JP2019536469A - ケモカイン受容体ccr4を標的にするキメラ抗原受容体(car)およびその使用 - Google Patents
ケモカイン受容体ccr4を標的にするキメラ抗原受容体(car)およびその使用 Download PDFInfo
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Abstract
Description
本出願は、2016年9月21日に出願された米国仮出願番号第62/397,810号の利益を主張しており、この仮出願はその全体が本明細書中に参考として援用される。
本発明は、悪性腫瘍の分野、特に、CCR4に特異的に結合するキメラ抗原受容体、および対象において悪性腫瘍を処置するなどの処置のためのその使用に関する。
C−Cモチーフケモカイン受容体4(CCR4)は、造血系の細胞上で選択的に発現される7回膜貫通Gタンパク質共役細胞表面受容体分子(あるいは、CD194と呼ばれる)である(YoshieおよびMatsushima、Int Immunol.2015年;27巻(1号):11〜20頁;SolariおよびPease、Eur J Pharmacol.2015年;. pii: S0014-2999(15)30011)。健康な個体の末梢血では、CD4+CD25+Foxp3+調節性T(Treg)細胞、TH2およびTH17T細胞ならびに血小板は、CCR4発現の優勢を示す(Hiraharaら、J Immunol.2006年;177巻(7号):4488〜4494頁;D'Ambrosioら、J Immunol.1998年;161巻(10号):5111〜5115頁;Annunziatoら、J Exp Med.2007年;204巻(8号):1849〜1861頁;Clemetsonら、Blood.2000年;96巻(13号):4046〜4054頁;Abi-Younesら、Thromb Res.2001年;101巻(4号):279〜289頁)。他のケモカイン受容体で見られるように、CCR4は、そのリガンド特異性においていくらかのレベルの混乱を示すが、C−CケモカインCCL17およびCCL22は、この受容体の主要な高親和性リガンドであり、一方MCP−1、MIP−1およびRANTESもまた、顕著なリガンド活性を示す(Andrewら、J Immunol.1998年;161巻(9号):5027〜5035頁;Imaiら、J Biol Chem.1998年;273巻(3号):1764〜1768頁;Zlotnikら、Immunity.2000年;12巻(2号):121〜127頁)。特にストロマ細胞によるCCL17およびCCL22の異常な過剰発現は、乳、卵巣、胃および食道がんを含む種々の新生物において、ならびにホジキン病などのリンパ系悪性腫瘍において見られる(Gobertら、Cancer Res.2009年;69巻(5号):2000〜2009頁;Fialova Aら、Int J Cancer.2013年;132巻(5号):1070〜1079頁;Curielら、Nat Med.2004年;10巻(9号):942〜949頁;Yangら、PLoS One.2015年;10巻(3号):e0120059頁;Maruyamaら、Dis Esophagus 2010年;23巻(5号):422〜429頁;Ishidaら、Cancer Res.2006年;66巻(11号):5716〜5722頁)。これは、有効な抗腫瘍免疫応答を妨害するだけでなく、腫瘍の輸送および転移も促進する、かかる悪性腫瘍の腫瘍微小環境中へのCCR4保有Tregの大々的な流入の主要な駆動因子である(Tsujikawaら、Int J Cancer.2013年;132巻(12号):2755〜2766頁)。
