JP7409669B2 - 抗dclk1抗体およびキメラ抗原受容体、ならびにこれらの組成物および使用方法 - Google Patents
抗dclk1抗体およびキメラ抗原受容体、ならびにこれらの組成物および使用方法 Download PDFInfo
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Description
本願は、2017年12月4日に出願された米国仮出願第62/594,464号の米国特許法第119条(e)項に基づく恩典を主張し、その内容は、参照により本開示中に組み入れられる。
本開示は、ヒト化抗DCLK1抗体およびキメラ抗原受容体(CAR)細胞およびこれらを含む組成物ならびに固形腫瘍の処置を含む治療のためにこれらを使用する方法に関する。DCLK1に対する免疫原性決定基を含有する単離されたペプチドおよび融合タンパク質も本明細書において提供される。
本開示の背景の以下の論述は、読者が本開示を理解する上での補助を与えるために提供されているにすぎず、本開示の従来技術を記載しまたは構成することを認めたものではない。
癌を検出する上で、多大な進歩が遂げられてきたが、癌の安全で効果的な処置に対する要望がなお存在する。本開示はこの要望を満たし、関連する利点も提供する。
遺伝的に改変操作されたキメラ抗原受容体(CAR)T細胞での自家処置を使用して、B細胞リンパ腫および白血病において最近前例のない結果が得られているため、数多くの研究室がこのアプローチを固形腫瘍に応用し始めた。CAR改変された細胞は、モノクローナル抗体のHLA非依存性標的特異性と、活性化されたT細胞の細胞溶解活性、増殖およびホーミング特性を併せ持つが、チェックポイント抑制には応答しない。抗原発現標的を直接死滅させる能力の故に、CAR細胞は任意の抗原陽性細胞または組織に対して極めて有毒であり、高度に特異的な抗体を用いてCARを構築する必要がある。このため、一態様において、本開示は、癌の処置のための標的としてDCLK1を提供する。DCLK1は、しばしば、腫瘍細胞上で発現される。このため、一態様において、組成物は、DCLK1を発現または過剰発現する固形腫瘍または対応する循環癌細胞の処置において特に有用である。一態様において、新規DCLK1抗体ならびに診断および治療での新規DCLK1抗体の使用方法が本明細書に開示されている。これに関して、重鎖(HC)免疫グロブリン可変ドメイン配列および軽鎖(LC)免疫グロブリン可変ドメイン配列を含む、または重鎖(HC)免疫グロブリン可変ドメイン配列および軽鎖(LC)免疫グロブリン可変ドメイン配列から本質的になる、または重鎖(HC)免疫グロブリン可変ドメイン配列および軽鎖(LC)免疫グロブリン可変ドメイン配列からなる単離された抗体であって、DCLK1のアイソフォームに結合する単離された抗体が本明細書に提供されている。
特定の実施形態では、例えば、以下が提供される:
(項目1)
(i)配列番号1~9および/もしくは16~24もしくはこれらの各々の等価物の群から選択される配列を含む重鎖(HC)免疫グロブリン可変ドメイン配列と、および/または
(ii)配列番号11~14および/もしくは26~30もしくはこれらの各々の等価物の群から選択される配列を含む軽鎖(LC)免疫グロブリン可変ドメイン配列と、
を含むヒト化抗DCLK1抗体。
(項目2)
(a)項目1に記載の抗DCLK1抗体の抗原結合ドメインおよび/または配列番号10および/もしくは25もしくはこれらの各々の等価物の群より選択される配列を含む配列を含む重鎖(HC)免疫グロブリン可変ドメイン配列および/または配列番号15および/もしくは31もしくはこれらの各々の等価物の群より選択される配列を含む軽鎖(LC)免疫グロブリン可変ドメイン配列と、(b)ヒンジドメインと、(c)膜貫通ドメインと、(d)ならびに細胞内シグナル伝達ドメインと、を含む、キメラ抗原受容体(CAR)。
(項目3)
(a)項目1に記載の抗DCLK1抗体の抗原結合ドメインおよび/または配列番号10および/もしくは25もしくはこれらの各々の等価物の群から選択される配列を含む配列を含む重鎖(HC)免疫グロブリン可変ドメイン配列および/または配列番号15および/もしくは31もしくはこれらの各々の等価物の群より選択される配列を含む軽鎖(LC)免疫グロブリン可変ドメイン配列と、(b)CD8αまたはIgG1ヒンジドメインと、(c)CD28またはCD8α膜貫通ドメインと、(d)1またはそれを超える共刺激シグナル伝達領域と、ならびに(e)CD3ζシグナル伝達ドメインと、をさらに含む、項目2に記載のCAR。
(項目4)
前記1またはそれを超える共刺激シグナル伝達領域が、CD27、CD28、4-IBB(CD137)、OX40、CD30、CD40、PD-1、ICOS、リンパ球機能関連抗原1(LFA-1)、CD2、CD7、CD27、LIGHT、NKG2CおよびB7-H3より選択される、項目3に記載のCAR。
(項目5)
抗DCLK1 HC可変領域と抗DCLK1 LC可変領域の間に位置するリンカーポリペプチドをさらに含む、項目2~4のいずれか一項に記載のCAR。
(項目6)
前記CARのリンカーポリペプチドが、配列(GGGGS)nのポリペプチドを含み、nが1~6の整数である、項目5に記載のCAR。
(項目7)
等価物が、ポリペプチドに対して少なくとも80%のアミノ酸同一性を有するポリペプチドまたは10 -12 M未満もしくは約10 -12 MのDCLK1ペプチドに対する結合親和性を有する前記ポリペプチドおよび/または抗体をコードするポリヌクレオチドの相補物に対して高いストリンジェンシーの条件下でハイブリッド形成するポリヌクレオチドによってコードされるポリペプチドを含む、項目1に記載の抗体または項目2~6のいずれか一項に記載のCAR。
(項目8)
検出可能なマーカーまたは精製マーカーをさらに含む、項目1に記載の抗体または項目2~7のいずれか一項に記載のCAR。
(項目9)
核酸配列が、本明細書に開示されている配列の任意の1つまたはこれらの各々の等価物より選択され、ならびに必要に応じてプロモーターおよび/またはエンハンサー要素に機能的に連結されている配列を含む、単離された核酸配列。
(項目10)
項目1に記載の抗体または項目2~8のいずれか一項に記載のCARをコードする単離された核酸配列。
(項目11)
抗DCLK1抗体の抗原結合ドメインの上流に位置するシグナルペプチドポリヌクレオチド配列をさらに含む、項目9または10に記載の単離された核酸配列。
(項目12)
前記CARをコードする単離された核酸が、抗DCLK1抗体の抗原結合ドメインまたはエンハンサーの上流に位置するコザックコンセンサスポリヌクレオチド配列をさらに含む、項目10または11に記載の単離された核酸配列。
(項目13)
前記CARをコードする単離された核酸が、前記抗DCLK1抗体の抗原結合ドメインの上流に位置する2A自己切断型ペプチド(T2A)をコードするポリヌクレオチド配列をさらに含む、項目10~12のいずれか一項に記載の単離された核酸配列。
(項目14)
前記CARをコードする単離された核酸が、抗生物質耐性をコードするポリヌクレオチド配列をさらに含む、項目10~13のいずれか一項に記載の単離された核酸配列。
(項目15)
前記CARをコードする単離された核酸が、前記CARの発現および/または活性化を調節するためのスイッチ機構をさらに含む、項目10~14のいずれか一項に記載の単離された核酸配列。
(項目16)
項目9~15のいずれか一項に記載の前記単離された核酸配列を含むベクター。
(項目17)
前記ベクターがプラスミドまたはウイルスベクターである、項目16に記載のベクター。
(項目18)
前記ベクターが、レトロウイルスベクター、レンチウイルスベクター、アデノウイルスベクターおよびアデノ随伴ウイルスベクターからなる群より選択される、項目19に記載のベクター。
(項目19)
前記ベクターがCRISPRベクターである、項目16に記載のベクター。
(項目20)
項目1に記載の抗体、項目2~8のいずれか一項に記載のCAR、および/または項目9~15のいずれか一項に記載の単離された核酸、および/または項目16~19のいずれか一項に記載のベクターを含む単離された細胞。
(項目21)
前記単離された細胞が免疫細胞である、項目20に記載の単離された細胞。
(項目22)
前記免疫細胞がT細胞またはナチュラルキラー(NK)細胞である、項目21に記載の単離された細胞。
(項目23)
担体と、項目1に記載の抗体、項目2~8のいずれか一項に記載のCAR、および/または項目9~15のいずれか一項に記載の単離された核酸、項目16~19のいずれか一項に記載のベクター、および/または項目20~22のいずれか一項に記載の単離された細胞の1つまたはそれより多くと、を含む組成物。
(項目24)
DCLK1タンパク質またはその断片を結合することが可能な抗原結合断片をさらに含む、項目23に記載の組成物。
(項目25)
前記抗体または抗原結合断片が細胞に付随している、項目24に記載の組成物。
(項目26)
前記抗体または抗原結合断片が固体支持体に結合されている、項目24に記載の組成物。
(項目27)
前記抗体または抗原結合断片が溶液中に配置されている、項目24に記載の組成物。
(項目28)
前記抗体または抗原結合断片がマトリックスに付随している、項目24に記載の組成物。
(項目29)
組換えDNA技術、ファージディスプレイ技術、リンパ球集団中におけるインビボでの産生を誘導することまたは組換え免疫グロブリンライブラリーもしくは高度に特異的な結合試薬のパネルをスクリーニングすることの適用を含む、項目1に記載の抗DCLK1抗体を作製する方法。
(項目30)
(i)項目2~8のいずれか一項に記載のCARをコードする核酸配列を免疫細胞の集団に導入すること、および
(ii)工程(i)の前記核酸配列で首尾よく形質導入された免疫細胞の亜集団を選択し、これにより抗DCLK1 CAR発現細胞を作製すること、
を含む、抗DCLK1 CAR発現細胞を作製する方法。
(項目31)
前記免疫細胞がT細胞またはNK細胞である、項目30に記載の方法。
(項目32)
前記免疫細胞の集団が、内在性免疫細胞受容体の発現を低下または除去するように改変されている、項目30または31に記載の方法。
(項目33)
前記免疫細胞の集団が、RNA干渉またはCRISPRを使用する方法を用いて改変された、項目32に記載の方法。
(項目34)
腫瘍の増殖を阻害し、および/または癌を処置し、および/または癌の再発を予防することを必要とする被験体において、腫瘍の増殖を阻害し、および/または癌を処置し、および/または癌の再発を予防する方法であって、有効量の項目30~33のいずれか一項にしたがって生成された抗DCLK1 CAR発現細胞および/または有効量の項目1に記載の抗DCLK1抗体を前記被験体に投与することを含む、方法。
