JP2021509817A - Clec12a発現癌を標的にするための組成物および方法 - Google Patents
Clec12a発現癌を標的にするための組成物および方法 Download PDFInfo
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Abstract
Description
本出願は、2018年1月9日に出願された米国特許仮出願第62/615,096号、2018年4月9日に出願された同第62/654,621号、2018年4月9日に出願された同第62/654,623号、2018年9月12日に出願された同第62/730,390号、2018年9月12日に出願された同第62/730,397号、2018年11月15日に出願された同第62/767,859号、および2018年11月15日に出願された同第62/767,865号の利益を主張し、これらは全て参照によりそれらの全体が本明細書に援用される。
本出願は、2019年1月6日に作成された「320103−2040配列表_ST25」と題するASCII.txtファイルとして電子形式で出願された配列表を含む。配列表の内容は、その全体が本明細書に援用される。
VLI−VHI−VLT−VHT、
VLT−VHT−VLI−VHI、
VHT−VLT−VHI−VLI、
VHI−VLI−VHT−VLT、
VLI−VHI−VHT−VLT、
VLT−VHT−VHI−VLI、
式中、「VLI」は、免疫細胞抗原に特異的な軽鎖可変ドメインであり、
「VHT」は、CLEC12Aに特異的な重鎖可変ドメインであり、
「VLT」は、CLEC12Aに特異的な軽鎖可変ドメインであり、
「VHI」は、免疫細胞抗原に特異的な重鎖可変ドメインであり、
「−」は、ペプチドリンカーまたはペプチド結合からなる。
み、VLドメインのCDR3配列は、アミノ酸配列QQWTSNPPT(配列番号15)を含む。
GAACTAATACTGGTGGAGTCTGGGGGAGGCTTAGTGAAGCCTGGAGGGTCCCTGAAACTCTCCTGTGCAGTCTCTGGATTCACTTTCAGTTCCTTTGCCATGTCTTGGGTTCGCCAGACTCCGGAGAAGAGGCTGGAGTGGGTCGCAACCATTAGTAGTGGTGGAGCTTACACCTTCTATAAAGACAGTGTGAAGGGGCGATTCACCATCTCCAGAGACAATGCCAAGAATACCCTGTACCTGCAAATGAGCAGTCTGAGGTCTGAGGACTCGGCCATGTATTACTGTGCAAGACATAGCGGCTATGATGGTTACTACCTCTATGCTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA(配列番号17、1F3H8)。
GGTGTCCAGTGTGAACTAATACTGGTGGAGTCTGGGGGAGGCTTAGTGAAGCCTGGAGGGTCCCTGAAACTCTCCTGTGCAGTCTCTGGATTCACTTTCAGTTCCTTTGCCGTGTCCTGGGTTCGCCAGACTCCGGAGAAGAGGCTGGAGTGGGTCGCAACCATTAGTAGTGGTGGAGCTTACACCTTCTATAAAGACAGTGTGAAGGGGCGATTCACCATCTCCAGAGACAATGCCAAGAATACCCTGTACCTGCAAATGAGCAGTCTGAGGTCTGAGGACTCGGCCATGTATTACTGTGCAAGACATAGCGGCTATGATGGTTACTACCTCTATGCTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA(配列番号19、1F3A10)。
GAGGTGCAGCTGGAGGAGTCTGGGGGAGGCTTAGTGCAGC
