JP2021530444A - 固形および液体悪性病変における多重car t細胞での複数抗原の標的化 - Google Patents
固形および液体悪性病変における多重car t細胞での複数抗原の標的化 Download PDFInfo
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Abstract
Description
本願は、35米国特許法第119条(e)に基づき、2018年6月28日に出願された米国仮出願第62/691,486号および2018年7月13日に出願された米国仮出願第62/697,526号の優先権の恩典を主張し、これらの各々の全体は、参照により本明細書に組み込まれる。
本発明は、国立衛生研究所によって授与された助成金番号DK105602−01号およびT32AI007386号の下で政府の援助によって為された。合衆国政府は、本発明に一定の権利を有する。
本発明の別の態様は、癌を処置する方法であって、a)複数の、二機能性分子の部分集団であって、前記複数がa1)治療的有効量の、第一の腫瘍関連抗原を特異的に結合する第一の標的化部分に共有結合された合成抗原を含む二機能性化合物の第一の部分集団と、a2)治療的有効量の、第二の腫瘍関連抗原を特異的に結合する第二の標的化部分に共有結合された合成抗原を含む二機能性化合物の第二の部分集団とを含む二機能性分子の部分集団または薬学的に許容され得るそれらの塩もしくは立体異性体と、ここで、前記第一および第二の標的化部分は、異なる腫瘍関連抗原を特異的に結合し、
b)治療的有効数のCAR−T細胞であって、合成抗原を特異的に結合する細胞外リガンドを含むCAR−T細胞と、
を癌を処置することを必要とする被験体に併用投与することを含む、方法を対象とする。
b)二機能性化合物の治療的有効量の複数の部分集団 治療的有効数のCAR−T細胞であって、前記合成抗原を特異的に結合する細胞外リガンドを含むCAR−T細胞を癌患者に併用投与するための説明書と、
を備える、キットを対象とする。上述されているように、いくつかの実施形態において、薬学的組成物は、二機能性化合物の複数の(2またはそれより多くの)部分集団を含有し得、各部分集団において、合成抗原は同一であり得るが、各標的化部分は同じ腫瘍関連抗原の異なるエピトープを結合する。したがって、いくつかの実施形態において、所定の組成物は、同じ腫瘍関連抗原の1またはそれより多くのエピトープを標的とし得る。他の実施形態において、組成物は、2またはそれより多くの腫瘍関連抗原(およびこの2またはそれより多くの腫瘍関連抗原の任意の1つまたはそれより多くの2またはそれより多くのエピトープ)を標的とし得る。
本発明の1つの枢要な側面は、腫瘍細胞死滅から腫瘍細胞標的化を切り離したことである。図1Aに模式的に示されているように、CAR T細胞は、腫瘍細胞に直接結合することなく腫瘍細胞を殺す。これは、その1つの機能的部分(合成抗原または遮蔽されていないプロ抗原)がCAR T細胞によって結合され、その第二の機能的部分が固形腫瘍関連抗原を特異的に結合する二機能性化合物の使用によって達成される。
合成抗原は、CAR−T細胞に対する標的としての役割を果たす小分子または代替的エピトープである。この抗原は、体内のいずれの正常な細胞上にも天然には存在しないという点で合成的であり、この抗原に結合するようにCAR T細胞を設計することができるという意味で抗原性である。
または薬学的に許容され得るそれらの塩もしくは立体異性体、を有し得る。
R4、R4’の各々は、独立にOまたはOHであり;
およびR5は、
nは、1〜12である;
または薬学的に許容され得るその塩もしくは立体異性体、を有し得る。
R4、R4’およびR5の各々は上に定義されているとおりである、
