JP2020520665A - 抗体−サイトカイングラフト化タンパク質及び癌の治療における使用方法 - Google Patents
抗体−サイトカイングラフト化タンパク質及び癌の治療における使用方法 Download PDFInfo
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Abstract
Description
本出願は、2017年5月24日に出願された米国仮特許出願第62/510533号の利益を主張するものであり、この仮特許出願の内容は、全体が参照により本明細書に援用される。
本出願は、ASCII形式で電子的に提出された配列表を含み、その全体が参照により本明細書に援用される。2018年4月5日に作成された前記ASCIIコピーは、PAT057462−WO−PCT_SL.txtと称され、69,489バイトのサイズである。
本開示は、公知の臨床で使用されている分子と比べて好ましい治療プロファイルを有する抗体のCDR配列にグラフト化されたIL2を提供する。詳細には、提供される抗体サイトカイングラフト化タンパク質組成物は、Treg細胞の活性を低下させる一方で、CD8+ Tエフェクター細胞を増加させるか又はそれを維持する。加えて、提供される組成物は、Proleukin(登録商標)などの組換えヒトIL2製剤と比べて向上した半減期、安定性及び産生性を付与する。従って本開示は、IL2高親和性受容体への結合が低下した、IL2低親和性受容体に結合し且つそれを通じた好ましいシグナル伝達を促進する抗体サイトカイングラフト化タンパク質を提供する。(i)重鎖可変領域(VH)を含む免疫グロブリン重鎖配列と(ii)軽鎖可変領域(VL)を含む免疫グロブリン軽鎖配列とを含む抗体−サイトカイングラフト化タンパク質が提供され、ここで抗体のVH又はVLの相補性決定領域(CDR)にIL2分子がグラフト化される。
(a)相補性決定領域(CDR)HCDR1、HCDR2、HCDR3を含む、重鎖可変領域(VH);及び
(b)LCDR1、LCDR2、LCDR3を含む、軽鎖可変領域(VL);及び
(c)VH又はVLのCDRにグラフト化されたインターロイキン2(IL2)分子
を含む抗体サイトカイングラフト化タンパク質を提供する。
「抗体」は、四量体構造単位を含む免疫グロブリンファミリーの分子を指す。各四量体が2つの同一のポリペプチド鎖対を含み、各対が、ジスルフィド結合で結び付けられた1つの「軽」鎖(約25kD)と1つの「重」鎖(約50〜70kD)とを有する。認められている免疫グロブリン遺伝子には、κ、λ、α、γ、δ、ε、及びμ定常領域遺伝子、並びに無数の免疫グロブリン可変領域遺伝子が含まれる。軽鎖はκ又はλのいずれかに分類される。重鎖はγ、μ、α、δ、又はεに分類され、ひいてはこれが免疫グロブリンクラス、それぞれIgG、IgM、IgA、IgD、及びIgEを定義する。抗体は、任意のアイソタイプ/クラス(例えば、IgG、IgM、IgA、IgD、及びIgE)、又は任意のサブクラス(例えば、IgG1、IgG2、IgG3、IgG4、IgA1、IgA2)であり得る。
本明細書には、抗体の相補性決定領域(CDR)にグラフト化されたIL2分子を含むタンパク質構築物が提供される。本開示の抗体サイトカイングラフト化タンパク質はヒト患者での使用に好適な特性を示し、例えば、天然又は組換えヒトIL2と同様の免疫刺激活性を保持している。しかしながら、負の効果、例えばTreg細胞の刺激は減少している。他の活性及び特徴もまた本明細書全体を通じて実証される。従って、これまで公知のIL2及び修飾IL2治療剤、例えばProleukin(登録商標)と比べて治療プロファイルが改善された抗体サイトカイングラフト化タンパク質、及び提供される抗体サイトカイングラフト化タンパク質の癌治療における使用方法が提供される。
特定の態様において、抗体サイトカイングラフト化構築物は、IL2配列を免疫グロブリン足場のCDR領域にグラフト化することにより作成される。重鎖及び軽鎖の両方の免疫グロブリン鎖が作製されて、最終的な抗体グラフト化タンパク質が生じる。抗体サイトカイングラフト化タンパク質はCD8 Tエフェクター細胞に好ましい治療活性を付与し、抗体サイトカイングラフト化タンパク質は、天然又は組換えヒトIL2(rhIL2又はProleukin(登録商標))又はFcに融合したIL2と比較したときTreg活性が低下している。