CGGGAGGGTCCCTGAAAGTCTCCTGTGCAGTTTCCGGACTCGCTTTCAGCAGCCATGACATGTCTTGGGTTCGCCAGACTCCGGAGAAGCGGCTGGAGTGGGTCGCATACATTAGTGGAGGTGGTACTAATATCTATTATTCAGACACTGTGAAGGGCCGATTCACCATCTCCAGAGACAATGCCAAGAACACCCTGTACCTGCAAATGAGCAGTCTGAAGTCTGAAGACACAGCCATTTATTACTGTGCAAGACCCAATTATAATTACGGCGGTTCCTGGTTTGCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCA(配列番号21、1F3F3)。
CAAATTGTTCTCACCCAGTCTCCAGAAATCATGTCTGCATCTCCAGGGGAGAAGGTCACCATGACCTGCAGTGCCAGCTCAAGTGTACATTACATGCACTGGTACCAGCAGAAGTCAGGCACCTCCCCCAAAAGATGGATTTATGACACATCCAAACTGGCTTCTGGAGTCCCTGGTCGCTTCAGTGGCAGTGGGTCTGGGACCTCTTACTCTCTCACAATCAGCAGCATGGAGTCTGAAGATGCTGCCACTTATTACTGCCAGCAGTGGACTAGTAACCCACCCACGTTCGGAGGGGGGACCAAGCTGGAAATTAAACG(配列番号23、1F3H8、1F3F3、1F3A10)。
ELILVESGGGLVKPGGSLKLSCAVSGFTFSSFAMSWVRQTPEKRLEWVATISSGGAYTFYKDSVKGRFTISRDNAKNTLYLQMSSLRSEDSAMYYCARHSGYDGYYLYAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSQIVLTQSPEIMSASPGEKVTMTCSASSSVHYMHWYQQKSGTSPKRWIYDTSKLASGVPGRFSGSGSGTSYSLTISSMESEDAATYYCQQWTSNPPTFGGGTKLEIK(配列番号25、1F3H8)。
GVQCELILVESGGGLVKPGGSLKLSCAVSGFTFSSFAVSWVRQTPEKRLEWVATISSGGAYTFYKDSVKGRFTISRDNAKNTLYLQMSSLRSEDSAMYYCARHSGYDGYYLYAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSQIVLTQSPEIMSASPGEKVTMTCSASSSVHYMHWYQQKSGTSPKRWIYDTSKLASGVPGRFSGSGSGTSYSLTISSMESEDAATYYCQQWTSNPPTFGGGTKLEIK(配列番号26、1F3A10)。
EVQLEESGGGLVQPGGSLKVSCAVSGLAFSSHDMSWVRQTPEKRLEWVAYISGGGTNIYYSDTVKGRFTISRDNAKNTLYLQMSSLKSEDTAIYYCARPNYNYGGSWFAYWGQGTLVTVSAGGGGSGGGGSGGGGSQIVLTQSPEIMSASPGEKVTMTCSASSSVHYMHWYQQKSGTSPKRWIYDTSKLASGVPGRFSGSGSGTSYSLTISSMESEDAATYYCQQWTSNPPTFGGGTKLEIK(配列番号27、1F3F3)。
QIVLTQSPEIMSASPGEKVTMTCSASSSVHYMHWYQQKSGTSPKRWIYDTSKLASGVPGRFSGSGSGTSYSLTISSMESEDAATYYCQQWTSNPPTFGGGTKLEIKGGGGSGGGGSGGGGSELILVESGGGLVKPGGSLKLSCAVSGFTFSSFAMSWVRQTPEKRLEWVATISSGGAYTFYKDSVKGRFTISRDNAKNTLYLQMSSLRSEDSAMYYCARHSGYDGYYLYAMDYWGQGTSVTVSS(配列番号28)。