または薬学的に許容され得るその塩もしくは立体異性体、を有し得る。
R6は、
nは、1〜12である;
または薬学的に許容され得るその塩もしくは立体異性体を有し得る。
いくつかの実施形態において、合成抗原は保護基を含有する。保護された合成抗原は、本明細書において、「プロ抗原」と称される。保護基は、本明細書において「遮蔽」または「かご」とも称される。プロ抗原は、適切な刺激への曝露に際して遮蔽されていないまたはかごに入れられていない状態にならなければ、それまで、CAR−T細胞を結合せず、その活性化を引き起こさないという意味で不活性であり、その例としては、保護基の除去を引き起こすある波長の光および反応性化学種が挙げられる。したがって、これらの実施形態において、「遮蔽」または「かご」は、固形腫瘍の部位を除き、CAR T細胞反応性を抑制する。
式中、R1は、独立に、O、OHまたは保護基であり、R1’は、独立に、C=O、O、OHまたは保護基であり、R2は、独立に、O、OHまたは保護基であり;R3は、
は不存在またはリンカーであり、およびnは1〜12であり;但し、R1、R1’およびR2の少なくとも1つは保護基である;
または薬学的に許容され得るそれらの塩もしくは立体異性体、を有し得る。いくつかの実施形態において、R1およびR2の両方またはR1’およびR2の両方が保護基である。
R1は、O、OHまたはボロン酸エステル保護基であり;
R2は、O、OHまたはボロン酸エステル保護基であり;
但し、R1およびR2の少なくとも1つは、ボロン酸エステル基であり、
R3は、
nは、1〜12であり;
ボロン酸エステル保護基は、
または薬学的に許容され得るその塩もしくは立体異性体、を有し得る。いくつかの実施形態において、R1およびR2の両方がボロン酸エステル保護基である。
R5は、
または薬学的に許容され得るその塩もしくは立体異性体、を有し得る。いくつかの実施形態において、R4およびR4’の両方が保護基である。
但し、R4およびR4’の少なくとも1つは保護基であり;ならびに
R5は、
または薬学的に許容され得るその塩もしくは立体異性体、を有し得る。
XはNHまたはOであり、RはC1−4アルキルまたはHであり、およびnは0〜3である、
である。いくつかの実施形態において、オルト−ニトロベンジルを基礎とする基は、
R6は、
を有する。
本発明の二機能性化合物の機能様式の1つを構成する標的化部分は、固形腫瘍関連抗原を特異的に結合する。
薬学的組成物は、治療的有効量の二機能性化合物と薬学的に許容され得る担体とを含む。いくつかの実施形態において、薬学的組成物は、同じ(例えば、第一の)腫瘍関連抗原の異なるエピトープを結合する第二の標的化部分に共有結合された第一の合成抗原を含む別の(第二の)二機能性化合物または薬学的に許容され得るその塩もしくは立体異性体をさらに含み得る。したがって、組成物は、2またはそれより多くの二機能性化合物を含み得、それらの全てが同じ腫瘍関連抗原を結合するが、二機能性化合物の少なくとも2つは同じ腫瘍関連抗原上の異なるエピトープを結合する。他の実施形態において、薬学的組成物は、異なる腫瘍関連抗原(例えば、第一のものとは異なる)を結合する第二の標的化部分に共有結合された合成抗原を含む別の(例えば、第二の)二機能性化合物または薬学的に許容され得るその塩もしくは立体異性体をさらに含み得る。したがって、組成物は、2またはそれより多くの二機能性化合物を含み得、それらの全てが異なる腫瘍関連抗原を結合し、二機能性化合物の少なくとも2つは異なる腫瘍関連抗原上の異なるエピトープを結合する。
CAR T細胞は、いずれの正常な細胞または癌細胞上にも天然に存在しない合成抗原または遮蔽されていないプロ抗原を結合するように改変操作される。したがって、腫瘍細胞標的化を腫瘍細胞死滅と切り離すことによって、(合成抗原または遮蔽されていないプロ抗原への)単一の特異性を有するCAR T細胞は、複数の腫瘍関連抗原を同時に標的とすることができる。