一部の実施形態では、(a)mAB2−3抗体の軽鎖可変ドメイン(VL)および重鎖可変ドメイン(VH)を含むscFvであって、CCR4に特異的に結合する、scFv;(b)CD8由来のヒンジおよび膜貫通ドメイン;(c)細胞内4−1BBシグナル伝達ドメイン;ならびに(d)細胞内CD3ゼータシグナル伝達ドメインを含むキメラ抗原受容体であって、(a)〜(d)が、N末端からC末端の順である、キメラ抗原受容体が開示される。一部の実施形態では、例えば、マウス免疫グロブリンシグナル配列であるがこれに限定されないシグナル配列が、scFvに対してN末端側に含まれる。具体的な非限定的な例では、重鎖可変ドメインは、重鎖相補性決定領域(HCDR)1、HCDR2およびHCDR3を含み、HCDR1は、配列番号1のアミノ酸26〜33を含み、HCDR2は、配列番号1のアミノ酸51〜58を含み、HCDR3は、配列番号1のアミノ酸99〜107を含み、軽鎖可変ドメインは、軽鎖相補性決定領域(LCDR)1、LCDR2およびLCDR3を含み、LCDR1は、配列番号2のアミノ酸27〜38を含み、LCDR2は、配列番号2のアミノ酸56〜61を含み、LCDR3は、配列番号2のアミノ酸95〜102を含む。
核酸配列およびアミノ酸配列は、米国特許施行規則第1.822条において定義されている通り、ヌクレオチド塩基については標準的な文字略号、およびアミノ酸については1文字コードを使用して示される。各核酸配列の一方の鎖のみが示されるが、示される鎖への任意の言及によって相補鎖が含まれると理解される。配列表は、2017年9月19日に作成された18.2KBのASCIIテキストファイルとして提出され、参照により本明細書に組み込まれる。添付の配列表において:
配列番号7は、CD8膜貫通ドメインのアミノ酸配列である。
抗CCR4抗体に由来するヒト化可変重(VH)鎖およびカッパ軽(VL)鎖部分を使用するCCR4を標的化するキメラ抗原受容体(CAR)を発現するように自家T細胞を遺伝子操作するために、遺伝子移入系を産生および使用した。CARを、いくつかの悪性腫瘍、具体的にはリンパ系悪性腫瘍の細胞を標的化することが報告されたT細胞中に導入した。CCR4標的化CARによってex vivo改変されたドナーT細胞は、抗原特異的様式で、CCR4を発現する患者由来腫瘍細胞株を効率的に溶解させることが示され、in vivo有効性が、成人T細胞白血病のモデルにおいて実証された。
特記しない限り、技術用語は、従来の用法に従って使用される。分子生物学における一般的な用語の定義は、Benjamin Lewin、Genes X、Jones & Bartlett Publishersによる出版、2009年;およびMeyersら(編)、The Encyclopedia of Cell Biology and Molecular Medicine、Wiley-VCHによる出版、全16巻、2008年;ならびに他の類似の参考文献において見出され得る。
1)アラニン(A)、セリン(S)、スレオニン(T);
2)アスパラギン酸(D)、グルタミン酸(E);
3)アスパラギン(N)、グルタミン(Q);
4)アルギニン(R)、リシン(K);
5)イソロイシン(I)、ロイシン(L)、メチオニン(M)、バリン(V);および
6)フェニルアラニン(F)、チロシン(Y)、トリプトファン(W)。
キメラ抗原受容体
開示されたCARは、CCR4に特異的に結合するモノクローナル抗体の抗原結合ドメインを含む。一部の実施形態では、CCR4に特異的に結合するmAb1567が、本明細書で開示されるキメラ抗原結合受容体において使用され得る。mAb2−3と呼ばれる、この抗体の親和性成熟したヒト化形態(参照により本明細書に組み込まれる、Changら、Mol Cancer Ther.2012年;11巻(11号):2451〜2461頁を参照のこと)もまた、CAR中に含まれ得る。CCR4に特異的に結合する他のモノクローナル抗体は、市販されており、当該分野で公知である。例えば、PLOS oneのウェブサイト(journals.plos.org_plosone_article?id=10.1371/journal.pone.0103776)上でオンラインで入手可能な、Hagemannら、PLOS One、2014年を参照のこと。CCR4に特異的に結合する任意の抗体またはその抗原結合性断片が、キメラ抗原受容体中に含まれ得る。