QIVLTQSPEIMSASPGEKVTMTCSASSSVHYMHWYQQKSGTSPKRWIYDTSKLASGVPGRFSGSGSGTSYSLTISSMESEDAATYYCQQWTSNPPTFGGGTKLEIKGGGGSGGGGSGGGGSGVQCELILVESGGGLVKPGGSLKLSCAVSGFTFSSFAVSWVRQTPEKRLEWVATISSGGAYTFYKDSVKGRFTISRDNAKNTLYLQMSSLRSEDSAMYYCARHSGYDGYYLYAMDYWGQGTSVTVSS(配列番号29)。
QIVLTQSPEIMSASPGEKVTMTCSASSSVHYMHWYQQKSGTSPKRWIYDTSKLASGVPGRFSGSGSGTSYSLTISSMESEDAATYYCQQWTSNPPTFGGGTKLEIKGGGGSGGGGSGGGGSEVQLEESGGGLVQPGGSLKVSCAVSGLAFSSHDMSWVRQTPEKRLEWVAYISGGGTNIYYSDTVKGRFTISRDNAKNTLYLQMSSLKSEDTAIYYCARPNYNYGGSWFAYWGQGTLVTVSA(配列番号30)。
本開示の組成物および方法に使用することができる抗体としては、任意のクラスの全免疫グロブリン(すなわち、無傷の抗体)、その断片、および少なくとも抗体の抗原結合可変ドメインを含有する合成タンパク質が挙げられる。可変ドメインは、抗体間で配列が異なり、その特定の抗原に対する各特定の抗体の結合および特異性に使用される。しかしながら、可変性は、通常、抗体の可変ドメインを通じて均等に分布していない。典型的には、軽鎖および重鎖可変ドメインの両方において相補性決定領域(CDR)または超可変領域と呼ばれる3つのセグメントに濃縮される。可変ドメインのより高度に保存された部分は、フレームワーク(FR)と呼ばれる。天然の重鎖および軽鎖の可変ドメインは、それぞれ4つのFR領域を含み、主にβシートの立体配置をとり、3つのCDRによって連結され、CDRは、ループを形成してβシート構造を連結し、場合によっては、その一部を形成する。各鎖中のCDRは、FR領域によって近接して一緒に保持され、他方の鎖からのCDRとともに、抗体の抗原結合部位の形成に寄与する。
ラリ内で産生され得る(Hoogenboom et al.,J.Mol.Biol.,227:381(1991)、Marks et al.,J.Mol.Biol.,222:581(1991))。CoteらおよびBoernerらの技術は、ヒトモノクローナル抗体の調製にも利用可能である(Cole et al.,Monoclonal Antibodies and Cancer Therapy,Alan R.Liss,p.77(1985)、Boerner et al.,J.Immunol.,147(1):86−95(1991))。
抗体の産生方法は、当業者に既知である。単鎖抗体は、短いペプチドリンカーを使用して重鎖および軽鎖の可変ドメインを一緒に融合することによって生成することができ、それによって、一分子上に抗原結合部位を再構成することができる。1つの可変ドメインのC末端が、15〜25個のアミノ酸ペプチドまたはリンカーを介して他方の可変ドメインのN末端に繋がれた単鎖抗体可変断片(scFv)は、抗原結合または結合の特異性を著しく妨害することがないように開発されている。リンカーは、重鎖および軽鎖が、それらの適切な立体構造の配向で、一緒に結合することできるように選択される。
薬学的に許容される担体中に開示される分子を含む医薬組成物もまた開示される。医薬担体は、当業者に既知である。これらは、最も典型的には、生理的pHにおける滅菌水、食塩水、および緩衝溶液などの溶液を含む、ヒトへの薬物投与のための標準的な担体であろう。例えば、好適な担体およびそれらの製剤は、Remington: The Science and Practice of Pharmacy(21 ed.) ed.PP.Gerbino,Lippincott Williams & Wilkins,Philadelphia,PA.2005に記載されている。典型的には、製剤中に適量の薬学的に許容される塩を使用して、製剤を等張性にする。薬学的に許容される担体の例としては、限定されないが、食塩水、リンゲル液、およびデキストロース溶液が挙げられる。溶液のpHは、好ましくは約5〜約8、より好ましくは約7〜約7.5である。溶液には、RNA分解酵素が含まれないようにすべきである。さらなる担体としては、抗体を含有する固体疎水性ポリマーの半透性マトリックス等の徐放性調製物が挙げられ、マトリックスは、成形品、例えば、フィルム、リポソームまたは微小粒子の形態である。当業者には明白であろうが、例えば、投与される組成物の投与経路および濃度に応じて、ある特定の担体がより好ましいことがある。