抗体サイトカイングラフト化タンパク質を同定するためのアッセイは当該技術分野において公知であり、本明細書に記載される。アゴニスト抗体サイトカイングラフト化タンパク質はIL2低親和性受容体に結合し、細胞内シグナル伝達を促進、誘導、刺激してCD8 Tエフェクター細胞増殖並びに他の免疫刺激効果をもたらす。
別の態様において、抗体サイトカイングラフト化タンパク質の重鎖及び軽鎖タンパク質をコードする単離核酸が提供される。抗体サイトカイングラフト化タンパク質は、限定はされないが、組換え発現、化学合成、及び抗体四量体の酵素消化を含め、当該技術分野において公知の任意の手段により作製することができる。組換え発現は、当該技術分野において公知の任意の適切な宿主細胞、例えば、哺乳類宿主細胞、細菌宿主細胞、酵母宿主細胞、昆虫宿主細胞等からであってよい。
薬学的に許容可能な担体と共に製剤化された抗体サイトカイングラフト化タンパク質を含む医薬組成物が提供される。任意選択で、医薬組成物は、所与の障害の治療又は予防に好適な他の治療剤を更に含む。薬学的に許容可能な担体は組成物を増強し、若しくは安定化させるか、又は組成物の調製を促進する。薬学的に許容可能な担体としては、生理的に適合性のある溶媒、分散媒、コーティング、抗細菌剤及び抗真菌剤、等張剤及び吸収遅延剤などが挙げられる。
一部の態様において、抗体サイトカイングラフト化タンパク質は製品(即ちキット)で提供される。提供される抗体サイトカイングラフト化タンパク質は、概してバイアル又は容器内にある。従って、製品は、容器及び容器上にある又はそれと関連付けられたラベル又は添付文書を含む。好適な容器としては、例えば、ボトル、バイアル、シリンジ、溶液バッグ等が挙げられる。適宜、抗体サイトカイングラフト化タンパク質は液体又は乾燥形態(例えば、凍結乾燥形態)であってもよい。容器は、それ自体で、又は別の組成物との組み合わせで、癌の治療、予防及び/又は改善用の組成物の調製に有効な組成物を保持する。ラベル又は添付文書は、組成物が癌の治療、予防及び/又は改善に使用されることを指示する。本明細書に記載されるとおりの抗体サイトカイングラフト化タンパク質を含む製品(キット)は、任意選択で1つ以上の追加的薬剤を含む。一部の実施形態において、製品(キット)は抗体サイトカイングラフト化タンパク質と薬学的に許容可能な希釈剤とを含む。一部の実施形態において、抗体サイトカイングラフト化タンパク質は、製品(キット)において1つ以上の追加的な活性薬剤と共に同じ製剤に(例えば、混合物として)提供される。一部の実施形態において、抗体サイトカイングラフト化タンパク質は製品(キット)において第2又は第3の薬剤と共に別個の製剤に(例えば、別個の容器に)提供される。特定の実施形態において、製品(キット)は抗体サイトカイングラフト化タンパク質のアリコートを含み、ここでアリコートは1用量以上を提供する。一部の実施形態において複数回投与用のアリコートが提供され、ここで用量は均一であるか、又は変化する。詳細な実施形態において、変化する投与レジメンは、適宜、漸増又は漸減するものである。一部の実施形態において、抗体サイトカイングラフト化タンパク質及び第2の薬剤の投薬量は、独立に均一であるか、又は独立に変化する。特定の実施形態において、製品(キット)は抗癌剤又は免疫チェックポイント分子などの追加的な薬剤を含む。1つ以上の追加的薬剤の選択は、投薬量、送達、及び治療しようとする疾患状態に依存することになる。
治療又は予防の対象となる病態
抗体サイトカイングラフト化タンパク質は、癌の治療、改善又は予防に使用が見出される。一態様において、本開示は、それを必要としている個体の癌の治療方法を提供し、この方法は、本明細書に記載されるとおりの抗体サイトカイングラフト化タンパク質の治療有効量を個体に投与することを含む。一部の実施形態において、個体の癌の治療又は予防における治療剤としての使用のための抗体サイトカイングラフト化タンパク質が提供される。更なる態様において、本開示は、それを必要としている個体の癌の治療又は改善における使用のためのかかる抗体サイトカイングラフト化タンパク質を含む組成物を提供する。