(項目35)
前記抗DCLK1 CAR発現細胞が、処置されている被験体にとって自家または同種異系である、項目34に記載の方法。
(項目36)
前記腫瘍、癌または癌幹細胞がDCLK1を発現または過剰発現する、項目34または35に記載の方法。
(項目37)
前記癌が、結腸癌、直腸癌、腸癌、胃癌、膵臓癌、前立腺癌、子宮頸癌もしくは卵巣癌、または繊維肉腫、多発性骨髄腫、肺癌、肝臓癌、食道癌、乳癌、大唾液腺癌腫、神経芽細胞腫または腎細胞癌腫である、項目34~36のいずれか一項に記載の方法。
(項目38)
前記腫瘍が固形腫瘍である、項目34~36のいずれか一項に記載の方法。
(項目39)
前記被験体が、ヒト、動物、非ヒト霊長類、イヌ、ネコ、ヒツジ、マウス、ウマまたはウシである、項目34~38のいずれか一項に記載の方法。
(項目40)
癌細胞または癌幹細胞の増殖を阻害する方法であって、有効量の項目30~33のいずれか一項にしたがって生成された抗DCLK1 CAR発現細胞および/または有効量の項目1に記載の抗DCLK1抗体と前記細胞を接触させることを含む、方法。
(項目41)
前記癌細胞または癌幹細胞が、接着性癌細胞または非接着性癌細胞である、項目40に記載の方法。
(項目42)
前記癌細胞または癌幹細胞が、結腸直腸癌細胞、膵臓癌細胞、繊維肉腫細胞、前立腺癌細胞、多発性骨髄腫細胞、子宮頸癌細胞、卵巣癌細胞、肺癌細胞、肝臓癌細胞、食道癌細胞、乳癌細胞、大唾液腺癌腫細胞、神経芽細胞腫細胞または腎細胞癌腫細胞である、項目40または41に記載の方法。
(項目43)
抗DCLK1治療のための被験体を選択する方法であって、前記被験体から単離された試料を項目1に記載の抗体と接触させること、および前記試料中の抗体-細胞複合体を検出することを含み、前記複合体の存在が前記治療のための前記被験体を選択する、方法。
(項目44)
有効量の、項目1に記載の抗体または項目2~8のいずれか一項に記載のCARを前記被験体に投与することをさらに含む、項目45に記載の方法。
(項目45)
被験体中の抗DCLK1治療をモニタリングする方法であって、前記被験体から単離された試料を項目1に記載の抗体と接触させること、および前記試料中の抗体-細胞複合体を検出すること、を含む、方法。
(項目46)
前記方法が、有効量の、項目1に記載の抗体または項目2~8のいずれか一項に記載のCARの前記被験体への投与前および/または投与後に実施される、項目45に記載の方法。
(項目47)
項目1に記載の抗体、項目2~8のいずれか一項に記載のCAR;および/または項目9~15のいずれか一項に記載の単離された核酸;項目16~19のいずれか一項に記載のベクター;項目20~22のいずれか一項に記載の単離された細胞;および/または項目23~28のいずれか一項に記載の組成物の1つまたはそれより多くと、使用説明書と、を備えるキット。
(項目48)
前記使用説明書が、項目29~42のいずれか一項に記載の方法を実施するための指示を与える、項目47に記載のキット。
定義
本開示は、記載されている特定の態様に限定されるものではなく、したがって、もちろん、変化し得ることが理解されなければならない。本開示の範囲は添付の特許請求の範囲によってのみ限定されるので、本明細書において使用される用語は特定の態様を記載することのみを目的としており、限定を意図していないことも理解されなければならない。
CTCGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCG
TTTTGGGTGCTGGTGGTGGTTGGTGGAGTCCTGGCTTGCTATAGCTTGCTAGTAACAGTGGCCTTTATTATTTTCTGGGTG
AAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTG
AGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCC
AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGCTAA
ヒトCD8αヒンジドメイン:
PAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIY
マウスCD8αヒンジドメイン:
KVNSTTTKPVLRTPSPVHPTGTSQPQRPEDCRPRGSVKGTGLDFACDIY
ネコCD8αヒンジドメイン:
PVKPTTTPAPRPPTQAPITTSQRVSLRPGTCQPSAGSTVEASGLDLSCDIY
ヒトCD8α膜貫通ドメイン:
IYIWAPLAGTCGVLLLSLVIT
マウスCD8α膜貫通ドメイン:
IWAPLAGICVALLLSLIITLI
ラットCD8α膜貫通ドメイン:
IWAPLAGICAVLLLSLVITLI
4-1BB共刺激シグナル伝達領域:
KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL
MLRLLLALNL FPSIQVTGNK ILVKQSPMLV AYDNAVNLSC KYSYNLFSRE FRASLHKGLDSAVEVCVVYG NYSQQLQVYS KTGFNCDGKL GNESVTFYLQ NLYVNQTDIY FCKIEVMYPPPYLDNEKSNG TIIHVKGKHL CPSPLFPGPS KPFWVLVVVG GVLACYSLLVTVAFIIFWVR SKRSRLLHSD YMNMTPRRPG PTRKHYQPYA PPRDFAAYRSおよびその等価物が含まれる。
ICOS共刺激シグナル伝達領域:
ACAAAAAAGA AGTATTCATC CAGTGTGCAC GACCCTAACG GTGAATACAT GTTCATGAGA GCAGTGAACA CAGCCAAAAA ATCCAGACTC ACAGATGTGA CCCTA
OX40共刺激シグナル伝達領域:
AGGGACCAG AGGCTGCCCC CCGATGCCCA CAAGCCCCCT GGGGGAGGCA GTTTCCGGAC CCCCATCCAA GAGGAGCAGG CCGACGCCCA CTCCACCCTG GCCAAGATC
CD3ζシグナル伝達ドメイン:
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
略号のリスト
本開示を実施するための様式
抗体およびその使用
抗DCLK1抗体
(a)軽鎖免疫グロブリン可変ドメイン配列が、開示された軽鎖配列のいずれかの軽鎖可変ドメインのCDRと少なくとも85%同一である1もしくはそれを超えるCDRを含み、または開示された軽鎖配列のいずれかの軽鎖可変ドメインのCDRと少なくとも85%同一である1もしくはそれを超えるCDRから本質的になり、または開示された軽鎖配列のいずれかの軽鎖可変ドメインのCDRと少なくとも85%同一である1もしくはそれを超えるCDRからなる;
(b)重鎖免疫グロブリン可変ドメイン配列が、開示された重鎖配列のいずれかの重鎖可変ドメインのCDRと少なくとも85%同一である1もしくはそれを超えるCDRを含み、または開示された重鎖配列のいずれかの重鎖可変ドメインのCDRと少なくとも85%同一である1もしくはそれを超えるCDRから本質的になり、または開示された重鎖配列のいずれかの重鎖可変ドメインのCDRと少なくとも85%同一である1もしくはそれを超えるCDRからなる;
(c)軽鎖免疫グロブリン可変ドメイン配列が、開示された軽鎖配列のいずれかの軽鎖可変ドメインと少なくとも85%同一である;
(d)HC免疫グロブリン可変ドメイン配列が、開示された軽鎖配列のいずれかの重鎖可変ドメインと少なくとも85%同一である;
(e)抗体が、開示された配列のいずれかによって結合されるエピトープと重複するエピトープを結合する。
抗体の特徴および機能
1)塩基性側鎖を有するアミノ酸:リジン、アルギニン、ヒスチジン;
2)酸性側鎖を有するアミノ酸:アスパラギン酸、グルタミン酸;
3)帯電していない極性側鎖を有するアミノ酸:アスパラギン、グルタミン、セリン、スレオニン、チロシン;
4)非極性側鎖を有するアミノ酸:グリシン、アラニン、バリン、ロイシン、イソロイシン、プロリン、フェニルアラニン、メチオニン、トリプトファン、システイン。
抗体を調製するための過程
使用の方法
治療上の応用。
キット
担体
組成物
本開示は、細胞外、膜貫通および細胞内ドメインを含む細胞活性化部分を含む、細胞外、膜貫通および細胞内ドメインを含む細胞活性化部分からなる、または細胞外、膜貫通および細胞内ドメインを含む細胞活性化部分から本質的になる、DCLK1に結合するキメラ抗原受容体(CAR)を提供する。細胞外ドメインは、抗原結合ドメインとも別称される標的特異的結合要素を含む。細胞内ドメインまたは細胞質ドメインは、少なくとも1つの共刺激シグナル伝達領域およびζ鎖部分を含む。
CARを調製するための過程
使用の方法
担体
親抗体配列の選択した部分をヒトフレームワーク配列と融合する複数のハイブリッド配列を作製することによって、ヒト化抗体を設計した。3Dモデルを使用して、抗原結合を保持する可能性が最も高い配列を単離するために、これらのヒト化配列を肉眼およびコンピュータモデリングによって系統的に分析した。最終目標は、元の抗体特異性を保持しながら、最終のヒト化抗体中のヒト配列の量を最大化することであった。
CBT-15A VHは、マウス生殖系列VH5-6-2である。CDR移植のための「アクセプター」フレームワークとして、ヒトVH3-23を選択した。CBT-15A VKは、マウス生殖系列VK8-20である。CDR移植のための「アクセプター」フレームワークとして、ヒトVK4-1を選択した。
実施例1および/または実施例2で生成されたヒト化抗DCLK1抗体に対するDNA配列を取得し、CARベクター、例えば、以下のタンデム遺伝子コザックコンセンサス配列;CD8シグナルペプチド;抗DCLK1重鎖可変領域;(グリシン4セリン)3柔軟ポリペプチドリンカー;それぞれの抗DCLK1可変領域;CD8ヒンジおよび膜貫通ドメイン;ならびにCD28、4-1BBおよびCD3ζ細胞内共刺激シグナル伝達ドメインからなるベクター中に組み込む。ヒンジ、膜貫通およびシグナル伝達ドメインDNA配列は、Carl Juneによる特許から確認される(米国特許出願公開第2013/0287748A1号参照)。ベクター宿主にアンピシリン耐性を付与するbla遺伝子を含有するpUC57ベクター骨格内に、Genewiz,Inc.(South Plainfield,NJ)によって、抗DCLK1 CAR遺伝子を合成する。