治療上有効量の開示される医薬組成物を対象に投与することによって、対象においてCLEC12A発現癌を治療するための方法も開示される。本方法は、対象に、フルダラビン、シタラビン、シクロホスファミド、イダルビシン、ダウノルビシン等の化学療法、またはイムブルビカ、ミドスタウリン、イデラリシブ等の標的阻害剤、またはPD1もしくはPDL1阻害剤等の免疫剤を投与することをさらに含むことができる。
CARは、一般に、リンパ球活性化に関与する膜貫通シグナル伝達モチーフを有するモノクローナル抗体(mAb)の単鎖可変断片(scFv)由来の抗原認識ドメインを組み込む(Sadelain M,et al.Nat Rev Cancer 2003 3:35−45)。CLEC12A特異的CARに対する抗腫瘍活性を増強するために、免疫エフェクター細胞内で発現することができるCLEC12A特異的キメラ抗原受容体(CAR)が、本明細書に開示される。
SP−CLEC12A−HG−TM−CSR−SD、または
SP−CLEC12A−HG−TM−SD−CSR、によって定義され、
式中、「SP」は、任意選択的なシグナルペプチドを表し、
「CLEC12A」は、CLEC12A結合領域を表し、
「HG」は、任意選択的なヒンジドメインを表し、
「TM」は、膜貫通ドメインを表し、
「CSR」は、1つまたは複数の共刺激シグナル伝達領域を表し、
「SD」は、シグナル伝達ドメインを表し、
「−」は、ペプチド結合またはリンカーを表す。
AR T細胞を除去し、さらなるオフ腫瘍効果なしに症状を緩和する。
を、CARの内部ドメインに付加して、T細胞に追加のシグナルを提供する。前臨床の研究では、第2世代のCARの設計により、T細胞の抗腫瘍活性が改善することが示されている。さらに最近では、第3世代CARは、複数のシグナル伝達ドメインを組み合わせることで、効力がさらに強化されている。これらのCARで移植されたT細胞は、共刺激受容体/リガンド相互作用とは無関係に、向上した増殖、活性化、持続性、および腫瘍根絶効率を示している(Imai C,et al.Leukemia 2004 18:676−84、Maher J,et al.Nat Biotechnol 2002 20:70−5)。
くともその膜貫通領域を含む)。あるいは、膜貫通ドメインは合成であってもよく、この場合、それは主に、ロイシンおよびバリンのような疎水性残基を含む。場合によっては、合成膜貫通ドメインの各末端に、フェニルアラニン、トリプトファン、およびバリンのトリプレットが見出されるであろう。2〜10アミノ酸長のような短いオリゴまたはポリペプチドリンカーは、膜貫通ドメインとCARのエンドプラズムドメインとの間に連結を形成し得る。
伝達領域(CSR)のみを含有することができるが、両方は含有しない。第2のCAR(または内因性T細胞)は、それが活性化された場合、欠損しているシグナルを提供する。例えば、開示されるCARがSDを含有するがCSRを含有しない場合、このCARを含有する免疫エフェクター細胞は、CSRを含有する別のCAR(またはT細胞)がそのそれぞれの抗原に結合する場合にのみ、活性化される。同様に、開示されるCARがCSRを含有するがSDを含有しない場合、このCARを含有する免疫エフェクター細胞は、SDを含有する別のCAR(またはT細胞)がそのそれぞれの抗原に結合する場合にのみ、活性化される。
