JP7479290B2 - Dll3に対するキメラ受容体及びその使用方法 - Google Patents
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Description
2018年4月10日に出願され、その全内容が参照により本明細書に組み込まれる米国仮特許出願第62/655,725号明細書に対する優先権が主張される。
本出願は、ASCIIフォーマットで電子的に提出された配列表を包含し、その配列表は、参照によりその全体が本明細書に組み込まれる。2019年4月10日に作成された前記ASCIIのコピーは、名称がA-2249-WO-PCT_SL.txtであり、サイズが86,327バイトである。
(a)1H2.1のVH領域のアミノ酸配列と10、9、8、7、6、5、4、3、2、1又は0個以下のアミノ酸残基だけ異なるVH領域及び1H2.1のVL領域のアミノ酸配列と10、9、8、7、6、5、4、3、2、1又は0個以下のアミノ酸残基だけ異なるVL領域、
(b)8D2のVH領域のアミノ酸配列と10、9、8、7、6、5、4、3、2、1又は0個以下のアミノ酸残基だけ異なるVH領域及び8D2のVL領域のアミノ酸配列と10、9、8、7、6、5、4、3、2、1又は0個以下のアミノ酸残基だけ異なるVL領域、
(c)6B2のVH領域のアミノ酸配列と10、9、8、7、6、5、4、3、2、1又は0個以下のアミノ酸残基だけ異なるVH領域及び6B2のVL領域のアミノ酸配列と10、9、8、7、6、5、4、3、2、1又は0個以下のアミノ酸残基だけ異なるVL領域
の少なくとも1つを含む抗原結合分子(及びこれらの分子を含むキメラ抗原受容体)であって、1つ又は複数のVH及びVL領域は、少なくとも1つのリンカーによって連結される、抗原結合分子(及びこれらの分子を含むキメラ抗原受容体)に関する。
LDNEKSNGTI IHVKGKHLCP SPLFPGPSKP
FWVLVVVGGV LACYSLLVTV AFIIFWV
RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS
IEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKP
RFSVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL
CD3は、ネイティブT細胞上のT細胞受容体の一要素であり、CARにおいて重要な細胞内活性化要素であることが示されている。好ましい実施形態では、CD3は、CD3ゼータであり、そのヌクレオチド配列は、配列番号9に記載される。
構造的に、これらのドメインは、免疫細胞に対する位置に対応することが理解されるであろう。したがって、これらのドメインは、(i)「ヒンジ」若しくは細胞外(EC)ドメイン(EC)、(ii)膜貫通(TM)ドメイン、及び/又は(iii)細胞内(細胞質)ドメイン(IC)の一部であり得る。細胞内構成要素は、部分的にCD3ファミリーのメンバー、好ましくはCD3ゼータを含むことが多く、これは、抗原結合分子がその標的に結合する際にT細胞を活性化することができる。一実施形態では、ヒンジドメインは、典型的には、本明細書で定義される少なくとも1つの共刺激ドメインからなる。
受容体を有する細胞に対して、本発明の改変T細胞は、抗原結合分子(scFvなど)、細胞外ドメイン(「ヒンジ」ドメインを含み得る)、膜貫通ドメイン及び細胞内ドメインを含むことが理解されるであろう。細胞内ドメインは、少なくとも部分的に活性化ドメインを含み、これは、好ましくは、CD3ゼータ、CD3イプシロン、CD3ガンマ又はそれらの一部などのCD3ファミリーメンバーからなる。更に、抗原結合分子(例えば、1つ以上のscFv)は、分子/コンストラクトの細胞外部分内に位置するように改変されるため、その標的を認識して結合することができることも理解されるであろう。
抗原結合分子は、本発明の範囲内にある。
養子免疫療法を用いて、ネイティブのT細胞を(i)患者から取り出し、(ii)少なくとも1つの腫瘍抗原に結合するキメラ抗原受容体(CAR)を発現するように遺伝子改変し、(iii)エクスビボで改変T細胞の大きい集団に増殖させ、且つ(iv)患者に再導入することができる。例えば、米国特許第7,741,465号明細書及び同第6,319,494号明細書、Eshhar et al.(Cancer Immunol、上記);Krause et al.(上記); Finney et al.(上記)を参照されたい。改変T細胞が患者に再導入された後、これらは、腫瘍抗原を発現している細胞に対する免疫応答を媒介する。例えば、Krause et al.,J.Exp.Med.,Volume 188,No.4,1998(619-626)を参照されたい。この免疫応答としては、T細胞によるIL-2及び他のサイトカインの分泌、腫瘍抗原を認識するT細胞のクローン増殖及びT細胞が媒介する特異的な標的陽性細胞の殺傷が挙げられる。Hombach et al.,Journal of Immun.167:6123-6131(2001)を参照されたい。