配列番号6:
EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKDPK
として示されるアミノ酸配列を含むまたはこれからなる免疫グロブリンドメインを含み得る。
膜貫通ドメインに関して、CARは、CARの細胞外ドメインに融合された膜貫通ドメインを含むように設計され得る。膜貫通ドメインは、天然供給源または合成供給源のいずれかに由来し得る。供給源が天然である場合、ドメインは、任意の膜結合型または膜貫通タンパク質由来であり得る。開示されたCARにおける使用のための例示的な膜貫通ドメインには、T細胞受容体のアルファ、ベータまたはゼータ鎖、CD28、CD3イプシロン、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154の膜貫通領域(単数または複数)を少なくとも含み得る。あるいは、膜貫通ドメインは合成であり得、この場合、膜貫通ドメインは、ロイシンおよびバリンなどの優勢に疎水性の残基を含む。いくつかの実施形態では、フェニルアラニン、トリプトファンおよびバリンの三つ組が、合成膜貫通ドメインの各末端に見出される。
ALSNSIMYFSHFVPVFLPAKPTTTPAPRPPTPAPTIASQP LSLRPEACRPAAGGAVHTRG LDFAC DIYIWAPLAGTCGVLLLSLVITLYCNHR(配列番号7)
を含むまたはこれからなるCD8膜貫通ドメインを含み得る。
配列番号19:IEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVR
を含むまたはこれからなる。
CARの細胞内領域は、CARが発現または配置されるT細胞の正常なエフェクター機能のうち少なくとも1つの活性化を担う1つまたは複数の細胞内T細胞シグナル伝達ドメインを含む。例示的なT細胞シグナル伝達ドメインは、本明細書で提供され、当業者に公知である。
KRGRKKLLYIFKQPFMRPVQTTQEEDG CSCRFPEEEEGGCEL(配列番号8)
として示されるアミノ酸配列を含むまたはこれからなる。
RVKFSRSADAPAYQQGQNQLYNELN LGRREEYDVLDKRRGRDPEM GGKPRRKNPQEGLYNELQKD KMAEAYSEIGMKGERRRGKG HDGLYQGLSTATKDTYDALH MQALPPR(配列番号9)
として示されるアミノ酸配列を含み得るまたはこれからなり得る。
D.CARのさらなる記載
ポリヌクレオチドおよび発現
ATGGACTTTCAAGTGCAGATCTTTAGTTTCCTGCTCATAAGCGCTAGTGTGATCATGTCCAGAGGA(配列番号11)
を含み得るまたはこれからなり得る。
GATATTGTGATGACTCAAAGCCCCGACAGTCTGGCCGTGTCTTTGGGCGAGAGAGCCACAATCAACTGCAAGTCCTCACAGAGTATCCTTTATTCCTCTAATCAGAAGAATTACCTCGCATGGTATCAACAAAAACCCGGACAGAGCCCTAAGCTTTTGATCTATTGGGCATCTACCCGAGAATCAGGAGTGCCGGACCGCTTCAGTGGATCAGGATCAGGCACAGACTTTACGCTGACAATATCCTCTCTTCAGGCCGAAGACGTTGCCGTGTACTACTGCCATCAATATATGTCAAGCTACACATTCGGCCAGGGCACCAAACTCGAGATTAAG(配列番号12)
を含み得るまたはこれからなり得る。