第一のドメインは、典型的には、BAT−CARポリペプチドのアミノ末端終末に存在し、したがって、T細胞の外側にあり、タグ結合ドメインが標的細胞に結合されているタグ化されたタンパク質へ自由に接近することを可能にする。タグ結合ドメインは、典型的には、抗体またはその抗原結合断片である。いくつかの実施形態において、抗体はヒトもしくはヒト化抗体またはその抗原結合断片である。
本発明のさらなる態様は、二機能性化合物の複数の部分集団と、自家、同種異系または同系であり得るCAR T細胞とを含む系を対象とする。
b)治療的有効量の複数の、二機能性化合物の部分集団 治療的有効数のCAR−T細胞であって、前記合成抗原を特異的に結合する細胞外リガンドを含むCAR−T細胞を癌患者に併用投与するための説明書と、
を含み得る。
本発明の方法は、癌を処置する方法を対象とする。この方法は、a)複数の、二機能性分子の部分集団であって、前記複数がa1)治療的有効量の、第一の腫瘍関連抗原を特異的に結合する第一の標的化部分に共有結合された合成抗原を含む二機能性化合物の第一の部分集団と、a2)治療的有効量の、第二の腫瘍関連抗原を特異的に結合する第二の標的化部分に共有結合された合成抗原を含む二機能性化合物の第二の部分集団とを含む二機能性分子の部分集団または薬学的に許容され得るそれらの塩もしくは立体異性体と、ここで、前記第一および第二の標的化部分は、異なる腫瘍関連抗原を特異的に結合し、
b)治療的有効数のCAR−T細胞であって、合成抗原を特異的に結合する細胞外リガンドを含むCAR−T細胞と、
を必要とする被験体に併用投与することを含む。本明細書において使用される「併用投与する」という用語は、二機能性化合物の複数の部分集団に関する場合、同じ処置レジメンの間に投与することを含む。複数の部分集団は、同時にまたは順次に(例えば、CAR T細胞および二機能性化合物の第一の部分集団の組み合わせに対して患者がもはや応答しなくなった後に投与され得る。
ある実施形態において、癌を処置する本発明の方法は、被験体が別の抗癌剤でも処置される併用療法の一部であり得る。「抗癌」剤は、例えば、癌細胞を死滅させ、癌細胞中にアポトーシスを誘導し、癌細胞の増殖速度を低下させ、転移の発生率もしくは数を低下させ、腫瘍サイズを低下させ、腫瘍増殖を阻害し、腫瘍もしくは癌細胞への血液供給を低下させ、癌細胞もしくは腫瘍に対する免疫応答を促進し、癌の進行を抑制もしくは阻害し、または癌を有する被験体の寿命を増加させることによって、被験体中の癌に悪影響を与えることができる。より一般的には、これらの他の組成物は、細胞を死滅させまたは細胞の増殖を阻害するのに有効な合わせた量で与えられるであろう。この過程は、癌細胞を、発現構築物および薬剤または複数の因子と同時に接触させることを含み得る。これは、両薬剤を含む単一の組成物もしくは薬理学的調合物と細胞を接触させることによって、または一方の組成物が発現構築物を含み、他方が第二の薬剤を含む2つの異なる組成物もしくは調合物と細胞を同時に接触させることによって達成され得る。
癌療法は、化学および放射線の両方を基礎とする処置との様々な併用療法も含む。併用化学療法としては、例えば、アブラキサン、アルトレタミン、ドセタキセル、ハーセプチン、メトトレキサート、ノバントロン、ゾラデックス、シスプラチン(CDDP)、カルボプラチン、プロカルバジン、メクロレタミン、シクロホスファミド、カンプトテシン、イホスファミド、メルファラン、クロラムブシル、ブスルファン、ニトロソウレア(nitrosurea)、ダクチノマイシン、ダウノルビシン、ドキソルビシン、ブレオマイシン、プリコマイシン(plicomycin)、マイトマイシン、エトポシド(VP16)、タモキシフェン、ラロキシフェン、エストロゲン受容体結合剤、タキソール、ゲムシタビエン(gemcitabien)、ナベルビン、ファルネシルタンパク質転移酵素阻害剤、トランスプラチナム(transplatinum)、5−フルオロウラシル、ビンクリスチン、ビンブラスチンおよびメトトレキサートまたは前述の任意の類縁体または誘導体バリアントおよびこれらの組み合わせも挙げられる。
