JP2021530233A - Steap1に対するキメラ受容体及びその使用方法 - Google Patents
Steap1に対するキメラ受容体及びその使用方法 Download PDFInfo
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Abstract
Description
(a)2F3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2F3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)11C2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11C2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)1A1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1A1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;
(d)7A4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7A4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;
(e)7A5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7A5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;
(f)14C1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14C1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領域が、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。
CD3は、天然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証明されている。好ましい実施形態では、CD3は、CD3ζであり、そのヌクレオチド配列は、配列番号9:
構造的に、これらのドメインが、免疫細胞に相対する位置に対応することは理解されるであろう。従って、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。細胞内成分は、抗原結合分子がその標的に結合するとT細胞を活性化することができる、CD3ファミリーのメンバー、好ましくはCD3ζを一部に含むことが多い。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を包含する。
受容体を担持する細胞に比較して、本発明の改変T細胞は、抗原結合分子(scFv等)、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は理解されるであろう。細胞内ドメインは、少なくとも一部には、好ましくはCD3ζ、CD3ε、CD3γ又はそれらの一部等のCD3ファミリーメンバーを包含する活性化ドメインを含む。更に、抗原結合分子(例えば、1つ以上のscFv)が、その1つ以上の標的を認識して結合できるように、分子/構築物の細胞外部分内に位置するように改変されていることも理解されるであろう。
抗原結合分子は、本発明の範囲内に含まれる。
養子免疫療法を用いて、天然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、組成物等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)鎖配向に影響を及ぼす残基:Gly、Pro;及び
f)芳香族:Trp、Tyr、Phe。
GGCGGTGGAGGCTCCGGAGGGGGGGGCTCTGGCGGAGGGGGCTCC(配列番号:80)
GGGTCTACATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGG(配列番号82)
KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL(配列番号85)
RRDQRLPPDAHKPPGGGSFRTPIQEEQADAHSTLAKI(配列番号86)
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。
上述の本明細書は、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。上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。