本発明のポリヌクレオチド、ポリペプチド、ベクター、抗原結合分子、免疫細胞、組成物などを製造するために様々な既知の技法を利用することができる。
a)疎水性:ノルロイシン、Met、Ala、Val、Leu、Ile;
b)中性親水性:Cys、Ser、Thr、Asn、Gln;
c)酸性:Asp、Glu;
d)塩基性:His、Lys、Arg;
e)鎖配向に影響する残基:Gly、Pro;及び
f)芳香族:Trp、Tyr、Phe。
CD28T DNA 細胞外、膜貫通、細胞内
クローン1H2.1 LC CDR2 AA:GASTRAT(配列番号48)
クローン1H2.1 LC CDR3 AA:QQYGTSPLT(配列番号49)
クローン8D2 HC DNA
クローン8D2 HC AA CDR2:WIDPNSGDTNYAQKFQG(配列番号53)
クローン8D2 HC AA CDR3:DPNRRSWYYGMDV(配列番号54)
クローン8D2 LC DNA
クローン8D2 LC AA CDR2:DASNLET(配列番号58)
クローン8D2 LHC AA CDR3:QHYDNLPLTF(配列番号59)
クローン6B2 HC DNA
クローン6B2 HC AA CDR2:WINPNSGDTSYAQRFLG(配列番号63)
クローン6B2 HC AA CDR3:EDDSSWYGSFDY(配列番号64)
クローン6B2 LC DNA
クローン6B2 LC AA CDR2:AASSLQS(配列番号68)
クローン6B2 LC AA CDR3:LQHDSDLRTF(配列番号69)
コンストラクト1H2.1 4-1BB DNA(シグナル配列は、太字)
scFv G4Sリンカー DNA
GGCGGTGGAGGCTCCGGAGGGGGGGGCTCTGGCGGAGGGGGCTCC(配列番号33)
scFv G4sリンカー:GGGGSGGGGSGGGGS(配列番号34)
scFv Whitlowリンカー DNA
GGGTCTACATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGG(配列番号35)
scFv Whitlowリンカー:GSTSGSGKPGSGEGSTKG(配列番号36)
4-1BB 核酸配列(細胞内ドメイン)
KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL(配列番号38)
OX40AA
RRDQRLPPDAHKPPGGGSFRTPIQEEQADAHSTLAKI(配列番号39)
本明細書において言及される全ての刊行物、特許及び特許出願は、各々の個々の刊行物、特許又は特許出願が具体的且つ個別に参照により組み込まれることが示された場合と同程度に参照により本明細書に組み込まれる。しかしながら、本明細書における参考文献の引用は、そのような参考文献が本発明の先行技術であることを認めるものとして解釈されるべきではない。参照により組み込まれる参考文献において提供される定義又は用語が、本明細書において提供される用語及び考察と異なる限り、本用語及び定義が優先される。
前述の本明細書は、当業者が本発明を実施するのに十分であると考えられる。前述の説明及び実施例は、本発明の特定の好ましい実施形態を詳細に説明し、本発明者らによって考えられた最良の形態を記載するものである。しかし、前述の内容がいかに詳細に記載されていたとしても、本発明は、多くの方法で実施され得、添付の特許請求の範囲及びその均等物に従って本発明が解釈されるべきであることが理解されるであろう。