DNA損傷を引き起こし、広く使用されてきた他の因子としては、ガンマ線、X線および/または腫瘍細胞への放射性同位体の誘導された送達として一般的に知られるものが挙げられる。マイクロ波およびUV照射などのDNA損傷因子の他の形態も想定される。これらの因子の全ては、DNAに対して、DNAの前駆体に対して、DNAの複製および修復に対して、ならびに染色体の組み立ておよび維持に対して幅広い損傷をもたらす可能性が最も高い。X線に対する投薬量範囲は、長期間(3〜4週)の50〜200レントゲンの1日線量から2000〜6000レントゲンの単回線量の範囲である。放射性同位体に対する投薬量範囲は広く変動し、同位体の半減期、放出される放射線の強さおよび種類ならびに新生物細胞による取り込みに依存する。
免疫療法は、一般に、癌細胞を標的とし、破壊するために、免疫エフェクター細胞および分子の使用に依存する。免疫エフェクターは、例えば、腫瘍細胞の表面上のあるマーカーに対して特異的な抗体であり得る。抗体単独で、治療のエフェクターとしての役割を果たし得、または実際に細胞死滅をもたらす他の細胞を補充し得る。抗体は、薬物または毒素(化学療法剤、放射性核種、リシンA鎖、コレラ毒素、百日咳毒素など)にも接合され得、単に標的化剤として役割を果たし得る。または、エフェクターは、直接的にまたは間接的に、腫瘍細胞標的と相互作用する表面分子を保有するリンパ球であり得る。様々なエフェクター細胞としては、細胞傷害性T細胞およびNK細胞が挙げられる。
さらに別の実施形態において、二次処置は、本発明の臨床実施形態の前、後または同時に治療用ポリヌクレオチドが投与される遺伝子治療である。細胞増殖の誘導物質、細胞増殖の阻害剤またはプログラムされた細胞死の制御物質を含む様々な発現産物が本発明に包含される。
癌を有する者のおよそ60%がある種類の手術を受け、予防的、診断的またはステージ決定の、治療的および対症療法的手術が含まれる。治療的手術は、他の治療、例えば、本発明の処置、化学療法、放射線療法、ホルモン療法、遺伝子治療、免疫療法および/または代替的療法と組み合わせ使用され得る癌処置である。
処置の治療的有効性を改善するために、他の薬剤が本発明とともに併用され得ることが想定される。これらのさらなる薬剤には、免疫調節剤、細胞表面受容体およびGAPジャンクションの上方制御に影響を与える薬剤、細胞分裂停止および分化剤、細胞接着の阻害剤またはアポトーシス誘導物質への過剰増殖性細胞の感度を増加させる薬剤が挙げられる。免疫調節剤としては、腫瘍壊死因子、インターフェロンα、βおよびγ;IL−2およびその他のサイトカイン;F42Kおよびその他のサイトカイン類縁体;またはMIP−1、MIP−1β、MCP−1、RANTESおよびその他のケモカインが含まれる。細胞表面受容体またはFas/Fasリガンド、DR4またはDR5/TRAILなどの細胞表面受容体のリガンドの上方制御は、過剰増殖性細胞に対する自己分泌または傍分泌効果の確立によって、本発明のアポトーシス誘導能を強化するであろうことがさらに想定される。GAPジャンクションの数を上昇させることによる細胞間シグナル伝達の増加は、隣接する過剰増殖性細胞集団に対する抗過剰増殖性効果を増加させるであろう。他の実施形態において、細胞分裂停止または分化剤は、処置の抗過剰増殖性効力を改善させるために、本発明とともに併用することができる。細胞接着の阻害剤は、本発明の効力を改善させることが想定される。細胞接着阻害剤の例は、接着斑キナーゼ(FAK)阻害剤およびロバスタチンである。抗体c225などの、アポトーシスに対する過剰増殖性細胞の感度を増加させる他の薬剤は、処置の有効性を改善させるために、本発明とともに併用され得ることがさらに想定される。