DCLK1抗原陽性および陰性ヒト細胞株を収集し、洗浄し、1.0×106細胞/mLの濃度で、完全培地中に再懸濁する。カルセイン-アセトキシメチル(AM)を、15μMで標的細胞試料に添加し、次いで、5%CO2の加湿された恒温槽中において、30分間、37℃でインキュベートする。染色された陽性および陰性標的細胞を2回洗浄し、遠心によって、完全培地中に再懸濁し、1.0×104細胞/ウェルで、96ウェルプレートに添加する。50:1、5:1および1:1のエフェクター対標的細胞比率で、完全培地中のプレートに、DCLK1 CAR T細胞を添加する。完全培地および2%tritonX-100を加えた完全培地中に懸濁された染色された標的細胞は、それぞれ、自発的放出対照および最大放出対照としての役割を果たす。恒温槽中に3時間戻す前に、365×gおよび20℃で2分間、プレートを遠心する。次いで、プレートを10分遠心し、黒色ポリスチレン96ウェルプレート上の各ウェルに細胞上清を分取し、それぞれ、485/20nmおよび528/20nmの励起および発光で、Bio-Tek(登録商標)Synergy(商標)HTマイクロプレートリーダー上において、蛍光を評価する。
DCLK1 CAR構築物1の配列
シグナルペプチドヒトCD8:MALPVTALLLPLALLLHAARP
KPTTTPAPRPPTPAPTIASQPLSLRPEASRPAAGGAVHTRGLDFASDKP
RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS
FWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMYMNMPPRRPGPTRKHYQYAPPYAPPRDFAAYRS
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMETGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
DCLK1 CAR構築物2の配列
KPTTTPAPRPPTPAPTIASQPLSLRPEASRPAAGGAVHTRGLDFASDKP
RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS
FWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMYMNMPPRRPGPTRKHYQYAPPYAPPRDFAAYRS
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMETGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
細胞株
ATCCからHela細胞を購入し、10%FBSおよび1%ペニシリン/ストレプトマイシンを加えたDMEM中で培養した。CD19の安定な発現を有するHela-CD19細胞を、10%FBS、ピューロマイシンおよびペニシリン/ストレプトマイシンを加えたDMEM中で維持した。Ficoll-Paque溶液(GE Healthcare)を使用するIRBによって承認されたプロトコールにしたがって、Stanford Hospital Blood Center、Stanford、CAにおいて得られた全血から、ヒト末梢血単核球(PBMC)を単離した。10%FBSおよびペニシリン/ストレプトマイシンを含有するDMEM中で、AlStem(Richmond、CA)から得たHEK293FT細胞を培養したATCCからSKOV-3細胞株を取得し、10%FBSおよびペニシリン/ストレプトマイシンを加えたRPMI中で培養した。Lonza社から正常なヒトケラチン生成細胞を取得し、製造業者のプロトコールにしたがって、ケラチン生成細胞培地(Lonza)中で培養した。ATCCからBxPC3、PANC-1、A1847、A375、A549およびHep-3Bを取得し、10%FBSおよびペニシリン/ストレプトマイシンを加えたDMEM中で培養した。細胞特異的表面マーカーを用いて本発明者らの研究室において、フローサイトメトリーによって、またはATCCによって、細胞株を認証した。HCT116、HT29、SW620 CaCo2、LS123、LoVo、HT1080、LNCaP、RPMI8226、MM1S、K562およびOVCAR-3をATCCから購入した。
Berahovich R,Xu S,Zhou H,et al.に記載されているように、293FT細胞、Lentivirus Packaging Mixおよび形質移入剤(ALSTEM)を用いるレンチウイルスの生成のために、レンチウイルスCARを使用した。FLAGタグを付加されたCD19特異的CAR-T細胞は、CD19を有する固形腫瘍細胞をインビトロおよびインビボで除去する。Front Biosci(Landmark Ed)2017;22:1644-1654。
300U/mLのIL-2(Thermo Fisher)とともに10%FBSを含有するAIM V-AlbuMAX培地(Thermo Fisher)中に、1×106細胞/mlでPBMCを懸濁した。等しい数のCD3/CD28Dynabeads(Invitrogen)でPBMCを活性化し、処理されていない24ウェルプレート中で培養した。24時間および48時間に、1μlのTransPlus形質導入エンハンサー(AlStem)とともに、5の感染多重度(MOI)で、レンチウイルスを培養物に添加した。2~3日おきに、CAR-T細胞を計数し、1×106細胞/mlの細胞密度を維持するために、300U/mlのIL-2を加えた新鮮な培地を培養物に添加した。
CAR発現を測定するために、5×105細胞を100mlの緩衝液(0.5%BSAを加えた1×PBS)中に懸濁し、1mlのヒト血清(Jackson Immunoresearch、West Grove、PA)とともに氷上で、10分間インキュベートした。次いで、1mlのアロフィコシアニン(APC)標識された抗CD3(eBioscience、San Diego、CA)、2mlの7-アミノアクチノマイシンD(7-AAD、BioLegend、San Diego、CA)および2mlの抗F(ab)2またはそのアイソタイプ対照を添加し、氷上で30分間、細胞をインキュベートした。細胞を緩衝液ですすぎ、FACSCalibur(BD Biosciences)上で取得した。まず、光散乱対7-AAD染色に対して、細胞を分析し、次いで、CD3染色体対F(ab)2染色またはアイソタイプ対照染色に対して、7-AAD-生きたゲートされた細胞をプロットした。いくつかの実験では、抗F(ab)2染色のみを行った。マウス腫瘍研究のために、1mlのAPC抗CD3、2mlのフルオレセインイソチオシアネート(FITC)標識された抗CD8a(eBioscience)、2mlの7-AADにより、室温で30分間、100mlの血液を染色した。3.5mlのRBC溶解溶液(150mM NH4Cl、10mM NaHCO3、1mM EDTA pH8)で赤血球を溶解し、次いで、遠心によって白血球を集め、取得前に、2mlの冷たい緩衝液ですすいだ。DCLK1の発現のために、10mg/ml濃度でマウスまたはヒト抗体(COARE Holdings Inc.,)を使用した。(BioLegend、San Diego、CA)から10mg/mlで、アイソタイプIgG1アイソタイプ抗体を使用した。
96ウェルE-プレート(Acea Biosciences、San Diego、CA)中に、1×104細胞/ウェルで、接着性標的細胞を播種し、インピーダンスベースのリアルタイム細胞分析(RTCA)iCELLigenceシステム(Acea Biosciences)を用いて、一晩、培養しながらモニターした。翌日、培地を除去し、10%FBS±1×105エフェクター細胞(CAR-T細胞または形質導入されていないT細胞)を含有するAIM V-AlbuMAX培地と3つ組で交換した。RTCAシステムを用いて、細胞をさらに2日間モニターし、インピーダンスを経時的にプロットした。(エフェクター細胞なしの標的細胞のインピーダンス-エフェクター細胞ありの標的細胞のインピーダンス)×100/エフェクター細胞なしの標的細胞のインピーダンスとして、細胞溶解を計算した。
3つ組で、10%FBSを含有する200μlのAIM V-AlbuMAX培地を加えたU底96ウェルプレート中において、1:1の比率で(それぞれ1×104細胞)、エフェクター細胞(CAR-T細胞または形質導入されていないT細胞)とともに標的細胞を培養した。16時間後に、150μlの上側培地をV底96ウェルプレートに移し、残存する全ての細胞を沈渣にするために、300gで5分間遠心した。いくつかの実験において、サイトカインELISAアッセイのために、E:T=10:1でのRTCAアッセイ後の上清を使用した。新しい96ウェルプレートに上清を移し、製造業者のプロトコールにしたがい、Thermo Fisherから得たキットを用いて、ヒトサイトカインレベル(IFN-γ、IL-2、IL-6)について、ELISAにより分析した。
マウスまたはヒト化DCLK-1 scFvは、G4Sx3リンカーで連結されたVLおよびVH配列を含有した。組換えDCLK-1 scFvタンパク質発現のために使用されたpYD11ベクター内のC末端ヒトFcと、scFvをインフレームで融合した。哺乳動物の発現されたScFvタンパク質を有する上清を、等量で結合アッセイのために使用した。抗ヒトFc抗体を用いたウェスタンブロットによって、発現に関して、全てのscFvをチェックした。ヒトDCLK-1タンパク質のヒト細胞外ドメインをマウスFcと融合し、DCLK-1 scFvを用いるELISAアッセイのために使用した。結合を検出するために、450nmでのOD読み取りを使用した。マウス配列に基づいて、ヒト化VHおよびVL配列に対して、コンピュータシミュレーションモデルを生成した。
Prismソフトウェア(GraphPad、San Diego、CA)を用いて、データを解析し、プロットした。二群間の比較は、対応のないスチューデントのt検定によって行い、三群間の比較は、注記されている場合を除き、チューキーの事後検定を用いる片側ANOVAによって行った。p値<0.05のとき、差を有意と考えた。
配列番号1 抗DCLK1抗体HC1
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLELVSAINSNGGSTYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHGGNYWYFDVWGQGTMVTVSS