異なるCARコンストラクトを含有する第3世代レンチウイルス導入ベクターをViraPower Lentiviral Packaging Mix(Life Technologies)と共に使用して、レンチウイルス上清を生成した。手短に言えば、600μlのOptiMEM培地中で15μgのDNAと22.5μlのポリエチレンイミン(Polysciences、1mg/ml)とを混合することによって形質移入混合物を生成した。この混合物を室温で5分間インキュベートした。同時に、293T細胞(ATCC)をトリプシン処理し、計数し、合計で10×106個の全細胞を形質移入混合物と共にT75フラスコに入れた。形質移入から3日後、上清を回収し、0.45μmのフィルターで濾過し、使用するまで-80℃で保存した。製造元の指示に従い、Ficoll-paque密度遠心分離を用いて健康なドナーのロイコパック(leukopaks)(Hemacare)からPBMCを単離した。R10培地+IL-2(300IU/ml、Proleukin(登録商標)、Prometheus(登録商標)Therapeutics and Diagnostics)中でOKT3(50ng/ml(Miltenyi Biotec))を用いてPBMCを刺激した。刺激から48時間後、MOI=10でレンチウイルスを用いて細胞に形質導入した。活性アッセイで使用する前に細胞を0.5~2.0×106個の細胞/mlに維持した。CARの発現を調べるため、4℃で30分間、染色緩衝液(BD Pharmingen)中のDLL3-Fc検出試薬(Amgen,Inc.)又はビオチン化タンパク質L(Thermo Scientific)によってT細胞を染色した。続いて、細胞を洗浄し、4℃で30分間、染色緩衝液中の抗-Fc-PE(Miltenyi Biotec)又はPEストレプトアビジン(BD Pharmingen)によって染色した。続いて、細胞を洗浄し、ヨウ化プロピジウム(BD Pharmingen)によって染色緩衝液中で再懸濁させてからデータを取得した。健康なドナーに由来するT細胞中のDLL3 CARの発現を図1に示す。各欄中の数字は、陽性集団の割合を示す。
レンチウイルスで形質導入したDLL3 CAR T細胞における細胞溶解活性を調べるために、エフェクター細胞をR10培地中で1:1のE:T比で標的細胞と共に培養した。共培養から16時間及び40時間後、上清をLuminex(EMD Millipore)によって分析し、CD3陰性細胞によるヨウ化プロピジウム(PI)取り込みのフローサイトメトリー分析によって標的細胞の生存率を評価した。健康なドナーに由来するレンチウイルスで形質導入したCAR T細胞の平均細胞溶解活性を図2に示し(EoL1細胞、は対照であり、H82及びEoL1-DLL3は、その表面にDLL3を発現する)、健康なドナーに由来するCAR T細胞によるサイトカインの産生を図3に示す。
DLL3を発現している標的細胞に応答したCAR T細胞の増殖を評価するために、R10培地中で1:1のE:T比で標的細胞と共培養する前にT細胞をCFSEで標識した。5日後、CFSEの希釈のフローサイトメトリー分析によってT細胞の増殖を評価した(図4)。DLL3 CAR T細胞の増殖を図5に示す。
インビボ抗腫瘍活性を調べるために、ヒトSCLCの異種モデルで使用するためのDLL3 CAR T細胞を生成した。ルシフェラーゼで標識したSHP-77細胞(2×106個/動物)を5~6週齢のメスNSGマウスに静脈内注射した。6日後、200μlのPBS中の6×106個のT細胞(約50%CAR+)を静脈内注射し、生物発光画像法を用いて動物の全身腫瘍組織量を毎週測定した。図6に示すように、DLL3 CAR T細胞の注射により、調べた全ての時点で全身腫瘍組織量は、有意に低下した(nt=形質移入されていない対照;CAR1=1H2.1-C28T-CD28-CD3ζ;CAR2=1H2.1-C28T-4-1BB-CD3ζ;CAR3=1H2.1-C8k-CD28-CD3ζ;CAR4=1H2.1-C8k-4-1BB-CD3ζ)。図6に示すように、1H2-CD28T又は1H2-4-1BBを発現するCAR T細胞の注射により、疑似形質導入された細胞を受けた動物と比較して有意な延命効果が得られたという生存率分析により、これは、更に裏付けられた。
Claims (15)
- DLL3に特異的に結合する抗原結合分子を含む、キメラ抗原受容体であって、
前記抗原結合分子は、以下の(a)~(i):
a)それぞれ配列番号42、配列番号43、及び配列番号44のアミノ酸配列を有する相補性決定領域(CDR)1、2、及び3を含む可変重鎖領域、及び、それぞれ配列番号47、配列番号48、及び配列番号49のアミノ酸配列を有するCDR1、2、及び3を含む可変軽鎖領域;又は
b)それぞれ配列番号52、配列番号53、及び配列番号54のアミノ酸配列を有する相補性決定領域(CDR)1、2、及び3を含む可変重鎖領域、及び、それぞれ配列番号57、配列番号58、及び配列番号59のアミノ酸配列を有するCDR1、2、及び3を含む可変軽鎖領域;又は