医師又は獣医師は、医薬組成物中に用いる抗体サイトカイングラフト化タンパク質の用量を所望の治療効果の実現に必要な用量よりも低いレベルで開始し、所望の効果が実現するまで投薬量を徐々に増加させることができる。一般に、組成物の有効用量は、治療されることになる具体的な疾患又は病態、投与手段、標的部位、患者の生理学的状態、患者がヒトか、それとも動物か、投与されている他の薬物療法、及び治療が予防的か、それとも療法的かを含め、多くの異なる要因に応じて変わる。治療投薬量は、安全性及び有効性を最適化するため典型的には滴定が必要である。抗体サイトカイングラフト化タンパク質を伴う投与について、投薬量は宿主体重の約0.0001〜100mg/kg、及びより通常は0.01〜5mg/kgの範囲である。例えば投薬量は1mg/kg体重又は10mg/kg体重又は1〜10mg/kgの範囲内であってもよい。投与は必要又は所望に応じて毎日、毎週、隔週、毎月、又はそれより多い若しくは少ない頻度であってもよい。例示的治療レジームは必然的に、週1回、2週間毎に1回又は月1回又は3〜6ヵ月毎に1回の投与を伴う。
用語「併用療法」は、本開示に記載される治療上の病態又は障害を治療するための2つ以上の治療剤の投与を指す。このような投与は、固定比の活性成分を有する単一のカプセルなどの、実質的に同時の様式でのこれらの治療剤の同時投与を包含する。或いは、このような投与は、各活性成分について、複数の、又は別々の容器(例えば、カプセル、粉末、及び液体)中での同時投与を包含する。粉末及び/又は液体は、投与前に所望の用量に再構成又は希釈され得る。さらに、このような投与は、ほぼ同時に又は異なる時間に、連続的様式での、それぞれのタイプの治療剤の使用も包含する。いずれの場合も、治療計画は、本明細書に記載される病態又は障害を治療する際に薬物の組合せの有益な効果を提供する。
IL2配列を様々な免疫グロブリン足場のCDR領域内に操作することにより抗体サイトカイングラフト化タンパク質を作成し、次に重鎖及び軽鎖の両方の免疫グロブリン鎖を使用して最終的な抗体サイトカインタンパク質を作成した。抗体サイトカイングラフト化タンパク質はIL2の好ましい治療特性を付与する;しかしながら、抗体サイトカイングラフト化タンパク質は、rhIL2と比較したときTreg細胞活性の増加などの望ましくない効果が低下している。
ナイーブCD−1マウスにI.P.投与し、投与前、投与後1時間、3、7、24、31、48、55及び72時間で全ての動物から採血した。血液試料を遠心し、血漿試料を入手した。得られた血漿試料を単一のポリプロピレンチューブに移し、−80℃で凍結した。全ての試料を分析し、IgG.IL2R67A.H1の血漿濃度をイムノアッセイを用いて測定した。半減期などの薬物動態パラメータを計算した。各試料はデュプリケートで実行し、デュプリケート分析の各々には、1:20希釈した5μLの試料が必要であった。捕捉:ヤギ抗ヒトIL−2ビオチン化抗体(R&D Systems BAF202)検出:Alexa 647抗ヒトIL−2、クローンMQ1−17H12(Biolegend #500315) イムノアッセイは全て、Gyrolab(登録商標)Bioaffy200をGyros CD−200と共に使用して行った。図2のグラフに示されるとおり、IgG.IL2R67A.H1の半減期は約12時間であり、次にその後48時間かけて減少する。Proleukin(登録商標)半減期は、その半減期が約4時間であるため、このグラフには図示できなかった。
IgG.IL2R67A.H1は、Tregと比べてProleukin(登録商標)投与で見られる有害事象を引き起こすことなくCD8 Tエフェクターを増大させる。1日目のマウスへの投与後、4日目、8日目及び11日目にCD8 Tエフェクターの拡大をモニタした。各時点でCD8 Tエフェクター細胞集団は大幅に拡大し、Tregの拡大はなかった。これは、等モル用量のIL−2で死亡及び罹患が観察されたProleukin(登録商標)及びIL−2Fc融合物と対照的であった。