PNT−2、LNCaP、PC−3、22Rv1、C4−2B及びDU145細胞株は、RPMI1640(Lonza)+10%のFBS(Corning)+1×ペニシリンストレプトマイシンL−グルタミン(Corning)(R10)培地中で培養し、0.5〜2.0×106個の細胞/mlの細胞密度で維持した。PNT−2及びDU145は、陰性対照細胞株である。細胞表面STEAP1発現を試験するために、細胞は、抗STEAP1抗体(2F3)又はIgG1アイソタイプ対照抗体(BD Pharmingen)と共に染色バッファー(BD Pharmingen)中で30分間、4℃でインキュベートした。細胞は、次にデータ取得前にヨウ化プロピジウム(BD Pharmingen)を含む染色バッファー中に再懸濁させた。標的細胞上でのSTEAP1発現は、図1に示した。
T7プロモーターをコードするプラスミド、CAR構築物及びβグロビン安定化配列は、EcoRI及びBamHI(NEB)を含む10μgのDNAを用いた一晩に渡る消化によって線形化した。DNAは、次にフェノール/クロロホルムを用いて精製したプロテイナーゼK(Thermo Fisher、600U/ml)を用いて50℃で2時間に渡り消化し、酢酸ナトリウム及び2容積のエタノールを添加することによって沈降させた。次にペレットを乾燥させ、RNAse/DNAseフリーの水に再懸濁させ、NanoDropを用いて定量した。次に、mMESSAGE mMACHINE T7 Ultra(Thermo Fisher)を製造業者の取扱説明書に従って使用するインビトロ転写のために、1μgの線状DNAを使用した。RNAは更に、MEGAClearキット(Thermo Fisher)を製造業者の取扱説明書に従って使用して精製し、NanoDropを用いて定量した。mRNAの完全性は、アガロースゲル上での移動度を用いて評価した。Ficoll−paque密度遠心分離装置を製造業者の取扱説明書に従って用いて、健常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7日後、T細胞をOpti−MEM培地(Thermo Fisher Scientific)中で2回洗浄し、Opti−MEM培地中で2.5×107個の細胞/mlの最終濃度で再懸濁させた。エレクトロポレーション1回当たり10μgのmRNAを使用した。2mmのキュベット内での0.5ミリ秒(ms)間に単一400Vパルスを送達するために、Gemini X2システム(Harvard Apparatus BTX)を使用して細胞のエレクトロポレーションを実施した。細胞を直ちにR10+IL−2培地に移し、6時間に渡り回復させた。CARの発現を調べるため、4℃で30分間、染色バッファー(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、染色バッファー中の抗LNGFR−PE−PEストレプトアビジン(BD Pharmingen)によって染色した。細胞を続いて洗浄し、データ取得の前に、ヨウ化プロピジウム(BD Pharmingen)を含む染色バッファー中で再懸濁させた。エレクトロポレーションにかけたT細胞中でのSTEAP1 CARの発現は、図2に示した。
エレクトロポレーションにかけたSTEAP1 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比で培養した。共培養の16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。エレクトロポレーションにかけたCAR T細胞の細胞溶解活性は、図3に示し、サイトカイン産生率は、図4に示した。
STEAP1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、T細胞は、R10培地中で1:1のE:T比で標的細胞と共培養する前にCFSEで標識した。5日後、CFSE希釈のフローサイトメトリー分析によってT細胞増殖を評価した。STEAP1 CAR T細胞の増殖は、図5に示した。
Claims (79)
- STEAP1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:
a)配列番号89、99、109、119、129又は139のアミノ酸配列とは3、2、1又は0個以下のアミノ酸残基だけ異なるアミノ酸配列を含む可変重鎖CDR1;又は
b)配列番号90、100、110、120、130又は140のアミノ酸配列とは3、2、1又は0個以下のアミノ酸残基だけ異なるアミノ酸配列を含む可変重鎖CDR2;又は
c)配列番号91、101、111、121、131又は141のアミノ酸配列とは3、2、1又は0個以下のアミノ酸残基だけ異なるアミノ酸配列を含む可変重鎖CDR3;又は
d)配列番号94、104、114、124、134又は144のアミノ酸配列とは3、2、1又は0個以下のアミノ酸残基だけ異なるアミノ酸配列を含む可変軽鎖CDR1;又は
e)配列番号95、105、115、125、135又は145のアミノ酸配列とは3、2、1又は0個以下のアミノ酸残基だけ異なるアミノ酸配列を含む可変軽鎖CDR2;又は