c)それぞれ配列番号62、配列番号63、及び配列番号64のアミノ酸配列を有する相補性決定領域(CDR)1、2、及び3を含む可変重鎖領域、及び、それぞれ配列番号67、配列番号68、及び配列番号69のアミノ酸配列を有するCDR1、2、及び3を含む可変軽鎖領域;又は
d)配列番号41のVH領域及び配列番号46のVL領域;又は
e)配列番号51のVH領域及び配列番号56のVL領域;又は
f)配列番号61のVH領域及び配列番号66のVL領域;又は
g)(d)において特定された配列に対して少なくとも90%の同一性、又は少なくとも95%の同一性を有するVH領域及びVL領域であって、それぞれ配列番号42、配列番号43、及び配列番号44のアミノ酸配列を有する相補性決定領域(CDR)1、2、及び3を含むVH領域、及び、それぞれ配列番号47、配列番号48、及び配列番号49のアミノ酸配列を有するCDR1、2、及び3を含むVL領域;又は
h)(e)において特定された配列に対して少なくとも90%の同一性、又は少なくとも95%の同一性を有するVH領域及びVL領域であって、それぞれ配列番号52、配列番号53、及び配列番号54のアミノ酸配列を有する相補性決定領域(CDR)1、2、及び3を含むVH領域、及び、それぞれ配列番号57、配列番号58、及び配列番号59のアミノ酸配列を有するCDR1、2、及び3を含むVL領域;又は
i)(f)において特定された配列に対して少なくとも90%の同一性、又は少なくとも95%の同一性を有するVH領域及びVL領域であって、それぞれ配列番号62、配列番号63、及び配列番号64のアミノ酸配列を有する相補性決定領域(CDR)1、2、及び3を含むVH領域、及び、それぞれ配列番号67、配列番号68、及び配列番号69のアミノ酸配列を有するCDR1、2、及び3を含むVL領域
から選択されるVH領域及びVL領域を含み、
前記キメラ抗原受容体は、少なくとも1つの共刺激ドメインを更に含み、
前記共刺激ドメインは、配列番号2、配列番号4、又は、配列番号6若しくは配列番号8と組み合わせた配列番号4の配列を有する配列を含む、又は、配列番号14、又は配列番号8と組み合わせた配列番号14の配列を有するCD8共刺激ドメインを含む、キメラ抗原受容体。 - 少なくとも一つの活性化ドメインをさらに含む、請求項1に記載のキメラ抗原受容体。
- 活性化ドメインはCD3を含み、前記CD3は、10、9、8、7、6、5、4、3、2、1又は0個以下のアミノ酸残基において配列番号10の配列と異なるCD3ゼータを含む、請求項2に記載のキメラ抗原受容体。
- 活性化ドメインは、配列番号10の配列を含む、請求項2に記載のキメラ抗原受容体。
- 請求項1に記載のキメラ抗原受容体をコードするポリヌクレオチド。
- 請求項5に記載のポリヌクレオチドを含み、レトロウイルスベクター、DNAベクター、プラスミド、RNAベクター、アデノウイルスベクター、アデノウイルス随伴ベクター、レンチウイルスベクター又はこれらの任意の組み合わせであるベクター。
- 請求項6に記載のベクターを含み、T細胞、腫瘍浸潤リンパ球(TIL)、NK細胞、TCR発現細胞、樹状細胞又はNK-T細胞である、免疫細胞。
- 同種異系のT細胞である、請求項7に記載の免疫細胞。
- 自己のT細胞である、請求項7に記載の免疫細胞。
- ベクターは、患者の身体から単離された細胞、又は患者の身体から採取された試料から増殖された細胞に導入される、請求項9に記載の免疫細胞。
- 請求項8に記載の免疫細胞を含む医薬組成物。
- VH及びVL領域は、少なくとも1つのリンカーによって連結され、リンカーは、scFv G4Sリンカー又はscFv Whitlowリンカーを含む、請求項1に記載のキメラ抗原受容体。
- 請求項1に記載のキメラ抗原受容体、請求項7に記載の細胞、又は請求項8に記載の免疫細胞を含む、治療が必要な対象における疾患又は障害を治療するための医薬組成物であって、前記疾患又は障害ががんである、医薬組成物。
- がんは、副腎、肝臓、腎臓、膀胱、乳房、胃、卵巣、子宮頸部、子宮、食道、結腸直腸、前立腺(例えば、前立腺腺癌)、膵臓、肺(小細胞及び非小細胞の両方)、甲状腺、癌腫、肉腫、グリア芽腫、頭頸部腫瘍、大細胞神経内分泌癌(LCNEC)、甲状腺髄様がん、グリア芽腫、神経内分泌前立腺がん(NEPC)、高悪性度胃腸膵がん(GEP)及び悪性黒色腫である、請求項13に記載の医薬組成物。
- ベクターはレンチウイルスベクターであり、前記レンチウイルスベクターは、pGARベクターである、請求項6に記載のベクター。
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