非肥満糖尿病(NOD)マウスは1型糖尿病を自然発症し、ヒト1型糖尿病の動物モデルとして使用されることが多い。実施例3に記載されるB6マウスについての同じプロトコルを用いて、IgG.IL2R67A.H1、IL2−Fc及びProleukin(登録商標)をProleukin(登録商標)等モル当量でNODマウスに投与した。この場合もやはり、図4Aのグラフに示されるとおり、この用量のIgG.IL2R67A.H1の投与はTregと比べてCD8 Tエフェクター細胞を優先的に拡大した。加えて、IgG.IL2R67A.H1の投与はNODマウスにおいて有害事象を示さなかったが、Proleukin(登録商標)治療群では5匹の瀕死マウス及び2匹の死亡があった。図4Bは、NODマウスモデルからの投薬量、細胞変化倍数及び細胞型を報告するグラフである。
IgG.IL2R67A.H1の安全性を調べた後、CT26マウスモデルでその単剤有効性を試験した。マウスCT26細胞は、500を超える既発表の研究で使用されている、急速に成長するグレードIV結腸癌細胞であり、薬剤開発においてよく使用される細胞株及びモデルの1つである。CT26(ATCC CRL−2638)細胞を5%CO2の37℃インキュベーターにおいて無菌条件で成長させた。細胞は、10%FBSを補足したRPMI 1640培地で培養した。細胞は3〜4日毎に継代した。注射当日、細胞を回収し(継代11代目)、HBSS中に2.5×106/mlの濃度で再懸濁した。細胞をマイコプラズマ及びマウスウイルスに関してRadil試験した。Balbcマウスを使用した。各マウスにつき0.25×106細胞を28g針(100μl注射容積)を使用して右側腹部に皮下注射で移植した。移植後、腫瘍が触知可能になったら、動物を週3回ノギスで測り、秤量した。ノギス測定値は(L×W×W)/2を用いて計算した。マウスには通常食を与え、実験動物の管理と使用に関する指針(Guide for Care and Use of Laboratory Animals)及び動物実験委員会(Institutional Animal Care and Use Committee)の規定に従いSPF動物施設で飼育した。
他の癌療法薬と併用したIgG.IL2R67A.H1の有効性を評価するため、B16F10メラノーママウスモデルを使用した。B16F10細胞(ATCC CRL−6475)を5%CO2の37℃インキュベーターにおいて無菌条件で2週間成長させた。B16F10細胞はDMEM+10%FBS中で培養した。細胞を回収し、FBS不含培地DMEMに1×106/100μlの濃度で再懸濁した。B16F10細胞をマイコプラズマ及びマウスウイルスに関してRadil試験した。28ゲージ針(100μl注射容積)を使用して細胞をB6マウスの右側腹部に移植した。移植後、腫瘍が触知可能になったらマウスを週2回ノギスで測り、秤量した。ノギス測定値は(L×W×W)/2を用いて計算した。
ヒトCD8 Tエフェクターに対するIgG.IL2R67A.H1の活性を試験するため、ヒト末梢血単核球(PBMC)をpSTAT5活性に関してアッセイした。PBMC細胞を無血清試験培地中に静置し、プレーティングした。PBMCにIgG.IL2R67A.H1、IgG.IL2F71A.H1又はProleukin(登録商標)を加え、37℃で20分間インキュベートした。20分後、細胞を1.6%ホルムアルデヒドで固定し、洗浄し、表面マーカーで染色した。室温で30分後、試料を洗浄し、再懸濁した細胞ペレットを−20℃メタノールで透過処理し、洗浄し、pSTAT5及びDNAインターカレーターに関して染色した。細胞をCytof(登録商標)にかけ、データをFlowJo(登録商標)ソフトウェアで分析することによりpSTAT5活性レベルを定量化した。図7の表は、IgG.IL2R67A.H1がCD8 Tエフェクター細胞に対して有する、且つTreg細胞の活性化を最小限に抑える優先的活性化を実証する。