f)配列番号96、106、116、126、136又は146のアミノ酸配列とは3、2、1又は0個以下のアミノ酸残基だけ異なるアミノ酸配列を含む可変軽鎖CDR3;又は
g)クローン2F3、クローン11C2、クローン1A1、クローン7A4又はクローン7A5又はクローン14C1の可変重鎖CDR1配列のアミノ酸配列を含む可変重鎖CDR1;又は
h)クローン2F3、クローン11C2、クローン1A1、クローン7A4又はクローン7A5又はクローン14C1の可変重鎖CDR2配列のアミノ酸配列を含む可変重鎖CDR2;又は
i)クローン2F3、クローン11C2、クローン1A1、クローン7A4又はクローン7A5又はクローン14C1の可変重鎖CDR3配列のアミノ酸配列を含む可変重鎖CDR3;又は
j)クローン2F3、クローン11C2、クローン1A1、クローン7A4又はクローン7A5又はクローン14C1の可変軽鎖CDR1配列のアミノ酸配列を含む可変軽鎖CDR1;又は
k)クローン2F3、クローン11C2、クローン1A1、クローン7A4又はクローン7A5又はクローン14C1の可変軽鎖CDR2配列のアミノ酸配列を含む可変軽鎖CDR2;又は
l)クローン2F3、クローン11C2、クローン1A1、クローン7A4又はクローン7A5又はクローン14C1の可変軽鎖CDR3配列のアミノ酸配列を含む可変軽鎖CDR3;又は
m)クローン2F3、クローン11C2、クローン1A1、クローン7A4、又はクローン7A5又はクローン14C1の可変重鎖配列とは10、9、8、7、6、5、4、3、2、1又は0個以下の残基だけ異なる可変重鎖配列;又は
n)クローン2F3、クローン11C2、クローン1A1、クローン7A4、又はクローン7A5又はクローン14C1の可変軽鎖配列とは10、9、8、7、6、5、4、3、2、1又は0個以下の残基だけ異なる可変軽鎖配列
を含む、キメラ抗原受容体。 - 少なくとも1つの共刺激ドメインを更に含む、請求項1に記載のキメラ抗原受容体。
- 少なくとも1つの活性化ドメインを更に含む、請求項1に記載のキメラ抗原受容体。
- 前記共刺激ドメインは、CD28、OX−40、4−1BB/CD137、CD2、CD7、CD27、CD30、CD40、プログラム細胞死−1(PD−1)、誘導性T細胞共刺激因子(ICOS)、リンパ球機能関連抗原−1(LFA−1、CDl−la/CD18)、CD3γ、CD3δ、CD3ε、CD247、CD276(B7−H3)、LIGHT、(TNFSF14)、NKG2C、Igα(CD79a)、DAP−10、Fcγ受容体、MHCクラスI分子、TNF受容体タンパク質、免疫グロブリンタンパク質、サイトカイン受容体、インテグリン、シグナル伝達リンパ球活性化分子(SLAMタンパク質)、活性化NK細胞受容体、BTLA、Tollリガンド受容体、ICAM−1、B7−H3、CDS、ICAM−1、GITR、BAFFR、LIGHT、HVEM(LIGHTR)、KIRDS2、SLAMF7、NKp80(KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL−2Rβ、IL−2Rγ、IL−7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA−6、CD49f、ITGAD、CDl−ld、ITGAE、CD103、ITGAL、CDl−la、LFA−1、ITGAM、CDl−lb、ITGAX、CDl−lc、ITGBl、CD29、ITGB2、CD18、LFA−1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1(CD226)、SLAMF4(CD244、2B4)、CD84、CD96(Tactile)、CEACAM1、CRT AM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100(SEMA4D)、CD69、SLAMF6(NTB−A、Lyl08)、SLAM(SLAMF1、CD150、IPO−3)、BLAME(SLAMF8)、SELPLG(CD162)、LTBR、LAT、GADS、SLP−76、PAG/Cbp、CD19a、CD83と特異的に結合するリガンド又はこれらの任意の組み合わせのシグナル伝達領域である、請求項2に記載のキメラ抗原受容体。
- 前記共刺激ドメインは、CD28を含む、請求項4に記載のキメラ抗原受容体。
- CD28共刺激ドメインは、配列番号2、配列番号4、配列番号6又は配列番号8の配列と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配列を含む、請求項5に記載のキメラ抗原受容体。
- CD8共刺激ドメインは、配列番号14の配列と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配列を含む、請求項3に記載のキメラ抗原受容体。
- 前記活性化ドメインは、CD3を含む、請求項3に記載のキメラ抗原受容体。
- 前記CD3は、CD3ζを含む、請求項7に記載のキメラ抗原受容体。