きなタンパク質系抗原としては、TSP−180、MAGE−4、MAGE−5、MAGE−6、RAGE、NY−ESO、pl85erbB2、pl80erbB−3、c−met、nm−23H1、PSA、CA19−9、CA72−4、CAM17.1、NuMa、K−ras、β−カテニン、CDK4、Mum−1、p15、p16、43−9F、5T4、791Tgp72、α−フェトプロテイン、β−HCG、BCA225、BTAA、CA125、CA15−3\CA27.29\BCAA、CA195、CA242、CA−50、CAM43、CD68\P1、CO−029、FGF−5、G250、Ga733\EpCAM、HTgp−175、M344、MA−50、MG7−Ag、MOV18、NB/70K、NY−CO−1、RCASl、SDCCAG16、TA−90\Mac−2結合タンパク質\シクロフィリンC−関連タンパク質、TAAL6、TAG72、TLP、TPS、GPC3、MUC16、LMP1、EBMA−1、BARF−1、CS1、CD319、HER1、B7H6、L1CAM、IL6、およびMETが挙げられる。
また、開示される免疫エフェクター細胞においてCLEC12A特異的CARの発現を可能にする、開示されるCLEC12A特異的CARをコードするポリヌクレオチドおよびポリヌクレオチドベクターも開示される。
提供する。選択された遺伝子は、当該技術分野で既知の技術を使用して、ベクターに挿入され、レトロウイルス粒子にパッケージングされ得る。次いで、組換えウイルスを単離し、インビボまたはエクスビボのいずれかで、対象の細胞に送達することができる。
文脈において、ベクターは、当該技術分野の任意の方法によって、宿主細胞、例えば、哺乳類、細菌、酵母、または昆虫細胞に容易に導入され得る。例えば、発現ベクターは、物理的、化学的、または生物学的手段によって宿主細胞に導入することができる。
また、開示されるCAR(本明細書では「CAR−T細胞」とも称される)を発現するように改変される免疫エフェクター細胞も開示される。これらの細胞は、好ましくは、治療される対象から得られる(すなわち、自己細胞である)。しかしながら、一部の実施形態では、免疫エフェクター細胞株またはドナーエフェクター細胞(同種)が使用される。免疫エフェクター細胞は、いくつかの供給源から得ることができ、末梢血単核細胞、骨髄、リンパ節組織、臍帯血、胸腺組織、感染部位からの組織、腹水、胸水、脾臓組織、およ
び腫瘍が含まれる。免疫エフェクター細胞は、Ficoll(商標)分離等の当業者に既知の任意の数の技術を使用して、対象から採取された血液から得ることができる。例えば、個体の循環血液からの細胞は、アフェレーシスによって得ることができる。一部の実施形態では、免疫エフェクター細胞は、例えば、PERCOLL(商標)勾配を介した遠心分離によって、または対向流遠心溶出によって、赤血球を溶解させ、単球を枯渇させることによって末梢血リンパ球から単離される。免疫エフェクター細胞の特定のサブ集団は、陽性または陰性選択技術によってさらに単離され得る。例えば、免疫エフェクター細胞は、例えば、所望の免疫エフェクター細胞の陽性選択に十分な期間、抗体結合ビーズとインキュベートすることによって、陽性選択細胞に固有の表面マーカーに対する抗体の組み合わせを使用して単離され得る。あるいは、免疫エフェクター細胞集団の濃縮は、陰性選択細胞に固有の表面マーカーに対する抗体の組み合わせを使用して、陰性選択によって達成することができる。
介性免疫をシャットダウンし、胸腺における陰性選択のプロセスから逃れた自己反応性T細胞を抑制することである。2つの主要なクラスのCD4+Treg細胞−内在性Treg細胞および適応性Treg細胞−が記載されている。
al.Leukemia 2006 20:732−733)が、NK細胞媒介性抗MM活性を増強する可能性がある手段は、開示されるCAR以前ではほぼ未調査であった。
2012 72(5):1116−25に記載されており、これらの教示のために、参照により援用される。
開示されるCARを発現する免疫エフェクター細胞は、CLEC12A発現癌細胞に対する抗腫瘍免疫応答を誘発することができる。開示されるCAR修飾免疫エフェクター細胞によって誘発される抗腫瘍免疫応答は、能動または受動免疫応答であってもよい。加えて、CAR媒介性免疫応答は、CLEC12Aに特異的な免疫応答をCAR修飾免疫エフェクター細胞が誘導する養子免疫療法の手法の一部であり得る。