Claims (45)
- 第一の腫瘍関連抗原を結合する第一の標的化部分に共有結合された第一の合成抗原を含む二機能性化合物または薬学的に許容され得るその塩もしくは立体異性体。
- 前記標的化部分が、脳腫瘍関連抗原を特異的に結合する、請求項1に記載の二機能性化合物。
- 前記標的化部分が、GD2、IL13Rα2、HER2、PDGFRα、EGFRvIII、CSPG4、EphA2およびCD133からなる群から選択される脳腫瘍関連抗原を特異的に結合する、請求項2に記載の二機能性化合物。
- 前記標的化部分が、血液腫瘍関連抗原を特異的に結合する、請求項1に記載の二機能性化合物。
- 前記標的化部分が、CD38、CS1、BCMA、CD20、CD19、CD22、CD30、CD138、CD40、CD56、CD70およびCD74からなる群から選択される血液腫瘍関連抗原を特異的に結合する、請求項4に記載の二機能性化合物。
- 前記標的化部分が、HER2に特異的に結合する、請求項1に記載の二機能性化合物。
- 前記合成抗原が蛍光性分子である、請求項1に記載の二機能性化合物。
- 前記蛍光性分子がフルオレセインまたはアントラセンである、請求項7に記載の二機能性化合物。
- 前記合成抗原が、4−[(6−メチルピラジン−2−イル)オキシ]ベンゾエート(MPOB)、アントラキノン−2−カルボキシレート(AQ)またはテトラキセタン(DOTA)である、請求項1に記載の二機能性化合物。
- 前記合成抗原が除去可能な保護基を含有する、請求項1に記載の二機能性化合物。
- 前記除去可能な保護基がボロン酸エステル基である、請求項10に記載の二機能性化合物。
- 前記除去可能な保護基が光切断可能な基である、請求項10に記載の二機能性化合物。
- 前記合成抗原がペプチド、グリコシドまたはヌクレオチド抗原である、請求項1に記載の二機能性化合物。
- 治療的有効量の、請求項1に記載の二機能性化合物または薬学的に許容され得る塩もしくは立体異性体と、薬学的に許容され得る担体とを含む薬学的組成物であって、前記二機能性化合物が第一の二機能性化合物である、薬学的組成物。
- 第一の腫瘍関連抗原を結合する第二の標的化部分に共有結合された前記第一の合成抗原を含む第二の二機能性化合物または薬学的に許容され得るその塩もしくは立体異性体をさらに含む、請求項14に記載の薬学的組成物。
- 複数の治療的有効量の、二機能性化合物の部分集団であって、前記第一の二機能性化合物の第一の部分集団を含み、第二の腫瘍関連抗原を特異的に結合する第二の標的化部分に共有結合された前記第一の合成抗原を含む第二の二機能性化合物の少なくとも第二の部分集団をさらに含む二機能性化合物の部分集団またはそれらの薬学的に許容され得る塩もしくは立体異性体を含む薬学的組成物であって、前記第一および第二の標的化部分が異なる腫瘍関連抗原を特異的に結合し、ならびに前記組成物中の二機能性化合物の各部分集団が、前記組成物中の他の部分集団中に含有される二機能性化合物とは異なる腫瘍関連抗原を結合する、請求項14に記載の薬学的組成物。
- 前記第一および第二の標的化部分が、GD2、IL13Rα2、HER2、PDGFRα、EGFRvIII、CSPG4、EphA2およびCD133からなる群から選択される脳腫瘍関連抗原を特異的に結合する、請求項16に記載の薬学的組成物。