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKRLELVSAINSNGGSTYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHGGNYWYFDVWGQGTMVTVSS
EVKLLESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKRLELVSAINSNGGSTYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHGGNYWYFDVWGQGTTVTVSS
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSAINSNGGSTYYPDTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKHGGNYWYFDVWGQGTLVTVSS
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSAINSNGGSTYYPDTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHGGNYWYFDVWGQGTLVTVSS
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVAAINSNGGSTYYPDTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHGGNYWYFDVWGQGTLVTVSS
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLELVAAINSNGGSTYYPDTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHGGNYWYFDVWGQGTLVTVSS
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSAINSSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHGGNYWYFDVWGQGTLVTVSS
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLELVAAINSSGGSTYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHGGNYWYFDVWGQGTLVTVSS
DVKLVESGGGLVKLGGSLKLSCAASGFTFSSYYMSWVRQTPEKRLELVAAINSNGGSTYYPDTVKGRFTISRDNAKNTLYLQMSSLKSEDTALYYCARHGGNYWYFDVWGAGTTVTVSS
DIVMTQSPDSLAVSLGERATINCKSSQSLLYSSNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSYPYTFGQGTKLEIK
METDTLLLWVLLLWVPGSTGDIVMTQSPDSLAVSLGERATINCKSSQSLLYSSNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
DIVMTQSPDSLAVSLGERATINCKSSQSLLYSSNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSYPYTFGQGTKLEIK
DIVMSQSPDSLAVSLGERATISCKSSQSLLYSSNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSYPYTFGQGTKLEIK
DIVMSQSPSSLAVSVGEKVTMSCKSSQSLLYSSNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPYTFGGGTKLEIK
MDPKGSLSWRILLFLSLAFELSYGEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLELVSAINSNGGSTYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHGGNYWYFDVWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIAKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG**
MDPKGSLSWRILLFLSLAFELSYGEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKRLELVSAINSNGGSTYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHGGNYWYFDVWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIAKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG**
MDPKGSLSWRILLFLSLAFELSYGEVKLLESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKRLELVSAINSNGGSTYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHGGNYWYFDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIAKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG**
MEFGLSWLFLVAKIKGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSAINSNGGSTYYPDTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKHGGNYWYFDVWGQGTLVTVSS
MEFGLSWLFLVAKIKGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSAINSNGGSTYYPDTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHGGNYWYFDVWGQGTLVTVSS
MEFGLSWLFLVAKIKGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVAAINSNGGSTYYPDTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHGGNYWYFDVWGQGTLVTVSS
MEFGLSWLFLVAKIKGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLELVAAINSNGGSTYYPDTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHGGNYWYFDVWGQGTLVTVSS
MEFGLSWLFLVAKIKGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSAINSSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHGGNYWYFDVWGQGTLVTVSS
MEFGLSWLFLVAKIKGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLELVAAINSSGGSTYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHGGNYWYFDVWGQGTLVTVSS
MNFGLRLIFLVLVLKGVLCDVKLVESGGGLVKLGGSLKLSCAASGFTFSSYYMSWVRQTPEKRLELVAAINSNGGSTYYPDTVKGRFTISRDNAKNTLYLQMSSLKSEDTALYYCARHGGNYWYFDVWGAGTTVTVSS
METDTLLLWVLLLWVPGSTGDIVMTQSPDSLAVSLGERATINCKSSQSLLYSSNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSYPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
METDTLLLWVLLLWVPGSTGDIVMTQSPDSLAVSLGERATINCKSSQSLLYSSNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSYPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
METDTLLLWVLLLWVPGSTGDIVMTQSPDSLAVSLGERATINCKSSQSLLYSSNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
MVLQTQVFISLLLWISGAYGDIVMTQSPDSLAVSLGERATINCKSSQSLLYSSNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSYPYTFGQGTKLEIK
MVLQTQVFISLLLWISGAYGDIVMSQSPDSLAVSLGERATISCKSSQSLLYSSNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSYPYTFGQGTKLEIK
MDSQAQVLMLLLLWVSGTCGDIVMSQSPSSLAVSVGEKVTMSCKSSQSLLYSSNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPYTFGGGTKLEIK
ATGGACCCCAAGGGCAGCCTGAGCTGGAGAATCCTGCTGTTCCTGAGCCTGGCCTTCGAGCTGAGCTACGGCGAGGTGCAACTGGTGGAGTCCGGAGGCGGACTGGTGCAGCCCGGAGGTAGCCTTAGGCTGAGCTGTGCCGCAAGTGGCTTCACCTTCAGCAGCTACTACATGAGCTGGGTGAGGCAGGCCCCTGGCAAGGGCCTGGAGCTGGTGAGCGCCATCAACAGCAACGGCGGCAGCACCTACTACCCCGACAGCGTGAAGGGCAGGTTCACCATCAGCAGGGACAATAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAGGGCCGAGGACACAGCCGTGTACTACTGCGCCAGGCATGGCGGCAACTACTGGTACTTCGACGTGTGGGGTCAAGGAACAATGGTGACAGTTAGTTCCGCTAGCACCAAGGGCCCCAGCGTGTTCCCTCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGAACCGCCGCCCTGGGCTGCCTGGTGAAGGACTACTTCCCCGAGCCCGTGACCGTGTCCTGGAACAGCGGCGCTCTGACCAGCGGAGTGCACACCTTCCCTGCCGTGCTGCAGAGCAGCGGCCTGTACTCCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGCAACGTGAACCACAAGCCCTCCAACACCAAGGTGGACAAGAAGGTGGAGCCTAAGAGCTGCGACAAGACCCACACCTGCCCTCCCTGCCCCGCCCCCGAGCTGCTGGGCGGACCCAGCGTGTTCCTGTTCCCTCCCAAGCCCAAGGACACCCTGATGATCAGCCGCACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGAGCCACGAGGACCCCGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCTCGGGAGGAGCAGTACAACTCCACCTACCGCGTGGTGAGCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGAGCAACAAGGCCCTGCCCGCTCCCATCGCAAAGACCATCAGCAAGGCCAAGGGCCAGCCCCGGGAGCCTCAGGTGTACACCCTGCCCCCCAGCCGCGACGAGCTGACCAAGAACCAGGTGAGCCTGACCTGCCTGGTGAAGGGCTTCTACCCCTCCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCTGAGAACAACTACAAGACCACCCCTCCCGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCCGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGAGCCCCGGATAGTAA
ATGGACCCCAAGGGCAGCCTGAGCTGGAGAATCCTGCTGTTCCTGAGCCTGGCCTTCGAGCTGAGCTACGGCGAGGTGCAACTGGTGGAGTCCGGAGGCGGACTGGTGCAGCCCGGAGGTAGCCTTAGGCTGAGCTGTGCCGCAAGTGGCTTCACCTTCAGCAGCTACTACATGAGCTGGGTGAGGCAGGCCCCTGGCAAGCGCCTGGAGCTGGTGAGCGCCATCAACAGCAACGGCGGCAGCACCTACTACCCCGACAGCGTGAAGGGCAGGTTCACCATCAGCAGGGACAATAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAGGGCCGAGGACACAGCCGTGTACTACTGCGCCAGGCATGGCGGCAACTACTGGTACTTCGACGTGTGGGGTCAAGGAACAATGGTGACAGTTAGTTCCGCTAGCACCAAGGGCCCCAGCGTGTTCCCTCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGAACCGCCGCCCTGGGCTGCCTGGTGAAGGACTACTTCCCCGAGCCCGTGACCGTGTCCTGGAACAGCGGCGCTCTGACCAGCGGAGTGCACACCTTCCCTGCCGTGCTGCAGAGCAGCGGCCTGTACTCCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGCAACGTGAACCACAAGCCCTCCAACACCAAGGTGGACAAGAAGGTGGAGCCTAAGAGCTGCGACAAGACCCACACCTGCCCTCCCTGCCCCGCCCCCGAGCTGCTGGGCGGACCCAGCGTGTTCCTGTTCCCTCCCAAGCCCAAGGACACCCTGATGATCAGCCGCACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGAGCCACGAGGACCCCGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCTCGGGAGGAGCAGTACAACTCCACCTACCGCGTGGTGAGCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGAGCAACAAGGCCCTGCCCGCTCCCATCGCAAAGACCATCAGCAAGGCCAAGGGCCAGCCCCGGGAGCCTCAGGTGTACACCCTGCCCCCCAGCCGCGACGAGCTGACCAAGAACCAGGTGAGCCTGACCTGCCTGGTGAAGGGCTTCTACCCCTCCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCTGAGAACAACTACAAGACCACCCCTCCCGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCCGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGAGCCCCGGATAGTAA
ATGGACCCCAAGGGCAGCCTGAGCTGGAGAATCCTGCTGTTCCTGAGCCTGGCCTTCGAGCTGAGCTACGGCGAGGTGAAACTGTTGGAGTCCGGAGGCGGACTGGTGCAGCCCGGAGGTAGCCTTAGGCTGAGCTGTGCCGCAAGTGGCTTCACCTTCAGCAGCTACTACATGAGCTGGGTGAGGCAGGCCCCTGGCAAGCGCCTGGAGCTGGTGAGCGCCATCAACAGCAACGGCGGCAGCACCTACTACCCCGACAGCGTGAAGGGCAGGTTCACCATCAGCAGGGACAATAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAGGGCCGAGGACACAGCCGTGTACTACTGCGCCAGGCATGGCGGCAACTACTGGTACTTCGACGTGTGGGGTCAAGGAACAACTGTGACAGTTAGTTCCGCTAGCACCAAGGGCCCCAGCGTGTTCCCTCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGAACCGCCGCCCTGGGCTGCCTGGTGAAGGACTACTTCCCCGAGCCCGTGACCGTGTCCTGGAACAGCGGCGCTCTGACCAGCGGAGTGCACACCTTCCCTGCCGTGCTGCAGAGCAGCGGCCTGTACTCCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACATCTGCAACGTGAACCACAAGCCCTCCAACACCAAGGTGGACAAGAAGGTGGAGCCTAAGAGCTGCGACAAGACCCACACCTGCCCTCCCTGCCCCGCCCCCGAGCTGCTGGGCGGACCCAGCGTGTTCCTGTTCCCTCCCAAGCCCAAGGACACCCTGATGATCAGCCGCACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGAGCCACGAGGACCCCGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCTCGGGAGGAGCAGTACAACTCCACCTACCGCGTGGTGAGCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGAGCAACAAGGCCCTGCCCGCTCCCATCGCAAAGACCATCAGCAAGGCCAAGGGCCAGCCCCGGGAGCCTCAGGTGTACACCCTGCCCCCCAGCCGCGACGAGCTGACCAAGAACCAGGTGAGCCTGACCTGCCTGGTGAAGGGCTTCTACCCCTCCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCTGAGAACAACTACAAGACCACCCCTCCCGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCCGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGAGCCCCGGATAGTAA
ATGGAGTTTGGGCTGAGCTGGCTTTTTCTTGTGGCTAAAATAAAAGGTGTCCAGTGTGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATTACATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGCTATTAACTCCAACGGTGGTAGCACATACTACCCAGACACCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAAACATGGGGGTAACTACTGGTACTTTGACGTCTGGGGCCAAGGAACCCTGGTCACCGTCTCCTCA