- 前記CD3ζは、配列番号10の配列と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配列を含む、請求項8に記載のキメラ抗原受容体。
- 前記共刺激ドメインは、配列番号2の配列と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配列を含み、及び前記活性化ドメインは、配列番号10の配列と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配列を含む、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をコードするポリヌクレオチド。
- 請求項12に記載のポリヌクレオチドを含むベクター。
- 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、請求項13に記載のベクター。
- 請求項13に記載のベクターを含む免疫細胞。
- 前記免疫細胞は、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、請求項15に記載の免疫細胞。
- 前記細胞は、自己T細胞である、請求項16に記載の免疫細胞。
- 前記細胞は、同種異系T細胞である、請求項16に記載の免疫細胞。
- 前記ベクターは、患者の身体から単離される、又は患者の身体から採取された試料から増殖させられる細胞に導入される、請求項15に記載の免疫細胞。
- 前記ベクターは、ドナーの身体から単離される、又は患者の身体から採取された試料から増殖させられる細胞に導入される、請求項15に記載の免疫細胞。
- 請求項15に記載の免疫細胞を含む医薬組成物。
- (a)クローン2F3のVH領域及びクローン2F3のVL領域;
(b)クローン11C2のVH領域及びクローン11C2のVL領域;
(c)クローン1A1のVH領域及びクローン1A1のVL領域:
(d)クローン7A4のVH領域及びクローン7A4のVL領域;
(e)クローン7A5のVH領域及びクローン7A5のVL領域;又は
(f)クローン14C1のVH領域及びクローン14C1のVL領域;
を含むキメラ抗原受容体であって、前記VH領域及びVL領域は、少なくとも1つのリンカーによって連結されている、キメラ抗原受容体。 - 前記リンカーは、scFv G4Sリンカー又はscFv Whitlowリンカーを含む、請求項22に記載のキメラ抗原受容体。
- 共刺激ドメインを更に含む、請求項22に記載のキメラ抗原受容体。
- 活性化ドメインを更に含む、請求項22に記載のキメラ抗原受容体。
- 前記共刺激ドメインは、CD28、OX−40、4−1BB/CD137、CD2、CD7、CD27、CD30、CD40、プログラム細胞死−1(PD−1)、誘導性T細胞共刺激因子(ICOS)、リンパ球機能関連抗原−1(LFA−1、CDl−la/CD18)、CD3γ、CD3δ、CD3ε、CD247、CD276(B7−H3)、LIGHT、(TNFSF14)、NKG2C、Igα(CD79a)、DAP−10、Fcγ受容体、MHCクラスI分子、TNF受容体タンパク質、免疫グロブリンタンパク質、サイトカイン受容体、インテグリン、シグナル伝達リンパ球活性化分子(SLAMタンパク質)、活性化NK細胞受容体、BTLA、Tollリガンド受容体、ICAM−1、B7−H3、CDS、ICAM−1、GITR、BAFFR、LIGHT、HVEM(LIGHTR)、KIRDS2、SLAMF7、NKp80(KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL−2Rβ、IL−2Rγ、IL−7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA−6、CD49f、ITGAD、CDl ld、ITGAE、CD103、ITGAL、CDl la、LFA−1、ITGAM、CDl lb、ITGAX、CDl lc、ITGBl、CD29、ITGB2、CD18、LFA−1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1(CD226)、SLAMF4(CD244、2B4)、CD84、CD96(Tactile)、CEACAM1、CRT AM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100(SEMA4D)、CD69、SLAMF6(NTB−A、Lyl08)、SLAM(SLAMF1、CD150、IPO−3)、BLAME(SLAMF8)、SELPLG(CD162)、LTBR、LAT、GADS、SLP−76、PAG/Cbp、CD19a、CD83と特異的に結合するリガンド又はこれらの任意の組み合わせのシグナル伝達領域である、請求項24に記載のキメラ抗原受容体。
- 請求項22に記載のキメラ抗原受容体を含む免疫細胞。