ムテインを含むIL2配列(配列番号4)を免疫グロブリン鎖足場のCDRループに挿入した。抗体サイトカイングラフト化タンパク質は、臨床セッティングで利用されている種々の既知の免疫グロブリン配列並びに生殖細胞系列抗体配列を使用して調製した。使用した抗体のうちの1つはその抗原としてRSVを有する。IL2をこの抗体のCDRにグラフト化するとRSVへの結合が低下又は消失したかどうかを決定するため、PBS又は炭酸塩緩衝液のいずれかにおいてRSVタンパク質に関するELISAアッセイを行った。図8に示すとおり、これはIL2グラフト化にどのCDRを選択したかに影響を受けるように見える。例えば、IgG.IL2R67A.H1は、元の非グラフト化(非修飾)抗体と同様のRSV結合を有する。対照的に、IL2をCDR3の軽鎖(CDR−L3)又はCDR−H3にグラフト化すると、結合が低下する。予想どおり、IL2を無関係の抗体(Xolair)にグラフト化すると、結合は生じない。これは、抗体サイトカイングラフト化タンパク質が抗体足場の元の標的に対する結合を保持し得ること、又はこの結合が低下し得ることを実証している。
Claims (50)
- (a)相補性決定領域(CDR)HCDR1、HCDR2、HCDR3を含む、重鎖可変領域(VH);及び
(b)LCDR1、LCDR2、LCDR3を含む、軽鎖可変領域(VL);及び
(c)VH又はVLのCDRにグラフト化されたインターロイキン2(IL2)分子
を含む抗体サイトカイングラフト化タンパク質。 - 前記IL2分子が重鎖CDRにグラフト化されている、請求項1に記載の抗体サイトカイングラフト化タンパク質。
- 重鎖CDRが、相補性決定領域1(HCDR1)、相補性決定領域2(HCDR2)、及び相補性決定領域3(HCDR3)から選択される、請求項2に記載の抗体サイトカイングラフト化タンパク質。
- 前記IL2分子がHCDR1にグラフト化されている、請求項3に記載の抗体サイトカイングラフト化タンパク質。
- 前記IL2分子が軽鎖CDRにグラフト化されている、請求項1に記載の抗体サイトカイングラフト化タンパク質。
- 前記軽鎖CDRが、相補性決定領域1(LCDR1)、相補性決定領域2(LCDR2)、及び相補性決定領域3(LCDR3)から選択される、請求項5に記載の抗体サイトカイングラフト化タンパク質。
- 前記IL2分子が、高親和性IL2受容体に対する前記IL2分子の親和性を低下させる突然変異を含む、請求項1〜6のいずれか一項に記載の抗体サイトカイングラフト化タンパク質。
- 前記抗体サイトカイングラフト化タンパク質によるCD8 Tエフェクター細胞増殖の刺激が組換えIL2又はProleukin(登録商標)よりも大きい、請求項1〜7のいずれか一項に記載の抗体サイトカイングラフト化タンパク質。
- 前記抗体サイトカイングラフト化タンパク質によるCD4 T制御性細胞増殖の刺激が組換えIL2又はProleukin(登録商標)よりも小さい、請求項1〜8のいずれか一項に記載の抗体サイトカイングラフト化タンパク質。
- 前記抗体サイトカイングラフト化タンパク質によるNK細胞増殖の刺激が組換えIL2又はProleukin(登録商標)よりも大きい、請求項1〜9のいずれか一項に記載の抗体サイトカイングラフト化タンパク質。
- 前記抗体サイトカイングラフト化タンパク質が天然IL2又はProleukin(登録商標)よりも長い半減期を有する、請求項1〜10のいずれか一項に記載の抗体サイトカイングラフト化タンパク質。
- 前記IL2分子が配列番号4からなる、請求項1〜11のいずれか一項に記載の抗体サイトカイングラフト化タンパク質。
- 前記IL2分子が配列番号6からなる、請求項1〜11のいずれか一項に記載の抗体サイトカイングラフト化タンパク質。
- IgGクラス抗体重鎖を更に含む、請求項1〜13のいずれか一項に記載の抗体サイトカイングラフト化タンパク質。
- 前記IgGクラス重鎖が、IgG1、IgG2、及びIgG4から選択される、請求項14に記載の抗体サイトカイングラフト化タンパク質。
- 標的に対する前記CDRの結合特異性が前記グラフト化されたIL2分子によって10%、20%、30%、40%、50%、60%、70%、80%、90%、95%、98%、99%、又は100%低下する、請求項1〜15のいずれか一項に記載の抗体サイトカイングラフト化タンパク質。