2つの既知の抑制性チェックポイント経路は、細胞傷害性Tリンパ球抗原−4(CTLA−4)およびプログラム死1(PD−1)受容体を介したシグナル伝達を伴う。これらのタンパク質は、T細胞機能のすべての段階にわたって重要な役割を果たす共シグナル伝達分子のCD28−B7ファミリーのメンバーである。PD−1受容体(CD279としても知られる)は、活性化T細胞の表面に発現される。そのリガンド、PD−L1(B7−H1、CD274)およびPD−L2(B7−DC、CD273)は、樹状細胞またはマクロファージ等のAPCの表面に発現される。PD−L1は、主なリガンドであり、一方、PD−L2は、はるかに制限された発現パターンを有する。リガンドがPD−1に結合すると、抑制性シグナルがT細胞に伝達され、サイトカイン産生を低減し、T細胞増殖を抑制する。チェックポイント阻害剤としては、PD−1(ニボルマブ(BMS−936558またはMDX1106)、CT−011、MK−3475)、PD−L1(MDX−1105(BMS−936559)、MPDL3280A、MSB0010718C)、PD−L2(rHIgM12B7)、CTLA−4(イピリムマブ(MDX−010)、トレメリムマブ(CP−675,206))、IDO、B7−H3(MGA271)、B7−H4、TIM3、LAG−3(BMS−986016)、が挙げられるが、これらに限定されない。
なmAbは、トラスツズマブ(ハーセプチン、Genentech)であり、HER2(ヒト上皮増殖因子受容体2)の発現を標的とすることによって、HER2陽性乳癌の治療に革命をもたらした。
−6、IL−7、IL−10、IL−12、IL−13、IL−15、IL−18、IL−23、IL−24、IL−27、IL−28a、IL−28b、IL−29、KGF、IFNa(例えば、INFa2b)、IFN、GM−CSF、CD40L、Flt3リガンド、幹細胞因子、アンセスチム、およびTNFaが挙げられる。好適なケモカインとしては、ヒトCXCおよびC−CケモカインファミリーからのIP−10、MCP−3、MIG、およびSDF−la等のGlu−Leu−Arg(ELR)−陰性ケモカインが含まれ得る。好適なサイトカインとしては、サイトカイン誘導体、サイトカイン変異体、サイトカイン断片、およびサイトカイン融合タンパク質が挙げられる。
挙げられる。
シグナル伝達を可能にするには、両方の抗原結合ドメインの結合が必要である。これらの2つのCAR設計は、異なる別個の抗原に対する結合親和性を有するため、それらは、「二重特異性」CARとも称される。
ンも放出するデュアル型または条件型CAR設計のいずれかを有するCAR−T細胞を生成することが可能である。一部の実施形態では、デュアル型−条件型CAR−T細胞は、それぞれ、それらのそれぞれの共刺激ドメインに結合する2つの異なる癌抗原に対する2つの別個の抗原結合ドメインを有する2つのCARを発現するように作製され得る。共刺激ドメインは、活性化分子が投与された後にのみ、刺激ドメインとともに機能的になる。このCAR−T細胞が有効であるためには、癌が両方の癌抗原を発現し、活性化分子が患者に投与される必要があり、それによって、デュアル型および条件型CAR−T細胞の両方の特徴が組み込まれる。
用語「アミノ酸配列」は、アミノ酸残基を表す略称、文字、記号または単語のリストを指す。本明細書で使用されるアミノ酸の略称は、アミノ酸の従来の1文字コードであり、以下のように表される。A.アラニン、B.アスパラギンまたはアスパラギン酸、C.システイン、D.アスパラギン酸、E.グルタミン酸、グルタミン酸、F.フェニルアラニン、G.グリシン、H.ヒスチジン、I.イソロイシン、K.リジン、L.ロイシン、M.メチオニン、N.アスパラギン、P.プロリン、Q.グルタミン、R.アルギニン、S.セリン、T.スレオニン、V.バリン、W.トリプトファン、Y.チロシン、Z.グルタミンまたはグルタミン酸。
dsFvダイアボディ、Fc、およびFd断片が挙げられる。抗体断片は、任意の方法によって産生され得る。例えば、抗体断片は、無傷の抗体の断片化によって酵素的または化学的に産生されてもよく、部分抗体配列をコードする遺伝子から組換えて産生されてもよく、または完全にもしくは部分的に合成されて産生されてもよい。抗体断片は、任意選択的に、単鎖抗体断片であってもよい。あるいは、断片は、例えばジスルフィド結合によって一緒に連結される、複数の鎖を含んでもよい。断片は、任意選択的に多分子複合体であってもよい。機能性抗体断片は、典型的には、少なくとも約50アミノ酸を含み、より典型的には、少なくとも約200アミノ酸を含む。