CAGGTTCAGCTCGTGCAATCAGGGGCAGAGGTCAAGAAGCCGGGTGCCTCTGTGAAGGTGTCATGTAAGGCCTCCGGGTATACTTTTGCCAGCGCCTGGATGCATTGGATGAGGCAGGCGCCCGGCCAGGGTCTGGAGTGGATTGGTTGGATTAATCCCGGAAACGTGAATACTAAGTATAACGAGAAGTTTAAGGGCAGGGCCACACTCACAGTCGACACAAGCACCAATACCGCGTACATGGAACTTTCCAGCCTCCGGTCCGAGGACACTGCGGTGTATTACTGCGCACGCTCCACCTATTACAGACCACTTGATTACTGGGGCCAAGGGACCCTGGTGACCGTGTCTAGC(配列番号13)
を含み得るまたはこれからなり得る。
TCTAGTGGTGGCGGAGGCAGTGGCGGAGGAGGCTCCGGGGGCGGAGGGTCC(配列番号14)
を含み得るまたはこれからなり得る。
GCACTCAGCAATTCCATCATGTACTTCTCTCATTTCGTGCCAGTATTTCTGCCTGCCAAGCCAACTACCACACCTGCGCCACGCCCTCCCACGCCCGCACCCACAATTGCTTCACAGCCTCTTTCTCTGCGGCCTGAGGCTTGTCGCCCAGCAGCCGGAGGCGCCGTGCATACGCGCGGCCTTGACTTCGCATGTGACATCTACATTTGGGCTCCTTTGGCTGGAACCTGCGGGGTGTTGTTGCTTAGTCTGGTGATTACCCTCTACTGCAATCATAGA(配列番号15)
を含み得るまたはこれからなり得る。
AAGCGGGGGCGAAAGAAACTTCTCTATATCTTCAAACAGCCTTTCATGCGACCAGTGCAGACAACCCAAGAGGAAGACGGATGCAGCTGTCGCTTTCCAGAGGAGGAAGAAGGGGGCTGCGAGCTG(配列番号16)
を含み得るまたはこれからなり得る。
を含み得るまたはこれからなり得る。
GCGGCCGCATGGACTTTCAAGTGCAGATCTTTAGTTTCCTGCTCATAAGCGCTAGTGTGATCATGTCCAGAGGAGATATTGTGATGACTCAAAGCCCCGACAGTCTGGCCGTGTCTTTGGGCGAGAGAGCCACAATCAACTGCAAGTCCTCACAGAGTATCCTTTATTCCTCTAATCAGAAGAATTACCTCGCATGGTATCAACAAAAACCCGGACAGAGCCCTAAGCTTTTGATCTATTGGGCATCTACCCGAGAATCAGGAGTGCCGGACCGCTTCAGTGGATCAGGATCAGGCACAGACTTTACGCTGACAATATCCTCTCTTCAGGCCGAAGACGTTGCCGTGTACTACTGCCATCAATATATGTCAAGCTACACATTCGGCCAGGGCACCAAACTCGAGATTAAGTCTAGTGGTGGCGGAGGCAGTGGCGGAGGAGGCTCCGGGGGCGGAGGGTCCCAGGTTCAGCTCGTGCAATCAGGGGCAGAGGTCAAGAAGCCGGGTGCCTCTGTGAAGGTGTCATGTAAGGCCTCCGGGTATACTTTTGCCAGCGCCTGGATGCATTGGATGAGGCAGGCGCCCGGCCAGGGTCTGGAGTGGATTGGTTGGATTAATCCCGGAAACGTGAATACTAAGTATAACGAGAAGTTTAAGGGCAGGGCCACACTCACAGTCGACACAAGCACCAATACCGCGTACATGGAACTTTCCAGCCTCCGGTCCGAGGACACTGCGGTGTATTACTGCGCACGCTCCACCTATTACAGACCACTTGATTACTGGGGCCAAGGGACCCTGGTGACCGTGTCTAGCGCACTCAGCAATTCCATCATGTACTTCTCTCATTTCGTGCCAGTATTTCTGCCTGCCAAGCCAACTACCACACCTGCGCCACGCCCTCCCACGCCCGCACCCACAATTGCTTCACAGCCTCTTTCTCTGCGGCCTGAGGCTTGTCGCCCAGCAGCCGGAGGCGCCGTGCATACGCGCGGCCTTGACTTCGCATGTGACATCTACATTTGGGCTCCTTTGGCTGGAACCTGCGGGGTGTTGTTGCTTAGTCTGGTGATTACCCTCTACTGCAATCATAGAAAGCGGGGGCGAAAGAAACTTCTCTATATCTTCAAACAGCCTTTCATGCGACCAGTGCAGACAACCCAAGAGGAAGACGGATGCAGCTGTCGCTTTCCAGAGGAGGAAGAAGGGGGCTGCGAGCTGAGAGTGAAATTCTCTCGCTCCGCTGACGCCCCCGCGTATCAACAGGGCCAGAATCAGCTCTACAACGAACTTAACCTTGGGCGGAGAGAAGAATACGATGTTCTCGACAAGCGCAGGGGGAGAGACCCTGAGATGGGCGGGAAACCGCGCCGCAAGAACCCCCAAGAAGGGTTGTATAACGAGCTCCAGAAGGACAAAATGGCTGAAGCCTACTCAGAGATAGGTATGAAGGGCGAGCGCCGCAGAGGGAAGGGACACGATGGTCTGTACCAAGGCCTTTCAACCGCCACCAAGGATACCTATGATGCACTGCACATGCAAGCCCTGCCTCCTCGCTAAGGATCC(配列番号18)
を含むまたはこれからなる。
腫瘍を処置するための方法が本明細書で開示され、腫瘍の細胞は、CCR4を発現し、具体的には、CCR4をコードするmRNAおよび/またはCCR4タンパク質を産生する。一部の実施形態では、腫瘍は、リンパ系悪性腫瘍などの悪性腫瘍である。リンパ系悪性腫瘍は、成人T細胞白血病、皮膚T細胞リンパ腫、未分化大細胞型リンパ腫、ホジキンリンパ腫またはびまん性大細胞型B細胞リンパ腫であり得る。成人T細胞白血病は、慢性、急性、くすぶり型またはリンパ腫型のタイプであり得る。皮膚T細胞リンパ腫は、菌状息肉症、パジェット様細網症、セザリー症候群、肉芽腫様弛緩皮膚、リンパ腫様丘疹症、慢性苔癬状粃糠疹、急性痘瘡状苔癬状粃糠疹、CD30+皮膚T細胞リンパ腫、続発性皮膚CD30+大細胞型リンパ腫、非菌状息肉症CD30−皮膚大細胞型T細胞リンパ腫、多形性T細胞リンパ腫、レンネルトリンパ腫、皮下型T細胞リンパ腫、血管中心性リンパ腫または芽球型NK細胞リンパ腫であり得る。具体的な非限定的な例では、皮膚T細胞リンパ腫は、末梢性T細胞リンパ腫(PTCL)/皮膚T細胞リンパ腫(CTCL)または菌状息肉症(MF)/セザリー症候群(SS)である。他の実施形態では、腫瘍は固形腫瘍であり、腫瘍の細胞は、CCR4を発現し、具体的には、CCR4をコードするmRNAおよび/またはCCR4タンパク質を産生する。固形悪性腫瘍などの固形腫瘍の具体的な非限定的な例は、乳、卵巣、胃または食道がんである。理論に束縛されないが、微小環境中のTregは、本明細書で開示されるCARを使用して標的化され得る。
ミド(ONX−0912)が含まれる。例示的なGITRアゴニストには、例えば、GITR融合タンパク質および抗GITR抗体(例えば、二価抗GITR抗体)、例えば、米国特許第6,111,090号、欧州特許第090505号B1、米国特許第8,586,023号、PCT公開第WO2010/003118号および同第2011/090754号に記載されるGITR融合タンパク質、または例えば、米国特許第7,025,962号、欧州特許第1947183号B1、米国特許第7,812,135号、米国特許第8,388,967号、米国特許第8,591,886号、欧州特許第EP1866339号、PCT公開第WO2011/028683号、PCT公開第WO2013/039954号、PCT公開第WO2005/007190号、PCT公開第WO2007/133822号、PCT公開第WO2005/055808号、PCT公開第WO1999/40196号、PCT公開第WO2001/03720号、PCT公開第WO1999/20758号、PCT公開第WO2006/083289号、PCT公開第WO2005/115451号、米国特許第7,618,632号およびPCT公開第WO2011/051726号に記載される抗GITR抗体などが含まれる。