- 前記第一および第二の標的化部分の各々が、IL13Rα2、EGFRvIIIおよびHER2からなる群から選択される脳腫瘍関連抗原を特異的に結合し、または前記第一および第二の標的化部分の各々が、GD2、PDGFRαおよびCD133からなる群から選択される脳腫瘍関連抗原を特異的に結合し、または前記第一および第二の標的化部分の各々が、EphA2およびCSPG4からなる群から選択される脳腫瘍関連抗原を特異的に結合する、請求項17に記載の薬学的組成物。
- 前記第一および第二の標的化部分が、CD38、CS1、BCMA、CD20、CD19、CD22、CD30、CD138、CD40、CD56、CD70およびCD74からなる群から選択される血液腫瘍関連抗原を特異的に結合する、請求項14に記載の薬学的組成物。
- 前記第一および第二の標的化部分の各々が、CD38、CS1およびBCMAからなる群から選択される血液腫瘍関連抗原を特異的に結合し、または前記第一および第二の標的化部分の各々が、CD19、CD20およびCD22からなる群から選択される血液腫瘍関連抗原を特異的に結合し、または前記第一および第二の標的化部分の各々が、CD30、CD40、CD56、CD70、CD74およびCD138からなる群から選択される血液腫瘍関連抗原を特異的に結合する、請求項19に記載の薬学的組成物。
- 癌を処置する方法であって、a)複数の、二機能性分子の部分集団であって、前記複数がa1)治療的有効量の、第一の腫瘍関連抗原を特異的に結合する第一の標的化部分に共有結合された合成抗原を含む二機能性化合物の第一の部分集団と、a2)治療的有効量の、第二の腫瘍関連抗原を特異的に結合する第二の標的化部分に共有結合された合成抗原を含む二機能性化合物の第二の部分集団とを含む二機能性分子の部分集団または薬学的に許容され得るその塩もしくは立体異性体と、ここで、前記第一および第二の標的化部分は、異なる腫瘍関連抗原を特異的に結合し、
b)治療的有効数のCAR−T細胞であって、合成抗原を特異的に結合する細胞外リガンドを含むCAR−T細胞と、
を癌を処置することを必要とする被験体に併用投与することを含む、方法。 - 前記治療的有効量の前記複数の、二機能性化合物の部分集団が同時に投与される、請求項21に記載の方法。
- 前記治療的有効量の前記複数の、二機能性化合物の部分集団が順次に投与される、請求項21に記載の方法。
- 前記複数の、二機能性化合物の部分集団が、単一の組成物中で投与される、請求項22に記載の方法。
- 前記複数の、二機能性化合物の部分集団が、異なる組成物中で投与される、請求項22に記載の方法。
- 治療的有効量の、前記二機能性化合物の前記第一および/または第二の部分集団の少なくとも1回のその後の投与をさらに含む、請求項21に記載の方法。
- 二機能性化合物の前記第一および/または第二の部分集団の少なくとも1回のその後の投与において、前記第一の標的化部分が、従前の投与における前記第一の標的化部分と比べて同一の腫瘍関連抗原上の異なるエピトープを結合し、前記第二の標的化部分が、従前の投与における前記第二の標的化部分と比べて同一の腫瘍関連抗原上の異なるエピトープを結合する、請求項26に記載の方法。
- 前記第一および第二の標的化部分と比べて異なる腫瘍関連抗原を結合する第三の標的化部分に共有結合された合成抗原を含む二機能性化合物の第三の部分集団を併用投与することをさらに含む、請求項21に記載の方法。
- 前記合成抗原が除去可能な保護基を含有し、前記CAR T細胞の前記細胞外リガンドが除去可能な保護基の除去後に合成抗原を結合する、請求項21に記載の方法。
- 前記被験体が脳癌を有し、前記第一および第二の標的化部分が異なる脳腫瘍関連抗原を特異的に結合する、請求項21に記載の方法。