- 前記免疫細胞は、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、請求項27に記載の免疫細胞。
- 自己T細胞である、請求項28に記載のT細胞。
- 同種異系T細胞である、請求項29に記載のT細胞。
- 請求項27に記載の細胞を含む医薬組成物。
- 請求項22に記載のキメラ抗原受容体をコードする配列を含む単離ポリヌクレオチド。
- 請求項32に記載のポリヌクレオチドを含むベクター。
- 請求項33に記載のベクターを含む免疫細胞。
- 前記免疫細胞は、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、請求項34に記載の免疫細胞。
- 自己T細胞である、請求項35に記載のT細胞。
- 同種異系T細胞である、請求項35に記載のT細胞。
- 構築物2F3−CD28T−CD28−41BB、構築物2F3−CD28T−CD28、構築物2F3−CD28T−41BB、構築物2F3−C8K−CD28、構築物2F3−C8K−41BB、構築物11C2−CD28T−CD28−41BB、構築物11C2−CD28T−CD28、構築物11C2−CD28T−41BB、構築物11C2−C8K−CD28、構築物11C2−C8K−41BB、構築物1A1−CD28T−CD28−41BB、構築物1A1−CD28T−CD28、構築物1A1−CD28T−41BB、構築物1A1−C8K−CD28、構築物1A1−C8K−41BB、構築物7A4−CD28T−CD28−41BB、構築物7A4−CD28T−CD28、構築物7A4−CD28T−41BB、構築物7A4−C8K−CD28、構築物7A4−C8K−41BB、構築物7A5−CD28T−CD28−41BB、構築物7A5−CD28T−CD28、構築物7A5−CD28T−41BB、構築物7A5−C8K−CD28、構築物7A5−C8K−41BB、構築物14C1−CD28T−CD28−41BB、構築物14C1−CD28T−CD28、構築物14C1−CD28T−41BB、構築物14C1−C8K−CD28又は構築物14C1−C8K−41BB2F3 CD28のアミノ酸配列を含む、単離ポリヌクレオチド。
- 請求項38に記載のポリペプチドをコードするベクター。
- 請求項38に記載のポリペプチドを含む免疫細胞。
- 前記免疫細胞は、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、請求項40に記載の免疫細胞。
- 自己T細胞である、請求項41に記載のT細胞。
- 同種異系T細胞である、請求項41に記載のT細胞。
- STEAP1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(CAR)若しくはT細胞受容体(TCR)をコードする単離ポリヌクレオチドであって、前記抗原結合分子は、クローン2F3、クローン11C2、クローン1A1、クローン7A4、クローン7A5又はクローン14C1の可変重鎖CDR3のアミノ酸配列を含む可変重鎖CDR3を含む、単離ポリヌクレオチド。
- 活性化ドメインを更に含む、請求項44に記載のポリヌクレオチド。
- 前記活性化ドメインは、CD3である、請求項45に記載のポリヌクレオチド。
- 前記CD3は、CD3ζである、請求項46に記載のポリヌクレオチド。
- 前記CD3ζは、配列番号9に記載されたアミノ酸配列を含む、請求項47に記載のポリヌクレオチド。
- 共刺激ドメインを更に含む、請求項44に記載のポリヌクレオチド。
- 前記共刺激ドメインは、CD28、OX−40、4−1BB/CD137、CD2、CD7、CD27、CD30、CD40、プログラム細胞死−1(PD−1)、誘導性T細胞共刺激因子(ICOS)、リンパ球機能関連抗原−1(LFA−1(CDl−la/CD18)、CD3γ、CD3δ、CD3ε、CD247、CD276(B7−H3)、LIGHT、(TNFSF14)、NKG2C、Igα(CD79a)、DAP−10、Fcγ受容体、MHCクラスI分子、TNF受容体タンパク質、免疫グロブリンタンパク質、サイトカイン受容体、インテグリン、シグナル伝達リンパ球活性化分子(SLAMタンパク質)、活性化NK細胞受容体、BTLA、Tollリガンド受容体、ICAM−1、B7−H3、CDS、ICAM−1、GITR、BAFFR、LIGHT、HVEM(LIGHTR)、KIRDS2、SLAMF7、NKp80(KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL−2Rβ、IL−2Rγ、IL−7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA−6、CD49f、ITGAD、CDl−ld、ITGAE、CD103、ITGAL、CDl−la、LFA−1、ITGAM、CDl−lb、ITGAX、CDl−lc、ITGBl、CD29、ITGB2、CD18、LFA−1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1(CD226)、SLAMF4(CD244、2B4)、CD84、CD96(Tactile)、CEACAM1、CRT AM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100(SEMA4D)、CD69、SLAMF6(NTB−A、Lyl08)、SLAM(SLAMF1、CD150、IPO−3)、BLAME(SLAMF8)、SELPLG(CD162)、LTBR、LAT、GADS、SLP−76、PAG/Cbp、CD19a、CD83と特異的に結合するリガンド又はこれらの任意の組み合わせのシグナル伝達領域である、請求項49に記載のポリヌクレオチド。