キット
(実施例1)
材料および方法
%溶解=[1−(CPS 実験 −CPS 最小 )]×100
(CPS最大−CPS最小)
(実施例2)
キメラ抗原受容体で改変されたT細胞の産生および使用
(実施例3)
マカク研究
(実施例4)
臨床試験
a)絶対的顆粒球計数≧1000K/uL、血小板計数≧75,000K/uLおよびヘモグロビン≧9g/dL。
b)ビリルビンおよびクレアチニン≦1.5×施設のULN。
c)AST、ALT≦3.0×施設のULN。
d)心エコー図によって決定される正常心駆出率
e)カルノフスキーパフォーマンススコア≧70%またはECOG≦1;ならびに
f)FEV1およびDLco>予測の60%。
1.症候性白血病性髄膜炎、中枢神経系(CNS)転移、>100,000細胞/mm3を有する白血病性合併症、GI管合併症、血清カルシウムまたはLDH>1.5×正常値の上限を有する対象は除外する。しかし、ATLおよび別のHTLV−1関連疾患、例えば熱帯性痙性不全対麻痺症(HAM/TSP)の両方を有する対象は、それらの症状の重症度に依存して、プロトコールに登録してもよい。
・ グレード4の好中球減少症が、細胞移入の日から21日間よりも長く持続する
・ グレード4の血小板減少症が、細胞移入の日から35日間よりも長く持続する
・ 以下を除く、グレード3および4の全ての毒性:
・ 3日以内に適切な医学的介入に応答し、≦グレード2まで回復する、グレード3のサイトカイン放出症候群(CRS)。
・ 敗血症グレード4の感染または出血の非存在下で7日未満持続する、グレード4の好中球減少症(ANC<500/mm3)またはグレード4の血小板減少症(血小板計数<25,000/mm3)。
・ 無併発性のグレード3の感染
・ 適切な医学的治療によって8時間以内に≦グレード2まで可逆的である、細胞注入後24時間以内に(細胞注入に関連して)起きる毒性。
・ 72時間またはそれ未満にわたる昇圧剤(>2mcg/分または等価なノルエピネフリン用量、2mcg/分未満またはそれと等しい用量は、DLTではない)による処置を必要とする低血圧。72時間は、昇圧剤が一時的に中断されその後再開される場合であっても、昇圧剤の最初の開始から測定する。
・ 7日以内にベースラインまたはグレード1に回復する、アラニンアミノトランスフェラーゼ、アスパラギン酸アミノトランスフェラーゼまたはビリルビンにおけるグレード4の上昇。
・ 3日未満持続するグレード3の悪心、嘔吐または下痢。
処置計画の全体的概要
1日目の詳細な処置計画:
2〜7日目の詳細な処置計画:
応答基準:
1.悪性リンパ腫についての応答の基準
2.ATLについての応答の基準
Claims (51)
- (a)軽鎖可変ドメイン(VL)および重鎖可変ドメイン(VH)を含む細胞外scFvであって、CCR4に特異的に結合する、細胞外scFv;
(b)CD8由来のヒンジおよび膜貫通ドメイン;
(c)細胞内4−1BBシグナル伝達ドメイン;ならびに
(d)細胞内CD3ゼータシグナル伝達ドメイン
を含むキメラ抗原受容体であって、(a)〜(d)が、N末端からC末端の順である、キメラ抗原受容体。 - 前記重鎖可変ドメインが、重鎖相補性決定領域(HCDR)1、HCDR2およびHCDR3を含み、前記HCDR1が、配列番号1のアミノ酸26〜33を含み、前記HCDR2が、配列番号1のアミノ酸51〜58を含み、前記HCDR3が、配列番号1のアミノ酸99〜107を含み、前記軽鎖可変ドメインが、軽鎖相補性決定領域(LCDR)1、LCDR2およびLCDR3を含み、前記LCDR1が、配列番号2のアミノ酸27〜38を含み、前記LCDR2が、配列番号2のアミノ酸56〜61を含み、前記LCDR3が、配列番号2のアミノ酸95〜102を含む、請求項1に記載のキメラ抗原受容体。