ATGGAGTTTGGGCTGAGCTGGCTTTTTCTTGTGGCTAAAATAAAAGGTGTCCAGTGTGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATTACATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGCTATTAACTCCAACGGTGGTAGCACATACTACCCAGACACCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGACATGGGGGTAACTACTGGTACTTTGACGTCTGGGGCCAAGGAACCCTGGTCACCGTCTCCTCA
ATGGAGTTTGGGCTGAGCTGGCTTTTTCTTGTGGCTAAAATAAAAGGTGTCCAGTGTGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATTACATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCGCAGCTATTAACTCCAACGGTGGTAGCACATACTACCCAGACACCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGACATGGGGGTAACTACTGGTACTTTGACGTCTGGGGCCAAGGAACCCTGGTCACCGTCTCCTCA
ATGGAGTTTGGGCTGAGCTGGCTTTTTCTTGTGGCTAAAATAAAAGGTGTCCAGTGTGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATTACATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGCTGGTCGCAGCTATTAACTCCAACGGTGGTAGCACATACTACCCAGACACCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGACATGGGGGTAACTACTGGTACTTTGACGTCTGGGGCCAAGGAACCCTGGTCACCGTCTCCTCA
ATGGAGTTTGGGCTGAGCTGGCTTTTTCTTGTGGCTAAAATAAAAGGTGTCCAGTGTGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATTACATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGCTATTAACTCCAGCGGTGGTAGCACATACTACGCTGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGACATGGGGGTAACTACTGGTACTTTGACGTCTGGGGCCAAGGAACCCTGGTCACCGTCTCCTCA
ATGGAGTTTGGGCTGAGCTGGCTTTTTCTTGTGGCTAAAATAAAAGGTGTCCAGTGTGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATTACATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGCTGGTCGCAGCTATTAACTCCAGCGGTGGTAGCACATACTACCCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGACATGGGGGTAACTACTGGTACTTTGACGTCTGGGGCCAAGGAACCCTGGTCACCGTCTCCTCA
ATGGAGACCGACACCCTGCTGCTCTGGGTGCTGCTGCTCTGGGTGCCCGGCTCCACCGGAGACATCGTGATGACCCAAAGCCCCGACTCCCTGGCGGTTAGCCTGGGCGAGAGGGCCACGATCAACTGCAAGAGCAGCCAGAGCCTGTTGTACAGCAGCAACCAGAAGAACTACCTGGCCTGGTATCAGCAGAAGCCTGGCCAACCCCCGAAGCTGCTCATCTACTGGGCCAGCACCCGGGAGAGCGGCGTGCCCGACAGGTTCAGCGGCAGTGGGAGCGGCACCGACTTCACCCTGACCATCAGCTCCTTGCAGGCTGAGGACGTGGCCGTGTACTACTGCCAGCAGTACTACAGCTACCCCTACACCTTCGGCCAGGGCACCAAACTGGAGATCAAGCGGACCGTGGCCGCCCCCAGCGTGTTCATCTTCCCTCCCAGCGACGAGCAGCTGAAGTCTGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGCGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGACTCCAAGGACAGCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGCGAGGTGACCCACCAGGGACTGTCTAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGCTAA
ATGGAGACCGACACCCTGCTGCTCTGGGTGCTGCTGCTCTGGGTGCCCGGCTCCACCGGAGACATCGTGATGACCCAAAGCCCCGACTCCCTGGCGGTTAGCCTGGGCGAGAGGGCCACGATCAACTGCAAGAGCAGCCAGAGCCTGTTGTACAGCAGCAACCAGAAGAACTACCTGGCCTGGTATCAGCAGAAGCCTGGCCAATCCCCGAAGCTGCTCATCTACTGGGCCAGCACCCGGGAGAGCGGCGTGCCCGACAGGTTCAGCGGCAGTGGGAGCGGCACCGACTTCACCCTGACCATCAGCTCCTTGCAGGCTGAGGACGTGGCCGTGTACTACTGCCAGCAGTACTACAGCTACCCCTACACCTTCGGCCAGGGCACCAAACTGGAGATCAAGCGGACCGTGGCCGCCCCCAGCGTGTTCATCTTCCCTCCCAGCGACGAGCAGCTGAAGTCTGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGCGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGACTCCAAGGACAGCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGCGAGGTGACCCACCAGGGACTGTCTAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGCTAA
ATGGAGACCGACACCCTGCTGCTCTGGGTGCTGCTGCTCTGGGTGCCCGGCTCCACCGGAGACATCGTGATGACCCAAAGCCCCGACTCCCTGGCGGTTAGCCTGGGCGAGAGGGCCACGATCAACTGCAAGAGCAGCCAGAGCCTGTTGTACAGCAGCAACCAGAAGAACTACCTGGCCTGGTATCAGCAGAAGCCTGGCCAACCCCCGAAGCTGCTCATCTACTGGGCCAGCACCCGGGAGAGCGGCGTGCCCGACAGGTTCAGCGGCAGTGGGAGCGGCACCGACTTCACCCTGACCATCAGCTCCGTGCAGGCTGAGGACGTGGCCGTGTACTACTGCCAGCAGTACTACAGCTACCCCTACACCTTCGGCGGAGGCACCAAAGTGGAGATCAAGCGGACCGTGGCCGCCCCCAGCGTGTTCATCTTCCCTCCCAGCGACGAGCAGCTGAAGTCTGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGCGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGACTCCAAGGACAGCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGCGAGGTGACCCACCAGGGACTGTCTAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGCTAA
ATGGTGTTGCAGACCCAGGTCTTCATTTCTCTGTTGCTCTGGATCTCTGGTGCCTACGGGGACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTTTGTTATACAGCTCCAACCAGAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAATATTATAGTTACCCTTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA
ATGGTGTTGCAGACCCAGGTCTTCATTTCTCTGTTGCTCTGGATCTCTGGTGCCTACGGGGACATCGTGATGTCCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCTCCTGCAAGTCCAGCCAGAGTTTGTTATACAGCTCCAACCAGAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAATATTATAGTTACCCTTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA
ATGAACTTCGGGCTCAGATTGATTTTCCTTGTCCTTGTTTTAAAAGGTGTCCTGTGCGACGTGAAGCTCGTGGAGTCTGGGGGAGGCTTAGTGAAGCTTGGAGGGTCCCTGAAACTCTCCTGTGCAGCCTCTGGATTCACTTTCAGTAGCTATTACATGTCTTGGGTTCGCCAGACTCCAGAGAAGAGGCTGGAGTTGGTCGCAGCCATTAATAGTAATGGTGGTAGCACCTACTATCCAGACACTGTGAAGGGCCGATTCACCATCTCCAGAGACAATGCCAAGAACACCCTGTACCTGCAAATGAGCAGTCTGAAGTCTGAGGACACAGCCTTGTATTACTGTGCAAGACATGGGGGTAACTACTGGTACTTCGATGTCTGGGGCGCAGGGACCACGGTCACCGTCTCCTCA