- CD28共刺激ドメインは、配列番号2に記載されたアミノ酸配列をコードする、請求項50に記載のポリヌクレオチド。
- 請求項41に記載のポリヌクレオチドを含むベクター。
- 請求項49に記載のベクターを含む免疫細胞。
- 前記免疫細胞は、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、請求項50に記載の免疫細胞。
- 自己T細胞である、請求項51に記載のT細胞。
- 同種異系T細胞である、請求項51に記載のT細胞。
- キメラ抗原受容体(CAR)又はT細胞受容体(TCR)をコードする単離ポリヌクレオチドであって、前記CAR又はTCRは、STEAP1に特異的に結合する抗原結合分子を含み、前記抗原結合分子は、
a.クローン2F3、クローン11C2、クローン1A1、クローン7A4、又はクローン7A5又はクローン14C1の可変重鎖配列と10、9、8、7、6、5、4、3、2、1又は0個以下の残基だけ異なる可変重鎖配列;及び/又は
b.クローン2F3、クローン11C2、クローン1A1、クローン7A4又はクローン7A5又はクローン14C1の可変軽鎖配列と10、9、8、7、6、5、4、3、2、1又は0個以下の残基だけ異なる可変軽鎖配列を含む、単離ポリヌクレオチド。 - 活性化ドメインを更に含む、請求項54に記載のポリヌクレオチド。
- 前記活性化ドメインは、CD3である、請求項55に記載のポリヌクレオチド。
- 前記CD3は、CD3ζである、請求項56に記載のポリヌクレオチド。
- 前記CD3ζは、配列番号9に記載されたアミノ酸配列を含む、請求項60に記載のポリヌクレオチド。
- 共刺激ドメインを更に含む、請求項57に記載のポリヌクレオチド。
- 前記共刺激ドメインは、CD28、OX−40、4−1BB/CD137、CD2、CD7、CD27、CD30、CD40、プログラム細胞死−1(PD−1)、誘導性T細胞共刺激因子(ICOS)、リンパ球機能関連抗原−1(LFA−1(CDl−la/CD18)、CD3γ、CD3δ、CD3ε、CD247、CD276(B7−H3)、LIGHT、(TNFSF14)、NKG2C、Igα(CD79a)、DAP−10、Fcγ受容体、MHCクラスI分子、TNF受容体タンパク質、免疫グロブリンタンパク質、サイトカイン受容体、インテグリン、シグナル伝達リンパ球活性化分子(SLAMタンパク質)、活性化NK細胞受容体、BTLA、Tollリガンド受容体、ICAM−1、B7−H3、CDS、ICAM−1、GITR、BAFFR、LIGHT、HVEM(LIGHTR)、KIRDS2、SLAMF7、NKp80(KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL−2Rβ、IL−2Rγ、IL−7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA−6、CD49f、ITGAD、CDl−ld、ITGAE、CD103、ITGAL、CDl−la、LFA−1、ITGAM、CDl−lb、ITGAX、CDl−lc、ITGBl、CD29、ITGB2、CD18、LFA−1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1(CD226)、SLAMF4(CD244、2B4)、CD84、CD96(Tactile)、CEACAM1、CRT AM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100(SEMA4D)、CD69、SLAMF6(NTB−A、Lyl08)、SLAM(SLAMF1、CD150、IPO−3)、BLAME(SLAMF8)、SELPLG(CD162)、LTBR、LAT、GADS、SLP−76、PAG/Cbp、CD19a、CD83と特異的に結合するリガンド又はこれらの任意の組み合わせのシグナル伝達領域である、請求項62に記載のポリヌクレオチド。
- CD28共刺激ドメインは、配列番号3に記載されたヌクレオチド配列を含む、請求項63に記載のポリヌクレオチド。
- CD28共刺激ドメインは、配列番号1に記載されたヌクレオチド配列を含む、請求項64に記載のポリヌクレオチド。