- 標的に対する前記CDRの結合特異性が前記グラフト化されたIL2分子の存在下で10%、20%、30%、40%、50%、60%、70%、80%、90%、95%、98%、99%、又は100%保持される、請求項1〜15のいずれか一項に記載の抗体サイトカイングラフト化タンパク質。
- 前記CDRの結合特異性が前記IL2分子の結合特異性と異なる、請求項1〜17のいずれか一項に記載の抗体サイトカイングラフト化タンパク質。
- 前記CDRの結合特異性が非ヒト抗原に対するものである、請求項1〜18のいずれか一項に記載の抗体サイトカイングラフト化タンパク質。
- 前記非ヒト抗原がウイルスである、請求項19に記載の抗体サイトカイングラフト化タンパク質。
- 前記ウイルスが呼吸器合胞体ウイルス(RSV)である、請求項20に記載の抗体サイトカイングラフト化タンパク質。
- 前記RSVが、RSVサブグループA及びRSVサブグループBから選択される、請求項21に記載の抗体サイトカイングラフト化タンパク質。
- 前記抗体サイトカイングラフト化タンパク質の前記抗体足場部分がヒト化又はヒトである、請求項1〜22のいずれか一項に記載の抗体サイトカイングラフト化タンパク質。
- (i)(a)配列番号13のHCDR1、(b)配列番号14のHCDR2、(c)配列番号15のHCDR3を含む重鎖可変領域及び(d)配列番号29のLCDR1、(e)配列番号30のLCDR2、及び(f)配列番号31のLCDR3を含む軽鎖可変領域;又は
(ii)(a)配列番号45のHCDR1、(b)配列番号46のHCDR2、(c)配列番号47のHCDR3を含む重鎖可変領域;及び(d)配列番号61のLCDR1、(e)配列番号62のLCDR2、及び(f)配列番号63のLCDR3を含む軽鎖可変領域
を含む抗体サイトカイングラフト化タンパク質。 - (i)配列番号19を含む重鎖可変領域(VH)、及び配列番号35を含む軽鎖可変領域(VL);又は
(ii)配列番号51を含む重鎖可変領域(VH)、及び配列番号67を含む軽鎖可変領域(VL)
を含む抗体サイトカイングラフト化タンパク質。 - 低下したエフェクター機能に対応する修飾Fc領域を更に含む、請求項1〜25のいずれか一項に記載の抗体サイトカイングラフト化タンパク質。
- 前記修飾Fc領域が、D265A、P329A、P329G、N297A、L234A、及びL235Aの1つ以上から選択される突然変異を含む、請求項26に記載の抗体サイトカイングラフト化タンパク質。
- 前記修飾Fc領域が、D265A/P329A、D265A/N297A、L234/L235A、P329A/L234A/L235A、及びP329G/L234A/L235Aの1つ以上から選択される突然変異の組み合わせを含む、請求項27に記載の抗体サイトカイングラフト化タンパク質。
- 配列番号13のHCDR1、配列番号14のHCDR2、配列番号15のHCDR3、配列番号29のLCDR1、配列番号30のLCDR2、配列番号31のLCDR3、突然変異D265A/P329Aを含む修飾Fc領域を含む抗体サイトカイングラフト化タンパク質であって、Proleukin(登録商標)と比較したとき低いTreg細胞の活性化を刺激する抗体サイトカイングラフト化タンパク質。
- 配列番号45のHCDR1、配列番号46のHCDR2、配列番号47のHCDR3、配列番号61のLCDR1、配列番号62のLCDR2、配列番号63のLCDR3、突然変異D265A/P329Aを含む修飾Fc領域を含む抗体サイトカイングラフト化タンパク質であって、Proleukin(登録商標)と比較したとき低いTreg細胞の活性化を刺激する抗体サイトカイングラフト化タンパク質。
- (i)配列番号22の重鎖及び配列番号38の軽鎖;又は(ii)配列番号54の重鎖及び配列番号70の軽鎖を含む抗体サイトカイングラフト化タンパク質をコードする単離核酸。
- 抗体サイトカイングラフト化タンパク質の産生に好適な組換え宿主細胞であって、前記抗体サイトカイングラフト化タンパク質の重鎖及び軽鎖ポリペプチドをコードする請求項31に記載の核酸と、任意選択で分泌シグナルとを含む組換え宿主細胞。