GACGTGAAGCTCGTGGAGTCTGGGGGAGGCTTAGTGAAGCTTGGAGGGTCCCTGAAACTCTCCTGTGCAGCCTCTGGATTCACTTTCAGTAGCTATTACATGTCTTGGGTTCGCCAGACTCCAGAGAAGAGGCTGGAGTTGGTCGCAGCCATTAATAGTAATGGTGGTAGCACCTACTATCCAGACACTGTGAAGGGCCGATTCACCATCTCCAGAGACAATGCCAAGAACACCCTGTACCTGCAAATGAGCAGTCTGAAGTCTGAGGACACAGCCTTGTATTACTGTGCAAGACATGGGGGTAACTACTGGTACTTCGATGTCTGGGGCGCAGGGACCACGGTCACCGTCTCCTCA
ATGGATTCACAGGCCCAGGTTCTTATGTTACTGCTGCTATGGGTATCTGGTACCTGTGGGGACATTGTGATGTCACAGTCTCCATCCTCCCTAGCTGTGTCAGTTGGAGAGAAGGTTACTATGAGCTGCAAGTCCAGTCAGAGCCTTTTATATAGTAGCAATCAAAAGAACTACTTGGCCTGGTACCAGCAGAAACCAGGGCAGTCTCCTAAACTGCTGATTTACTGGGCATCCACTAGGGAATCTGGGGTCCCTGATCGCTTCACAGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTGTGAAGGCTGAAGACCTGGCAGTTTATTACTGTCAGCAATATTATAGCTATCCGTACACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA
GACATTGTGATGTCACAGTCTCCATCCTCCCTAGCTGTGTCAGTTGGAGAGAAGGTTACTATGAGCTGCAAGTCCAGTCAGAGCCTTTTATATAGTAGCAATCAAAAGAACTACTTGGCCTGGTACCAGCAGAAACCAGGGCAGTCTCCTAAACTGCTGATTTACTGGGCATCCACTAGGGAATCTGGGGTCCCTGATCGCTTCACAGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTGTGAAGGCTGAAGACCTGGCAGTTTATTACTGTCAGCAATATTATAGCTATCCGTACACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA
MSFGRDMELEHFDERDKAQRYSRGSRVNGLPSPTHSAHCSFYRTRTLQTLSSEKKAKKVRFYRNGDRYFKGIVYAISPDRFRSFEALLADLTRTLSDNVNLPQGVRTIYTIDGLKKISSLDQLVEGESYVCGSIEPFKKLEYTKNVNPNWSVNVKTTSASRAVSSLATAKGSPSEVRENKDFIRPKLVTIIRSGVKPRKAVRILLNKKTAHSFEQVLTDITDAIKLDSGVVKRLYTLDGKQVMCLQDFFGDDDIFIACGPEKFRYQDDFLLDESECRVVKSTSYTKIASSSRRSTTKSPGPSRRSKSPASTSSVNGTPGSQLSTPRSGKSPSPSPTSPGSLRKQRSSQHGGSSTSLASTKVCSSMDENDGPGEEVSEEGFQIPATITERYKVGRTIGDGNFAVVKECVERSTAREYALKIIKKSKCRGKEHMIQNEVSILRRVKHPNIVLLIEEMDVPTELYLVMELVKGGDLFDAITSTNKYTERDASGMLYNLASAIKYLHSLNIVHRDIKPENLLVYEHQDGSKSLKLGDFGLATIVDGPLYTVCGTPTYVAPEIIAETGYGLKVDIWAAGVITYILLCGFPPFRGSGDDQEVLFDQILMGQVDFPSPYWDNVSDSAKELITMMLLVDVDQRFSAVQVLEHPWVNDDGLPENEHQLSVAGKIKKHFNTGPKPNSTAAGVSVIALDHGFTIKRSGSLDYYQQPGMYWIRPPLLIRRGRFSDEDATRM
MSFGRDMELEHFDERDKAQRYSRGSRVNGLPSPTHSAHCSFYRTRTLQTLSSEKKAKKVRFYRNGDRYFKGIVYAISPDRFRSFEALLADLTRTLSDNVNLPQGVRTIYTIDGLKKISSLDQLVEGESYVCGSIEPFKKLEYTKNVNPNWSVNVKTTSASRAVSSLATAKGSPSEVRENKDFIRPKLVTIIRSGVKPRKAVRILLNKKTAHSFEQVLTDITDAIKLDSGVVKRLYTLDGKQVMCLQDFFGDDDIFIACGPEKFRYQDDFLLDESECRVVKSTSYTKIASSSRRSTTKSPGPSRRSKSPASTSSVNGTPGSQLSTPRSGKSPSPSPTSPGSLRKQRSSQHGGSSTSLASTKVCSSMDENDGPGEEVSEEGFQIPATITERYKVGRTIGDGNFAVVKECVERSTAREYALKIIKKSKCRGKEHMIQNEVSILRRVKHPNIVLLIEEMDVPTELYLVMELVKGGDLFDAITSTNKYTERDASGMLYNLASAIKYLHSLNIVHRDIKPENLLVYEHQDGSKSLKLGDFGLATIVDGPLYTVCGTPTYVAPEIIAETGYGLKVDIWAAGVITYILLCGFPPFRGSGDDQEVLFDQILMGQVDFPSPYWDNVSDSAKELITMMLLVDVDQRFSAVQVLEHPWVNDDGLPENEHQLSVAGKIKKHFNTGPKPNSTAAGVSVIATTALDKERQVFRRRRNQDVRSRYKAQPAPPELNSESEDYSPSSSETVRSPNSPF
MLELIEVNGTPGSQLSTPRSGKSPSPSPTSPGSLRKQRSSQHGGSSTSLASTKVCSSMDENDGPGEEVSEEGFQIPATITERYKVGRTIGDGNFAVVKECVERSTAREYALKIIKKSKCRGKEHMIQNEVSILRRVKHPNIVLLIEEMDVPTELYLVMELVKGGDLFDAITSTNKYTERDASGMLYNLASAIKYLHSLNIVHRDIKPENLLVYEHQDGSKSLKLGDFGLATIVDGPLYTVCGTPTYVAPEIIAETGYGLKVDIWAAGVITYILLCGFPPFRGSGDDQEVLFDQILMGQVDFPSPYWDNVSDSAKELITMMLLVDVDQRFSAVQVLEHPWVNDDGLPENEHQLSVAGKIKKHFNTGPKPNSTAAGVSVIALDHGFTIKRSGSLDYYQQPGMYWIRPPLLIRRGRFSDEDATRM
MLELIEVNGTPGSQLSTPRSGKSPSPSPTSPGSLRKQRSSQHGGSSTSLASTKVCSSMDENDGPGEEVSEEGFQIPATITERYKVGRTIGDGNFAVVKECVERSTAREYALKIIKKSKCRGKEHMIQNEVSILRRVKHPNIVLLIEEMDVPTELYLVMELVKGGDLFDAITSTNKYTERDASGMLYNLASAIKYLHSLNIVHRDIKPENLLVYEHQDGSKSLKLGDFGLATIVDGPLYTVCGTPTYVAPEIIAETGYGLKVDIWAAGVITYILLCGFPPFRGSGDDQEVLFDQILMGQVDFPSPYWDNVSDSAKELITMMLLVDVDQRFSAVQVLEHPWVNDDGLPENEHQLSVAGKIKKHFNTGPKPNSTAAGVSVIATTALDKERQVFRRRRNQDVRSRYKAQPAPPELNSESEDYSPSSSETVRSPNSPF
DDGLPENEHQLSVAGKIKKHFNTGPKPNSTAAGVSVIALDHGFTIKRSGSLDYYQQPGMYWIRPPLLIRRGRFSDEDATRM
DYYQQPGMYWIRPPLLIRRGRFSDEDATRM
AGVSVIALDHGFTIKRSGSLDYYQQPGMYW
DDGLPENEHQLSVAGKIKKHFNTGPKPNSTAAGVSVIATTALDKERQVFRRRRNQDVRSRYKAQPAPPELNSESEDYSPSSSETVRSPNSPF
DDGLPENEHQLSVAGKIKKHFNTGPKPNSTAAGVSVIALDHGFTIKRSGSLDYYQQPGMYWIRPPLLIRRGRFSDEDATRM
DDGLPENEHQLSVAGKIKKHFNTGPKPNSTAAGVSVIATTALDKERQVFRRRRNQDVRSRYKAQPAPPELN
APTKAPDVFPIISGCRHPKDNSPVVLACLITGYHPTSVTVTWYMGTQSQPQRTFPEIQRRDSYYMTSSQLSTPLQQWRQGEYKCVVQHTASKSKKEIFRWPESPKAQASSVPTAQPQAEGSLAKATTAPATTRNTGRGGEEKKKEKEKEEQEERETKTPECPSHTQPLGVYLLTPAVQDLWLRDKATFTCFVVGSDLKDAHLTWEVAGKVPTGGVEEGLLERHSNGSQSQHSRLTLPRSLWNAGTSVTCTLNHPSLPPQRLMALREPAAQAPVKLSLNLLASSDPPEAASWLLCEVSGFSPPNILLMWLEDQREVNTSGFAPARPPPQPGSTTFWAWSVLRVPAPPSPQPATYTCVVSHEDSRTLLNASRSLEVSYVTDHGPMK
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDISVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
ASTKGPSVFPLAPCSRSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYTCNVNHKPSNTKVDKRVELKTPLGDTTHTCPRCPEPKSCDTPPPCPRCPEPKSCDTPPPCPRCPEPKSCDTPPPCPRCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPREEQYNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKLTVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSLSPGK
GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITLSWKYKNNSDISSTRGFPSVLRGGKYAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNPRKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWLGQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSVTISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTISRPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSAPMPEPQAPGRYFAHSILTVSEEEWNTGETYTCVAHEALPNRVTERTVDKSTGKPTLYNVSLVMSDTAGTCY
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
ASPTSPKVFPLSLCSTQPDGNVVIACLVQGFFPQEPLSVTWSESGQGVTARNFPPSQDASGDLYTTSSQLTLPATQCLAGKSVTCHVKHYTNPSQDVTVPCPVPSTPPTPSPSTPPTPSPSCCHPRLSLHRPALEDLLLGSEANLTCTLTGLRDASGVTFTWTPSSGKSAVQGPPERDLCGCYSVSSVLPGCAEPWNHGKTFTCTAAYPESKTPLTATLSKSGNTFRPEVHLLPPPSEELALNELVTLTCLARGFSPKDVLVRWLQGSQELPREKYLTWASRQEPSQGTTTFAVTSILRVAAEDWKKGDTFSCMVGHEALPLAFTQKTIDRLAGKPTHVNVSVVMAEVDGTCY
ASPTSPKVFPLSLDSTPQDGNVVVACLVQGFFPQEPLSVTWSESGQNVTARNFPPSQDASGDLYTTSSQLTLPATQCPDGKSVTCHVKHYTNPSQDVTVPCPVPPPPPCCHPRLSLHRPALEDLLLGSEANLTCTLTGLRDASGATFTWTPSSGKSAVQGPPERDLCGCYSVSSVLPGCAQPWNHGETFTCTAAHPELKTPLTANITKSGNTFRPEVHLLPPPSEELALNELVTLTCLARGFSPKDVLVRWLQGSQELPREKYLTWASRQEPSQGTTTFAVTSILRVAAEDWKKGDTFSCMVGHEALPLAFTQKTIDRMAGKPTHVNVSVVMAEVDGTCY
TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
別段の定義がなければ、本明細書において使用される全ての技術用語および科学用語は、当業者によって一般的に理解されているものと同じ意味を有する。
Claims (26)
- 抗ダブルコルチン様キナーゼ1(抗DCLK1)キメラ抗原受容体(CAR)であって、
(a)(i)重鎖(HC)免疫グロブリン可変ドメイン配列および(ii)軽鎖(LC)免疫グロブリン可変ドメイン配列を含むヒト化抗DCLK1抗体の抗原結合ドメインであって、(i)および(ii)が、以下の配列番号の対:
配列番号1と配列番号11;
配列番号1と配列番号12;
配列番号1と配列番号13;
配列番号2と配列番号11;
配列番号2と配列番号12;
配列番号2と配列番号13;
配列番号3と配列番号11;
配列番号3と配列番号12;
配列番号3と配列番号13;
配列番号4と配列番号11;
配列番号5と配列番号11;または
配列番号6と配列番号12
から選択される、ヒト化抗DCLK1抗体の抗原結合ドメインと、
(b)ヒンジドメインと、
(c)膜貫通ドメインと、
(d)細胞内シグナル伝達ドメインと、
を含む、抗ダブルコルチン様キナーゼ1(抗DCLK1)キメラ抗原受容体(CAR)。 - (b)がCD8αまたはIgG1ヒンジドメインとしてさらに定義され、(c)がCD28またはCD8α膜貫通ドメインとしてさらに定義され、(d)が1またはそれを超える共刺激シグナル伝達領域と、CD3ζシグナル伝達ドメインを含むものとしてさらに定義される、請求項1に記載の抗DCLK1 CAR。
- 前記1またはそれを超える共刺激シグナル伝達領域が、CD27、CD28、4-IBB(CD137)、OX40、CD30、CD40、PD-1、ICOS、リンパ球機能関連抗原1(LFA-1)、CD2、CD7、CD27、LIGHT、NKG2CおよびB7-H3より選択される、請求項2に記載の抗DCLK1 CAR。
- 抗DCLK1 HC可変領域と抗DCLK1 LC可変領域の間に位置するリンカーポリペプチドをさらに含む、請求項1~3のいずれか一項に記載の抗DCLK1 CAR。
- 検出可能なマーカーまたは精製マーカーをさらに含む、請求項1~4のいずれか一項に記載の抗DCLK1 CAR。
- 請求項1~5のいずれか一項に記載の抗DCLK1 CARをコードする配列を含む、単離された核酸セグメント。
- 前記核酸セグメントが、プロモーターおよび/またはエンハンサー要素に機能的に連結されている、請求項6に記載の単離された核酸セグメント。
- 前記抗DCLK1抗体の抗原結合ドメインの上流に位置するシグナルペプチドポリヌクレオチド配列をさらに含む、請求項6または7に記載の単離された核酸セグメント。
- 前記抗DCLK1 CARをコードする単離された核酸が、前記抗DCLK1抗体の抗原結合ドメインまたはエンハンサーの上流に位置するコザックコンセンサスポリヌクレオチド配列をさらに含む、請求項8に記載の単離された核酸セグメント。
- 前記抗DCLK1 CARをコードする単離された核酸が、前記抗DCLK1抗体の抗原結合ドメインの上流に位置する2A自己切断型ペプチド(T2A)をコードするポリヌクレオチド配列をさらに含む、請求項6~9のいずれか一項に記載の単離された核酸セグメント。
- 前記抗DCLK1 CARをコードする単離された核酸が、抗生物質耐性をコードするポリヌクレオチド配列をさらに含み、そしてさらに、前記抗DCLK1 CARをコードする単離された核酸が、前記抗DCLK1 CARの発現および/または活性化を調節するためのスイッチ機構をさらに含み、前記抗DCLK1 CARをコードする単離された核酸がベクター中に組み込まれ、そしてさらに、前記ベクターがプラスミドまたはウイルスベクターである、請求項10に記載の単離された核酸セグメント。
- 請求項1~5のいずれか一項に記載の抗DCLK1 CAR、および/または請求項6~11のいずれか一項に記載の単離された核酸セグメントを含む単離された細胞。
- 前記単離された細胞が免疫細胞である、請求項12に記載の単離された細胞。
- 前記免疫細胞がT細胞またはナチュラルキラー(NK)細胞である、請求項13に記載の単離された細胞。
- 担体と、請求項1~5のいずれか一項に記載の抗DCLK1 CAR、および/または請求項6~11のいずれか一項に記載の単離された核酸セグメント、および/または請求項12~14のいずれか一項に記載の単離された細胞の1つまたはそれより多くと、を含む組成物。
- (i)請求項1~5のいずれか一項に記載の抗DCLK1 CARをコードする核酸セグメントを免疫細胞の集団に導入すること、および
(ii)工程(i)の前記核酸セグメントで首尾よく形質導入された免疫細胞の亜集団を選択し、これにより抗DCLK1 CAR発現細胞を作製すること、
を含む、抗DCLK1 CAR発現細胞を作製する方法。 - 前記免疫細胞がT細胞またはNK細胞であるか、あるいは前記免疫細胞の集団が、内在性免疫細胞受容体の発現を低下または除去するように改変されているか、あるいは前記免疫細胞の集団が、RNA干渉またはCRISPRを使用する方法を用いて改変された、請求項16に記載の方法。
- 腫瘍の増殖を阻害し、および/または癌を処置し、および/または癌の再発を予防することを必要とする被験体において、腫瘍の増殖を阻害し、および/または癌を処置し、および/または癌の再発を予防するための組成物であって、請求項1~5のいずれか一項に記載の抗DCLK1 CARを発現する細胞を含む、組成物。
- 前記抗DCLK1 CARを発現する細胞が、処置されている被験体にとって自家または同種異系である、請求項18に記載の組成物。
- 前記腫瘍、癌または癌幹細胞がDCLK1を発現または過剰発現する、請求項18または19に記載の組成物。
- 前記癌が、結腸癌、直腸癌、腸癌、胃癌、膵臓癌、前立腺癌、子宮頸癌もしくは卵巣癌、または繊維肉腫、多発性骨髄腫、肺癌、肝臓癌、食道癌、乳癌、大唾液腺癌腫、神経芽細胞腫または腎細胞癌腫であるか、あるいは前記腫瘍が固形腫瘍である、請求項20に記載の組成物。
- 前記被験体が、ヒト、動物、非ヒト霊長類、イヌ、ネコ、ヒツジ、マウス、ウマまたはウシである、請求項18~21のいずれか一項に記載の組成物。
- 癌細胞または癌幹細胞の増殖を阻害するための組成物であって、請求項1~5のいずれか一項に記載の抗DCLK1 CARを発現する細胞を含み、前記組成物が、前記癌細胞または癌幹細胞と接触させられることを特徴とする、組成物。
- 前記癌細胞または癌幹細胞が、接着性癌細胞または非接着性癌細胞であるか、あるいは前記癌細胞または癌幹細胞が、結腸直腸癌細胞、膵臓癌細胞、繊維肉腫細胞、前立腺癌細胞、多発性骨髄腫細胞、子宮頸癌細胞、卵巣癌細胞、肺癌細胞、肝臓癌細胞、食道癌細胞、乳癌細胞、大唾液腺癌腫細胞、神経芽細胞腫細胞または腎細胞癌腫細胞である、請求項23に記載の組成物。
- 請求項1~5のいずれか一項に記載の抗DCLK1 CAR;および/または請求項6~11のいずれか一項に記載の単離された核酸セグメント;請求項12~14のいずれか一項に記載の単離された細胞;および/または請求項15および18~24のいずれか一項に記載の組成物の1つまたはそれより多くと、使用説明書と、を備えるキット。
- 前記使用説明書が、請求項16または17に記載の前記方法を実施するための指示を与える、請求項25に記載のキット。
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