- 前記第一および第二の標的化部分の各々が、GD2、IL13Rα2、HER2、PDGFRα、EGFRvIII、CSPG4、EphA2およびCD133からなる群から選択される脳腫瘍関連抗原を特異的に結合する、請求項30に記載の方法。
- 前記第一および第二の標的化部分の各々が、IL13Rα2、EGFRvIIIおよびHER2からなる群から選択される脳腫瘍関連抗原を特異的に結合し、または前記第一および第二の標的化部分の各々が、GD2、PDGFRαおよびCD133からなる群から選択される脳腫瘍関連抗原を特異的に結合し、または前記第一および第二の標的化部分の各々が、EphA2およびCSPG4からなる群から選択される脳腫瘍関連抗原を特異的に結合する、請求項30に記載の方法。
- 前記脳癌が神経膠腫である、請求項30に記載の方法。
- 前記神経膠腫がびまん性内在性橋膠腫(DIPG)である、請求項33に記載の方法。
- 前記脳癌が神経膠芽腫(GBM)である、請求項30に記載の方法。
- 前記被験体が血液癌を有し、前記第一および第二の標的化部分が異なる血液腫瘍関連抗原を特異的に結合する、請求項21に記載の方法。
- 前記第一および第二の標的化部分の各々が、CD38、CS1、BCMA、CD20、CD19、CD22、CD30、CD138、CD40、CD56、CD70およびCD74からなる群から選択される血液腫瘍関連抗原を特異的に結合する、請求項36に記載の方法。
- 前記第一および第二の標的化部分の各々が、CD38、CS1およびBCMAからなる群から選択される血液腫瘍関連抗原を特異的に結合し、または前記第一および第二の標的化部分の各々が、CD19、CD20およびCD22からなる群から選択される血液腫瘍関連抗原を特異的に結合し、または前記第一および第二の標的化部分の各々が、CD30、CD40、CD56、CD70、CD74およびCD138からなる群から選択される血液腫瘍関連抗原を特異的に結合する、請求項37に記載の方法。
- 前記血液癌が、多発性骨髄腫(MM)、急性リンパ芽球性白血病(ALL)、急性骨髄性白血病(AML)、急性リンパ芽球性白血病(ALL)、慢性リンパ球性白血病(CLL)、慢性骨髄性白血病(CML)、非ホジキンリンパ腫(NHL)、ホジキンリンパ腫または大顆粒リンパ球性(LGL)白血病である、請求項36に記載の方法。
- 前記癌がHER2+癌である、請求項21に記載の方法。
- 前記癌が、乳癌、肺癌、結腸直腸癌、脳癌、卵巣癌または膵臓癌である、請求項40に記載の方法。
- a)およびb)より前に、前記被験体が一次癌処置を受けた、請求項21に記載の方法。
- 前記一次癌処置が、抗原逃避の結果として無効となった、請求項42に記載の方法。
- 前記被験体がヒトである、請求項21に記載の方法。
- 治療的有効量の複数の、二機能性化合物または薬学的に許容され得るその塩もしくは立体異性体の部分集団であって、第一の部分集団中の各二機能性化合物が、第一の腫瘍関連抗原を特異的に結合する第一の標的化部分に共有結合された第一の合成抗原を含み、および第二の部分集団中の各二機能性化合物が、第二の腫瘍関連抗原を特異的に結合する第二の標的化部分に共有結合された前記第一の合成抗原を含む部分集団と、ここで、前記第一および第二の標的化部分は異なる腫瘍関連抗原を特異的に結合し、ならびに患者に投与される二機能性化合物の各部分集団は前記第一の合成抗原を含有するが、異なる腫瘍関連抗原を特異的に結合し、前記複数の、二機能性化合物の部分集団は同一のまたは別個の容器中に配置されており、
b)前記治療的有効量の複数の、二機能性化合物の部分集団、治療的有効数のCAR−T細胞であって、前記合成抗原を特異的に結合する細胞外リガンドを含むCAR−T細胞を癌患者に併用投与するための説明書と、
を備える、キット。
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