- STEAP1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(CAR)又はT細胞受容体(TCR)をコードする単離ポリヌクレオチドであって、前記抗原結合分子重鎖は、CDR1(配列番号89)、CDR2(配列番号90)及びCDR3(配列番号91)を含み、前記抗原結合分子軽鎖は、CDR1(配列番号94)、CDR2(配列番号95)及びCDR3(配列番号96)を含む、単離ポリヌクレオチド。
- STEAP1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(CAR)又はT細胞受容体(TCR)をコードする単離ポリヌクレオチドであって、前記抗原結合分子重鎖は、CDR1(配列番号99)、CDR2(配列番号100)及びCDR3(配列番号101)を含み、前記抗原結合分子軽鎖は、CDR1(配列番号104)、CDR2(配列番号105)及びCDR3(配列番号106)を含む、単離ポリヌクレオチド。
- STEAP1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(CAR)又はT細胞受容体(TCR)をコードする単離ポリヌクレオチドであって、前記抗原結合分子重鎖は、CDR1(配列番号109)、CDR2(配列番号110)及びCDR3(配列番号111)を含み、前記抗原結合分子軽鎖は、CDR1(配列番号114)、CDR2(配列番号115)及びCDR3(配列番号116)を含む、単離ポリヌクレオチド。
- STEAP1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(CAR)又はT細胞受容体(TCR)をコードする単離ポリヌクレオチドであって、前記抗原結合分子重鎖は、CDR1(配列番号119)、CDR2(配列番号120)及びCDR3(配列番号121)を含み、前記抗原結合分子軽鎖は、CDR1(配列番号124)、CDR2(配列番号125)及びCDR3(配列番号126)を含む、単離ポリヌクレオチド。
- STEAP1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(CAR)又はT細胞受容体(TCR)をコードする単離ポリヌクレオチドであって、前記抗原結合分子重鎖は、CDR1(配列番号129)、CDR2(配列番号130)及びCDR3(配列番号131)を含み、前記抗原結合分子軽鎖は、CDR1(配列番号134)、CDR2(配列番号135)及びCDR3(配列番号136)を含む、単離ポリヌクレオチド。
- STEAP1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(CAR)又はT細胞受容体(TCR)をコードする単離ポリヌクレオチドであって、前記抗原結合分子重鎖は、CDR1(配列番号139)、CDR2(配列番号140)及びCDR3(配列番号141)を含み、前記抗原結合分子軽鎖は、CDR1(配列番号144)、CDR2(配列番号145)及びCDR3(配列番号146)を含む、単離ポリヌクレオチド。
- 治療を必要とする対象において疾患又は障害を治療する方法であって、請求項12、44、57、66、67、68、69、70又は71に記載のポリヌクレオチドを前記対象に投与するステップを含む方法。
- 治療を必要とする対象において疾患又は障害を治療する方法であって、請求項38に記載のポリペプチドを前記対象に投与するステップを含む方法。
- 治療を必要とする対象において疾患又は障害を治療する方法であって、請求項1又は22に記載のキメラ抗原受容体を前記対象に投与するステップを含む方法。
- 治療を必要とする対象において疾患又は障害を治療する方法であって、請求項15、27、34、40又は53に記載の細胞を前記対象に投与するステップを含む方法。
- 治療を必要とする対象において疾患又は障害を治療する方法であって、請求項21又は31に記載の医薬組成物を前記対象に投与するステップを含む方法。
- 前記疾患又は障害は、がんである、請求項72、73、74、75又は76の何れか一項に記載の方法。
- 前記がんは、前立腺がんである、請求項77に記載の方法。
- 前記がんは、転移性去勢抵抗性前立腺がんである、請求項78に記載の方法。
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JP2017535292A (ja) * | 2014-11-17 | 2017-11-30 | アディセット バイオ, インコーポレイテッド | 改変γδT細胞 |
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CA3106653A1 (en) | 2020-01-23 |
KR20210033025A (ko) | 2021-03-25 |
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PH12021550120A1 (en) | 2021-10-04 |
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