胞で核酸を発現させる。
るFv断片を指す。1つまたは複数のscFv断片は、1つまたは複数の抗原認識部位を有する抗体構築物を形成するために、他の抗体断片(重鎖または軽鎖の定常ドメイン等)に連結されてもよい。
一次スクリーニングから選択されるハイブリドーマをサブクローニングした。ELISAプレートを、DPBS(LONZA、カタログ#17−512F、ロット#0000615334)で1ug/mlに希釈したCLEC12A抗原(Thermo Fisher、カタログ#11896H07H50、ロット#LCL07JL0401)を用いて、室温で1時間コーティングし、次いで、100ul/ウェルの1%BSA/DPBSを用いて、室温で1時間ブロックした。次いで、モノクローナルハイブリドーマ由来の上清を、コーティングされたプレートに添加した(50ul/ウェル)。ヤギ抗マウスIg−HRP(1010−05)を、TBST中で1:4000、50ul/ウェル、室温で45分間、続いて、ABTS/H2O2を10分間、使用して抗体を検出した。クローン1F3、1F8、1G3、2A10、3F12、4E3、4E10、5B2、5F10、6C7、9A2、11C7、11H1、および12D6は、CLEC12Aへの陽性結合を示した。
について、およびT細胞のサブセット(図3Cおよび3F)について分析した。EFF=エフェクター、EM=エフェクターメモリー、CM=セントラルメモリー、N=未処理。
Claims (23)
- CLEC12A抗原結合ドメイン、膜貫通ドメイン、細胞内シグナル伝達ドメイン、および共刺激シグナル伝達領域を含む、キメラ抗原受容体(CAR)ポリペプチド。
- 前記CLEC12A抗原結合ドメインが、CLEC12Aに特異的に結合する抗体の単鎖可変断片(scFv)である、請求項1に記載のポリペプチド。
- 前記scFvが、CDR1、CDR2およびCDR3配列を有する可変重(VH)ドメイン、ならびにCDR1、CDR2およびCDR3配列を有する可変軽(VL)ドメインを含み、前記VHドメインの前記CDR1配列が、アミノ酸配列:配列番号1、配列番号2、または配列番号3を含み、前記VHドメインの前記CDR2配列が、アミノ酸配列:配列番号4、配列番号5、または配列番号6を含み、前記VHドメインの前記CDR3配列が、アミノ酸配列:配列番号7、配列番号8、または配列番号9を含み、前記VLの前記CDR1配列が、アミノ酸配列:配列番号10、配列番号11、または配列番号12を含み、前記VLドメインの前記CDR2配列が、アミノ酸配列:配列番号13、または配列番号14を含み、前記VLドメインの前記CDR3配列が、アミノ酸配列:配列番号15を含む、請求項2に記載のポリペプチド。
- 前記共刺激シグナル伝達領域が、CD27、CD28、4−1BB、OX40、CD30、CD40、PD−1、ICOS、リンパ球機能関連抗原−1(LFA−1)、CD2、CD7、LIGHT、NKG2C、B7−H3、CD83と特異的に結合するリガンド、およびこれらの任意の組み合わせからなる群から選択される共刺激分子の細胞質ドメインを含む、請求項1〜3のいずれか一項に記載のポリペプチド。
- 前記CARポリペプチドが、式
SP−CLEC12A−HG−TM−CSR−ISD、または
SP−CLEC12A−HG−TM−ISD−CSR
によって定義され、式中、「SP」は、シグナルペプチドを表し、
「CLEC12A」は、CLEC12A結合領域を表し、
「HG」は、任意選択的なヒンジドメインを表し、
「TM」は、膜貫通ドメインを表し、
「CSR」は、共刺激シグナル伝達領域を表し、
「ISD」は、細胞内シグナル伝達ドメインを表し、
「−」は、二価リンカーを表す、請求項1〜4のいずれか一項に記載のポリペプチド。 - 前記細胞内シグナル伝達ドメインが、CD3ゼータ(CD3ζ)シグナル伝達ドメインを含む、請求項1〜5のいずれか一項に記載のポリペプチド。
