOs: 16、17、18に示される;並びに、
(4)前記VH CDRs 1、2、3アミノ酸配列は、それぞれSEQ ID NOs: 19、20、21に示され、且つ前記VL CDRs 1、2、3アミノ酸配列は、それぞれSEQ ID NOs: 22、23、24に示される;
から成る群から選択される、OX40(TNF受容体スーパーファミリーメンバー4)に結合する抗体又はその抗原結合フラグメント。 - 前記VHは、それぞれSEQ ID NOs: 1、2及び3に示されるアミノ酸配列を有するCDRs 1、2、3を含み、且つ前記VLは、それぞれSEQ ID NOs: 4、5及び6に示されるアミノ酸配列を有するCDRs 1、2、3を含む、又は、前記VHは、それぞれSEQ ID NOs: 13、14及び15に示されるアミノ酸配列を有するCDRs 1、2、3を含み、且つ前記VLは、それぞれSEQ ID NOs: 16、17及び18に示されるアミノ酸配列を有するCDRs 1、2、3を含む、請求項1に記載の抗体又はその抗原結合フラグメント。
- ポリペプチドをコードするポリヌクレオチドを含む核酸であって、前記ポリペプチドは、
(1)SEQ ID NOs: 53、54、55又は79に示されるアミノ酸配列を含む重鎖可変領域(VH)を含む免疫グロブリン重鎖、及び、SEQ ID NOs: 56、57、58又は80に示されるアミノ酸配列を含む軽鎖可変領域(VL)を含む免疫グロブリン軽鎖;
(2)SEQ ID NOs: 59、60、61又は81に示されるアミノ酸配列を含む重鎖可変領域(VH)を含む免疫グロブリン重鎖、及び、SEQ ID NOs: 62、63、64、65又は82に示されるアミノ酸配列を含む軽鎖可変領域(VL)を含む免疫グロブリン軽鎖;
(3)SEQ ID NOs: 66、67、68又は83に示されるアミノ酸配列を含む重鎖可変領域(VH)を含む免疫グロブリン重鎖、及び、SEQ ID NOs: 69、70、71、72又は84に示されるアミノ酸配列を含む軽鎖可変領域(VL)を含む免疫グロブリン軽鎖;
(4)SEQ ID NOs: 73、74、75又は85に示されるアミノ酸配列を含む重鎖可変領域(VH)を含む免疫グロブリン重鎖、及び、SEQ ID NOs: 76、77、78又は86に示されるアミノ酸配列を含む軽鎖可変領域(VL)を含む免疫グロブリン軽鎖;
を含む、核酸。 - 請求項3に記載の核酸を含むベクター。
- 請求項4に記載のベクターを含む、細胞。
- 抗体又はその抗原結合フラグメントを産生する方法であって、
(a)請求項5に記載の細胞に前記抗体又は抗原結合フラグメントを産生させるために十分な条件下で、前記細胞を培養すること;及び
(b)前記細胞によって産生された前記抗体又は抗原結合フラグメントを収集すること、を含む方法。 - 重鎖可変領域(VH)及び軽鎖可変領域(VL)を含む、OX40に結合する抗体又はその抗原結合フラグメントにおいて、
前記重鎖可変領域(VH)は、選択されたVH配列と同一であるアミノ酸配列を含み、前記軽鎖可変領域(VL)は、選択されたVL配列と同一であるアミノ酸配列を含み、ここで、前記選択されたVH配列及び前記選択されたVL配列は、以下のいずれか1つである、抗体又はその抗原結合フラグメント。
(1)前記選択されたVH配列は、SEQ ID NOs: 53、54、55又は79であり、且つ前記選択されたVL配列は、SEQ ID NOs: 56、57、58又は80であること;
(2)前記選択されたVH配列は、SEQ ID NOs: 59、60、61又は81であり、且つ前記選択されたVL配列は、SEQ ID NOs: 62、63、64、65又は82であること;
(3)前記選択されたVH配列は、SEQ ID NOs: 66、67、68又は83であり、且つ前記選択されたVL配列は、SEQ ID NOs: 69、70、71、72又は84であること;及び、
(4)前記選択されたVH配列は、SEQ ID NOs: 73、74、75又は85であり、且つ前記選択されたVL配列は、SEQ ID NOs: 76、77、78又は86であること。 - (1)前記VHは、SEQ ID NO: 53の配列を含み、且つ前記VLは、SEQ ID NO: 56の配列を含む;
(2)前記VHは、SEQ ID NO: 55の配列を含み、且つ前記VLは、SEQ ID NO: 58の配列を含む;
(3)前記VHは、SEQ ID NO: 55の配列を含み、且つ前記VLは、SEQ ID NO: 56の配列を含む;又は、
(4)前記VHは、SEQ ID NO: 73の配列を含み、且つ前記VLは、SEQ ID NO: 77の配列を含む;
請求項7に記載の抗体又はその抗原結合フラグメント。 - VH CDRs1、2、3を含む重鎖可変領域(VH)及びVL CDRs1、2、3を含む軽鎖可変領域(VL)を含む、OX40に結合する抗体又はその抗原結合フラグメントであって、
(1)前記VH CDRs1、2、3は、SEQ ID NO: 55における相補性決定領域と同一である、且つ、前記VL CDRs1、2、3は、SEQ ID NO: 56における相補性決定領域と同一である;
(2)前記VH CDRs1、2、3は、SEQ ID NO: 59における相補性決定領域と同一である、且つ、前記VL CDRs1、2、3アミノ酸配列は、SEQ ID NO: 62における相補性決定領域と同一である;
(3)前記VH CDRs1、2、3は、SEQ ID NO: 66における相補性決定領域と同一である、且つ、前記VL CDRs1、2、3は、SEQ ID NO: 69における相補性決定領域と同一である;又は、
(4)前記VH CDRs1、2、3は、SEQ ID NO: 73における相補性決定領域と同一である、且つ、前記VL CDRs1、2、3は、SEQ ID NO: 76における相補性決定領域と同一である、
抗体又はその抗原結合フラグメント。 - 治療剤と共有結合する請求項1、7及び9のいずれか1項に記載の抗体又はその抗原結合フラグメントを含む、抗体-薬物複合体であって、
前記治療剤は、細胞傷害性薬又は細胞増殖抑制薬である、
抗体-薬物複合体。 - 請求項1、7及び9のいずれか1項に記載の抗体又はその抗原結合フラグメント、及び薬学的に許容される担体を含む医薬組成物。
- 請求項1、8、および9のいずれか一項に記載の抗体又はその抗原結合フラグメントを含む、癌を阻害または治療するための組成物であって、
前記癌が、切除不能な黒色腫、転移性黒色腫、肉腫、小細胞肺がん、非小細胞肺がん(NSCLC)、頭頸部扁平上皮がん(SCCHN)、腎細胞がん(RCC)、黒色腫、膀胱がん、トリプルネガティブ乳がん(TNBC)及び、大腸がんから選択される、
組成物。
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KR102634374B1 (ko) | 2024-02-06 |
KR20200088810A (ko) | 2020-07-23 |
RU2020116668A3 (ja) | 2021-12-27 |
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