- CD8由来の前記ヒンジおよび前記膜貫通ドメインが、配列番号7として示されるアミノ酸配列を含む、請求項1または請求項2に記載のキメラ抗原受容体。
- 前記細胞内4−1BBシグナル伝達ドメインが、配列番号8として示されるアミノ酸配列を含む、請求項1から3のいずれか一項に記載のキメラ抗原受容体。
- 前記CD3ゼータシグナル伝達ドメインが、配列番号9として示される核酸配列を含む、請求項1から4のいずれか一項に記載のキメラ抗原受容体。
- 配列番号10として示されるアミノ酸配列を含む、請求項1から5のいずれか一項に記載のキメラ抗原受容体。
- 請求項1から6のいずれか一項に記載のキメラ抗原受容体をコードする、単離された核酸分子。
- 前記VLをコードする核酸配列が、配列番号12に対して少なくとも95%同一であり、コードされたLCDR1が、配列番号2のアミノ酸27〜38を含み、前記LCDR2が、配列番号2のアミノ酸56〜61を含み、前記LCDR3が、配列番号2のアミノ酸95〜102を含む、請求項7に記載の単離された核酸分子。
- 前記VLをコードする核酸配列が、配列番号13に対して少なくとも95%同一であり、コードされたHCDR1が、配列番号1のアミノ酸26〜33を含み、前記HCDR2が、配列番号1のアミノ酸51〜58を含み、前記HCDR3が、配列番号1のアミノ酸99〜107を含む、請求項7に記載の単離された核酸分子。
- 前記VHが、配列番号13の核酸配列によってコードされ、かつ/または前記VLが、配列番号12の核酸配列によってコードされる、請求項8または請求項9に記載の単離された核酸分子。
- scFvがリンカーを含み、前記リンカーが、配列番号14の核酸配列によってコードされる、請求項7から10のいずれか一項に記載の単離された核酸分子。
- 前記キメラ抗原受容体が、免疫グロブリンシグナル配列を含み、前記免疫グロブリンシグナル配列が、配列番号11に対して少なくとも80%同一な核酸配列によってコードされ、コードされたタンパク質が、シグナル配列として機能する、請求項7から11のいずれか一項に記載の単離された核酸分子。
- 配列番号11の核酸配列を含む、請求項12に記載の単離された核酸分子。
- 前記CD8膜貫通ドメインおよびヒンジが、配列番号15に対して少なくとも80%同一な核酸配列によってコードされ、コードされたタンパク質が、CD8膜貫通ドメインおよびヒンジとして機能する、請求項7から13のいずれか一項に記載の単離された核酸分子。
- 配列番号15の核酸配列を含む、請求項14に記載の単離された核酸分子。
- 前記4−1BBシグナル伝達分子が、配列番号16に対して少なくとも80%同一な核酸配列によってコードされ、コードされたタンパク質が、4−1BBシグナル伝達分子として機能する、請求項7から15のいずれか一項に記載の単離された核酸分子。
- 配列番号16の核酸配列を含む、請求項16に記載の単離された核酸分子。
- 前記CD3ゼータシグナル伝達分子が、配列番号17に対して少なくとも80%同一な核酸配列によってコードされ、コードされたタンパク質が、CD3ゼータシグナル伝達分子として機能する、請求項7から17のいずれか一項に記載の単離された核酸分子。
- 配列番号17の核酸配列を含む、請求項18に記載の単離された核酸分子。
- ヒト細胞における発現のためにコドン最適化される、請求項7から19のいずれか一項に記載の単離された核酸分子。
- 配列番号18の核酸配列を含む、請求項20に記載の単離された核酸分子。
- 請求項7から21のいずれか一項に記載の核酸分子を含む、発現ベクター。
- ウイルスベクターである、請求項22に記載の発現ベクター。
- 前記ウイルスベクターが、レンチウイルスベクターまたはガンマレトロウイルスベクターである、請求項23に記載のベクター。
- 請求項22から24のいずれか一項に記載のベクターを形質導入された、CD3+T細胞またはナチュラルキラー細胞。
- 前記CD3+T細胞が、CD3+CD4+T細胞またはCD3+CD8+T細胞である、請求項25に記載のCD3+T細胞。