- 哺乳類細胞株である、請求項32に記載の組換え宿主細胞。
- 前記哺乳類細胞株がCHO細胞株である、請求項33に記載の組換え宿主細胞。
- 請求項1〜30のいずれか一項に記載の抗体サイトカイングラフト化タンパク質と薬学的に許容可能な担体とを含む医薬組成物。
- それを必要としている個体の癌の治療方法であって、請求項1〜30のいずれか一項に記載の抗体サイトカイングラフト化タンパク質又は請求項35に記載の医薬組成物の治療有効量を前記個体に投与することを含む方法。
- 前記癌が、黒色腫、肺癌、結腸直腸癌、前立腺癌、乳癌及びリンパ腫からなる群から選択される、請求項36に記載の方法。
- 前記抗体サイトカイングラフト化タンパク質又は医薬組成物が別の治療剤と併用して投与される、請求項36又は37に記載の方法。
- 前記治療剤が別の抗体サイトカイングラフト化タンパク質である、請求項38に記載の方法。
- 前記治療剤が免疫チェックポイント阻害薬である、請求項38に記載の方法。
- 前記免疫チェックポイントが、PD−1、PD−L1、PD−L2、TIM3、CTLA−4、LAG−3、CEACAM−1、CEACAM−5、VISTA、BTLA、TIGIT、LAIR1、CD160、2B4及びTGFRからなる群から選択される、請求項40に記載の方法。
- それを必要としている患者におけるCD8 Tエフェクター細胞の拡大方法であって、請求項1〜30のいずれか一項に記載の抗体サイトカイングラフト化タンパク質又は請求項35に記載の医薬組成物を前記患者に投与することを含む方法。
- 前記CD8 Tエフェクター細胞が拡大され、且つTreg細胞が拡大されない、請求項42に記載の方法。
- 前記CD8 Tエフェクター細胞が拡大され、且つNK細胞が拡大されない、請求項42に記載の方法。
- 免疫チェックポイント阻害薬の投与を更に含む、請求項42〜44のいずれか一項に記載の方法。
- 前記免疫チェックポイントが、PD−1、PD−L1、PD−L2、TIM3、CTLA−4、LAG−3、CEACAM−1、CEACAM−5、VISTA、BTLA、TIGIT、LAIR1、CD160、2B4及びTGFRからなる群から選択される、請求項45に記載の方法。
- 癌の治療における、
(i)(a)配列番号13のHCDR1、(b)配列番号14のHCDR2、(c)配列番号15のHCDR3を含む重鎖可変領域及び(d)配列番号29のLCDR1、(e)配列番号30のLCDR2、及び(f)配列番号31のLCDR3を含む軽鎖可変領域;又は
(ii)(a)配列番号45のHCDR1、(b)配列番号46のHCDR2、(c)配列番号47のHCDR3を含む重鎖可変領域;及び(d)配列番号61のLCDR1、(e)配列番号62のLCDR2、及び(f)配列番号63のLCDR3を含む軽鎖可変領域
を含む抗体サイトカイングラフト化タンパク質の使用。 - 前記抗体サイトカイングラフト化タンパク質が別の治療剤と併用して投与される、請求項47に記載の使用。
- 前記治療剤が免疫チェックポイント阻害薬である、請求項48に記載の使用。
- 前記免疫チェックポイントが、PD−1、PD−L1、PD−L2、TIM3、CTLA−4、LAG−3、CEACAM−1、CEACAM−5、VISTA、BTLA、TIGIT、LAIR1、CD160、2B4及びTGFRからなる群から選択される、請求項49に記載の使用。
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A911 | Transfer to examiner for re-examination before appeal (zenchi) |
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A912 | Re-examination (zenchi) completed and case transferred to appeal board |
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