- 請求項1〜6のいずれか一項に記載の組換えポリペプチドをコードする単離された核酸配列。
- 請求項7に記載の単離された核酸配列を含むベクター。
- 請求項8に記載のベクターを含む細胞。
- 前記細胞が、αβT細胞、γδT細胞、ナチュラルキラー(NK)細胞、ナチュラルキラーT(NKT)細胞、B細胞、自然リンパ球細胞(ILC)、サイトカイン誘導キラー(CIK)細胞、細胞傷害性Tリンパ球(CTL)、リンホカイン活性化キラー(LAK)細胞、制御性T細胞、またはこれらの任意の組み合わせからなる群から選択される、請
求項9に記載の細胞。 - 前記細胞が、前記CARの前記抗原結合ドメインがCLEC12Aに結合するときに、抗腫瘍免疫を示す、請求項10に記載の細胞。
- 請求項1に記載のキメラ抗原受容体(CAR)ポリペプチドを含む、細胞。
- 前記細胞が、自己または同種のエプスタインバーウイルス(EBV)特異的細胞傷害性リンパ球である、請求項12に記載の細胞。
- CLEC12A発現癌を有する対象において抗癌免疫を提供する方法であって、前記方法が、前記対象に有効量の、請求項1〜6のいずれか一項に記載のCARポリペプチドを発現するように遺伝子改変された免疫エフェクター細胞を投与することによって、哺乳動物における抗腫瘍免疫を提供することを含む、方法。
- 前記免疫エフェクター細胞が、T細胞、ナチュラルキラー(NK)細胞、細胞傷害性Tリンパ球(CTL)、および制御性T細胞、からなる群から選択される、請求項14に記載の方法。
- 前記免疫エフェクター細胞が、自己または同種のエプスタインバーウイルス(EBV)特異的細胞傷害性リンパ球である、請求項14または15に記載の方法。
- 前記対象にチェックポイント阻害剤を投与することをさらに含む、請求項14〜16のいずれか一項に記載の方法。
- 前記チェックポイント阻害剤が、抗PD−1抗体、抗PD−L1抗体、抗CTLA−4抗体、またはこれらの組み合わせを含む、請求項17に記載の方法。
- 前記癌が、骨髄異形成症候群、急性骨髄性白血病、または混合表現型(bi−phenotypic)白血病を含む、請求項14〜18のいずれか一項に記載の方法。
- 以下の式を含む融合ポリペプチドであって、
VLI−VHI−VLT−VHT、
VLT−VHT−VLI−VHI、
VHT−VLT−VHI−VLI、
VHI−VLI−VHT−VLT、
VLI−VHI−VHT−VLT、
VLT−VHT−VHI−VLI、
式中、「VLI」は、免疫細胞抗原に特異的な軽鎖可変ドメインであり、
「VHT」は、CLEC12Aに特異的な重鎖可変ドメインであり、
「VLT」は、CLEC12Aに特異的な軽鎖可変ドメインであり、
「VHI」は、前記免疫細胞抗原に特異的な重鎖可変ドメインであり、
「−」は、ペプチドリンカーまたはペプチド結合からなる、融合ポリペプチド。 - 前記免疫細胞抗原が、CD3である、請求項20に記載の融合ポリペプチド。
- 前記VHTが、CDR1、CDR2、およびCDR3配列を含み、前記VLTが、CDR1、CDR2、およびCDR3配列を含み、前記VHドメインの前記CDR1配列が、アミノ酸配列:配列番号1、配列番号2、または配列番号3を含み、前記VHドメインの前記CDR2配列が、アミノ酸配列:配列番号4、配列番号5、または配列番号6を含み
、前記VHドメインの前記CDR3配列が、アミノ酸配列:配列番号7、配列番号8、または配列番号9を含み、前記VLの前記CDR1配列が、アミノ酸配列:配列番号10、配列番号11、または配列番号12を含み、前記VLドメインの前記CDR2配列が、アミノ酸配列:配列番号13、または配列番号14を含み、前記VLドメインの前記CDR3配列が、アミノ酸配列:配列番号15を含む、請求項20または21に記載の融合ポリペプチド。 - 対象において癌を治療するための方法であって、薬学的に許容される担体中の、治療上有効量の請求項20〜22のいずれか一項に記載の融合ポリペプチドを、前記対象に投与することを含む、方法。
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