- ヒトT細胞である、請求項25または26に記載のCD3+T細胞またはナチュラルキラー細胞。
- 請求項22から24のいずれか一項に記載のベクターの有効量または請求項25から27のいずれか一項に記載のCD3+T細胞および/もしくはナチュラルキラー細胞の治療有効量、ならびに薬学的に許容される担体を含む、医薬組成物。
- CCR4 mRNAを産生する悪性腫瘍を有する対象を処置するための方法であって、請求項28に記載の医薬組成物の治療有効量を前記対象に投与し、それによって、前記対象においてCCR4 mRNAを産生する前記悪性腫瘍を処置するステップを含む、方法。
- 前記医薬組成物が前記T細胞を含む、請求項29に記載の方法。
- 前記T細胞が、前記対象にとって自家である、請求項30に記載の方法。
- 前記医薬組成物が、CD3+CD4+T細胞および/またはCD3+CD8+T細胞を含む、請求項30または請求項31に記載の方法。
- 前記悪性腫瘍が、成人T細胞白血病、皮膚T細胞リンパ腫、未分化大細胞型リンパ腫、ホジキンリンパ腫またはびまん性大細胞型B細胞リンパ腫である、請求項29から32のいずれか一項に記載の方法。
- 前記成人T細胞白血病が慢性成人T細胞白血病である、請求項33に記載の方法。
- 前記対象においてFoxp3+CD4+Treg細胞の数を低減させる、請求項29から34のいずれか一項に記載の方法。
- CCR4 mRNAを産生する悪性腫瘍を有する対象を処置するための方法であって、
前記対象由来のCD3+T細胞および/またはナチュラルキラー細胞に、請求項22から24のいずれか一項に記載の発現ベクターを形質導入して、前記キメラ抗原受容体を発現する自家の形質導入された細胞を産生するステップ;ならびに
前記キメラ抗原受容体を発現する前記自家の形質導入された細胞の治療有効量を前記対象に投与し、それによって、前記対象においてCCR4 mRNAを産生する前記悪性腫瘍を処置するステップ
を含む、方法。 - 前記悪性腫瘍が、成人T細胞白血病、皮膚T細胞リンパ腫、未分化大細胞型リンパ腫、ホジキンリンパ腫またはびまん性大細胞型B細胞リンパ腫である、請求項36に記載の方法。
- 前記成人T細胞白血病が、慢性成人T細胞白血病、急性成人T細胞白血病、くすぶり型T細胞白血病またはリンパ腫型T細胞白血病である、請求項37に記載の方法。
- 前記対象がヒトである、請求項29から38のいずれか一項に記載の方法。
- 前記悪性腫瘍がリンパ系悪性腫瘍である、請求項29から32、35または39のいずれか一項に記載の方法。
- 前記悪性腫瘍が固形腫瘍である、請求項29から32、35または39のいずれか一項に記載の方法。
- 前記固形腫瘍が、乳、卵巣、胃または食道がんである、請求項41に記載の方法。
- 対象において悪性腫瘍を処置するための、請求項28に記載の医薬組成物の使用であって、前記悪性腫瘍がCCR4 mRNAを産生する、使用。
- 前記悪性腫瘍が、成人T細胞白血病、皮膚T細胞リンパ腫、未分化大細胞型リンパ腫、ホジキンリンパ腫またはびまん性大細胞型B細胞リンパ腫である、請求項43に記載の使用。
- 前記成人T細胞白血病が、慢性成人T細胞白血病、急性成人T細胞白血病、くすぶり型T細胞白血病またはリンパ腫型T細胞白血病である、請求項44に記載の使用。
- 前記悪性腫瘍が固形腫瘍である、請求項43に記載の使用。
- 前記固形腫瘍が、乳、卵巣、胃または食道がんである、請求項46に記載の使用。
- 前記対象がヒトである、請求項43から47のいずれか一項に記載の使用。
- 前記医薬組成物が前記T細胞を含む、請求項43から48のいずれか一項に記載の使用。
- 前記T細胞が、前記対象にとって自家である、請求項49に記載の使用。
- 前記T細胞が、CD3+CD4+T細胞および/またはCD3+CD8+T細胞である、請求項49または50に記載の使用。
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